WO2016130417A1

WO2016130417A1 - Omega-3 fatty acid prodrug compounds and uses thereof

Info

Publication number: WO2016130417A1
Application number: PCT/US2016/016719
Authority: WO
Inventors: Lin Zhi
Original assignee: Omthera Pharmaceuticals Inc
Priority date: 2015-02-11
Filing date: 2016-02-05
Publication date: 2016-08-18

Abstract

Provided herein are prodrug compounds, their preparation and their uses, such as treating liver diseases or non-liver diseases via intervening in the molecular pathways in the liver. Novel prodrug compounds of eicosapentaenoic and docosahexaenoic acids, their preparation and their uses are described. Some embodiments are related to novel prodrug compounds that are absorbed in the intestine and taken up via the hepatic portal vein to the liver. Some embodiments are directed to the use of the prodrugs to change eicosapentaenoic and docosahexaenoic acids absorption routes. Another aspect includes the use of prodrugs to treat diseases that benefit from enhanced eicosapentaenoic and docosahexaenoic acids distribution to the liver and like tissues and cells, including but not limited to fatty liver, and metabolic and cardiovascular diseases where the liver is involved in the production and/or the homeostasis control of the biochemical end products, e.g. glucose, cholesterol, fatty acids, triglycerides, lipoproteins, and apolipoproteins.

Description

OMEGA-3 FATTY ACID PRODRUG COMPOUNDS AND USES THEREOF FIELD

Compositions and methods in the field of medicine and chemistry are disclosed. Some of the disclosed embodiments are directed to medicinal prodrug compounds, medicinal compositions, as well as processes for their preparation and methods of their use. Some embodiments include prodrug compounds of certain omega-3 free fatty acids such as eicosapentaenoic and docosahexaenoic acids, their preparation and their uses. In some embodiments, such prodrug compounds are useful to selectively deliver

eicosapentaenoic and docosahexaenoic acids to the liver.

BACKGROUND

The following description of the background is provided to aid in understanding the invention, but is not admitted to be, or to describe, prior art to the invention.

Fatty acids are a class of compounds that have a carboxylic acid attached to a long aliphatic chain of up to 28 carbons or more. Naturally occurring fatty acids are an essential component of life, mainly as a source of energy, and exist in the form of triglycerides, a tri- ester of glycerol and three fatty acid molecules. Triglycerides are found in vegetable oil and animal fats, for example. Dietary triglycerides cannot be absorbed directly in the gastrointestinal (GI) tract and are broken down into free fatty acids and monoglycerol in the intestine by pancreatic lipase. Once absorbed, the free fatty acids and monoglycerol are reassembled into triglycerides at the site of absorption, called an enterocyte, and packaged into chylomicron particles to be transported into lymphatic system and then systemic blood circulation available for the cells in the body. Only a small percentage of the triglycerides, mainly with shorter fatty acid chains, go through the hepatic portal vein to the liver.

Most fatty acids can also be synthesized from glucose in the liver, assembled into triglycerides that are packaged into very-low-density-lipoprotein (VLDL) particles and then released to the blood to complement the dietary triglycerides in chylomicrons for cells to use as energy source or to deposit in adipose tissues as energy storage. Triglycerides are packaged with cholesterol in the lipoprotein particles including LDL and HDL and the triglyceride level in circulation directly reflects the composition of cholesterol containing lipoprotein particles. Triglycerides are involved in whole body energy balance and lipid homeostasis and an excess of triglycerides can lead to many metabolic diseases. Fasting triglyceride levels are used to estimate cardiovascular health and elevated triglyceride level is an independent risk factor of heart disease and stroke. Triglycerides in circulation after fasting are derived from the liver that handles metabolic balance and lipid homeostasis by controlling glucose and lipid production, circulation, and metabolism.

Certain types of fatty acids play significant physiological roles in the body and some act as vitamins. Certain omega-3 fatty acids cannot be synthesized in the human body and have important functions in body metabolism. It has been found that consuming foods having a high content of omega-3 fatty acids has many health benefits. High concentration omega-3 fatty acids have been used to treat hypertriglyceridemia to reduce cardiovascular disease risks. The mechanism of the triglyceride lowering activity is believed to be involved in reduction of triglyceride biosynthesis (e.g., see A. Pirillo and A. L. Catapano Inter J Cardiol 170:S16-S20 (2013)). The prescription strength of omega-3 fatty acids can be given in a single eicosapentaenoic acid formulation (Vascepa) or a mixture of multiple omega-3 fatty acids (Lovaza and Epanova). Ethyl ester forms of the omega-3 fatty acids are hydrolyzed in the intestines by pancreatic lipase before absorption and the free acid forms are directly absorbed, providing better oral bioavailability (e.g., see E. Offman, et al. Vase Health Risk Manag 9:563-573 (2013)). After absorption, the omega-3 fatty acids are assembled into triglycerides and then packaged into chylomicrons for lymphatic delivery.

Prodrugs are frequently used to improve certain properties of pharmacological agents for a preferred route of administration, including physicochemical,

biopharmaceutical or pharmacokinetic properties. Certain prodrugs (also called soft drugs) are designed by tissue selective activation or deactivation to achieve therapeutic advantages (e.g., See J. Rautio, et al. Nature Reviews Drug Discovery 7:255-270 (2008)). Carboxylic simple esters such as methyl or ethyl esters are not frequently used as prodrugs of carboxylic acid drugs since they are readily hydrolyzed in the intestine by pancreatic lipase. Many phosphate prodrugs involve a carboxylic ester as a surrogate hydrolysis trigger (e.g., See S. Hecker and M. D. Erion J Med Chem 51 :2328-2345 (2008)). Prodrugs of certain omega-3 fatty acids have been described in a conjugate amide form (e.g., See J. C. Milne, et al. US 8,304,551) and an ester form (e.g., M. Kandula, et al. US 8,445,707). SUMMARY

Novel prodrug compounds of eicosapentaenoic and docosahexaenoic acids, their preparation and their uses are described. Some embodiments are related to novel prodrug compounds that are absorbed in the intestine and taken up via the hepatic portal vein to the liver. Some embodiments are directed to the use of the prodrugs to change

eicosapentaenoic and docosahexaenoic acids absorption routes. Another aspect includes the use of prodrugs to treat diseases that benefit from enhanced eicosapentaenoic and docosahexaenoic acids distribution to the liver and like tissues and cells, including but not limited to fatty liver, and metabolic and cardiovascular diseases where the liver is involved in the production and/or the homeostasis control of the biochemical end products, e.g. glucose, cholesterol, fatty acids, triglycerides, lipoproteins, and apolipoproteins. Examples of such diseases include diabetes, hyperlipidemia, atherosclerosis, obesity, and the like. In another aspect, prodrugs are used to increase the pharmacological or clinical activity of eicosapentaenoic and docosahexaenoic acids. Some additional embodiments relate to a method of making prodrugs.

Some embodiments provided herein include a com ound of Formula I:

(I)

wherein:

R¹ and R² are each independently selected from the group consisting of H, OH, OP(0)(OH)₂, OP(0)(OMe)₂, OP(0)(Me)OH, CH₂OH, CH₂OP(0)(OH)₂, and

CH(OH)CH₂OH; or R¹ and R² together optionally form an oxo (=0);

X is O or NH;

m is 4 or 5;

n is 0 when m is 5; or n is 1 when m is 4;

p is 0 or 1;

or a stereoisomer or a pharmaceutically acceptable salt thereof.

Some embodiments relate to a compound of Formula II:

(Π)

wherein:

R³ and R⁴ are each independently selected from the group consisting of OH, H₂, Me, and OMe;

Y is selected from the group consisting of O, NH, and CH₂;

m is 4 or 5;

n is 0 when m is 5; or n is 1 when m is 4;

or a stereoisomer or a pharmaceutically acceptable salt thereof.

Some embodiments relate to a com ound of Formula III:

(Ilia) (nib)

wherein:

R⁵ and R⁶ are each independently selected from the group consisting of H, OC(0)Me, and OP(0)(OH)₂; or R⁵ and R⁶ are together optionally to form an oxo (=0) when X is NH;

R⁷ and R⁸ are each independently selected from the group consisting of OH, NH₂, Me, NHMe, and OMe; or R⁷ and R⁸ are linked to form -OCH₂CH₂0-;

R⁹ is selected from the group consisting of H, Me, CH₂OH, CH₂C0₂H,

CH2CONH2, and CH₂(lH-imidazol-4-yl);

X is O or NH; in proviso that X is not O when R⁵ and R⁶ are both H, and R⁷ and R^! are both OH or OMe;

m is 4 or 5;

n is 0 when m is 5; or n is 1 when m is 4;

or a stereoisomer or a pharmaceutically acceptable salt thereof.

Some embodiments relate to a compound of Formula IV:

(IVa) (IVb)

wherein:

R⁹ is selected from the group consisting of H, Me, CH₂OH, CH2CO2H, CH2CO H2, and CH₂(lH-imidazol-4-yl);

R¹⁰ and R¹¹ are H or together form an oxo (=0);

R¹² is selected from the group consisting of H, CH2OH, and pyridyl;

m is 4 or 5;

n is 0 when m is 5; or n is 1 when m is 4;

or a stereoisomer or a pharmaceutically acceptable salt thereof.

Some embodiments relate to a com ound of Formula V:

(V)

wherein:

U is O or S;

V is N or CH;

m is 4 or 5;

n is 0 when m is 5; or n is 1 when m is 4;

or a stereoisomer or a pharmaceutically acceptable salt thereof.

Some embodiments relate to a compound selected from the group consisting of:

and a stereoisomer or a pharmaceutically acceptable salt thereof.

Some embodiments relate to a pharmaceutical composition comprising any of the above compounds and a pharmaceutically acceptable excipient.

Some embodiments relate to a method of treating a disease, disorder or condition comprising administering an effective amount of any of the above compounds.

In some embodiments, the disease, disorder or condition is a disease, disorder or condition of the liver.

In some embodiments, the disease, disorder or condition is a metabolic, or cardiovascular disease in which the liver is involved in the production and/or the homeostasis control of the biochemical end products of the disease, disorder or condition.

In some embodiments, the disease, disorder or condition is selected from the group consisting of fatty liver, diabetes, hyperlipidemia, atherosclerosis, obesity, and

dyslipidemia.

Some embodiments relate to a method of treating a disease comprising

administering an effective amount of a compound of any of the above compounds to a subject in need thereof.

Some embodiments relate to a method of treating dyslipidemia comprising administering to a subject in need thereof an effective amount of the compound of any of the above compounds.

Some embodiments further comprise administering an effective amount of at least one additional therapeutic agent to the subject in need thereof.

In some embodiments, the subject is a mammal.

In some embodiments, the subject is human.

In some embodiments, the cell is in vivo.

In some embodiments, the cell is ex vivo.

In some embodiments, the cell is a hepatocyte.

In some embodiments, the cell is mammalian.

In some embodiments, the cell is human.

Some embodiments of the compounds, compositions, and methods provided herein include a pharmaceutical composition comprising any of the compounds provided herein and a pharmaceutically acceptable excipient. Some embodiments of the compounds, compositions, and methods provided herein include a method of treating a disease or condition in the liver in a subject comprising administering an effective amount of any of the compounds provided herein to a subject in need thereof.

Some embodiments also include administering an effective amount of one or more additional therapeutic agents to the subject in need thereof.

In some embodiments, the subject is a mammal.

In some embodiments, the subject is a human.

Some embodiments of the compounds, compositions, and methods provided herein include the use of any one or more of the compounds provided herein for treating a disease in the liver or a disease or condition in which the physiological or pathogenic pathways involve the liver in a subject.

Some embodiments also include the use of any one of the compounds provided herein in combination with an additional therapeutic agent.

Some embodiments of the compounds, compositions, and methods provided herein include any one of the compositions provided herein for use in the preparation of a medicament for treating a disease or condition in the liver or a disease or condition in which the physiological or pathogenic pathways involve the liver.

DETAILED DESCRIPTION

The present embodiments are directed to compositions and methods related to novel prodrug compounds of eicosapentaenoic and docosahexaenoic acids, their preparation and their uses. These prodrug compounds and their stereoisomers and pharmaceutically acceptable salts are re resented by Formula I, II, III, IV, and V:

(I)

wherein:

CH(OH)CH₂OH; or R¹ and R² together optionally form an oxo (=0);

X is O or NH; m is 4 or 5;

n is 0 when m is 5; or n is 1 when m is 4; and

p is 0 or 1.

(Π)

wherein:

Y is selected from the group consisting of O, NH, and CH₂;

m is 4 or 5; and

n is 0 when m is 5 or n is 1 when m is 4.

(Ilia) (nib)

wherein:

R⁹ is selected from the group consisting of H, Me, CH₂OH, CH₂C0₂H,

CH2CONH2, and CH₂(lH-imidazol-4-yl);

m is 4 or 5; and

n is 0 when m is 5; or n is 1 when m is 4.

(IVa) (IVb)

wherein:

R⁹ is selected from the group consisting of H, Me, CH₂OH, CH2CO2H,

CH2CO H2, and CH₂(lH-imidazol-4-yl);

R¹⁰ and R¹¹ are H or together form an oxo (=0);

R¹² is selected from the group consisting of H, CH2OH, and pyridyl;

m is 4 or 5; and

n is 0 when m is 5; or n is 1 when m is 4.

(V)

wherein:

U is O or S;

V is N or CH;

m is 4 or 5; and

n is 0 when m is 5; or n is 1 when m is 4.

In one aspect, the prodrug compounds are pro-drugs of EPA. In another aspect, the pro-drug compounds are pro-drugs of DHA.

These prodrug compounds and their stereoisomers and pharmaceutically acceptable salts are represented by individual compound selected from the group consisting of:

In some embodiments, the prodrug compounds of Formula I-V and the individual compounds are absorbed via the hepatic portal vein to the liver and activated by liver enzymes such as cytochrome p450 isozymes CYP3 As (a family of monooxygenase), dehydrogenases, esterases, and amidases. In some embodiments, the novel prodrug compounds of Formula I-V are not substrates of pancreatic lipase in the intestine.

CYP3 A4 is expressed in the liver in a level much higher than other tissues

(DeWaziers et al. J Pharm Exp Ther 253 :387 (1990)). Majority of prodrug compounds of Formula I-V and the individual compounds are predominantly activated via CYP3 A4 in the liver. In some embodiments, the prodrug compounds of Formula I-V have high efficiency in liver-targeting via selective delivery of eicosapentaenoic and

docosahexaenoic acids to the liver.

Many types of esterases, dehydrogenases, and amidases are expressed in the liver in high levels. Certain prodrugs of Formula III and IV and the individual compounds may be activated via the enzymes other than CYP3 A4 family in the liver. Pancreatic lipase is activated by co-enzyme colipase in the duodenum to digest triglyceride esters. Ester prodrugs of Formula III and IV are less prone to hydrolysis by the pancreatic lipase and absorbed as prodrugs to go through the hepatic portal vein to the liver.

In some embodiments, due to the liver-targeting nature of the prodrug compounds of Formula I-V and the individual compounds, the compounds may be used to treat diseases that benefit from enhanced drug distribution to the liver and like tissues and cells, including but not limited to diseases in the liver, such as fatty liver, metabolic and cardiovascular diseases where the liver is involved in the production and/or the

homeostasis control of biochemical end products, e.g. cholesterol, fatty acids, bile acids, triglycerides (e.g. hyperlipidemia, atherosclerosis and obesity), lipoproteins,

apolipoproteins, and sex hormone-binding globulin (SUBG).

In some embodiments, the disclosed prodrugs may be used to prolong

pharmacodynamic half-life of eicosapentaenoic and docosahexaenoic acids. In addition, the disclosed prodrug methodology may be used to achieve sustained delivery of the parent drug. In some embodiments, a method of making these prodrugs is described.

Certain compounds of Formula I-V and the individual compounds have asymmetric centers where the stereochemistry is unspecified, and the diastereomeric mixtures of these compounds are included, as well as the individual stereoisomers when referring to a compound of Formula I, II, III, IV, and V, and the individual compounds generally. In certain embodiments, compounds are of the invention are provided in >50%, >60%, >70%, >80%, >90%, >95% or >99% diastereomeric excess. In certain embodiments, compounds are of the invention are provided in >50%, >60%, >70%, >80%, >90%, >95% or >99% enantiomeric excess.

Some embodiments of the compounds, compositions and methods provided herein include a pharmaceutical composition comprising a compound provided herein and a pharmaceutically acceptable carrier.

Some embodiments of the compounds, compositions and methods provided herein include a pharmaceutical composition comprising a compound provided herein.

Some embodiments also include administering an effective amount of a second or multiple therapeutic agents in combination with a compound provided herein to the subject in need thereof. Some embodiments of the compounds, compositions and methods provided herein include a method of treating dyslipidemia comprising administering an effective amount of a compound provided herein.

In some embodiments, the subject is mammalian.

In some embodiments, the subject is human.

Some embodiments of the compounds, compositions and methods provided herein include use of a compound provided herein in the treatment of a disease in the liver.

Some embodiments of the compounds, compositions and methods provided herein include use of a compound provided herein in the treatment of a disease or condition by intervening in a molecular pathway in the liver.

Some embodiments include the use of a compound provided herein in combination with additional therapeutic agent(s) for the treatment of a disease or condition by intervening in a molecular pathway in the liver.

Some embodiments include the use of a compound provided herein in the manufacture of a medicament for the treatment of a disease or condition by intervening in a molecular pathway in the liver.

In some embodiments, compounds of Formula I, II, III, IV, and V, and the individual compounds are prodrugs of eicosapentaenoic and docosahexaenoic acids that are mainly absorbed via the lymphatic route, thereby bypassing the liver after oral administration. The disclosed compounds of Formula I, II, III, IV, and V, and the individual compounds are absorbed after oral administration via the hepatic portal vein to the liver.

Definitions

In accordance with the present disclosure and as used herein, the following terms are defined with the following meanings, unless explicitly stated otherwise. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the subject matter claimed. In this application, the use of the singular includes the plural unless specifically stated otherwise. In this application, the use of "or" means "and/or" unless stated otherwise. Furthermore, use of the term "including" as well as other forms, such as "includes," and "included" is not limiting. As used herein, ranges and amounts can be expressed as "about" a particular value or range. "About" also includes the exact amount. Hence "about 10%" means "about 10%" and also "10%."

As used herein, "optional" or "optionally" means that the subsequently described event or circumstance does or does not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, an optionally substituted group means that the group is unsubstituted or is substituted.

As used herein, the singular forms "a," "an" and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to a

composition comprising "a therapeutic agent" includes compositions with one or a plurality of therapeutic agents.

The phrase "therapeutically effective amount" means an amount of a compound or a combination of compounds that partially or fully ameliorates, attenuates or eliminates one or more of the symptoms of a particular disease or condition or prevents, modifies, or delays the onset of one or more of the symptoms of a particular disease or condition. Such amount can be administered as a single dosage or can be administered according to a regimen, whereby it is effective. Repeated administration may be needed to achieve a desired result (e.g., treatment of the disease and/or condition).

The term "pharmaceutically acceptable salt" includes salts of compounds of Formula I, II, III, IV, and V, and the individual compounds and their prodrugs derived from the combination of a compound of the present embodiments and an organic or inorganic acid or base. Suitable acids include acetic acid, adipic acid, benzenesulfonic acid, (+)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptane-l-methanesulfonic acid, citric acid, 1,2- ethanedisulfonic acid, dodecyl sulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glucuronic acid, hippuric acid, hydrochloride hemiethanolic acid, HBr, HC1, HI, 2- hydroxyethanesulfonic acid, lactic acid, lactobionic acid, maleic acid, methanesulfonic acid, methylbromide acid, methyl sulfuric acid, 2-naphthalenesulfonic acid, nitric acid, oleic acid, 4,4'-methylenebis-[3-hydroxy-2-naphthalenecarboxylic acid], phosphoric acid, polygalacturonic acid, stearic acid, succinic acid, sulfuric acid, sulfosalicylic acid, tannic acid, tartaric acid, terphthalic acid, and p-toluenesulfonic acid. . Suitable bases include NaOH, KOH, Ca(OH)₂, Zn(OH)₂, Mg(OH)₂, diethylamine, ethanolamine, diethanolamine, choline, lysine, meglumine, benzathine, and tromethamine. The term "patient" refers to an animal being treated including a mammal, such as a dog, a cat, a cow, a horse, a sheep, and a human. In some embodiments the patient is a mammal, either male or female. In some embodiments, the patient is a male or female human.

The term "prodrug" as used herein refers to any compound that when administered to a biological system generates a biologically active compound as a result of spontaneous chemical reaction(s), enzyme catalyzed chemical reaction(s), and/or metabolic chemical reaction(s), or a combination of each. Standard prodrugs are formed using groups attached to functionality, e.g. HO-, HS-, HOOC-, HOOPR2-, associated with the drug, that cleave in vivo. Standard prodrugs include but are not limited to carboxylate esters where the group is alkyl, aryl, aralkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl as well as esters of hydroxyl, thiol and amines where the group attached is an acyl group, an alkoxycarbonyl, aminocarbonyl, phosphate or sulfate. The groups illustrated are examples, not exhaustive, and one skilled in the art could prepare other known varieties of prodrugs. Prodrugs must undergo some form of a chemical transformation to produce the compound that is biologically active or is a precursor of the biologically active compound. In some cases, the prodrug is biologically active, usually less than the drug itself, and serves to improve drug efficacy or safety through improved oral bioavailability, pharmacodynamic half-life, etc. Prodrug forms of compounds may be utilized, for example, to improve bioavailability, improve subject acceptability such as by masking or reducing unpleasant characteristics such as bitter taste or gastrointestinal irritability, alter solubility such as for intravenous use, provide for prolonged or sustained release or delivery, improve ease of formulation, or provide site specific delivery of the compound.

The term "stereoisomer" refers to the relative or absolute spatial relationship of the R group(s) attached to the stereogenic centers either carbon or phosphorus atoms, and refers to individual or any combination of the individual isomers such as a racemic mixture and a diastereomeric mixture. When a compound has two stereogenic centers, there are 4 potential stereoisomers.

The term "liver" refers to the liver organ.

The term "enhanced oral bioavailability" refers to an increase of at least about 50% of the absorption of the dose of the parent drug. In an additional aspect, the increase in oral bioavailability of the prodrug (compared to the parent drug) is at least about 100%, or a doubling of the absorption. Measurement of oral bioavailability usually refers to measurements of the prodrug, drug, or drug metabolite in blood, plasma, tissues, or urine following oral administration compared to measurements following parenteral

administration.

The term "therapeutic index" refers to the ratio of the dose of a drug or prodrug that produces a therapeutically beneficial response relative to the dose that produces an undesired response such as death, an elevation of markers that are indicative of toxicity, and/or pharmacological side effects.

The term "sustained delivery" refers to an increase in the period in which there is a prolongation of therapeutically-effective drug levels due to the presence of the prodrug.

The terms "treating" or "treatment" of a disease includes inhibiting the disease (slowing or arresting or partially arresting its development), preventing the disease, providing relief from the symptoms or side effects of the disease (including palliative treatment), and/or relieving the disease (causing regression of the disease).

The terms "biological agent" refers to a compound that has biological activity or that has molecular properties that can be used for therapeutic or diagnosis purposes, such as a compound carrying a radioactive isotope or a heavy atom.

The terms "molecular pathway" refers to a series of molecular events in tissues such as a receptor modulating sequence, an enzyme modulating sequence, or a biosynthesis sequence that is involved in physiological or pathophysiological functions of a living animal.

Formulations

The disclosed compounds may be used alone or in combination with other treatments. These compounds, when used in combination with other agents, may be administered as a daily dose or an appropriate fraction of the daily dose (e.g., bid). The compounds may be administered after a course of treatment by another agent, during a course of therapy with another agent, administered as part of a therapeutic regimen, or may be administered prior to therapy with another agent in a treatment program.

Compositions containing the active ingredient may be in any form suitable for the intended method of administration. In some embodiments, the compounds of a method and/or composition described herein can be provided via oral administration. When the compounds are administered via oral administration, for example, tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs may be prepared. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation. Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipient which are suitable for manufacture of tablets are acceptable. These excipients may be, for example, inert diluents, such as calcium or sodium carbonate, lactose, calcium or sodium phosphate; granulating and disintegrating agents, such as maize starch, or alginic acid; binding agents, such as starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.

Formulations for oral use may be also presented as hard gelatin capsules where the active ingredient can be mixed with an inert solid diluent, for example calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient can be mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.

In some embodiments unit dosage formulations contain a daily dose or unit, daily sub-dose, or an appropriate fraction thereof, of a drug. It will be understood, however, that the specific dose level for any particular patient will depend on a variety of factors including the activity of the specific compound employed; the age, body weight, general health, sex and diet of the individual being treated; the time and route of administration; the rate of excretion; other drugs which have previously been administered; and the severity of the particular disease undergoing therapy, as is well understood by those skilled in the art.

Synthesis of compounds

The following procedures for the preparation of the cyclic prodrug compounds illustrate the general procedures used to prepare the prodrug compounds of a carboxylic acid containing drugs. Prodrugs can be introduced at different stages of synthesis of a drug. In some embodiments, they are made at a later stage, because of the general sensitivity of these groups to various reaction conditions. Optically pure prodrugs containing a single isomer at the phosphorus center can be made, for example, by separation of the diastereomers by a combination of column chromatography and/or crystallisation, or by enantioselective synthesis of chiral activated phosph(on)ate intermediates.

Scheme I describes general strategies of synthesis of the cyclic ether prodrug compounds of Formula I. The dihydroxyl compound of structure 1 is condensed with an aldehyde of structure 2 in the presence of catalytic amount of acid to give a product of structure 3. Aldehyde compound of structure 2 is prepared from the corresponding carboxylic acid by the standard procedure in the literature.

SCHEME I

Scheme II describes the general procedure for preparing the cyclic bisphosphonate prodrug compounds of Formula II via a base catalyzed alkylation routes. Condensation reaction of a bisphosphonate of structure 4 with the acetate derivative of structure 5 in the presence of a base provides the product of structure 6.

SCHEME II

Compounds of Formula III, IV, and V are prepared by using standard conditions in the literature from the corresponding acids and alcohols (e.g., See J. E. Starrett, Jr., et al. J Med Chem 37: 1857-1864 (1994) and J. K. Dickson, et al. J Med Chem 39:661-664 (1996)).

EXAMPLES

Some compounds of Formula I, II, III, IV, and V are prepared as outlined below. EXAMPLE 1

(±)-(2-((4Z,7Z, \0Z, \3Z,\ 6Z)-Nonadeca-4,7, 10, 13, 16-pentaen- 1 -yl)- 1 ,3 -dioxolan-4- yl)methanol (C mpound 101)

Compound 101 was prepared according to the general procedure of Scheme I as a mixture of diastereomers from eicosapentaenoic aldehyde and glycerol. [M+H]⁺ calcd for C23H36O3 : 361.27; found: 361.3. ¾ NMR (400MHz, CDCb) 5.46-5.30 (m, 10H), 5.02 (t, J= 4.9, 0.5H), 4.92 (t, J= 4.6, 0.5H), 4.26-4.15 (m, 1H), 4.11 (t, J= 8.4, 0.5H), 3.96-3.49 (m, 4.5H), 2.96-2.77 (m, 8H), 2.18-2.04 (m, 4H), 1.65-1.40 (m, 4H), 0.98 (t, J= 7.5, 3H). EXAMPLE 2

(2, 5 -cis)-2-((4Z,7Z, 10Z, 13Z, 16Z)-Nonadeca-4,7, 10, 13,16-pentaen- 1 -yl)- 1 , 3 - dioxan-5-ol (Com ound 102)

Compound 102 was prepared according to the general procedure of Scheme I from eicosapentaenoic aldehyde and glycerol and isolated as a single isomer. [M+H]⁺ calcd for C23H36O3 : 361.27; found: 361.3. ¾ NMR (400MHz, CDCb) 5.40-5.33 (m, 10H), 4.58 (t, J= 5.2, 1H), 4.02 (d, J= 11.2, 2H), 3.90 (d, J= 11.2, 2H), 3.53 (bs, 1H), 2.95-2.83 (m, 8H), 2.13-2.05 (m, 4H), 1.68-1.65 (m, 2H), 1.53-1.45 (m, 2H), and 0.98 (t, J= 7.6, 3H). EXAMPLE 3

(2, 5 -trans)-2-((4Z, 7Z, 10Z, 13Z, 16Z)-Nonadeca-4, 7, 10,13, 16-pentaen- 1 -yl)- 1 , 3 - dioxan-5-ol (Com ound 103)

Compound 103 was prepared according to the general procedure of Scheme I from eicosapentaenoic aldehyde and glycerol and isolated as a single isomer. [M+H]⁺ calcd for C23H36O3 : 361.27; found: 361.3. ¾ NMR (400MHz, CDCb) 5.42-5.30 (m, 10H), 4.40 (t, J= 4.8, 1H), 4.16 (dd, J= 11.2 and 5.6, 2H), 3.86 (bs, 1H), 3.34 (t, J= 11.2, 2H), 2.85- 2.73 (m, 8H), 2.13-2.02 (m, 4H), 1.66-1.42 (m, 4H), and 0.95 (t, J= 7.6, 3H). EXAMPLE 4

2-((4Z,7Z, 1 OZ, 13Z, 16Z)-Nonadeca-4,7, 10,13, 16-pentaen- 1 -yl)- 1 ,3 -dioxan-5-one (Compound 104)

Compound 104 was prepared from Compound 102 via oxidation by 2- iodoxybenzoic acid in acetonitrile. [M+H]⁺ calcd for C23H34O3 : 359.25; found: 359.3. ¾ NMR (400MHz, CDCb) 5.45-5.33 (m, 10H), 4.89 (d, J= 4.8, 1H), 4.40 (d, J= 18.4, 2H), 4.27 (d, J= 18.4, 2H), 2.87-2.82 (m, 8H), 2.14-2.08 (m, 4H), 1.77-1.73 (m, 2H), 1.56-1.54 (m, 2H), 0.98 (t, J = 7.6, 3H).

EXAMPLE 5

(2, 5-cw)-2-((4Z,7Z, 10Z, 13Z, 16Z)-Nonadeca-4,7, 10, 13,16-pentaen- 1 -yl)- 1,3- dioxan-5-yl dih drogen phosphate (Compound 105)

Compound 105 was prepared as a partial triethylamine salt from Compound 102 via treatment with phosphorus oxychloride in the presence of triethylamine in hexane. [M+H]⁺ calcd for C23H37O6P: 441.23; found: 441.3. ¾ NMR (400MHz, CDCb) 5.41-5.34 (m, 10H), 4.51 (s, 1H), 4.21 (d, J= 10.4, 2H), 4.07 (d, J= 6.8, 1H), 3.84 (d, J= 10.4, 2H), 2.83-2.79 (m, 8H), 2.11-2.04 (m, 4H), 1.60 (s, 2H), 1.44-1.42 (m, 2H), and 0.97 (t, J= 7.6, 3H).

EXAMPLE 6

(±)-(2, 5-cis)-2-((4Z,7Z, 10Z, 13Z, 16Z)-Nonadeca-4,7, 10, 13,16-pentaen- 1 -yl)- 1,3- dioxan-5-yl hydro en methylphosphonate (Compound 106)

Compound 106 was prepared as a partial triethylamine salt from Compound 102 via treatment with methylphosphonic dichloride in the presence of triethylamine in hexane. [M-H]⁺ calcd for C24H39O5P: 437.25; found: 437.3. ¾ NMR (400MHz, CDCb) 5.41-5.32 (m, 10H), 4.53 (t, J= 4.8, 1H), 4.21 (bs, 1H), 4.18 (d, J= 11.6, 2H), 3.89 (d, J= 11.6, 2H), 2.83-2.79 (m, 8H), 2.11-2.04 (m, 4H), 1.60 (bs, 2H), 1.50 (s, 3H), 1.49-1.32 (m, 2H), and 0.97 (t, J = 7.6, 3H).

EXAMPLE 7

(±)-(2-((4Z,7Z, 1 OZ, 13Z, 16Z)-Nonadeca-4,7, 10,13,16-pentaen- 1 -yl)- 1 ,3 -dioxolan- 4-yl)m ethyl ihydrogen phosphate (Compound 107)

Compound 107 was prepared as a mixture of stereoisomers and as a partial triethylamine salt from Compound 102 via treatment with phosphorus oxy chloride in the presence of triethylamine in hexane. [M+H]⁺ calcd for C23H37O6P: 441.23; found: 441.3. ¾ NMR (400MHz, CDCI3) 5.41-5.35 (m, 10H), 4.99-4.97 (m, 0.5H), 4.85-4.84 (m, 0.5H), 4.27-4.25 (m, 1H), 4.12-4.11 (m, 0.5H), 3.97-3.78 (m, 3H), 3.74-3.66 (m, 0.5H), 3.08 (q, J = 7.2, 3H), 2.85-2.77 (m, 8H), 2.12-2.06 (m, 4H), 1.66-1.64 (m, 2H), 1.48-1.46 (m, 2H), 1.32 (t, J= 6.8, 4H), and 0.98 (t, J= 7.6, 3H).

EXAMPLE 8

((2S,4S, 5R)-2-((4Z,7Z, 10Z, 13Z, 16Z)-Nonadeca-4,7, 10, 13,16-pentaen- 1 -yl)- 1,3- dioxolane-4,5-diyl)dimethanol (Compound 108)

Compound 108 was prepared as a single isomer by a modified procedure from eicosapentaenoic aldehyde and weso-erythritol. Briefly, weso-erythritol was treated with benzoyl chloride in l-mtheyl-2-pyrrolidinone to give 4-benzoyloxy-2,3-dihydroxybutyl benzoate and then the protected diol was condensed with eicosapentaenoic aldehyde according the general procedure in Scheme I to provide the bis-benzoyl protected product as a single diastereomer. Deprotection with potassium carbonate in methanol at room temperature afforded Compound 108 as an oil. [M+H]⁺ calcd for C24H38O4: 391.28;

found: 391.3. ¾ NMR (400MHz, CDCb) 5.46-5.29 (m, 10H), 4.95 (t, J= 4.6, 1H), 4.22- 4.16 (m, 2H), 3.87-3.64 (m, 4H), 2.93-2.75 (m, 8H), 2.18-2.07 (m, 4H), 1.75-1.66 (m, 2H), 1.57-1.47 (m, 2H), and 0.98 (t, J= 7.6, 3H). EXAMPLE 9

(±)- 1 -((2,4-cw)-2-((4Z,7Z, 10Z, 13Z, 16Z)-Nonadeca-4,7, 10, 13, 16-pentaen- 1 -yl)-l ,3- dioxolan-4-yl)ethane-l 2-diol (Compound 109)

Compound 109 was prepared as a minor isomer in the preparation of Compound 108. [M+H]⁺ calcd for C24H38O4: 391.28; found: 391.3. ¾ NMR (400MHz, CDCb) 5.46- 5.29 (m, 10H), 4.87 (t, J= 4.8, 1H), 4.08-3.99 (m, 2H), 3.96-3.64 (m, 4H), 2.93-2.75 (m, 8H), 2.18-2.07 (m, 4H), 1.75-1.66 (m, 2H), 1.57-1.47 (m, 2H), and 0.98 (t, J= 7.6, 3H). EXAMPLE 10

(2-((4Z,7Z, 10Z, 13Z, 16Z)-Nonadeca-4,7, 10, 13,16-pentaen- 1 -yl)- 1 ,3 -dioxan-5- yl)methanol (Compound 110)

Compound 110 was prepared as a mixture of two stereoisomers according to the general procedure described in Scheme I from eicosapentaenoic aldehyde and 2- hydroxymethyl-l,3-propanediol. [M+H]⁺ calcd for C24H38O3 : 375.28; found: 375.3. ¾ NMR (400MHz, CDCb) 5.40-5.29 (m, 10H), 4.87 (bs, 1H), 4.55 (t, J= 4.8, 0.5H), 4.45 (t, J= 4.8, 0.5H), 4.19-3.97 (m, 4H), 3.52-3.45 (m, 2H), 2.87-2.80 (m, 8H), 2.30-2.16 (m, 1H), 2.12-2.05 (m, 4H), 1.70-1.48 (m, 4H), and 0.98 (t, J= 7.6, 3H).

EXAMPLE 11

((4S,5S)-2-((4Z,7Z, 10Z, 13Z, 16Z)-Nonadeca-4,7, 10, 13,16-pentaen- 1 -yl)- 1,3- dioxolane-4,5-diyl)dimethanol (Compound 111)

Compound 111 was prepared as a single isomer according to the general procedure described in Scheme I from eicosapentaenoic aldehyde and L-threitol. [M+H]⁺ calcd for

C24H38O4: 391.28; found: 391.3. ¾ NMR (400MHz, CDCb) 5.50-5.32 (m, 10H), 5.10 (t, J= 4.8, 1H), 3.99 (bs, 2H), 3.88-3.70 (m, 4H), 2.90-2.81 (m, 8H), 1.93 (bs, 2H), 1.75-1.67 (m, 2H), 1.57-1.50 (m, 2H), and 0.99 (t, J= 7.6, 3H). EXAMPLE 12

(2-((4Z, 7Z, 10Z, 13Z, 16Z)-Nonadeca-4, 7, 10, 13,16-pentaen- 1 -yl)- 1 , 3 -dioxan-5 , 5 - diyl)dimethanol (Compound 112)

Compound 112 was prepared as a mixture of two stereoisomers according to the general procedure described in Scheme I from eicosapentaenoic aldehyde and 2,2- di(hydroxymethyl)- 1,3 -propanediol. [M+H]⁺ calcd for C25H40O4: 405.29; found: 405.3. ¾ NMR (400MHz, CDCh) 5.44-5.30 (m, 10H), 4.46 (t, J= 4.8, 1H), 4.03 (s, 2H), 4.01 (d, J= 11.6, 2H), 3.54 (d, J= 11.6, 2H), 3.47 (s, 2H), 2.31 (bs, 2H), 2.87-2.80 (m, 8H), 2.31 (bs, 2H), 2.33-2.06 (m, 4H), 1.67-1.62 (m, 2H), 1.53-1.45 (m, 2H), and 0.98 (t, J= 7.6, 3H).

EXAMPLE 13

(5R)-3,4-Dihydroxy-5-((4S)-2-((4Z,7Z, 10Z, 13Z, 16Z)-nonadeca-4,7, 10, 13, 16- pentaen-l-yl)-l 3-dioxolan-4-yl)furan-2(5H)-one (Compound 113)

Compound 113 was prepared as a mixture of two stereoisomers according to the general procedure described in Scheme I from eicosapentaenoic aldehyde and L-ascorbic acid. [M+H]⁺ calcd for CielfeOe: 444.25; found: 444.3. ¾ MR (400MHz, CDCh) 7.35 (bs, 2H), 5.47-5.30 (m, 10H), 4.93 (bs, 0.5H), 4.83 (bs, 0.5H), 4.48-4.41 (m, 1H), 4.22- 4.10 (m, 2H), 3.89 (bs, 1H), 2.84-2.77 (m, 8H), 2.09-2.01 (m, 4H), 1.68-1.40 (m, 4H), and 0.96 (t, J= 7.6, 3H).

EXAMPLE 14

(2R,4aR,6R,7R,8R,8a5)-6-Methoxy-2-((4Z,7Z, 10Z,13Z,16Z)-nonadeca- 4,7, 10,13, 16- entaen-l-yl)hexahydropyrano[3,2-d][l,3]dioxine-7,8-diol (Compound 114)

Compound 114 was prepared according to the general procedure described in Scheme I from eicosapentaenoic aldehyde and (2R,3,S',4₎S',5R,6R)-2-(hydroxymethyl)-6- methoxytetrahydro-2H-pyran-3,4,5-triol that was prepared from D-glucose. [M+H]⁺ calcd for C27H42O6: 463.30; found: 463.4. ¾ NMR (400MHz, CD3OD) 5.40-5.33 (m, 10H), 4.68 (d, J= 3.6, 1H), 4.59 (t, J= 4.8, 1H), 4.07 (dd, J= 9.6 and 4.4, 1H), 3.73 (t, J= 9.2, 1H), 3.62-3.44 (m, 3H), 3.42 (s, 3H), 3.20 (t, J= 9.2, 1H), 2.91-2.83 (m, 8H), 2.14-2.06 (m, 4H), 1.70-1.61 (m, 2H), 1.56-1.48 (m, 2H), and 0.99 (t, J= 7.6, 3H).

EXAMPLE 15

(±)-2-((4Z,7Z, 10Z, 13Z, 16Z)-Nonadeca-4,7, 10, 13, 16-pentaen- 1 -yl)- 1 ,3 -dioxolan-4- one (Compound 115

Compound 115 was prepared according to the general procedure described in Scheme I from eicosapentaenoic aldehyde and 2 -hydroxy acetic acid. [M+H]⁺ calcd for C22H32O3: 345.24; found: 345.2. ¾ NMR (400MHz, CDCb) 5.61 (t, J= 4.6, 1H), 5.49- 5.22 (m, 10H), 4.32 (d, J= 14.8, 1H), 4.20 (d, J= 14.8, 1H), 2.90-2.78 (m, 8H), 2.19-2.01 (m, 4H), 1.84-1.80 (m, 2H), 1.55-1.49 (m, 2H), and 0.97 (t, J= 7.4, 3H).

EXAMPLE 16

(±)-2-((4Z,7Z, 10Z, 13Z, 16Z)-Nonadeca-4,7, 10, 13, 16-pentaen- 1 -yl)oxazolidin-4- one (Compound 116

Compound 116 was prepared according to the general procedure described in Scheme I from eicosapentaenoic aldehyde and 2 -hydroxy acetic amide. [M+H]⁺ calcd for C22H33NO2: 344.25; found: 344.3. ¾ NMR (400MHz, CDCb) 7.83 (bs, 1H), 5.50-5.20 (m, 11H), 4.23 (d, J= 13.6, 1H), 4.17 (d, J= 13.6, 1H), 2.92-2.74 (m, 8H), 2.21-2.01 (m, 4H), 1.78-1.65 (m, 2H), 1.58-1.39 (m, 2H), and 0.98 (t, J= 7.5, 3H).

EXAMPLE 17

2,4-Dihydroxy-6-((4Z,7Z, 10Z, 13Z, 16Z)-nonadeca-4,7, 10, 13,16-pentaen- 1 -yl)- 1,3,5,2,4-trioxadiphosphinane 2,4-dioxide (Compound 117) cr^p-? Compound 117 was prepared as a triethylamine salt according to the general procedure described in Scheme II from pyrophosphoric acid and (5Z,8Z,11Z,14Z, 17Z)-1- chloroicosa-5,8,11, 14,17-pentaen- 1-yl acetate that was prepared from eicosapentaenoic aldehyde. [M+H]⁺ calcd for C20H32O7P2: 447.16; found: 447.00. ¾ MR (400MHz, CD3OD) 5.73-5.68 (m, 1H), 5.38-5.30 (m, 10H), 3.19 (q, J= 9.0, 12H), 2.89-2.80 (m, 8H), 2.18-2.06 (m, 4H), 1.83-1.75 (m, 2H), 1.61-1.48 (m, 2H), 1.30 (t, J= 9.0, 18H), and 0.96 (t, J= 10.0, 3H).

EXAMPLE 18

2,4-Dihydroxy-6-((4Z,7Z, 10Z, 13Z, 16Z)-nonadeca-4,7, 10, 13,16-pentaen- 1 -yl)- 1,5,2,4-dioxadiphosphinane 2,4-dioxide (Compound 118)

Compound 118 was prepared as a triethylamine salt according to the general procedure described in Scheme II from methylenebis(phosphonic acid)and

(5Z, 8Z, 11Z, 14Z, 17Z)- 1 -chloroicosa-5,8, 11,14, 17-pentaen- 1 -yl acetate that was prepared from eicosapentaenoic aldehyde. [M+H]⁺ calcd for C20H32O7P2: 445.18; found: 445.05. ¹H MR (400MHz, CD3OD) 5.67 (quintet, J= 4.0, 1H), 5.41-5.30 (m, 10H), 3.18 (q, J = 9.0, 12H), 2.89-2.80 (m, 8H), 2.45-2.26 (m, 2H), 2.18-2.03 (m, 4H), 1.83-1.75 (m, 2H), 1.61-1.48 (m, 2H), 1.30 (t, J= 9.0, 18H), and 0.97 (t, J= 10.0, 3H).

EXAMPLE 19

(±)-(5Z,8Z, 11Z, 14Z, 17Z)-Icosa-5,8, 11 , 14, 17-pentaen- 1 -yl methyl

methylphosphoramidate (Compound 119)

Compound 119 was prepared with standard procedure from (5Z,8Z, 11Z, 14Z, 17Z)- icosa-5,8, l l,14, 17-pentaen-l-ol and methyl phosphorodichlondate. Briefly, the alcohol was treated with phosphorodichloridate in hexane in the presence of triethylamine and then the mixture was quenched with methylamine. [M+H]⁺ calcd for C22H38NO3P: 396.26; found: 396.3. ¹H MR (400MHz, CDCb) 5.42-5.33 (m, 10H), 4.04-3.98 (m, 2H), 3.72 (d, J= 10.8, 3H), 2.85-2.80 (m, 8H), 3.61 (d, J= 12, 3H), 2.14-2.06 (m, 4H), 1.72-1.70 (m, 2H), 1.49-1.45 (m, 2H), and 0.98 (t, J= 7.6, 3H).

EXAMPLE 20

(5Z, 8Z, 11Z, 14Z, 17Z)-Icosa-5, 8, 11, 14,17-pentaen- 1 -yl phosphorodiamidate (Compound 120

Compound 120 was prepared with standard procedure from (5Z,8Z, 11Z, 14Z, 17Z)- icosa-5,8, 11,14, 17-pentaen- l-ol, phosphorus oxychlonde, and ammonia. [M+H]⁺ calcd for C20H35N2O2P: 367.24; found: 367.2. ¾ NMR (400MHz, CDCb) 5.38-5.30 (m, 10H), 4.00 (q, J= 6.4, 2H), 2.85-2.81 (m, 12H), 2.13-2.06 (m, 4H), 1.70-1.66 (m, 2H), 1.49-1.43 (m, 2H), and 0.98 (t, J= 7.6, 3H).

EXAMPLE 21

Dimethyl ((5Z,8Z, 11Z, 14Z, 17Z)-icosa-5,8, 11,14, 17-pentaen- l-yl)phosphoramidate (Compound 121

Compound 121 was prepared with standard procedure from (5Z,8Z, 11Z, 14Z, 17Z)- icosa-5, 8, 11,14, 17-pentaen-l-amine and dimethyl phosphorochlondate. [M+H]⁺ calcd for C22H38NO3P: 396.26; found: 396.3. ¾ NMR (400MHz, CD3OD) 5.43-5.30 (m, 10H), 3.68 (d, 7= 11.6, 6H), 2.93-2.82 (m, 10H), 2.16-2.08 (m, 4H), 1.57-1.51 (m, 2H), 1.49- 1.40 (m, 2H), and 0.99 (t, 7= 7.6, 3H).

EXAMPLE 22

N-((5Z, 8Z, 11 Z, 14Z, 17Z)-Icosa-5,8, 11,14, 17-pentaen- 1 -yl)methanesulfonamide (Compound 122)

Compound 122 was prepared with standard procedure from (5Z,8Z, 11Z, 14Z, 17Z)- icosa-5, 8, 11,14, 17-pentaen-l-amine and dimethyl phosphorochlondate. [M+H]⁺ calcd for C21H35NO2S: 366.24; found: 366.3. ¾ NMR (400MHz, CDCb) 5.42-5.31 (m, 10H), 4.28 (bs, 1H), 3.14 (q, J= 6.8, 2H), 2.96 (s, 3H), 2.85-1.82 (m, 8H), 2.12-2.07 (m, 4H), 1.63- 1.60 (m, 3H), 1.46-1.44 (m, 2H), and 0.98 (t, J= 7.2, 3H).

EXAMPLE 23

((5Z,5Z,77Z, 7 Z,77Z)-icosa-5,8, l l,14, 17-pentaen-l-yl)-J-proline (Compound 123)

H

Compound 123 was prepared with standard procedure from (3Z,6Z,9Z, 12Z, 15Z)- 20-bromoicosa-3,6,9,12, 15-pentaene and methyl J-prolinate. [M+H]⁺ calcd for

C25H39NO2: 385.30; found: 385.3. ¾ NMR (400MHz, CDCb) 6.17 (bs, 1H), 5.48-5.19 (m, 10H), 3.96 (quintet, J= 6.0, 1H), 3.69 (dd, J= 8.8 and 6.4, 1H), 3.27-3.15 (m, 1H), 3.05-2.92 (m, 1H), 2.89-2.68 (m, 8H), 2.40-2.18 (m, 2H), 2.14-1.92 (m, 6H), 1.85-1.70 (m, 2H), 1.51-1.35 (m, 2H), and 0.95 (t, J= 7.6, 3H).

EXAMPLE 24

4-((5Z, 8Z, 11 Z, 14Z, 17Z)-Icosa-5 , 8, 11, 14,17-pentaen- 1 -yl)piperazine- 1 - carboxamide Compound 124)

Compound 124 was prepared with standard procedure from (3Z,6Z,9Z, 12Z, 15Z)- 20-bromoicosa-3,6,9,12, 15-pentaene and methyl tert-butyl piperazine-l-carboxylate.

[M+H]⁺ calcd for C25H41N3O: 400.32; found: 400.3. ¾ NMR (400MHz, CDCb) 5.48- 5.32 (m, 10H), 4.53 (bs, 2H), 3.39 (t, J= 4.8, 4H), 2.89-2.74 (m, 8H), 2.40 (t, J= 4.8, 4H), 2.34 (t, J= 7.6, 2H), 2.14-2.01 (m, 4H), 1.56-1.45 (m, 2H), 1.44-1.33 (m, 2H), and 0.96 (t, J= 7.6, 3H).

EXAMPLE 25

((5Z,5Z,77Z, 7 Z,77Z)-icosa-5,8, l 1,14, 17-pentaen- l-yl)-J-proline (Compound 125)

Compound 125 was prepared with standard procedure from (5Z,8Z, 11Z, 14Z, 17Z)- icosa-5,8, 11,14, 17-pentaen- 1 -amine and ethyl 2-bromoacetate. [M+H]⁺ calcd for

C22H35NO2: 346.27; found: 346.3. ¾ NMR (400MHz, CD3OD) 5.45-5.33 (m, 10H), 3.80 (s, 2H), 3.03 (t, J= 7.6, 2H), 2.89-2.80 (m, 8H), 2.20-2.08 (m, 4H), 1.80-1.70 (m, 2H), 1.56-1.45 (m, 2H), and 0.99 (t, J= 7.6, 3H).

EXAMPLE 26

2-Amino-N-((5Z,8Z, 11 Z, 14Z, 17Z)-icosa-5, 8, 11, 14, 17-pentaen- 1 -yl)acetamide (Compound 126)

Compound 126 was prepared with standard procedure from (5Z,8Z, 11Z, 14Z, 17Z)- icosa-5,8, 11,14, 17-pentaen- 1 -amine and N-Boc-glycine. [M+H]⁺ calcd for C22H36N2O: 345.28; found: 345.4. ¾ NMR (400MHz, CD3OD) 5.40-5.30 (m, 10H), 3.24 (s, 2H), 3.21 (t, J= 6.8, 2H), 2.88-2.80 (m, 8H), 2.12-2.05 (m, 4H), 1.56-1.50 (m, 2H), 1.46-1.40 (m, 2H), and 0.97 (t, J = 7.6, 3H).

EXAMPLE 27

Dimethyl ((5Z,8Z, 11Z, 14Z, 17Z)-icosa-5,8, 11,14, 17-pentaenoyl)phosphoramidate (Compound 127

Compound 127 was prepared with standard procedure from eicosapentaenoic amide and dimethyl phosphorochlondate. [M+H]⁺ calcd for C22H36NO4P: 410.24; found: 410.3. ¾ MR (400MHz, CDCb) 7.97 (bs, 1H), 5.39-5.30 (m, 10H), 3.83 (d, J= 11.6, 6H), 2.85-2.80 (m, 8H), 2.36 (t, J= 7.6, 2H), 2.14-2.03 (m, 4H), 1.75-1.70 (m, 2H), and 0.95 (t, J= 7.6, 3H).

EXAMPLE 28

(5Z,8Z, l lZ, 14Z, 17Z)-N-(5,5-Dimethoxy-2-oxido-l,3,2-dioxaphosphinan-2- yl)icosa-5,8,l l 14,17-pentaenamide (Compound 128)

Compound 128 was prepared with standard procedure from eicosapentaenoic amide and 2-chloro-5,5-dimethoxy-l,3,2-dioxaphosphinane 2-oxide. [M+H]⁺ calcd for C25H40NO6P: 482.26; found: 482.2. ¾ NMR (400MHz, CD3OD) 5.43-5.35 (m, 10H), 4.51 (dd, J= 10.4 and 3.6, 2H), 4.42-4.34 (m, 2H), 3.36 (s, 3H), 3.28 (s, 3H), 2.87-2.82 (m, 8H), 2.34 (t, J= 7.6, 2H), 2.14-2.08 (m, 4H), 1.70-1.66 (m, 2H), and 0.94 (t, J= 7.6, 3H). EXAMPLE 29

((5Z, 8Z, 11 Z, 14Z, 17Z)-Icosa-5 , 8, 11 , 14, 17-pentaenoyl)-J-serine (Compound 129)

Compound 129 was prepared with standard procedure from eicosapentaenoic acid and methyl J-serinate. [M+H]⁺ calcd for CisftoNOeP: 482.26; found: 482.2. ¾ MR (400MHz, CD₃OD) 5.43-5.35 (m, 10H), 4.51 (dd, J= 10.4 and 3.6, 2H), 4.42-4.34 (m, 2H), 3.36 (s, 3H), 3.28 (s, 3H), 2.87-2.82 (m, 8H), 2.34 (t, J= 7.6, 2H), 2.14-2.08 (m, 4H), 1.70-1.66 (m, 2H), and 0.94 (t, J= 7.6, 3H).

EXAMPLE 30

(±)-(5Z,8Z, 11Z, 14Z, 17Z)-l-((Hydroxy(phosphonooxy)phosphoryl)oxy)icosa- 5,8, 11,14, 17-pentaen-l- l acetate (Compound 130)

Compound 130 was prepared as a triethylamine salt according to the general procedure described in Scheme II from pyrophosphoric acid and (5Z,8Z,11Z,14Z, 17Z)-1- chloroicosa-5, 8,11, 14,17-pentaen-l-yl acetate that was prepared from eicosapentaenoic aldehyde. [M-H]⁺ calcd for C22H36O9P2: 505.18; found: 504.90.

EXAMPLE 31

l,3-Dioxan-5-yl (5Z,8Z, 1 lZ, 14Z, 17Z)-icosa-5, 8, 11, 14,17-pentaenoate (Compound

131)

Compound 131 was prepared with standard procedure from eicosapentaenoic acid and l,3-dioxan-5-ol. [M+H]⁺ calcd for C24H36O4: 389.26; found: 389.4. ¹H MR

(400MHz, CDCb) 5.54-5.24 (m, 10H), 4.97 (d, J= 6.0, 1H), 4.83 (d, J= 6.4, 1H), 4.79- 4.72 (m, 1H), 4.33 (t, J= 6.8, 1H), 4.02 (dd, J= 12 and 2.0, 2H), 3.95 (dd, J= 12 and 3.2, 2H), 2.95-2.79 (m, 8H), 2.44 (t, J= 7.6, 2H), 2.22-1.99 (m, 4H), 1.76 (sextet, J= 7.2, and 1.00 (t, J= 7.6, 3H).

EXAMPLE 32

2-(Hydroxymethyl)- 1 ,3 -dioxan-5-yl (5Z,8Z, 11 Z, 14Z, 17Z)-icosa-5,8, 11,14,17- pentaenoate (Com ound 132)

Compound 132 was prepared with standard procedure from eicosapentaenoic acid and 2-((tert-butyl(diphenyl)silyl)oxymethyl)-l,3-dioxan-5-ol. [M+H]⁺ calcd for C25H38O5 : 419.27; found: 419.4. ¾ NMR (400MHz, CDCb) 5.40-5.21 (m, 10H), 4.85 (td, J= 10.3 and 5.2, 1H), 4.51 (t, J= 4.4, 1H), 4.21 (dd, J= 11.0 and 5.3, 2H), 3.57 (d, J= 3.5, 2H), 3.43 (t, J= 10.6, 2H), 2.83-2.67 (m, 8H), 2.23 (t, J= 7.5, 2H), 2.07 - 1.94 (m, 4H), 1.66- 1.59 (m, 2H), and 0.91 (t, J= 7.6, 3H).

EXAMPLE 33

2-(Pyridin-3 -yl)- 1 ,3 -dioxan-5-yl (5Z, 8Z, 11Z, 14Z, 17Z)-icosa-5, 8, 11, 14,17- pentaenoate Compound 133)

Compound 133 was prepared as a mixture of two diastereomers with standard procedure from eicosapentaenoic acid and 2-(pyridin-3-yl)-l,3-dioxan-5-ol. [M+H]⁺ calcd for C29H39NO4: 466.29; found: 466.3. ¾ NMR (400MHz, CDCb) 8.64 (d, J= 2.0, 1H), 8.56 (dd, J= 4.8 and 1.5, 1H), 7.75 (dt, J= 5.6 and 1.5, 1H), 7.26 (dd, J= 8.0 and 4.8, 1H), 5.79 (s, 1H), 5.63-5.27 (m, 10H), 4.43-4.38 (m, 1H), 4.16-4.14 (m, 2H), 4.07 (t, J= 8.0, 1H), 3.89 (dd, J= 8.8 and 5.2, 1H), 2.77-2.72 (m, 8H), 2.27 (t, J= 7.2, 2H), 2.04-2.00 (m, 4H), 1.75-1.61 (m, 2H), and 0.90 (t, J= 7.6, 3H).

EXAMPLE 34

(2-(Pyridin-3-yl)-l,3-dioxolan-4-yl)methyl (5Z,8Z,1 lZ,14Z, 17Z)-icosa- 5,8, 11,14, 17-pentaenoate (Compound 134)

Compound 134 was prepared as a mixture of stereoisomers with standard procedure from eicosapentaenoic acid and (2-(pyridin-3-yl)-l,3-dioxolan-4-yl)methanol. [M+H]⁺ calcd for C29H39NO4: 466.29; found: 466.3. ¾ NMR (400MHz, CDCb) 8.66 (s, 1H), 8.56 (d, J= 3.6, 1H), 7.75 (d, J= 7.6, 1H), 7.27 (dd, J= 7.6 and 5.2, 1H), 5.95 (s, 1H), 5.63-5.27 (m, 10H), 4.49-4.43 (m, 1H), 4.26-4.20 (m, 3H), 3.80 (dd, J= 8.4 and 6.8, 1H), 2.77-2.72 (m, 8H), 2.35 (t, J= 7.2, 2H), 2.13-2.01 (m, 4H), 1.77-1.64 (m, 2H), and 0.96 (t, J= 7.6, 3H).

EXAMPLE 35

(±)-(2w, 5/)-2-Methoxy-2-oxido- 1 , 3 ,2-oxazaphosphinan-5 -yl (5Z, 8Z, 11 Z, 14Z, 17Z)- icosa-5,8, l l,14 17-pentaenoate (Compound 135)

Compound 135 was prepared with standard procedure from eicosapentaenoic acid and 5-hydroxy-2-methoxy-l,3,2-oxazaphosphinane 2-oxide. [M+H]⁺ calcd for

C24H38NO5P: 452.25; found: 452.3. ¾ NMR (400MHz, CDCb) 5.34-5.31 (m, 10H), 5.03- 4.98 (m, 1H), 4.35-4.45 (m, 1H), 4.13 (q, J= 10.8, 1H), 3.77 (d, J= 11.2, 3H), 3.60-3.45 (m, 1H), 3.18-3.06 (m, 1H), 3.00 (bs, 1H), 2.89-2.74 (m, 8H), 2.30 (t, J= 7.2, 2H), 2.15- 2.03 (m, 4H), 1.75-1.60 (m, 2H), and 0.97 (t, J= 7.6, 3H).

EXAMPLE 36

(±)-(2w,5w)-2-Methoxy-2-oxido-l,3,2-oxazaphosphinan-5-yl (5Z,8Z,11Z,14Z,17Z)- icosa-5,8, l l,14 17-pentaenoate (Compound 136)

Compound 136 was prepared with standard procedure from eicosapentaenoic acid and 5-hydroxy-2-methoxy-l,3,2-oxazaphosphinane 2-oxide. [M+H]⁺ calcd for

C24H38NO5P: 452.25; found: 452.3. ¾ NMR (400MHz, CDCb) 5.34-5.31 (m, 10H), 4.72 (bs, 1H), 4.44-4.35 (m, 2H), 3.76 (d, J= 10.8, 3H), 3.44-3.30 (m, 2H), 3.00 (bs, 1H), 2.90- 2.75 (m, 8H), 2.40 (t, J= 7.6, 2H), 2.19-2.05 (m, 4H), 1.75-1.60 (m, 2H), and 0.97 (t, J = 7.6, 3H). 2-((4Z,7Z, 10Z, 13Z, 16Z)-Nonadeca-4,7, 10,13, 16-pentaen- 1 -yl)- lH-imidazole

Compound 137 was prepared with standard procedure from eicosapentaenoic aldehyde, glyoxal, and ammonium hydrogen carbonate. [M+H]⁺ calcd for C22H32N2: 325.26; found: 325.3. ¾ MR (400MHz, CD3OD) 7.02 (s, 2H), 5.29-5.20 (m, 10H), 2.80-2.69 (m, 8H), 2.10-1.95 (m, 4H), 1.75-1.65 (m, 2H), and 0.86 (t, J= 7.6, 3H).

EXAMPLE 38

2-((4Z,7Z, 10Z, 13Z, 16Z)-Nonadeca-4,7, 10,13, 16-pentaen- 1 -yl)- 1 ,3 ,4-thiadiazole (Compound 138)

Compound 138 was prepared with standard procedure from eicosapentaenoic hydrazide, carboxylic acid, and P2S5. [M+H]⁺ calcd for C21H30N2S: 343.21; found: 343.3. ¾ NMR (400MHz, CDCh) 9.04 (s, 1H), 5.50-5.25 (m, 10H), 3.16 (t, J= 7.6, 2H), 2.85- 2.69 (m, 8H), 2.13-1.88 (m, 6H), and 0.94 (t, J= 7.6, 3H).

In some embodiments, any one or more of the above examples may be individually disclaimed from the present embodiments.

Biological Examples

Examples of use of the method include the following. It will be understood that the following are examples and that the method is not limited solely to these examples.

Example A: Liver Tissue Distribution Following Oral Administration of eicosapentaenoic acid and their Prodrugs

Wistar rats of 7-9 weeks old weighing 200-300 grams are acclimated for at least 3 days on low omega-3 diet. Eicosapentaenoic acid and their prodrugs are administered at 5- 20 mg/kg to fasted rats by oral gavage formulated in safflower oil. Individual groups are used for each time point of sample collection. Plasma concentrations of eicosapentaenoic acid (in both acid and ester forms) and prodrug in circulation, in the hepatic portal vein, in the liver, small intestine, and other organs are measured by LC -MS/MS method developed for each compound.

Example B: Evaluation of Eicosapentaenoic Acid and Their Prodrugs in a Diet Induced Hypertriglyceridemia Rat Model

Wistar male rats of 7-9 weeks old weighing 200-300 grams are acclimated for at least 3 days on regular diet and then grouped according to their weight into two groups with regular diet (control) and high fructose diet (dosing groups). Rats are single housed per cage with a unique cage number for food intake measuring. All dosing group rats are then fed with a high fructose diet for 1-2 weeks to develop hypertriglyceridemia. The animals are randomly divided into one vehicle group and 6-8 dosing groups based on body weight 3 days prior to the first dosing. All testing articles are formulated in safflower oil and administered daily by oral gavage for 2 weeks. Blood samples are collected from submandibular vein and processed to plasma samples within two hours of collection.

Plasma samples are stored at -80 °C for later analysis. Plasma lipid levels including total cholesterol, triglycerides, HDL, and LDL are checked at day one, seven, thirteen, and fourteen of dosing. Blood samples collected at day fourteen are in overnight fasting state. The lipoprotein particles are measured by automatic biochemistry analyzer and

triglycerides are measured with commercial kits. At the end of the study, liver samples are collected for the liver triglycerides and eicosapentaenoic acid (both in acid and ester forms) levels.

Results

The experiments described above and variants thereon demonstrated that the compounds tested were generally liver selective in these models and generally released EPA in the liver.

The experiments also demonstrated that EPA itself after oral administration is also largely taken up in the liver in this model (liver / plasma exposure ratio of about 15), although it is believed by a different metabolic route, potentially limiting the benefit of a liver-selective pro-drug.

Examples 8, 2 and 20 were tested according to Example B, alongside EPA and a regular diet group. None of the compounds of the Examples, nor EPA itself showed significant triglyceride reduction in this experiment, suggesting dosage levels may have been too small. However the liver EPA levels achieved by Example 20, at least at 20mg/kg dose in this model, suggest that only half the amount of Example 20 compared to EPA itself might be needed to achieve the same liver EPA levels.

All numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification are to be understood as being modified in all instances by the term "about." Accordingly, unless indicated to the contrary, the numerical parameters set forth herein are approximations that may vary depending upon the desired properties sought to be obtained. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of any claims in any application claiming priority to the present application, each numerical parameter should be construed in light of the number of significant digits and ordinary rounding approaches.

Language of degree used herein, such as the terms "approximately," "about," "generally," and "substantially" as used herein represent a value, amount, or characteristic close to the stated value, amount, or characteristic that still performs a desired function or achieves a desired result. For example, the terms "approximately", "about", "generally," and "substantially" may refer to an amount that is within less than 10% of, within less than 5% of, within less than 1% of, within less than 0.1% of, and within less than 0.01% of the stated amount. As another example, in certain embodiments, the terms "generally parallel" and "substantially parallel" refer to a value, amount, or characteristic that departs from exactly parallel by less than or equal to 15°, 10°, 5°, 3°, 1°, 0.1°, or otherwise. Similarly, in certain embodiments, the terms "generally perpendicular" and "substantially

perpendicular" refer to a value, amount, or characteristic that departs from exactly perpendicular by less than or equal to 15°, 10°, 5°, 3°, 1°, 0.1°, or otherwise.

The above description discloses several methods and materials. This invention is susceptible to modifications in the methods and materials, as well as alterations in the fabrication methods and equipment. Such modifications will become apparent to those skilled in the art from a consideration of this disclosure or practice of the invention disclosed herein. Consequently, it is not intended that this invention be limited to the specific embodiments disclosed herein, but that it cover all modifications and alternatives coming within the true scope and spirit of the invention.

All references cited herein, including but not limited to published and unpublished applications, patents, and literature references, are incorporated herein by reference in their entirety and are hereby made a part of this specification. To the extent publications and patents or patent applications incorporated by reference contradict the disclosure contained in the specification, the specification is intended to supersede and/or take precedence over any such contradictory material.

Claims

WHAT IS CLAIMED IS:

1. A compound of Formula I:

(I)

wherein:

CH(OH)CH₂OH; or R¹ and R² together optionally form an oxo (=0);

X is O or H;

m is 4 or 5;

n is 0 when m is 5; or n is 1 when m is 4;

p is 0 or 1;

or a stereoisomer or a pharmaceutically acceptable salt thereof. 2. A compound of Formula II:

(Π)

wherein:

R³ and R⁴ are each independently selected from the group consisting of OH, NH₂, Me, and OMe;

Y is selected from the group consisting of O, NH, and CH₂;

m is 4 or 5;

n is 0 when m is 5; or n is 1 when m is 4;

or a stereoisomer or a pharmaceutically acceptable salt thereof.

3. A compound of Formula Ilia or Illb:

Ilia)

(nib)

wherein:

R⁷ and R⁸ are each independently selected from the group consisting of OH, NH₂, Me, HMe, and OMe; or R⁷ and R⁸ are linked to form -OCH₂CH₂0-;

R⁹ is selected from the group consisting of H, Me, CH₂OH, CH₂C0₂H,

CH2CONH2, and CH₂(lH-imidazol-4-yl);

m is 4 or 5;

n is 0 when m is 5; or n is 1 when m is 4;

or a stereoisomer or a pharmaceutically acceptable salt thereof.

4. A com ound of Formula IVa or IVb:

(IVa) (IVb)

wherein:

R⁹ is selected from the group consisting of H, Me, CH₂OH, CH2CO2H,

CH2CONH2, and CH₂(lH-imidazol-4-yl);

R¹⁰ and R¹¹ are H or together form an oxo (=0);

R¹² is selected from the group consisting of H, CH₂OH, and pyridyl; m is 4 or 5;

n is 0 when m is 5; or n is 1 when m is 4;

or a stereoisomer or a pharmaceutically acceptable salt thereof. A compound of Formula V:

(V)

wherein:

U is O or S;

V is N or CH;

m is 4 or 5;

n is 0 when m is 5; or n is 1 when m is 4;

or a stereoisomer or a pharmaceutically acceptable salt

A compound selected from the group consisting of:

and a stereoisomer or a pharmaceutically acceptable salt thereof.

7. A compound selected from the group consisting of:

and a stereoisomer or a pharmaceutically acceptable salt thereof.

8. A compound selected from

or a pharmaceutically acceptable salt thereof.

9. A com ound which is

or a pharmaceutically-acceptable salt thereof.

10. A pharmaceutical composition comprising a compound of any of Claims 1-9 and a pharmaceutically acceptable excipient.

11. A method of treating a disease, disorder or condition comprising administering an effective amount of a compound of any of Claims 1-9.

12. The method of Claim 11, wherein the disease, disorder or condition is a disease, disorder or condition of the liver.

13. The method of Claim 11, wherein the disease, disorder or condition is a metabolic, or cardiovascular disease in which the liver is involved in the production and/or the homeostasis control of the biochemical end products of the disease, disorder or condition.

14. The method of Claim 11, wherein the disease, disorder or condition is selected from the group consisting of fatty liver, diabetes, hyperlipidemia, atherosclerosis, obesity, and dyslipidemia.

15. A method of treating a disease comprising administering an effective amount of a compound of any of Claims 1-9 to a subject in need thereof.

16. A method of treating dyslipidemia comprising administering to a subject in need thereof an effective amount of a compound of any of Claims 1-9.

17. The method of any of Claim 11-16 further comprising administering an effective amount of at least one additional therapeutic agent.

18. The method of any of Claims 15-16, wherein the subject is a mammal.

19. The method of any of Claims 15-16, wherein the subject is human.

20. Use of a compound of any of Claims 1-9 for treating a disease in the liver or a disease or condition in which the physiological or pathogenic pathways involve the liver a subject.

21. Use of a compound of any of Claims 1-9 in combination with an additional therapeutic agent for treating a disease in the liver or a disease or condition in which the physiological or pathogenic pathways involve the liver in a subject.

22. The use of Claim 20 or 21, wherein the subject is a mammal.

23. The use of Claim 20 or 21, wherein the subject is human.