WO2011149766A2

WO2011149766A2 - Lipid-tailored pharmaceutical agents

Info

Publication number: WO2011149766A2
Application number: PCT/US2011/037270
Authority: WO
Inventors: Jingxuan Kang
Original assignee: Individual
Current assignee: Individual
Priority date: 2010-05-23
Filing date: 2011-05-20
Publication date: 2011-12-01
Anticipated expiration: 2012-11-23
Also published as: WO2011149766A3

Abstract

The invention generally relates to novel therapeutic agents. More particularly, the invention relates to novel compounds having a moiety that provides the benefits of omega-3 fatty acids and a moiety that provides beneficial therapeutic benefits such as lowering blood cholesterol dampening inflammation, reducing triglyceride, increasing high-density lipoprotein, etc. Such therapeutic agents improve drug metabolism and pharmacokinetics, provide better efficacy, and reduce side effects.

Description

LIPID-TAILORED PHARMACEUTICAL AGENTS

Field of the Invention

[0001] The invention generally relates to novel therapeutic agents. More particularly, the invention relates to novel compounds having a moiety that provides the benefits of omega-3 fatty acids and a moiety thai provides beneficial therapeutic benefits such as lowering blood cholesterol, dampening inflammation, reducing triglyceride, increasing high-density lipoprotein, etc. Such therapeutic agents improve drag metabolism and pharmacokinetics, provide better efficacy, and reduce side effects.

Background of the Invention

[0002] In recent decades, drug companies continue to hunt for magical blockbuster molecules, i.e., single drug agents that reverse or disrupt disease by attacking a single specific cellular target. Despite limited success, the blockbuster strategy has in general fallen short is creating new -medicines. There are many reasons why such an approach has not been prod uctive as hoped for, one of whi ch may very well be the "single-minded" approach where the drug developer focuses on a single biological target, for example an enzyme or a protein invol ved in a single biological process, while ignoring the complex, intertwined biological systems of the human body.

[0003] Thus, a critical need in drug discovery and development is novel approaches that look at the problems from a fresh perspective.

Summary of the Invention

[0004] The invention is based in part on a novel approach to drag candidate design and development. The invention described herein allows one to improve the efficacy of existing drugs and provide complementary benefits and/or reduce their side effects. For examples, the invention described herein can significantly improve drug metabolism and pharmacokinetics (DMPK), e.g., absorption, distribution, metabolism, excretion, and/or toxicit (ADMET).

[0005] In one aspect, the invention generally relates to a compound ha ving the structural .formula of:

wherein

at least one of R_f, R₂ and R₃ is a group selected from column 1 of Table J ; and at least one of Rt, R> and ;! is a group selected from column 2 of Table 1, wherein if any of Rj, R₂ and R₃ is not selected from either column 1 or column 2 of Table 1, it is a hydrogen atom, a salt, or an organic group comprising from about i to about 6 carbon atoms. Table 1

[0006] In another aspect, the invention -generally relates to a compound havin the structural formula of:

wherein

R) is a radical formed from an omega-3 fatty acid having a -COOH group when the OH moiety is removed; R₃ is a radical formed from a therapeutic agent having an -C^'OOH group when, the OH moiety is removed; and R₂ is a hydrogen atom, a salt, or an organic group comprising from about 1 to about ⁽ carbon atoms R₅ or R₃. In some preferred embodiments, the therapeutic agent is niacin. Ih some embodiments, the therapeutic agent is aspirin. In. some embodiments, the therapeutic agent is a fibrate.

[0007] In another aspect, the invention generally relates to a pharmaceutical composition

comprising a compound having the structural formula of:

wherein i is a radical formed from an omega-3 fatty acid having a -COOH group when its OH moiet is removed; Rj is a radical formed from a therapeutic agent having an -COOH group when the OH moiety is removed; and ¾ is a hydrogen atom, R■ or R¾.

[0008] in another aspect, the invention generally relate to a pharmaceutical composition comprising a compound having the chemical formula of:

wherein R_t is a radical formed from an omega-3 fatty acid having a -COOH group when its OH moiety is removed; R? is a radical formed from a therapeutic agent having an -COOH group when the OH moiety is removed; ¾ is a hydrogen atom, a salt, or an organic group comprising from about 1 to about carbon atoms, R_t or R_:!; L is a linker atom or group, and each of X_s, X₂, and X¾ is independently an O or S. In certain preferred embodiments, each of X₅, X₂, and ₃ is O,

Description of the Invention

[0009] The invention described herein allows one to improve the efficacy of existing drugs and provide complementary benefits and/or reduce their side effects. For examples, the invention described herein can significantly improve drug metabolism and pharmacokinetics (DMF ), e.g. , absorption, distribution, metabolism, excretion, atui or toxicity (ADMET),

[001 ] For a compound to reach a tissue, it usually must be taken into the bloodstream, for example, via mucous surfaces like the digestive tract (intestinal absorption). Absorption significantly determines a compound's bioavailability. Drugs that absorb poorly when taken orally must be administered in some less desirable way, like intravenously or by inhalation. Drag molecules need to be carried to the site where they exert a biological effect, often via the bloodstream. From there, the drug molecules may distribute into tissues and organs, usually to differing extents. After entry into the systemic circulation, either by intrascuiar injection or fay absorption from any of the varioos extracellular sites, the drag is subjected to a distribution process that tends to lower its plasma concentration. Factors affecting distribution include blood flow rates and the drug binding to serum proteins,

[001 1] The majority of small-molecule drug metabolism is carried out in the liver. As metabolism occurs, the drug molecule is converted to new compounds called metabolites. When metabolites are pharmacologically inert, metabolism deacti vates the administered dose of paren t drag and this usually reduces the effects on the body. MetaboUtes may also be pharmacologically active, sometimes more so than the parent drag. Drug molecules and their metabolites are removed from the body via excretion., usually through the kidneys (urine) or in the feces.

[00123 In one aspect, the invention generaiiy relates to a compound having the structural formula of:

wherein

at least one of R_f , ¾ and R_? is a group selected from column !. of Table I; and at least one of Rj, R₂ and R_? is a group selected from column 2 of Table 1. wherein if any of t, R_?. and R_; is not selected from either column I or column 2 of Table 1, it is a hydrogen atom, a salt, or an organic group comprising .from about 1 to about 6 carbon atoms.

Table 1

[0013] In another aspect, the invention generally relates to a. compound having the structural formula of:

wherein

R.{ is a radical formed from an omega-3 fatty acid having a -COOH group when, the OH oiety is removed; R,_¾ is a radical formed from a therapeutic agent having an -COOH group when the OH

S moiety is removed; and R; is a hydrogen atom, a salt, or an organic group comprising from about 1 to about 6 carbon atoms Rj or R_;S.

[001 ] In some embodiments, the therapeutic agent is niacin.

[0015] Niacin, also known as nicotinic acid or vitamin B3, is a derivative of pyridine with the following structural formula.

[001 ] Other forms of vitamin B3 include the corresponding amide, nicotinamide ("maemamide"), where the earboxyl group has been replaced by a carboxaraide group (CON¾), as well as more- complex amides and a variety of esters.

[0 17] iacin is converted to nicotinamide and then to nicotinamide adenine cSiuucieotide (NAD) and nicotinamide adenine dinucleot ide phosphate (NADP) in vivo. In pharmacological doses, niacin has been shown to reverse atherosclerosis by reducing total cholesterol triglyceride, very-low-density lipoprotein (VLDL), and low-density lipoprotein (LDL), and increasing high-density lipoprotein (HDL). Niacin has been proposed to have the ability to tower fipoprotein(a), which is beneficial at reducing thrombotic tendency , ("Guidelines for Niac in Therapy For the Treatment of Elevated lipoprotein a (Lpa)", Rush Hemophilia & Thrombophilia Center. August 15, 2002, Revised July 27, 2005,) Niacin, prescribed in doses between 1,000 rag and 2,000 mg two to three times daily, was shown to block the breakdown of tats in adipose tissue, more specifically the very-low-density lipoprotein (VLDL), a precursor of low-density lipoprotein (LDL) or "bad" cholesterol (Marks, jay W. (2005). "Niacin Monograph". MedicineNet, Inc.) Since niacin blocks breakdown of fats, it causes a decrease in free fatly acids in the blood and, as a consequence, decreased secretion of VLDL and cholesterol by the liver, ( aizung, Bertram G. (2006), Basic and clinical pharmacology, New York; McGraw-Hill Medical Publishing Division,)

[0 18] By lowering VLDL levels, niacin also increases the level of high-density lipoprotein (HDL) or "good" cholesterol in blood; therefore, it is sometimes prescribed fo patients with low HDL, who arc also at high risk of a heart attack. (McGovera ME (2005). "Taking aim at HDL-C. Raising levels to reduce cardiovascular risk". Postgrad Med 1 17 (4): 29-30, 33-5, 39; Canner, ct al (1986), "Fifteen year mortality in Coronary Drug Project patients: long-term benefit with niacin", J. Am. Coll. Cardiol. 8 (6): 1245-55.)

[0019] Pharmacological doses of niacin ( 1,500 rng - 6,000 mg per day) often lead to side-effects that can include dermatological complaints such as skin flushing and itching, dry skin, skin rashes including acanthosis nigricans, Gastrointestinal complaints, such as dyspepsia (indigestion) and liver toxicity (fulminant hepatic failure) have also been reported. Side effects of hyperglycemia and cardiac arrhythmias, (Parker, e£ al. (2006), Goodman & Oilman's the pharmacological basis of therapeutics. New York: McGraw-Hill.) The flush lasts for about 1.5 to 30 minutes, and is sometimes accompanied by a prickly or itching sensation. High-dose niacin may also elevate blood sugar, thereby worsening diabetes meiittus. Hyperuricemia is another side-effect of taking high-dose niacin, and may exacerbate gout. (Capuzzi. et al. (2000), "Niacin dosing: relationship to benefits and adverse effects", C rrAthemscler Rep 2 (I): 64-71.)

[0020] Upon entering the body, the covalent links of the compound is expected to hydrolyze in vivo, allowing the omega-3 fatty acid moiety and the therapeutic moiety of the therapeutic agent (e.g., niacin) to separate and carry out their respective functions. This therapeutic agent's DMP profiles ma be improved profoundly,

[0021 ] Despite such broad lipid effects and evidence of powerful cardiovascular protection, nicotinic acid remains vastly under utilized, primarily due to a vasocutancous flushing reaction— the niacin flush. This side effect of niacin consists of skin reddening, itching and/or burning starting 10- 20 rain after oral ingestion of the drug and lasting about 60-90 min. As man as 40% of patients started on nicotinic acid eventually discontinue therapy. The niacin flush is mediated by the

arachidonic acid, metabolite prostaglandin i¾ (PGDj). Following systemic absorption, nicotinic acid activates GP.R 1 A on dermal endritic cells or dermal macrophages, and the subsequent mobilization of arachidonic acid and its conversion to vasodilatory prostaglandins (PGDj and PGE₂) by

cycJooxygenases results in the characteristic flushing response. Elimination of the flush would improve iolerabithy of nicotinic acid and would extend the beneficial cardiovascular effects of this drag to a larger population of at risk individuals. (Pike (2005). "Flushing out the role of GPRI09A (HM74A) in the clinical efficacy of nicotinic acid", ./ Clin. Invest. 1.15 (1.2): 3400-3402.)

[0022] Omega-3 fatty acid are the counterparts of the omega-6 arachidonic acid, and can act through multiple mechanisms to reduce PGIV PGE_: production. Incorporation of omega-3 fatty adds into membrane phospholipids can reduce the availabili ty and mobilization of arachidonic acid.

Omega-3 fatty acids can also compete with arachidonic acid for eycloexygenases. Furthermore, omega-3 fatty acids can downregulate cyclooxygenase expression. Omega-3 fatty acids may thus be highly effective in reducing PGD₂/ PGE> production and niacin flushing. In addition, omega-3 fatty acids also have protective effects against liver toxicity and cardiac arrhythmias, and can significantly reduce blood triglycerides and increase HDL.

[00.23] In some embodiments, the therapeutic agent is selected from statins, or HMG-CoA

reductase inhibitors, which is a class of drug used to lower plasma, cholesterol level. Statins are believed to have the effect of lowering cholesterol by inhibiting the enzyme HMG-CoA reductase, the rate-limiting enzyme of the meva!onate pathway of cholesterol synthesis, it is believed, that inhibition of this enzyme in the liver results in decreased cholesterol synthesis and increased synthesis of LDL receptors. A result of using statins is an mcreased clearance of low-deasity Hpoproteia (LDL) from the bloodstream. Examples of statins include: atorvastatin (Lipitor), fluvastatin (Lesco!), lovastatin (Mevacor), pravastatin (Pravachol), rosuvastatin (Crestor), simvastatin (Zocor), and pravastatin (Livaio). Structures and other information of some exemplary statins are. provided in Table 2.

Table 2 Exemplary Statins

[0024] In some embodiments, die therapeutic agent is aspirin.

[0025] Aspirin, also known as aceryi.saHcyi.ie acid, is a. salicylate drug, often used as an analgesic to relieve minor aches and pains, as an antipyretic to reduce fever, and as an anti-inflammatory

medication. Aspirin also has an antiplatelet effect by inhibiting the production of thromboxane, which under normal circumstances binds platelet molecules together to create a patch over damage of the walls within Mood vessels. Because the platelet patch can become too large and also block blood flow, locally and downstream, aspirin is also used long-term, at low doses, to help prevent heart attacks, strokes, and blood clot formation in people at high risk for developing blood clots. (Lewis, et at (1983-08-18), "Protective effects of aspirin against acute myocardial infarction and death in men with unstable angina. Results of a Veterans Administration Cooperative Study", New England Journal of Medicine 309 (7): 396-403.) it has also been shown that lo doses of aspirin may he given immediately after a heart attack to reduce the risk of another heart attack or of the death of cardiac tissue. (Julian, et ai. (1996), "A comparison of aspirin and anticoagulation following thrombolysis for myocardial infarction (the AFTER study): a multicentre unblinded randomised clinical trial", Briifsh Medical. Journal 313 (7070): 1429- 1431 ; Krumholz, et al. (1995), "Aspirin in the Treatment of Acute Myocardial. Infarction in. Elderl Medicare Beneficiaries: Patterns of Use and Outcomes", Circulation 92 (10): 2841-2847.) [0026] In some embodiments, the therapeutic agent is a fibs-ate. Fibrates are a class of amphipathic cafboxylic acids. They are used for a range of metabolic disorders, mainly hypercholesterolemia

(high cholesterol), and are therefore hypolipidemic agents. Examples of fibrates include; bezafibrate (e.g.. Bezalip), ciprofibrate (e.g. Modalim), gemfibrozil (e.g. Lopid), fenofibrate (e.g. TriCor), drawn below.

[0027] 'Omega- 3 fatty acids" are long-chain polyunsaturated fatty acids ( .8-22 carbon atoms in chain length, or LC-PUFA with the first of the double bonds ("unsaturations") beginning with, the third carbon atom. They are referred to as "polyunsaturated" because their molecules have two or more double bonds in their carbohydrate chain.

[00.28] The LC~PL1FA family of oils for food compositions includes: alpha-iinolenic acid (ALA), 18:3 (n-3); siearidonic acid,, 18:4 (n-3); eicosatetraeiioic acid, 20:4 (n-3); eicosapmtacnoic acid (EPA), 20:5 (n-3); docosapenfacnoic acid, 22:5 (n-3) and docosahexaenoie acid ( DHA), 22:6 (n-3). ALA is the "base" omega-3 fatty acid, from which SDA i made in the body through a series of enzymatic reactions. The synthesis processes from ALA are called "elongation" (She molecule becomes longer by incorporating new carbon atoms) and "desatitration" (new double bonds are created), respectively.

[0029] In nature, ALA is primarily found in certain, plant seeds (e.g., flax seeds). mportant nutritionally essential n-3 fatty acids are; ee-Hnofenic acid (ALA), eieosapentaenoic acid (EPA), and docosahexaenoie acid (DHA), ail of which are polyunsaturated. The hitman body cannot synthesize 0 -3 fatty acids de novo, but. it can form 20-carbon unsaturated n-3 fatty acids (like EPA and 22- carbon unsaturated n-3 fatty acids (like DHA) from the eighteen-carbon n-3 fatty acid ct-imoiemc acicl . Synthesis of the longer n -3 fatty acids from lioolenie acid within the body is compe titively slowed by the n~6 analogues.

[0030] Th omega-3 fatty acid may he any omega-3 fatty acids such as ALA, EPA or DHA, as well as others. Some exemplary omega-3 fatty acids are listed in Table 3.

Table 3 Common Omega-3 Fatty Acids

[0031] Many current drugs on the market have unwanted side effects and/or are limited in efficacy. Omega-3 fatty acids ha ve many beneficial biological effects, including anti-iaflammation, lipid- lowering, anti-oxidation, anti-proliferation, etc. as well as multiple well-known health benefits.

Omega-3 fatty acids are also safe and natural compounds,

[0032] Research has shown that consumption of omega-3 fatty acids, such as EP A and OHA (n-3) fatty acids, may reduce the risk of coronary heart disease. DHA has been shown to support the normal development of the brain, eyes and nerves.

[0033] Studies have shown that certain omeg -3 fatty acids may have anti-cancer effects

(particularly breast, colon and prostate cancer). (Augustsson, et al, (2003) "A prospective study of intake of fish and marine fatty acids and prostate cancer". Cancer Epidemiology^;, Biomat-kers ά Prevention 12 (1 ): 64-67; De Deckere (1999) "Possible beneficial effect of fish and fish n-3 polyunsaturated fatty acids in breast and colorectal cancer", EurJ Cancer Prev 8 (3): 2.13-223 ;

CaygiSl, et i (1995), "Fish, n-3 fatty acids and human colorectal and breast cancer mortality", £»r./ Cancer Prev 4 (4): 329-332,) Omega-3 fatty acids reduced, prostate tumor growth, slowed histopaihoJogka! progression, and increased survival. (Yang, et al (2007), "Modulation of prostate cancer genetic risk by omega~3 and oaiega-6 fatty acids", ./ Clin Invest 1 1 ? (7): 1866-75.) High ievels of doeosahexaenoie acid, the most abundant «-3 PUFA in erythrocyte membranes, were associated with a reduced risk of breast cancer. (Pala, et i. (2001), "Erythrocyte Membrane Fatty Acids and Subsequent Breast Cancer: a Prospective Italian Study", JNCL 93 (14): 1088.)

[0034] A 2007 systematic review of omega-3 fatty acids and cachexia found evidence that oral n-3 fatty acid supplements benefit cancer patients, improving appetite, weight and quality of life. A 2009 trial found that a .supplement of eicosapentaenoic acid helped cancer patients retain muscle mass. (Colomer, el «/. (May 2007). "N-3 fatty acids, cancer and cachexia: a systematic review of the literature*. Br. J. Nutr. 97 (5): 823-31 ,)

[0035] Omega-3 fatty acids are essential nutrients and are safe for consumption. When entering the G3 tract, omega-3 fatty acids are easily absorbed into the bloodstream and participate in lipid metabolism in the liver. The fatty acids can be readily taken up by almost ail the ceils in the body and incorporated into the cellular membrane. Omega-3 fatty acids can serve as building blocks of the ceil membrane, especially in the brain. They can also be utilized to produce energy and are metabolized to form bioactivc signaling molecules. They have many biological effects, including anti-inflammation, antioxidation, anti-proliferation, Hpid-lowering, anti-thrombosis, ants -arrhythmia, aiiti-neuroii- apoptosis, and anti-angiogenesis. All these biological effects can reduce side effects or toxicity of certain dregs. Omega-3 fatty acids and their metabolites act in both direct and indirect manners: they directly bind to functional proteins, and indirectly regulate gene expression.

[0036] Both laboratory and clinical research have demonstrated that omega-3 fatty acids are effec tive in prevention and treatment in a number of major diseases, including cardio vascular disease, cancer, diabetes, Alzheimer's disease, and also promotes general health, especially brain growth and development.

[0037] In another aspect, the invention generally relates to a pharmaceutical composition comprising a compound having the structural formula of:

wherein Ri is a radical formed from an omega-3 fatty acid having a -COOH group when its OH moiet is removed; R? is a radical formed from a therapeutic agent having an -COOH group when the OH moiet is removed; and ₂ is a hydrogen atom, R_k- or _?,

[0038] in another aspect, the invention generally relate to a pharmaceutical composition comprising a compound having the chemical formula of:

wherein ¾ is a radical formed from an omega-3 fatty acid having a -CO0H group when its OH moiety is removed; R¾ is a radical formed from a therapeutic agent having an -COOH group when the OH moiety is removed; R₂ is a hydrogen atom, a salt, or an organic group comprising from about I to about 6 carbon atoms, R_{ or R¾; L is a linker atom or group, and each of X_2> and X₃ is independently an O or S.

[0039] In certain embodiments, each of X_}, X;, and X_s is O. In some embodiments, L is AL In sortie other embodiments,

i

[0040] The therapeutic agent may be niacin, a statin such as Lipitor, Aspirin, Fibrate, for example. The omega-3 fatty acid may be ALA, EPA, DBA, for example, in some embodiments, the therapeutic agent is an anti-cancer agent, such as a chemotherapeulic agent, such as alkylating agents, an antimetabolites, plant alkaloids and terpenoids, podophyilofoxin, taxanes, which may be chemically modified as needed.

[004.1 ] Pharmaceutically acceptable salts, esters, prodrugs, tautomers, hydrates and solvates of the compounds presently disclosed are also within the scope of the present disclosure,

[0042] Compounds and compositions disclosed herein can be effective candidates in prevention and treatment in a number of major diseases, including cardiovascular disease, cancer, diabetes, Alzheimer^' s disease, and also promotes general health, especially brain growth and development.

[0043] Presently disclosed compounds that are basic in nature are generally capabie of forming a wide variety of di fferent salts with various inorganic and/or organic acids. Although such salts are generally pharmaceutically acceptable for administration to animals and humans, it may be desirable in practice to initiall isolate a compound from the reaction mixture as a pharmaceutically unacceptable salt aad then simply convert the latter back to the free base compound by treatment with m alkaline reagent, and subsequently convert the free base to a pharmaceutically acceptable acid addition salt. The acid addition salts of the base compounds can be readily prepared using

conventional techniques, e.g., by treating the base compound with a substantially equivalent amount of t he chosen mineral or organic acid in an aqueous solvent medium or in a suitable organic sol vent such as, for example, methanol or ethanol. Upon careful evaporation of the solvent, the desired solid salt is obtained.

[0044] Acids which can be used to prepare the pharmaceutically acceptable acid-addition salts of the base compounds are those which can form non-toxic acid-addition salts, i.e., salts containing pharmacologically acceptable anions, such as chloride, bromide, iodide, nitrate, sulfate or hi sulfate, phosphate or acid phosphate, acetate, lactate, citrate or acid citrate, tartrate or bi tartrate, succinate, ma!eate, fumarate, gluconate, saccharate, benzoate, methanesuifonate and pamoate (i.e., 1 J'- mefhylene )is-(2-hydfoxy-3-naphthoate)j salts.

[0045] Presently disclosed compounds that are acidic in nature, e.g., contain a COOH or tetrazole moiety, are generally capable of forming a wide variety of dierent salts with various inorganic and/or organic bases. Although such salts are generall pharmaceutically acceptable for administration to animals and humans, it may be desirable in practice to initially isolate a compound from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert die latter back to the free acid compound by treatment with an acidic reagent, and subsequently convert the free acid to a

.pharmaceutically acceptable base addition salt. These base addition salts can be readily prepared using conventional techniques, e.g., by treating the corresponding acidic compounds with an aqueous solution containing the desired pharmacologically acceptable cations, and then evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, they also can be prepared by mixing lower alkanolic solutions of the acidic compounds and the desired alkali metal alkoxide together, and then evaporating the resulting solution to dryness in the same manner as before. In either case, stoichiometric quantities of reagents are preferably employed in order to ensure completeness of reaction and maximum product yields of the desired solid salt.

[0046] Bases which can be used to prepare the pharmaceutically acceptable base-addition salts of the base compounds are those which can form non-toxic base-addition salts, i.e., salts containing pharmacologically acceptable cations, such as, alkali metal cations (e.g., potassium and sodium), alkaline eardi metal cations (e.g., calcium and magnesium), ammonium or other water-soluble amine addition salts such as -methylglncamine-Cmegluraine), lower

alkanolamraomuM. and other such bases of organic amines.

[0047] Isotopicaily-labeied compounds are also within the scope of the present disclosure. As used herein, an "isotopicaliy-labeled compound" refers to a presently disclosed compound including pharmaceutical salts and prodrugs thereof, each as described herein, in which one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds presently disclosed include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as ¾ ¾ C, C, "N, ^l¾ ^{! 7}Q, ^{? i}P, ¾ ³⁵S, ^{S S}F, and ^¾Ci, respectively.

[0048] By isotopically-labelmg the presently disclosed compounds, the compounds may be useful in drug and/or substrate tissue distribution assays, Tritiated (Tf) and earbon-14 ( ) labeled compounds are particularly preferred for their ease of preparation and detectability. Further,

substitution with heavier isotopes such as deuterium (Ή) can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labeled compounds presently disclosed, including pharmaceutical salts, esters, and prodrugs thereof, can be prepared by any means known in the art.

[0049] Further, substitution of normally abundant hydrogen (Ή) with heavier isotopes such as deuterium can afford certain therapeutic, advantages, e.g., resulting from improved absorption, distribution, metabolism and/or excretion (ADME) properties, creating drugs with improved efficacy, safety, and/or tolerability. Benefits may also be obtained from replacement of normally abundant ^{iC with ^BC. See, WO 2007/005643, WO 2007/005644, WO 2007/ 16361 , and WO 2007/ 1 431.

[0050] Stereoisomers (e.g., cis and trans isomers) and ail optica! isomers of a presentl disclosed compound (e.g., R and S cnan tiomers), as well as racemic, diastereomeric and other mixtures of such isomers are within the scope of the present, disclosure.

[0051 ] The compounds, salts, esters, prodrugs, hydrates, and solvates presently disclosed can. exist in several tautomeric forms, including the enol and imine form, and the keto and ena rae form and geometric isomers and .mixtures thereof Taatomers exist as mixtures of a tautomeric set in solution, hi solid form., usually one tautomer predominates. Even though one tautomer may be described, all tautomers are within the scope of the present disclosure.

[0052] Atropi.so.mers are also within the scope of the present disclosure. Airopisoniers refer to compounds that can be separated into ro atioually restricted isomers.

[0053 ] The present disclosure also provides pharmaceutical compositions comprising at least one presently disclosed compound and at least one pharmaceutically acceptable carrier. The

pharmaceutically acceptable carrier can be any such carrier known in the art including those described in, for example, Remington's Pharmaceutical Sciences, Mack Publishing Co., (A. R. Gennaro edit. 1 85). Pharmaceutical compositions of the compounds presently disclosed may be prepared by methods known in the art including, for example, mixing at least one presently disclosed compound with a pharmaceutically acceptable carrier.

0054] Presently disclosed pharmaceutical compositions can be used in an animal or human. Thus, a presently disclosed coropoiuid can be formulated as a pharmaceutical composition for oral, buccal, parenteral (&g., intravenous, intramuscular or subcutaneous), topical, rectal or intranasal,

administration or in a form suitable for administration by inhalation or insufflation.

[0055] The compounds presently disclosed ma also be formulated for sustained delivery according to methods well known to those of ordinary ski ll in the art. Examples of such formulations can be found in United States Patents 3,1 19,742; 3,492,397; 3,538,214; 4,060,598: and 4, 173,624 [0056] For oral administration, the pharmaceutical composition may take the form of, for example, a tablet or capsule prepared by conventional methods with a pharmaceutically acceptable exeipieni(s) such as a binding agent (e.g., prcgelatiiiized maize starch, polyvinylpyrrolidone or hydroxypropyl mefhylcellulose); filler (e.g., lactose, mierocrystaifiae cellulose or calcium phosphate); lubricant (e.g., magnesium stearate, talc or silica); disintegrant (e.g., potato starch or sodium starch glycolate); and/or wetting agent (e.g., sodium lauryl sulphate). The tablets may be coated by methods well known in the art. Liquid preparations for oral administration may take the fo m of a, for example, soiution, syrup or suspension, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional methods with a pharmaceutically acceptable additive(s) such as a suspending agent (e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agent (e.g., lecithin or acacia); non-aqueous vehicle {e.g., almond oil, oily esters or ethyl, alcohol); and/or preservati ve (e.g., methyl or propyl p~ hydroxybenzoates or sorbic acid).

[0057] For buccal administration, the composition may take the form of tablets or lozenges formulated in a conventional manner. Presentl disclosed compounds ma be formulated for parenteral administration by injection, including using conventional catheterization techniques or infusion. Formulations for injection ma be presented in unit dosage form, e.g., in ampules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain a formulating agent such as a suspending, stabilizing and/or dispersing agent recognized by those of skill in the art.

Alternatively, the active ingredient may be in powder form for reconstitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use. For topical administration, a presently disclosed compound may be formulated as an ointment or cream. Presently disclosed compounds may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glyeerides,

[0058] For intranasal administration or administration by inhalation, presently disclosed compounds may be conveniently delivered in the form of a solution, o suspension from a pump spray container that is squeezed or pumped by the patient or as an aerosol spray presentation, from a pressurized container or a nebulizer, with the use of a suitable propellant, e.g.,

dlchlorodifluorometliane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. Th pressurized, container or nebulizer may contain a solution or suspension of the presently disclosed compound . Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator may be formulated containing a powder mix of a presently disclosed compound and a suitable powder base such as lactose or starch,

[0059] A proposed dose of a presently disclosed compound for oral, parenteral or buccal administration to the average adult human for the treatment or prevention of an SK-reiated disease state is about 0.1 mg to about 2000 nig. tn certain embodiments, the proposed dose is from about 0. 1 nig to about 200 mg of the active ingredient per unit dose, irrespective of the amount of the proposed dose, administration of the compound can occur, for example, 1 to 4 times per day.

[0060] Aerosol formulations for the treatment or prevention of the conditions referred to above in the average adult human are preferably arranged so that each metered dose or "puff of aerosol contains about 20 ¾ to about 10,000 μ§, preferably, about 20 pg to about 1 00 pg of a presently disclosed, compoimd. The overail daily dose with an aerosol will be within the range from about 100 pg to about .100 mg. In certain embodiments, the overall daily dose with an aerosol generally wi.il be within the range from about 100 pg to about 1.0 mg. Administration may be several times daily, for example 2, 3, 4 or 8 times, giving for example, 1, 2 or 3 doses each time.

[0061 ] Aerosol combination formulations for the treatment or prevention of the conditions referred to above in the average adult human are preferably arranged so that each metered dose or "puff of aerosol contai ns from about 0.01 mg to about .1000 mg of a combination comprising a presently disclosed compound. In certain embodiments, each metered dose or ^"put?' of aerosol contains about 0. 1 mg to about 1.00 mg of a combination comprising a presently disclosed compound. In certain embodiments, each metered dose or "puff of aerosol contains about 1 mg to about 10 mg of a combination comprising a presently disclosed compound. Administration ma be several times daily, for example 2, 3, 4 or 8 times, giving for example, 2 or 3 doses each time.

[0062] Pharmaceutical compositions and methods of treatment or prevention comprising administering of at least one presently disclosed compound are also within the scope of the present disclosure.

Examples

[0063] Although specific embodiments of the present disclosure will now be described with reference to the preparations and schemes, it should be understood that such embodiments are by way of example only and merely illustrative of bu a small number of the many possible specific

embodiments that can represent applications of the principles of the present disclosure. Vari ous changes and modifications will be obvious to those of skill in the art given the benefit of the present disclosure and are deemed to be within, the spirit and scope of the present disclosure asd further defined in the appended claims.

[0064] Unless defined otherwise, technical and scientific terms used herein have the same meaning as commonly understood b one having Or inary skill m the a t to which this disclosure belongs. Although other compounds or methods can be used in. practice or test ng, certain, preferred methods are now described in the context of the following preparations and schemes.

Tri-aluroinum salt consisting of two omega-3 fatty acids (EPA) and one molecule of niacin.

Synthesis of the chemical compound:

[0065] Some 4 g of tri-isobutyi aluminum were dissolved in 150 ml of ietralwdrofuran, and the solution, was cooled to 5° C with dry tee. Under nitrogen gas current a solution of about 3 g of niacin dissoived in 50 ml of tetrahydrofuran was added dropwise little by little to the tri-isobutyi aluminum solution. After completion of the dropwise addition, the mixture was agitated tor 10 minutes, and a solution of about 12 g of eicosapentaenoic acid dissolved in 300 ml of ietrahydroiuran was added little by little to the mixture, following which agitation was conducted for 10 minutes. After completion of the reaction, the tetrahydrofuran was distilled off. As a. result, a powdery aluminum mono-(niacm) bis-iescosapentaenoic acid) was obtained. The characterization of this structure purification was by HPLC mass spectrometry,

P armacological effects:

[0066] Mice were fed with a lipogenic diet to create hyperlipodemia. One group was treated with niacin ( 100 mg kg) by gavage technique daily, and the other group was given our combined formula (about 400 mg/kg, of whic h the niacin coo ten t is less than 1 0 rag kg). The lipid profile and niacin flushing was monitored. Following the 30-day treatment, the combined, treatment exhibited a mote significant lipid-lowering effect than niacin alone. More importantly, the side effect of flushing as monitored by measurement ofFGDj and cutaneous vasodilation was much less in the combined drug group compared to the niacin group. These data indicate that our combined formula can improve the efficacy and reduce the side effects of niacin.

Incorporation by Reference

[0067] References and citations to other documents, such as patents,, patent applications, patent publications, journals, books, papers, web contents, have been made in this disclosure. All such documents are hereby incorporated herein by reference in their entirety for all purposes.

Equivalents

[0068] The representative examples are intended to help illustrate the invention, and are not intended to, nor should they he construed to, limit the scope of the invention, indeed, various modifications of the invention and many further embodiments thereof, in addition to those shown and described herein, will become apparent to those skilled in the art from the full contents of this document, including the examples and the references to the scientific and patent literature included herein. The examples contain important additional information, exemplification and guidance which can be adapted to the practice of this invention in its various embodiments and equivalents thereof.

Claims

i . A compound having the simctural formula of:

wherein

at least one of _s, R₂ and R₃ is a group selected -from column 1 of Table ; and

at least one. of R_ls R_*. and R_;5 is a group selected from column 2 of Table L wherein if any of R_{! t} ;; and R₃ is not selected from either column 1 or column 2 of Table I , it is a hydrogen atom, a salt, or an organic group comprising from about 1 to about 6 carbon atoms.

Table J

The compound. f Claim \ , wherein _s

The compound, of Claim 1, wherein R< is

and

Each of R a d < is

The compound of Claim i , wherein each of R>, and R_;; is

a d

The compound of Claim 1, wherein Ri is

R_;; is H; and

The compound of Claim 1, wherein Ri is

and

Each of " and R_; is

The compoimd of Claim 1 , wherein each of ¾ and R₂ is

and

: is

The compound of Claim I, wherein

R₂ is H; and

R; is

The compound of Claim I, wherein each of _t and R_:

and

i is

0. The compound of Claim !., wherein R_{ is

R_;.is H; and

1, The compound of Claim. 1, wherein R; is

and

Each. of RJ and R¾ is

The compound of Claim 1 _s wherein each of Ri and R₂ is and

R; IS

A compound having the structural formula of:

wherein

i is a radical formed from an ornega-3 fatty acid having a -COOH group when its OH moiety is removed;

j is a radical formed from a therapeutic agent having an -COOH group when the OH moiety is removed; and

R₂ is a hydrogen atom, a salt, or an organic group comprising f om: about 1 to about 6 carbon atoms. _t or ¾.

14. The compound of Claim 1 3, wherein the therapeutic agent is niacin.

15. The compound of Claim i 3_t wherein the therapeutic agent is a statin.

16. The compound of Claim ί 3, wherein the statin is Lipitor.

Ϊ ?. The compound of Claim 13, wherein the therapeutic agent is Aspirin.

18. The compound of Claim 13, wherein the therapeutic agent is Ft brate.

19. The compound of Claim 13, wherein the ornega-3 fatty acid is ALA.

20. The compound of Claim 13, wherein the omega-3 fatty acid is EPA.

21. The compound of Claim 13, wherein the omega-3 fatty acid is DHA.

22. A pharmaceutical compositioo comprising a compound ha vin the structural formula of:

wherein

i is a radical formed from an omega-3 fatty acid having a -COOH group when its OH moiety is removed;

R_:; is a radical formed from a therapeutic agent having an -COOH group when the OH moiety is removed; and

R_? is a hydrogen atom, a salt or an organic group comprising from about 1 to about 6 carbon atoms, Rt or R₅.

23. The compound of Claim 22, wherein the therapeutic agent is niacin.

24. The compound of Claim 22, wherein the therapeutic agent is a statin.

25. The compound of Claim 22, wherein the statin is Lipitor.

26. The compound of Claim 22, wherein the therapeutic agent is Aspirin,

27. The compound of Claim 22, wherein the therapeutic agent is Fibrate.

B The compound. f Claim 22, wherein the omega-3 fatty acid is ALA.

The compound of Claim 22, wherein the omega-3 fatty acid is EPA .

The compound of Claim 22, wherein the omega-3 fatty acid is DHA.

A pharmaceutical composition comprising a compound having the structural formula of;

wherein

R, is a radical formed from an omega-3 fatty acid having a -COOH group when its OH moiety is removed;

R is a radical formed from a therapeutic agent having an -COOH group when the OH moiety is .removed; and

¾ is a hydrogen atom, a salt, or an organic group comprising from about 1. to about 6 carbon atoms, Rj or R _s,

L is a linker atom or group, and

each of Xu ;;, and X¾ is independently an O or S.

The pharmaceutical composition of Claim 31 , wherein each of Xj , X?., and X is O.

The pharmaceutical composition of Claim 3i , wherein L is Ai„

The pharmaceutical compositi

35. The compound of Claim 31, wherein the therapeutic agent is niacin.

36. The compound of Claim 31, wherein the therapeutic agent is a statin.

37. The compound of Claim 31, wherein the statin is Lipitor.

The compound of Claim 3.1 , wherein the therapeutic agent is Aspirin.

39. The compound of Claim 3.1 , wherein the therapeutic agent is Fibrate.

40, The compound of Claim 3.1 , wherein the omega-3 fatty acid is ALA, The compound of Claim 31 , whereis the omega-3 fatty acid is EPA . The compound of Claim 31 , wherein the omega-3 fatty acid is DHA.