TW201306838A - Niacin mimetics, and methods of use thereof - Google Patents

Abstract

Disclosed are heterocyclylalkyl-substituted and heteroaralkyl-substituted pyridines, and pharmaceutically acceptable salts and prodrugs thereof, that are active against a range of mammalian therapeutic indications.

Description

Nicotinic acid mimics and methods of use thereof [related application]

The priority of the PCT application No. 11/041,869, filed on Jun. 24, 2011, and the PCT application No. 11/041,878, filed on Jun. Into this article.

The present invention relates to nicotinic acid analogs having desirable pharmacological and pharmacokinetic properties for the treatment of a range of metabolic diseases without the undesirable side effects associated with niacin therapy.

Hyperlipidemia and hypercholesterolemia are conditions that are well-defined to be associated with an increased risk of other conditions such as heart attack, atherosclerosis, and other harmful diseases. There are a number of agents that can be used to lower cholesterol and lipid levels, including gemfibrizol, probucol, and recent "statins" (such as lovastatin).

Niacin (nicotinic acid) is a water-soluble B multivitamin that is used orally to treat hyperlipidemia. Niacin has been shown to be effective in reducing total plasma cholesterol (C), low density lipoprotein LDL-C and very low density lipoprotein triglyceride (VLDL-triglyceride), all of which are associated with health risks. At the same time, patients with type II, III, IV and V hyperlipoproteinemia who are elevated in niacin are considered to be "healthy" lipoproteins of high-density lipoprotein (HDL-C). Serum content.

Although the mechanism by which nicotinic acid alters lipid profiles is not well understood, its mechanism of action has been shown to inhibit the release of free fatty acids from adipose tissue (see Carlson, LA, Froberg, SO and Nye, ER, Nicotinic acid in the rat. Acute effects of nicotinic acid on plasma, liver, heart, and muscle lipids, Acta Med Scand 180: 571-579, 1966) and increased lipoprotein lipase activity (see Priego, JG, Pina, M., Armijo, M. , Sunkel, C. and Maroto, ML, Action of etofibrate, clofibrate and nicotinic acid on the metabolism of lipids in normolipemic rats. Short term effects and method of action, Arch Farmacol Toxicol 5: 29-42, 1979). More than 30 million Americans have high blood LDL-C levels. The HMG-CoA reductase inhibitor (statin) is the most widely used class of drugs for the treatment of patients with high LDL-C levels. However, niacin is the only drug recommended by the American Heart Association to improve HDL in primary prevention of cardiovascular disease, in addition to lowering LDL-C. Nicotinic acid therapy is not only highly effective as a monotherapy, but also as a combination therapy because it complements the effects of other classes of lipid-lowering drugs. However, niacin is the second or third option for isolated hypercholesterolemia because of the high incidence of side effects associated with oral niacin therapy. Nonetheless, when it is desired to lower LDL-C with triglycerides, such as for patients with severe combined hyperlipidemia, it has therapeutic advantages as a monotherapy.

Niacin can also be used in combination with other cholesterol lowering agents such as "statin" to maximize lipid lowering activity. A study showing that niacin/Lovastatin combination is highly effective in lowering LDL-C, triglyceride and lipoprotein (a) (Lp(a)) while retaining the potency of niacin to increase HDL-C (Kashyap, ML, Evans R., Simmons, PD, Kohler, RM and McGoven, ME, New combination niacin/statin formulation shows pronounced effects on major lipoproteins and well tolerated, J Am Coll Card Suppl. A 35: 326, 2000) .

Niacin has been widely used to lower serum cholesterol levels because it is considered a cost-effective treatment. Oral daily dose of 2-3 g of nicotinic acid in humans reduces the total -C and LDL-C content by 20% to 30%, and the triglyceride content by 35% to 55%, making HDL-C Increase 20% to 35% and decrease Lp(a). Niacin also reduces overall mortality and mortality from coronary artery disease (see The Coronary Drug Project Research Group, JAMA 231: 360-381, 1975; and Canner, PL, Berge, KG, Wenger, NK, Stamler, J., Friedman, L., Prineas, RJ and Friedewald, W., Fifteen year mortality in Coronary Drug Project patients: long-term benefit with niacin, J Am Coll Cardiol 8: 1245-1255, 1986), and it helps to slow or Reversing the progression of atherosclerosis (see Blankenhorn, DH, Nessim, SA, Johnson, RL, Samnarco, ME, Azen, SP and Cashin-Hemphill, L., Beneficial effects of combined colestipol-niacin therapy on coronary atherosclerosis and coronary venous Bypass grafts, JAMA 257: 3233-3240, 1987; and Cashin-Hemphill L.; Mack, WJ, Pogoda, JM, Samnarco, ME, Azen, SP and Blankenhorn, DH, Beneficial effects of colestipol-niacin on coronary atherosclerosis. 4-year follow-up, JAMA 264: 3013-3017, 1990).

Regrettably, oral niacin therapy has side effects that limit its utility. Although niacin is a vitamin, it must be used at a therapeutic dose to lower cholesterol. At these doses, both immediate release and sustained release of niacin have several side effects. The most common side effect of niacin is flushing, a warming sensation of the skin, usually accompanied by redness and sometimes itching. Although flushing is not dangerous, most patients find it extremely uncomfortable, which severely limits the patient's compliance with nicotinic acid therapy. Niacin-induced flushing can be substantially attenuated by pretreatment with a cyclooxygenase inhibitor, suggesting that vasodilation is caused by prostaglandin-mediated mechanisms (see Carlson, LA, Nicotinic acid and inhibition of fat mobilizing lipolysis. Present status, of effects on lipid metabolism, Adv Exp Med Biol 109: 225-23 8, 1978).

Liver function tests are always monitored in patients taking niacin because niacin treatment causes elevated serum transaminase levels and sustained release of niacin formula results in more severe liver problems (see McKenney, JM, Proctor) , JD, Harris, S. and Chinchili, VM, A comparison of the efficacy and toxic effects of sustained-vs immediate-release niacin in hypercholesterolemic patients, JAMA 271: 672-777, 1994; and Stafford, RS, Blumenthal, D. And Pasternak, RC, Variations in cholesterol management practices of US physicians, J Am Coll Cardiol 29: 139-146, 1997). Other known side effects of oral niacin therapy include activation of peptic ulcer, gout, and deterioration of diabetes control. Therefore, the safety and efficacy of oral niacin therapy is compromised by careful clinical monitoring and side-effects of the compound.

One aspect of the invention pertains to niacinic acid analogs as defined herein, and methods of use thereof for one or more mammalian or human therapeutic indications.

One aspect of the invention pertains to heterocyclylalkyl substituted and heteroaralkyl substituted pyridines which are active against a range of mammalian diseases, and pharmaceutically acceptable salts thereof. In certain embodiments, the pyridine or salt thereof comprises a substituent at the 3 or 5 position, and comprises a functional group that is substantially anionic at physiological pH. In certain embodiments, the pyridine or salt thereof comprises a substituent at the 2- or 6-position, and includes a functional group that supplies a pyridine ring electron. In certain embodiments, the pyridine or salt thereof comprises a substituent at the 5-position, comprising a functional group that is substantially anionic at physiological pH; and a substituent at the 2-position, comprising an electron that supplies a pyridine ring Functional group.

One aspect of the present invention is a method of reducing serum or plasma content of at least one lipid selected from the group consisting of total cholesterol, low density lipoprotein (LDL) cholesterol, triglyceride, and lipoprotein (a), A niacinic acid analog or a pharmaceutically acceptable salt thereof for oral administration to a human in need thereof, wherein the oral administration is characterized by immediate release of smoke with oral administration of a molar dose Compared with alkaline acid, it reduces flushing and reduces liver cell damage.

In one embodiment, the peak concentration ( _Cmax ) of the nicotinic acid analog is 40% or less of the _Cmax of the immediate release nicotinic acid of the oral molar dose.

In one particular example, the ratio of the area under the curve (C _max / AUC _0-24) was 0.35 h ^-1 or less at the peak concentration and niacin analogs for 24 hours.

In one embodiment, the time ( _tmax ) at which the nicotinic acid analog reaches a peak concentration is in the range of 1 to 5 hours.

In one particular example, nicotinic acid analogs to inhibit protein β- (β-arrestin) GPR109A function is mediated EC ₅₀ of niacin to inhibit ₅₀ β- least 10 times larger protein mediated functions at GPR109A EC .

In one embodiment, the nicotinic acid analog also increases the serum or plasma content of high density lipoprotein (HDL) cholesterol when administered orally to a human.

In one embodiment, oral administration is characterized by substantially no increase in serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), or both.

In a specific example, the method further comprises administering a human statin. In one embodiment, the statin is selected from the group consisting of atorvastatin, cerivastatin, fluvastatin, lovastatin, and beauty. Mevastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin.

In a specific embodiment, the method further comprises administering to the human at least one additional therapeutic agent selected from the group consisting of: an 11β HSD-1 inhibitor, a 5HT transporter inhibitor, a 5HT2c agonist, 5- LO or FLAP inhibitor, α-glucosidase inhibitor, ABCA1 enhancer, ACC inhibitor, thiol CoA: cholesterol O-thiol transferase inhibitor, thiol-estrogen, antidiabetic agent, anti-lipid abnormality agent , antihypertensive agents, antioxidants, Apo A1 mimetic, Apo A1 modulator, Apo E mimetic, apolipoprotein-B secretion/microsomal triglyceride transfer protein (apo-B/MTP) inhibitor, appetite Inhibitor, aspirin, β3 agonist, cholic acid reuptake inhibitor, bile acid chelating agent, bombesin agonist, BRS3 agonist, CB ₁ antagonist/reverse agonist , CCK-A agonist, cholesterol absorption inhibitor, cholesterol transport inhibitor, cholesterol ester transfer protein (CETP) inhibitor, CNTF, CNTF agonist/regulator, ezetimibe and simvastatin And/or combination of atorvastatin, CSL-111, dehydroepiandrosterone, delipidated HDL, DGAT antisense oligo , DGAT1 inhibitor, DGAT2 inhibitor, dicarboxylate transporter inhibitor, dopamine agonist, DP receptor antagonist, ezetimibe, FAS inhibitor, fatty acid binding protein (FABP) inhibitor, fatty acid Transporter inhibitors, fatty acid transporter protein (FATP) inhibitors, flushing inhibitors, FXR receptor modulators, galanin receptor antagonists, gemcabene, ghrelin antagonists, brain sausage Peptide antibody, GLP-1 agonist, glycosidin-like peptide-1 receptor agonist, glucocorticoid agonist/antagonist, glucose transporter inhibitor, HDL mimetic, HMG CoA reductase inhibitor compound , HMG-CoA synthetase inhibitor, hormone sensitive lipase antagonist, human wild mouse color related protein (AGRP), H ₃ antagonist / inverse agonist, inorganic cholesterol clamp, L-4f, lapastat ( Lapaquistat), leptin agonist/modulator, leptin, lipase inhibitor, lipoprotein synthesis inhibitor, lorapoprant, low-density lipoprotein receptor inducer or activator, Lp(a) reduction Agent, LXR receptor agonist, lyn kinase inhibitor, Mc3r agonist, Mc4 r agonist, MCH1R antagonist, MCH2R agonist/antagonist, melanin-concentrating hormone antagonist, mGluR5 antagonist, microsomal triglyceride transport inhibitor, monoamine reuptake inhibitor, natural water-soluble fiber, NE transporter inhibitor, neuromodulin U receptor agonist, neuropeptide-Y antagonist, nicotinic acid or nicotinic acid receptor agonist, niacin, norepinephrine-induced appetite Inhibitor (noradrenergic anorectic agent), NPY1 antagonist, NPY2 agonist, NPY4 agonist, NPY5 antagonist, non-steroidal anti-inflammatory agent (NSAID), omega-3 fatty acid, opioid antagonist, orexin Body antagonists, PDE inhibitors, phentermines, phosphate transporter inhibitors, phytopharm compounds 57, plant stanols and/or fatty alcohol esters of plant stanols, Platelet aggregation inhibitor, PPAR-α agonist, PPAR-δ agonist, PPAR-δ partial agonist, PPAR-γ agonist, probucol, renin angiotensin inhibitor, reverse-4F , SCD-1 inhibitor, serotonin reuptake inhibitor, SGLT2 inhibitor, horn shark Alkenyl epoxidase inhibitor, squalene synthesis inhibitor, sterol biosynthesis inhibitor, sympathomimetic agonist, thyroid hormone β agonist, thyrotropin, topiramate, triglyceride synthesis Inhibitor, UCP-1 activator, UCP-2 activator, UCP-3 activator, and urocortin binding protein antagonist.

One aspect of the present invention is a pharmaceutical composition comprising a nicotinic acid analog or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient; wherein the composition is formulated for use Oral administration; a nicotinic acid analog reduces at least one member selected from the group consisting of total cholesterol, low density lipoprotein (LDL) cholesterol, triglyceride, and lipoprotein (a) when administered orally to a human. The serum or plasma content of the lipid; and the oral administration of the composition is characterized by reducing flushing and reducing hepatocyte damage as compared to administration of a molar oral dose of niacin.

In certain embodiments, the invention relates to any one of the aforementioned compositions, wherein the peak serum or plasma concentration ( _Cmax ) of the nicotinic acid analog is 40% of the _Cmax of the oleic acid of the oral molar dose or smaller. In one embodiment, the peak serum or plasma concentration ( _Cmax ) of the niacin analog is 35% or less of the _Cmax of the oleic acid of the oral molar dose. In one embodiment, the peak serum or plasma concentration ( _Cmax ) of the niacin analog is 30% or less of the _Cmax of the oleic acid of the oral molar dose. In one embodiment, the peak serum or plasma concentration ( _Cmax ) of the niacin analog is 25% or less of the _Cmax of the oleic acid of the oral molar dose. In one embodiment, the peak serum or plasma concentration ( _Cmax ) of the niacin analog is 20% or less of the _Cmax of the oleic acid of the oral molar dose. In one embodiment, the peak serum or plasma concentration ( _Cmax ) of the niacin analog is 15% or less of the _Cmax of the oleic acid of the oral molar dose. In one embodiment, the peak serum or plasma concentration ( _Cmax ) of the niacin analog is 10% or less of the _Cmax of the oleic acid of the oral molar dose. In one embodiment, the peak serum or plasma concentration ( _Cmax ) of the niacin analog is 5% or less of the _Cmax of the oleic acid of the oral molar dose. In one embodiment, the peak serum or plasma concentration ( _Cmax ) of the niacin analog is 1% or less of the _Cmax of the oleic acid of the oral molar dose. For each of the foregoing specific examples, it should be understood that it is compared to an immediate release formulation of niacin. Suitable methods for measuring the concentration are disclosed in detail below.

In certain embodiments, the invention relates to any of the foregoing compositions, wherein the ratio of peak serum or plasma concentration ( _Cmax ) of the nicotinic acid analog to the area under the curve at 24 hours (AUC _0-24 ) (also That is, the ratio C _max /AUC _0-24 ) is 0.35 h ^-1 or less. In one particular example, the ratio of the area under the curve (C _max / AUC _0-24) was 0.30 h ^-1 or less at the peak concentration and niacin analogs for 24 hours. In one particular example, the ratio of the area under the curve (C _max / AUC _0-24) was 0.25 h ^-1 or less at the peak concentration and niacin analogs for 24 hours. In one particular example, the ratio of the area under the curve (C _max / AUC _0-24) was 0.20 h ^-1 or less at the peak concentration and niacin analogs for 24 hours. In one particular example, the ratio of the area under the curve (C _max / AUC _0-24) was 0.15 h ^-1 or less at the peak concentration and niacin analogs for 24 hours. In one particular example, the ratio of the area under the curve (C _max / AUC _0-24) was 0.10 h ^-1 or less at the peak concentration and niacin analogs for 24 hours. In one particular example, the ratio of the area under the curve (C _max / AUC _0-24) was 0.05 h ^-1 or less at the peak concentration and niacin analogs for 24 hours. In one particular example, the ratio of the area under the curve (C _max / AUC _0-24) was 0.01 h ^-1 or less at the peak concentration and niacin analogs for 24 hours.

In certain embodiments, the invention relates to any of the foregoing compositions, wherein the time ( _tmax ) at which the nicotinic acid analog reaches a peak serum or plasma concentration is in the range of 30 minutes to 5 hours. In one embodiment, the time ( _tmax ) at which the nicotinic acid analog reaches a peak concentration is in the range of 1 to 5 hours. In one embodiment, the time ( _tmax ) at which the nicotinic acid analog reaches a peak concentration is in the range of 1 to 4 hours. In one embodiment, the time ( _tmax ) at which the nicotinic acid analog reaches a peak concentration is in the range of 1 to 3 hours. In one embodiment, the time ( _tmax ) at which the nicotinic acid analog reaches a peak concentration is in the range of 1 to 2 hours.

In one particular example, nicotinic acid analogs of β- mediated inhibition of protein function GPR109A EC ₅₀ of niacin β- inhibition of at least 10 times the ₅₀ protein-mediated functions at GPR109A EC.

In one embodiment, the nicotinic acid analog also increases the serum or plasma content of high density lipoprotein (HDL) cholesterol when administered orally to a human.

In one embodiment, the nicotinic acid analog does not substantially administer the serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), or both when administered orally to humans. Any increase.

In one embodiment, the nicotinic acid analog does not substantially increase any of the serum levels of uric acid, glucose, or both when administered orally to a human.

Another aspect of the invention relates to a pharmaceutical composition comprising a compound of the invention or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient. A further aspect of the invention relates to a pharmaceutical composition comprising a compound of the invention or a pharmaceutically acceptable salt thereof; nicotinic acid; and a pharmaceutically acceptable excipient.

Another aspect of the invention relates to a pharmaceutical composition comprising a compound of the invention or a pharmaceutically acceptable salt thereof; a statin selected from the group consisting of: atorvastatin, cisivava Statins, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin; and pharmaceutically acceptable excipients. The invention also relates to a pharmaceutical composition comprising a compound of the invention or a pharmaceutically acceptable salt thereof; nicotinic acid; a statin selected from the group consisting of atorvastatin, cerivastatin , fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin; and pharmaceutically acceptable excipients. Other therapeutic agents that can be co-administered with the compounds of the invention are discussed below.

Although niacin or niacin has a definitive effect for the treatment of dyslipidemia, the clinical use of niacin is limited by skin flushing (i.e., a recognized related side effect). Flushing, estimated to be as high as 25% to 40%, has been listed as the main reason for discontinuing niacin therapy. Many studies have demonstrated that moderate doses of prostaglandin inhibitors reduce the skin flushing response caused by niacin administration. Other strategies to reduce flushing include regular coherent administration, use of extended release formulations, patient education, administration at meal or bedtime, and avoidance of alcohol, hot beverages, spicy foods, and hot water after administration or administration. Bath or shower. In certain embodiments, the compounds of the invention may reduce or reduce the severity of flushing when administered to an animal, particularly a human patient.

For example, as measured by laser Doppler flowmetry, when administered at doses up to 100 mg/kg and even better when administered as much as 200, 300 or even 500 mg At a dose of /kg, the compounds of the invention did not cause flushing in the male C57BL/6 murine flushing model.

In certain embodiments, the compounds of the invention may be characterized by when administered orally, when compared to the molar amount of NIASPAN (Nicotine extended release lozenges, Abbott Laboratories) caused less flushing when compared. In some specific examples, when compared with the molar amount of NIASPAN In contrast, the compounds of the invention, when administered orally to the average patient population, showed a decrease in the number of patients whose flushness was greater than or equal to 5 according to the oral visual scale in the oral mode.

The invention also relates to a method of treating a disease, disorder or condition selected from the group consisting of hyperlipidemia, hypercholesterolemia, lipid dystrophy, dyslipidemia, atherosclerosis and coronary artery disease, including A step of treating a therapeutically effective amount of a compound or pharmaceutical composition of the invention in a mammal in need thereof.

Another aspect of the invention relates to a method of treating a disease, disorder or condition selected from the group consisting of metabolic syndrome, obesity, fatty liver disease and diabetes, comprising administering to a mammal in need thereof a therapeutically effective amount The step of the compound of the invention or the pharmaceutical composition.

Another aspect of the invention is directed to a method of increasing serum high density lipoprotein (HDL) levels comprising the step of administering to a mammal in need thereof a therapeutically effective amount of a compound or pharmaceutical composition of the invention.

Another aspect of the invention relates to a method of lowering serum low density lipoprotein (LDL) content or reducing serum lipoprotein (a) content comprising administering to a mammal in need thereof a therapeutically effective amount of a compound or medicament of the invention The steps of the composition.

Another aspect of the invention relates to a method of increasing the total serum concentration of adiponectin comprising the step of administering to a mammal in need thereof a therapeutically effective amount of a compound or pharmaceutical composition of the invention.

Another aspect of the invention relates to a method of treating a disease, disorder or condition selected from the group consisting of: congestive heart failure, cardiovascular disease, hypertension, coronary heart disease, colic, rough skin Disease, Hartnup's syndrome, carcinoid tumor syndrome, arterial obstructive disease, hypothyroidism, vasoconstriction, osteoarthritis, rheumatoid arthritis, Alzheimer's disease, Peripheral and central nervous system disorders, hematological diseases, cancer, inflammation, respiratory diseases, and gastrointestinal disorders include the step of administering to a mammal in need thereof a therapeutically effective amount of a compound or pharmaceutical composition of the invention.

The invention further provides a packaged pharmaceutical preparation of the invention, comprising an insert, a label or other form of instructions for explaining to the patient that the niacin analog is administered once a day for 2 or 3 hours, depending on the situation and food. together.

Other aspects, specific examples, and advantages of the invention are discussed in detail below.

One aspect of the invention pertains to niacinic acid analogs for use in raising serum HDL levels in mammals. In certain embodiments, the compounds of the invention have the same or higher ability to increase HDL as nicotinic acid, with less or no tendency to induce flushing, while flushing is sufficient for niacin itself to increase The dose of serum HDL is undesirable for side effects. Some non-tidal nicotinic acid analogs are described in U.S. Patent Application Publication No. 2009/0312355, the disclosure of which is incorporated herein by reference in its entirety. In certain embodiments, the key structural features of the compounds disclosed herein appear to include the placement of a heterocyclylalkyl or heteroarylalkyl group in the nicotinic acid in the para position.

definition

For convenience, certain terms used in the specification, examples, and accompanying claims are hereby incorporated. All definitions, as defined and used herein, are substituted for dictionary definitions, definitions in the documents incorporated by reference, and/or ordinary meaning of the defined terms.

The article "a/an" is used herein to mean a grammatical object of the article (one) or one or more (ie, at least one). For example, "an element" means an element or more than one element.

As used herein in the specification and patent application, the term "and/or" should be understood to mean the element that means "either or both", that is, the element is In some cases it exists in combination and in other cases it exists. The elements listed in "and/or" should be interpreted in the same way, that is, the elements of "one or more". Other than the elements specifically identified by the "and/or" clause, other elements may also be present, regardless of whether they are related to their particular identified elements. Thus, by way of non-limiting example, reference to "A and / or B (A and / or B)", when used in conjunction with an open language such as "comprising", in one specific example, may refer to only A (as appropriate, including elements other than B), in another specific example, may refer to only B (as the case may include elements other than A); in yet another embodiment, may refer to A and B (as appropriate) Other elements); and so on.

"or" shall be taken to have the same meaning as "and/or" as defined above, as used in the specification and claims. For example, when the items are separated from the list, "or" or "and/or" should be construed as being inclusive, that is, including at least one of the plurality or listed elements and including one Above, and there are other items not listed as appropriate. Terms that are clearly indicated to the contrary, such as "only one of" or "exactly one of", or when used in the context of a patent application. "Consisting of" will mean the only one of a large number or listed elements. In general, the term "or" as used herein is used in such terms as "either" or "one of" or "only one of" Or the exclusive term of "the only one of the words" should be interpreted only as an alternative to indicate exclusive (ie "one species" or another (one species) rather than two species (one or the other). But not both)" "Consisting essentially of" should have its ordinary meaning in the field of patent law when used in the scope of patent application.

As used herein in the specification and claims, the term "at least one" is used in the context of the description of one or more elements to mean that at least one An element of any one or more of the elements listed in the element, but does not necessarily include the elements listed in the at least one element list and does not exclude any combination of elements in the item list. This definition also allows that elements other than the elements identified by the term "at least one" should be considered as being relevant, regardless of whether they are related to their particular identified elements. Thus, as a non-limiting example, "at least one of A and B" (or equivalently, "at least one of A or B" Or, equivalently, "at least one of A and / or B", in one specific example, may mean at least one, as the case may include more than one A, but does not exist. B (and optionally includes elements other than B); in another specific example, may refer to at least one, as the case may include more than one B, but there is no A (and optionally includes elements other than A); In a specific example, it may mean at least one, as the case may include more than one A, and at least one, including more than one B as appropriate (and optionally other elements);

It is also to be understood that the order of the steps or acts of the method is not necessarily limited to the order of the steps or acts of the method.

In the scope of the patent application and the above description, all transitional words such as "comprising", "including", "carrying", "having", "containing", " "involving", "holding", "composed of" and the like are to be understood as open-ended, meaning to include but not limited to. As described in Section 2111.03 of the Patent Office Manual of the United States Patent Examination Procedure, only the transitional words "consisting of" and "consisting essentially of" should be It is a closed or semi-closed transition word.

The term "co-administration/co-administering" means simultaneous administration (administering two or more therapeutic agents simultaneously) and not at the same time (unlike administration of one or more therapeutic agents) Time to administer other therapeutic agents) as long as the therapeutic agent is present in the patient to some extent.

The term "solvate" refers to a pharmaceutically acceptable form of a given compound having one or more solvent molecules and retaining the biological effects of the compound. Examples of the solvate include a combination of the compound of the present invention and a solvent such as water (formation of hydrate), isopropanol, ethanol, methanol, dimethyl hydrazine, ethyl acetate, acetic acid, ethanolamine or acetone. Formulations such as mixtures of solvates of the compounds of the invention with two or more solvents are also included.

The definition of individual expressions, such as alkyl, m, n, and the like, is intended to be independent of its definition elsewhere in the same structure when it occurs more than once in any structure.

It should be understood that "substitution" or "substituted with" includes an implicit restriction that the substitution is consistent with the permissible valence of the substituted atom and the substituent, and that the substitution results in a stable compound, such as A compound that spontaneously undergoes transformation, such as by rearrangement, cyclization, elimination, or other reactions.

The term "substituted" also encompasses all permissible substituents including organic compounds. In a generalized form, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of the organic compound. Exemplary substituents include, for example, the substituents described below. The permissible substituents may be one or more and may be the same or different for the appropriate organic compound. For the purposes of the present invention, a hetero atom such as nitrogen may have a hydrogen substituent and/or any permissible substituent of an organic compound described herein that satisfies the valence of a hetero atom.

The term "lower" when attached to any of the groups listed below indicates that the group contains less than 7 carbons (i.e., 6 carbons or less). For example, "lower alkyl" means that the alkyl group contains from 1 to 6 carbons, and "lower alkenyl" means that the alkenyl group contains 2 to 6 carbons.

The term "unsaturated" as used herein means that the compound and/or group has at least one carbon-carbon double bond or carbon-carbon bond.

The term "aliphatic" as used herein means that the compound and/or group is linear or branched, but not cyclic (also known as "acyclic" or "open chain". (open-chain)" group).

The term "cyclic" as used herein means that the compound and/or group has one ring or two or more rings (eg, a spiro ring, a fused ring, a bridged ring). "Monocyclic" means that the compound and/or group has one ring; and "bicyclic" means that the compound and/or group has two rings.

The term "aromatic" refers to a planar or polycyclic structure characterized by a portion of a cyclic conjugated molecule containing 4n + 2 (where n is the absolute value of an integer) electrons. An aromatic molecule containing a fused or joined ring is also referred to as a bicyclic aromatic ring. For example, a bicyclic aromatic ring containing a hetero atom in a hydrocarbon ring structure is referred to as a bicyclic heteroaryl ring.

The term "hydrocarbon" as used herein means that the organic compound consists entirely of hydrogen and carbon.

For the purposes of the present invention, chemical elements are identified according to the Periodic Table of the Elements (CAS version) of the cover in Handbook of Chemistry and Physics, 67th Edition, 1986-87.

The term "heteroatom" as used herein is art-recognized and refers to an atom of any element other than carbon or hydrogen. Exemplary heteroatoms include boron, nitrogen, oxygen, phosphorus, sulfur, and selenium.

The term "alkyl" means an aliphatic or cyclic hydrocarbon group containing from 1 to 20, from 1 to 15, or from 1 to 10 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, Neopentyl, n-hexyl, 2-methylcyclopentyl, 1-(1-ethylcyclopropyl)ethyl and 1-cyclohexylethyl.

The term "cycloalkyl" is a subset of alkyl groups and refers to cyclic hydrocarbon groups containing from 3 to 15, 3 to 10 or 3 to 7 carbon atoms. Representative examples of cycloalkyl include, but are not limited to, cyclopropyl and cyclobutyl.

The term "alkenyl" as used herein means a straight or branched chain hydrocarbon group containing from 2 to 10 carbons and containing at least one carbon-carbon double bond formed by the removal of two hydrogens. Representative examples of alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptene Base, 2-methyl-1-heptenyl and 3-decenyl.

The term "alkynyl" as used herein means a straight or branched chain hydrocarbon group containing from 2 to 10 carbon atoms and containing at least one carbon-carbon reference. Representative examples of alkynyl include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and 1-butynyl.

The term "alkylene" is art-recognized and as used herein refers to a diradical obtained by the removal of two hydrogen atoms of an alkyl group as defined above.

The term "carbocyclyl" as used herein, means a monocyclic or polycyclic ring containing from 3 to 12 carbon atoms fully saturated or having one or more unsaturated bonds (eg, bicyclic, tri Acyclic, etc.) hydrocarbon groups, and to avoid causing suspicion, the unsaturation does not produce an aromatic ring system (such as a phenyl group). Examples of the carbocyclic group include 1-cyclopropyl, 1-cyclobutyl, 2-cyclopentyl, 1-cyclopentenyl, 3-cyclohexyl, 1-cyclohexenyl, and 2-cyclopentenyl base.

The term "heterocyclyl" as used herein, refers to a non-aromatic ring system group, including but not limited to monocyclic, bicyclic, and tricyclic rings, which may be fully saturated or may contain one or To avoid suspicion of multiple unsaturation units, the unsaturation does not produce an aromatic ring system and it has from 3 to 12 atoms, including at least one hetero atom such as nitrogen, oxygen or sulfur. For illustrative purposes and should not be construed as limiting the scope of the invention, the following are examples of heterocycles: aziridine, azacyclopropenyl, oxiranyl, thietyl, thiacyclopropene Dioxiranyl, diazirinyl, azetyl, oxetane, oxetyl, sulphur Heterocyclobutane, thietyl, diazetanyl, dioxetane, dioxobutenyl, dithiolanyl, disulfide Dithietyl, furyl, dioxolane, pyrrolyl, Azyl, thiazolyl, imidazolyl, Diazolyl, thiadiazolyl, triazolyl, tri Base, isothiazolyl, isomeric Azyl, thienyl, pyrazolyl, tetrazolyl, pyridyl, anthracene Base, pyrimidinyl, pyridyl Base, three Base, four Base, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, pyridopyridyl Base, benzo Azolyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzo Diazolyl, benzothiadiazolyl, fluorenyl, benzotriazolyl, Pyridyl, azepine, azetidinyl, morpholinyl, pendant oxypiperidinyl, pendant oxypyrrolidinyl, piperidine Base, piperidinyl, pyrrolidinyl, Pyridyl, thiomorpholinyl, tetrahydropyranyl and tetrahydrofuranyl. The heterocyclic group of the present invention is substituted by 0, 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, halo, halo Base, fluoroalkyl, hydroxy, alkoxy, alkenyloxy, alkynyloxy, carboepoxy, heterocyclooxy, haloalkoxy, fluoroalkoxy, sulfhydryl, alkylthio, haloalkyl Thio group, fluoroalkylthio group, alkenylthio group, alkynylthio group, sulfonic acid, alkylsulfonyl group, haloalkylsulfonyl group, fluoroalkylsulfonyl group, alkenylsulfonyl group, alkynylsulfonyl group , alkoxysulfonyl, haloalkoxysulfonyl, fluoroalkoxysulfonyl, alkenoxysulfonyl, alkynylsulfonyl, aminosulfonyl, sulfinic acid, alkyl Sulfosyl, haloalkylsulfinyl, fluoroalkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, alkoxysulfinyl, haloalkoxysulfin , fluoroalkoxysulfinyl, olefinoxysulfinyl, alkynyl sulfinyl, aminosulfinyl, carbenyl, alkylcarbonyl, haloalkylcarbonyl, fluoroalkyl Carbonyl, alkenylcarbonyl, alkynylcarbonyl, carboxy, alkoxycarbonyl, haloalkoxycarbonyl , fluoroalkoxycarbonyl, olefinoxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxy, haloalkylcarbonyloxy, fluoroalkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkane Sulfosulfonyloxy, haloalkylsulfonyloxy, fluoroalkylsulfonyloxy, alkenylsulfonyloxy, alkynylsulfonyloxy, haloalkoxysulfonyloxy, fluoroalkoxysulfonate Alkoxy, allyloxysulfonyloxy, alkynyloxysulfonyloxy, alkylsulfinyloxy, haloalkylsulfinyloxy, fluoroalkylsulfinyloxy, alkenylsulfin Alkoxy, alkynylsulfinyloxy, alkoxysulfinyloxy, haloalkoxysulfinyloxy, fluoroalkoxysulfinyloxy, oxysulfinyloxy, Alkynoxysulfinyloxy, aminosulfinyloxy, amine, decylamino, aminosulfonyl, aminosulfinyl, cyano, nitro, azide, phosphinyl And a phosphonium group, a decyl group, a decyloxy group, and any such substituents bonded to the heterocyclic group via an alkylene moiety (for example, a methylene group).

The term "aryl" as used herein means phenyl, naphthyl, phenanthryl or anthracenyl. The aryl group of the present invention may be optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl, Fluoroalkyl, hydroxy, alkoxy, alkenyloxy, alkynyloxy, carboepoxy, heterocyclooxy, haloalkoxy, fluoroalkoxy, sulfhydryl, alkylthio, haloalkylthio , fluoroalkylthio, olefinylthio, alkynylthio, sulfonic acid, alkylsulfonyl, haloalkylsulfonyl, fluoroalkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, alkane Oxysulfonyl, haloalkoxysulfonyl, fluoroalkoxysulfonyl, alkenyloxysulfonyl, alkynylsulfonyl, aminosulfonyl, sulfinic acid, alkylsulfin Sulfhydryl, haloalkylsulfinyl, fluoroalkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, alkoxysulfinyl, haloalkoxysulfinyl, Fluoroalkoxysulfinyl, olefinoxysulfinyl, alkynyl sulfinyl, aminosulfinyl, carbenyl, alkylcarbonyl, haloalkylcarbonyl, fluoroalkylcarbonyl, Alkenylcarbonyl, alkynylcarbonyl, carboxy, alkoxycarbonyl, haloalkoxy a fluoroalkoxycarbonyl group, an alkenyloxycarbonyl group, an alkynyloxycarbonyl group, an alkylcarbonyloxy group, a haloalkylcarbonyloxy group, a fluoroalkylcarbonyloxy group, an alkenylcarbonyloxy group, an alkynylcarbonyloxy group, Alkylsulfonyloxy, haloalkylsulfonyloxy, fluoroalkylsulfonyloxy, alkenylsulfonyloxy, alkynylsulfonyloxy, haloalkoxysulfonyloxy, fluoroalkoxy Sulfomethoxy, eneoxysulfonyloxy, alkynylsulfonyloxy, alkylsulfinyloxy, haloalkylsulfinyloxy, fluoroalkylsulfinyloxy, alkenyl Sulfomethoxy, alkynylsulfinyloxy, alkoxysulfinyloxy, haloalkoxysulfinyloxy, fluoroalkoxysulfinyloxy, oxyoxysulfinyloxy , alkynyl sulfinyloxy, aminosulfinyloxy, amine, amidino, aminosulfonyl, aminosulfinyl, cyano, nitro, azide, phosphine oxide A group, a phosphonium group, a decyl group, a decyloxy group, and any such substituents bonded to a heterocyclic group via an alkylene moiety (e.g., a methylene group).

The term "arylene" is art-recognized and as used herein refers to a diradical obtained by the removal of two hydrogen atoms of an aryl ring as defined above.

The term "arylalkyl" or "aralkyl" as used herein means an aryl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of aralkyl groups include, but are not limited to, benzyl, 2-phenylethyl, 3-phenylpropyl, and 2-naphthalen-2-ylethyl.

The term "biaryl" as used herein means an aryl-substituted aryl group, an aryl-substituted heteroaryl group, a heteroaryl-substituted aryl group or a heteroaryl-substituted heteroaryl group, wherein a aryl group The base and heteroaryl are as defined herein. Representative examples include 4-(phenyl)phenyl and 4-(4-methoxyphenyl)pyridinyl.

The term "heteroaryl" as used herein includes an aromatic ring system group including, but not limited to, monocyclic, bicyclic, and tricyclic rings having from 3 to 12 atoms, including at least one. A hetero atom such as nitrogen, oxygen or sulfur. For illustrative purposes and should not be construed as limiting the scope of the invention, the following examples exist: aminobenzimidazole, benzimidazole, fluorenyl, benzo(b)thienyl, benzimidazolyl, benzene Furanyl, benzo Azolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzo Diazolyl, furyl, imidazolyl, imidazopyridinyl, fluorenyl, porphyrinyl, oxazolyl, isoindolyl, iso Azyl, isothiazolyl, isoquinolinyl, Diazolyl, Azyl, fluorenyl, piperidyl, pyridyl , pyrazolyl, pyridyl, pyrimidinyl, pyrrolyl, pyrrolo[2,3-d]pyrimidinyl, pyrazolo[3,4-d]pyrimidinyl, quinolinyl, quinazolinyl, tri Azyl, thiazolyl, thienyl, tetrahydroindenyl, tetrazolyl, thiadiazolyl, thienyl, thiomorpholinyl, triazolyl or Alkyl (tropanyl). The heteroaryl group of the present invention is substituted with 0, 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, halo, halo Base, fluoroalkyl, hydroxy, alkoxy, alkenyloxy, alkynyloxy, carboepoxy, heterocyclooxy, haloalkoxy, fluoroalkoxy, sulfhydryl, alkylthio, haloalkyl Thio group, fluoroalkylthio group, alkenylthio group, alkynylthio group, sulfonic acid, alkylsulfonyl group, haloalkylsulfonyl group, fluoroalkylsulfonyl group, alkenylsulfonyl group, alkynylsulfonyl group , alkoxysulfonyl, haloalkoxysulfonyl, fluoroalkoxysulfonyl, alkenoxysulfonyl, alkynylsulfonyl, aminosulfonyl, sulfinic acid, alkyl Sulfosyl, haloalkylsulfinyl, fluoroalkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, alkoxysulfinyl, haloalkoxysulfin , fluoroalkoxysulfinyl, olefinoxysulfinyl, alkynyl sulfinyl, aminosulfinyl, carbenyl, alkylcarbonyl, haloalkylcarbonyl, fluoroalkyl Carbonyl, alkenylcarbonyl, alkynylcarbonyl, carboxy, alkoxycarbonyl, haloalkoxycarbonyl , fluoroalkoxycarbonyl, olefinoxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxy, haloalkylcarbonyloxy, fluoroalkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkane Sulfosulfonyloxy, haloalkylsulfonyloxy, fluoroalkylsulfonyloxy, alkenylsulfonyloxy, alkynylsulfonyloxy, haloalkoxysulfonyloxy, fluoroalkoxysulfonate Alkoxy, allyloxysulfonyloxy, alkynyloxysulfonyloxy, alkylsulfinyloxy, haloalkylsulfinyloxy, fluoroalkylsulfinyloxy, alkenylsulfin Alkoxy, alkynylsulfinyloxy, alkoxysulfinyloxy, haloalkoxysulfinyloxy, fluoroalkoxysulfinyloxy, oxysulfinyloxy, Alkynoxysulfinyloxy, aminosulfinyloxy, amine, decylamino, aminosulfonyl, aminosulfinyl, cyano, nitro, azide, phosphinyl , phosphonium, decyl, decyloxy and any such substituents bonded to the heteroaryl via an alkyl moiety (eg, a methylene group).

The term "heteroarylene" is art-recognized and as used herein refers to a diradical obtained by the removal of two hydrogen atoms of a heteroaryl ring as defined above.

The term "heteroarylalkyl" or "heteroaralkyl" as used herein means that a heteroaryl group, as defined herein, is attached to the parent molecular moiety through an alkyl group, as defined herein. . Representative examples of heteroarylalkyl include, but are not limited to, pyridin-3-ylmethyl and 2-(thien-2-yl)ethyl.

The term "fused bicyclyl" as used herein, means a bicyclic ring system group in which two rings are ortho-fused, and each ring includes two fused atoms and contains a total of 4 , 5, 6 or 7 atoms (ie carbon and heteroatoms), and each ring may be fully saturated, may contain one or more units of unsaturation, or may be completely unsaturated (for example in some cases Aromatic). To avoid doubt, the degree of unsaturation in the fused bicyclic group does not result in an aryl or heteroaryl moiety.

The term "halo" or "halogen" means -Cl, -Br, -I or -F.

The term "haloalkyl" means that at least one hydrogen in an alkyl group, as defined herein, is replaced by a halogen as defined herein. Representative examples of haloalkyl include, but are not limited to, chloromethyl, 2-fluoroethyl, trifluoromethyl, pentafluoroethyl, and 2-chloro-3-fluoropentyl.

The term "fluoroalkyl" means that some or all of the hydrogens of the alkyl groups as defined herein are replaced by fluorine.

The term "haloalkylene" as used herein refers to a diradical obtained by the removal of two hydrogen atoms of a haloalkyl group as defined above.

The term "hydroxy" as used herein means an -OH group.

The term "alkoxy" as used herein means that an alkyl group, as defined herein, is attached to the parent molecular moiety through an oxygen atom. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy. The terms "alkyenyloxy", "alkynyloxy", "carbocyclyloxy" and "heterocyclyloxy" are also defined.

The term "haloalkoxy" as used herein means that at least one hydrogen of an alkoxy group, as defined herein, is replaced by a halogen as defined herein. Representative examples of haloalkoxy include, but are not limited to, chloromethoxy, 2-fluoroethoxy, trifluoromethoxy, and pentafluoroethoxy. The term "fluoroalkyloxy" is likewise defined.

The term "aryloxy" as used herein means that an aryl group, as defined herein, is attached to the parent molecular moiety via oxygen. The term "heteroaryloxy" as used herein means that a heteroaryl group, as defined herein, is attached to the parent molecular moiety via oxygen. The term "heteroaryloxy" is likewise defined.

The term "arylalkoxy/arylalkyloxy" as used herein means an arylalkyl group, as defined herein, attached to the parent molecular moiety via oxygen. The term "heteroarylalkoxy" is likewise defined. Representative examples of aryloxy and heteroarylalkoxy include, but are not limited to, 2-chlorophenylmethoxy, 3-trifluoromethyl-phenylethoxy, and 2,3-dimethylpyridyl Oxygen.

The term "sulfhydryl" or "thio" as used herein means a -SH group.

The term "alkylthio" as used herein means an alkyl group, as defined herein, attached to the parent molecular moiety via sulfur. Representative examples of alkylthio include, but are not limited to, methylthio, ethylthio, tert-butylthio, and hexylthio. The terms "haloalkylthio", "fluoroalkylthio", "alkyenylthio", "alkynylthio", "carbocyclylthio" and "Heterocyclylthio" is also defined.

The term "arylthio" as used herein means that an aryl group, as defined herein, is attached to the parent molecular moiety via sulfur. The term "heteroarylthio" is likewise defined.

The term "arylalkylthio/aralkylthio" as used herein means an arylalkyl group, as defined herein, attached to the parent molecular moiety via sulfur. The term "heteroarylalkylthio" is likewise defined.

The term "sulfonyl" as used herein refers to a -S(=O) _2- group.

The term "sulfonic acid" as used herein refers to -S(=O) ₂ OH.

The term "alkylsulfonyl" as used herein means that an alkyl group, as defined herein, is attached to the parent molecular moiety via a sulfonyl group, as defined herein. Representative examples of alkylsulfonyl include, but are not limited to, methylsulfonyl and ethylsulfonyl. The terms "haloalkylsulfonyl", "fluororalkylsulfonyl", "alkenylsulfonyl", "alkynylsulfonyl", "carbocycle" Carbocyclylsulfonyl, "heterocyclylsulfonyl", "arylsulfonyl", "aralkylsulfonyl", "heteroarylsulfonyl" The definition of "heteroarylsulfonyl" and "heteroaralkylsulfonyl" is also defined.

The term "alkoxysulfonyl" as used herein means that an alkoxy group, as defined herein, is attached to the parent molecular moiety through a sulfonyl group, as defined herein. Representative examples of alkoxysulfonyl include, but are not limited to, methoxysulfonyl, ethoxysulfonyl, and propoxysulfonyl. The terms "haloalkoxysulfonyl", "fluoroalkoxysulfonyl", "alkenyloxysulfonyl", "alkynyloxysulfonyl" , "carbocyclyloxysulfonyl", "heterocyclyloxysulfonyl", "aryloxysulfonyl", "aralkyloxysulfonyl" "Heteroaryloxysulfonyl" and "heteroaralkyloxysulfonyl" are also defined.

The terms trifly, tosyl, mesyl and honaflyl are technically recognized and refer to trifluoromethanesulfonyl, respectively. , p-toluenesulfonyl, methanesulfonyl and nonafluorobutylsulfonyl. The terms triflate, tosylate, mesylate and nonaflate are technically recognized and refer to triflate, respectively. , p-toluenesulfonate, mesylate and nonafluorobutanesulfonate functional groups and molecules containing such groups.

The term "aminosulfonyl" as used herein means that an amine group, as defined herein, is attached to the parent molecular moiety via a sulfonyl group.

The term "sulfinyl" as used herein refers to a -S(=O)- group. The sulfinyl group is as defined above for the sulfonyl group. The term "sulfinic acid" as used herein refers to -S(=O)OH.

The term "oxy" refers to a -O- group.

The term "carbonyl" as used herein means a -C(=O)- group.

The term "thiocarbonyl" as used herein means a -C(=S)- group.

The term "formyl" as used herein means a -C(=O)H group.

The term "acyl" as used herein refers to any group of the formula -C(=O)R (wherein R is an organic group). An example of a fluorenyl group is an ethyl group (-C(=O)CH ₃ ).

The term "alkylcarbonyl" as used herein means that an alkyl group, as defined herein, is attached to the parent molecular moiety via a carbonyl group, as defined herein. Representative examples of alkylcarbonyl include, but are not limited to, ethenyl, 1-oxopropyl, 2,2-dimethyl-1-oxopropyl, 1-sided oxybutyl, and 1-side Oxypentyl. The terms "haloalkylcarbonyl", "fluoroalkylcarbonyl", "alkenylcarbonyl", "alkynylcarbonyl", "carbocyclylcarbonyl", " "Heterocyclylcarbonyl", "arylcarbonyl", "aralkylcarbonyl", "heteroarylcarbonyl" and "heteroaralkylcarbonyl" are likewise defined. .

The term "carboxyl" as used herein means a -CO ₂ H group.

As used herein, "asostere of a carboxyl group" refers to a group that is isosteric with a carboxyl group. Examples of the carboxy-isomeric alignment include a tetrazolyl group, Zyridinone, 3-iso Azyl group Azolyl, sulfonic acid, sulfinic acid, mercaptosulfonamide, phosphonic acid, phosphinic acid, intramethylene urea, pyrrolidinone, boric acid, hydroxamic acid, mercapto cyanamide and Azoxalidone group.

The term "alkoxycarbonyl" as used herein means that an alkoxy group, as defined herein, is attached to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of alkoxycarbonyl include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, and tert-butoxycarbonyl. The terms "haloalkoxycarbonyl", "fluoroalkoxycarbonyl", "alkenyloxycarbonyl", "alkynyloxycarbonyl", "carbo-oxycarbonyl" Carbocyclyloxycarbonyl), "heterocyclyloxycarbonyl", "aryloxycarbonyl", "aralkyloxycarbonyl", "heteroaryloxycarbonyl" and "heteroaryl" The same is defined for "heteroaralkyloxycarbonyl".

The term "alkylcarbonyloxy" as used herein means an alkylcarbonyl group, as defined herein, attached to the parent molecular moiety through an oxygen atom. Representative examples of alkylcarbonyloxy include, but are not limited to, ethoxycarbonyl, ethylcarbonyloxy, and tert-butylcarbonyloxy. The terms "haloalkylcarbonyloxy", "fluoroalkylcarbonyloxy", "alkenylcarbonyloxy", "alkynylcarbonyloxy", "carbocycle" Carbocyclylcarbonyloxy", "heterocyclylcarbonyloxy", "arylcarbonyloxy", "aralkylcarbonyloxy", "heteroarylcarbonyloxy" The definition of "heteroarylcarbonyloxy" and "heteroaralkylcarbonyloxy" is also defined.

The term "alkylsulfonyloxy" as used herein means an alkylsulfonyl group, as defined herein, attached to the parent molecular moiety through an oxygen atom. The term "haloalkylsulfonyloxy", "fluoroalkylsulfonyloxy", "alkenylsulfonyloxy", "alkynylsulfonyloxy" , "carbocyclylsulfonyloxy", "heterocyclylsulfonyloxy", "arylsulfonyloxy", "aralkylsulfonyloxy" "Heteroarylsulfonyloxy", "heteroar alkylsulfonyloxy", "haloalkoxysulfonyloxy", "fluoroalkoxysulfonate" Ole (fluoroalkoxysulfonyloxy), "alkenyloxysulfonyloxy", "alkynyloxysulfonyloxy", "carbocyclyloxysulfonyloxy", "heterocycle" "heterocyclyloxysulfonyloxy", "aryloxysulfonyloxy", "aralkyloxysulfonyloxy", "heteroaryloxysulfonyloxy" (hete) "roaryloxysulfonyloxy)" and "heteroaralkyloxysulfonyloxy" are also defined.

The term "amino" or "amine" as used herein refers to -NH ₂ and substituted derivatives thereof, wherein one or two hydrogens are independently selected from the group consisting of: Substituent substitution of the group: alkyl, haloalkyl, fluoroalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, alkylcarbonyl , haloalkylcarbonyl, fluoroalkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, carbocyclic carbonyl, heterocyclylcarbonyl, arylcarbonyl, aralkylcarbonyl, heteroarylcarbonyl, heteroarylalkylcarbonyl and A sulfonyl and sulfinyl group as defined herein; or when two hydrogens are replaced together by an alkyl group (forming a ring containing nitrogen). Representative examples include, but are not limited to, methylamino, ethionyl and dimethylamino.

The term "amido" as used herein means that an amine group, as defined herein, is attached to the parent molecular moiety via a carbonyl group.

The term "cyaho" as used herein means a -C≡N group.

The term "nitro" as used herein means a -NO ₂ group.

As used herein the term "azido (azido)" means the group -N _3.

As used herein, the substituent term "phosphinyl group (phosphinyl)" or "phosphino group (phosphino)" includes -PH ₃ and 1, 2 or 3 hydrogen group selected from those by consisting of, independently-yl Substituted substituted derivatives: alkyl, haloalkyl, fluoroalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkoxy , haloalkoxy, fluoroalkoxy, alkenyloxy, alkynyloxy, carboepoxy, heterocyclooxy, aryloxy, aralkyloxy, heteroaryloxy, heteroaralkyloxy and Amine.

The term "phosphoryl" as used herein means that -P(=O)OH ₂ and one or both of its hydroxyl groups are independently substituted with a substituent selected from the group consisting of: Derivatives: alkyl, haloalkyl, fluoroalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, alkoxy, haloalkyl Oxyl, fluoroalkoxy, alkenyloxy, alkynyloxy, carboepoxy, heterocyclooxy, aryloxy, aralkyloxy, heteroaryloxy, heteroaralkyloxy and amine groups.

The term "silyl" as used herein includes H ₃ Si- and its 1, 2 or 3 hydrogen-substituted derivatives which are independently substituted with substituents selected from alkyl, haloalkyl, Fluoroalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, aralkyl, heteroaryl and heteroarylalkyl. Representative examples include trimethylsulfonyl (TMS), tert-butyldiphenyldecyl (TBDPS), tert-butyldimethylalkyl (TBS/TBDMS), triisopropyldecyl (TIPS) And [2-(trimethyldecyl)ethoxy]methyl (SEM).

The term "silyloxy" as used herein means that a decyl group, as defined herein, is attached to the parent molecule via an oxygen atom.

The abbreviations Me, Et, Ph, Tf, Nf, Ts and Ms represent methyl, ethyl, phenyl, trifluoromethanesulfonyl, nonafluorobutylsulfonyl, p-toluenesulfonyl and methylsulfonyl, respectively. A more comprehensive list of abbreviations used by organic chemists with ordinary skill in the art is presented in the first issue of the Journal of Organic Chemistry ; the list is typically a list of standard abbreviations ( Standard List) The table of the Abbreviations is presented.

The term "treating" as used herein encompasses the administration and/or administration of one or more compounds described herein for the purpose of preventing or managing and/or remedying a condition. "Treatment" for the purposes of the present invention may, but does not necessarily provide, a cure; more specifically, "treatment" may take the form of a management condition. When a compound described herein is used to treat unwanted proliferating cells, including cancer, "treating" includes partially or completely destroying unwanted proliferating cells with minimal disruption to normal cells. The desired mechanism for treating unwanted rapidly proliferating cells, including cancer cells, is apoptosis at the cellular level.

The term "to treat" as used herein thus includes not only healing but also slowing the progression and/or reducing the severity of the disease, disorder or condition. In one specific example, "treat" may cover "prevent".

The term "preventing" as used herein includes the beginning of a preclinical phase of a disease that completely prevents or slows the onset of clinically apparent disease progression or prevents or slows the disease in an individual at risk. This includes prophylactic treatment of individuals at risk of developing the disease.

The term "subject" includes, for therapeutic purposes, any human or animal subject who has been diagnosed with a condition, has a symptom of the condition, or is at risk of developing the condition. For prophylactic methods, the individual is any human or animal individual.

The term "optionally deuterated" as used herein means that one or more of any of the groups described above has been replaced by a hydrazine. Examples of the alkylene group include -CD ₂ H and -CD ₃ .

The term "polyol" as used herein refers to small molecules and polymers having more than one hydroxyl group.

As used herein, "carbohydrate" (or equivalently, "sugar") is a sugar (including monosaccharides, oligosaccharides, and polysaccharides) and/or from one or more monosaccharides, for example, by reduction. A carbonyl group, a oxidized one or more terminal groups is a carboxylic acid, a molecule (including an oligomer or a polymer) derived by substituting one or more hydroxyl groups with a hydrogen atom, an amine group, a thiol group or a similar hetero atom group. The term "carbohydrate" also includes derivatives of such compounds. In some cases, the carbohydrate may be a pentose (ie, having 5 carbons) or a hexose (ie, having 6 carbons); and in some cases, the carbohydrate may be a pentose and/or hexose The oligosaccharide of the unit includes, for example, the above.

As used herein, "carbohydrate" and "sugar" also include sugar mimetics and sugar-like parts. Sugar mimetics are well known to those skilled in the art and include "Essentials of Glycobiology", edited by Varki, A. et al., Cold Spring Harbor Laboratory Press. Cold Spring Harbor, N. Y. 2002. For example, a sugar mimetic group encompassed by the present invention, as defined by the IUPAC regulations, includes a cyclic polyol, such as a cycloalkane containing one hydroxyl group on each of three or more ring atoms. In other embodiments, the cyclic polyol moiety comprises inositol, such as scyllo-inositol. Suitable sugar-like moieties include acyclic sugar groups. Such groups include, for example, linear alkantols and erythritol. It will be appreciated that the sugar group can be in a cyclic or acyclic form. Thus, the invention encompasses a sugar group acyclic form in a suitable sugar-like moiety.

The term "polythiol" as used herein refers to small molecules and polymers having more than one thiol.

Compound

Niacin, also known as nicotinic acid, has the following structure:

One aspect of the invention pertains to a compound represented by structure I or a pharmaceutically acceptable salt thereof:

Wherein A is a heterocyclic or heteroaryl group optionally having 5 to 12 ring atoms including X and N, optionally substituted by 1 to 3 groups selected from the group consisting of: Base substitution: alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, halogen, nitro, cyano, sulfonic acid, alkyl thiooxy, aryl thiooxy ,heteroarylthiooxy, aralkylthiooxy, heteroaralkylthiooxy, alkenylthiooxy, alkynylthiooxy, alkylsulfonyl, arylsulfonyl, heteroaryl Sulfonyl, aralkylsulfonyl, heteroaralkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, hydroxy, alkoxy, aryloxy, heteroaryloxy, aralkyloxy , heteroaralkyloxy, alkenyloxy, alkynyloxy, thiol, alkylthio, arylthio, aralkylthio, heteroaralkylthio, alkylthio, alkynylthio, decyl, Sulfhydryl, methyl methoxy, decyloxy, methylthio, thiol, amine, alkylamine, arylamine, heteroarylamine, aralkylamine, heteroarylalkylamine, alkenylamine , alkynylamine, formamylamine, mercaptoamine, carboxyl, alkoxycarbonyl, Oxycarbonyl, heteroaryloxycarbonyl, aralkyloxycarbonyl, heteroaralkyloxycarbonyl, decylamino, alkylaminecarbonyl, arylaminecarbonyl, heteroarylaminecarbonyl, aralkylaminecarbonyl and hetero Aralkylamine carbonyl; X is O, S, N or N(R ⁶ ); Z is Or a homo-electron arrangement of carboxyl groups; X ¹ is O or S; X ² is O or S; R is hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, heterocyclyl Alkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, fused bicyclic, carboxyalkyl, arylalkenylaryl, decylamino substituted alkylaminoalkyl, carboxy substituted Ethylaminoalkyl, hydroxyalkylthioalkylthio, alkoxycarbonyloxyalkyl, alkylcarbonyloxyalkyl or decylalkyl; R ² is hydrogen, lower alkane , lower alkenyl, lower alkynyl, halogen, hydroxy, amine, carboxyl, cycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cyano or nitro; R ³ is hydrogen , lower alkyl, lower alkenyl, lower alkynyl, halogen, hydroxy, amine, carboxy, cycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cyano or nitro; Each occurrence of R ⁵ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, halogen, nitro , cyano, sulfonic acid, alkyl thiooxy, aryl thiooxy, hetero Thioryloxy, aralkylthiooxy, heteroaralkylthiooxy, alkenylthiooxy, alkynylthiooxy, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl , aralkylsulfonyl, heteroarylalkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, hydroxy, alkoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaryl Alkoxy, alkenyloxy, alkynyloxy, thiol, alkylthio, arylthio, aralkylthio, heteroaralkylthio, alkylthio, alkynylthio, decyl, fluorenyl, Methoxy, methoxy, methyl thio, thiol, amine, alkylamine, arylamine, heteroarylamine, aralkylamine, heteroarylalkylamine, alkenylamine, alkynyl Amine, formylamine, mercaptoamine, carboxyl, alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, aralkoxycarbonyl, heteroaralkyloxycarbonyl, decylamino, alkylaminecarbonyl , arylamine carbonyl, heteroaryl carbonyl amines, aralkyl amines and carbonyl heteroaralkyl aminocarbonyl; R ⁶ is hydrogen or lower alkyl; and M is 3 or 4.

In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein A represents a heterocyclic group.

In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein A represents a heteroaryl group.

In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein A is a monocyclic group having 5, 6 or 7 ring atoms.

In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein A is a bicyclic group having 9, 10, 11 or 12 ring atoms.

In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein X is O.

In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein X is S.

In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein X is N.

In certain instances, the present invention relates to any one of the aforementioned compounds, wherein X is N (R ^6).

In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein X is N(H).

In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein A is pyrrolidinyl, imidazolidinyl, thiazolidinyl, isothiazolidinyl, Azolidinyl, Diazolidinyl, piperidinyl, piperid Base, thiomorpholinyl or morpholinyl.

In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein A is imidazolyl, pyrazolyl, isomeric Azolyl, Azyl, isoxazolyl, thiazolyl, Base, furfuryl, Diazolyl, thiadiazolyl, triazolyl, dithiazolyl, di base, Base Base, three Base, four Base, diazepine or thiazolidine.

In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein A is substituted with 1 to 3 substituents independently selected from the group consisting of lower alkyl, halogen, nitro, cyanide Base, sulfonic acid, hydroxy, alkoxy, thiol, alkylthio, decyl, decyl, methyl methoxy, decyloxy, methylthio, thiol, amine, alkylamine, A Mercaptoamine, mercaptoamine and carboxyl.

In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein A is substituted with one substituent independently selected from the group consisting of lower alkyl, halo, nitro, cyano, Sulfonic acid, hydroxy, alkoxy, thiol, alkylthio, decyl, decyl, methyl methoxy, decyloxy, methylthio, thiol, amine, alkylamine, formazan Amine, mercaptoamine and carboxyl.

In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein A is unsubstituted.

In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R ² is hydrogen or lower alkyl.

In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R ² is hydrogen.

In certain instances, the present invention relates to any one of the aforementioned compounds, wherein R ³ is hydrogen or lower alkyl.

In certain instances, the present invention relates to any one of the aforementioned compounds, wherein R ³ is hydrogen.

In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R ² is hydrogen; and R ³ is lower alkyl.

In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R ² is lower alkyl; and R ³ is hydrogen.

In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R ² is hydrogen; and R ³ is hydrogen.

In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein m is 1.

In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein m is 2.

In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein m is 3.

In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein m is 4.

In certain instances, the present invention relates to any one of the aforementioned compounds, wherein R ⁵ at each occurrence is independently selected from the group consisting of the following consisting of: hydrogen, lower alkyl, halo, nitro, cyano , sulfonic acid, hydroxy, alkoxy, thiol, alkylthio, decyl, decyl, methyl methoxy, decyloxy, methylthio, thiol, amine, alkylamine, formazan Alkylamine, mercaptoamine and carboxyl group.

In certain instances, the present invention relates to any one of the aforementioned compounds, wherein R ⁵ is hydrogen.

In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Z is a carboxy group.

In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Z is a carboxy-isomeric alignment.

In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Z is tetrazolyl, Zyridinone, sulfonic acid, sulfinic acid, decylsulfonamide, phosphonic acid, phosphinic acid, beta-urea, pyrrolidone, 3-iso Azolyl or boric acid.

In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Z is .

In certain instances, the present invention relates to any one of the aforementioned compounds, wherein X ¹ is O.

In certain instances, the present invention relates to any one of the aforementioned compounds, wherein X ¹ is S.

In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein X ² is O.

In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein X ² is S.

In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein X ¹ is O; and X ² is O.

In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R is lower alkyl.

In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R is hydrogen.

In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R is

In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R represents an aliphatic group which can be hydrolyzed to a carboxyl group under physiological conditions.

Another aspect of the invention pertains to a compound represented by structure II or a pharmaceutically acceptable salt thereof,

Wherein, at each occurrence, independently, W is a polyol or a polythiol; p is from 2 to 500, including 2 and 500; R ¹ is And attached to the polyhydric alcohol via an oxygen atom of the polyol or via a sulfur atom of the polythiol; A is a heterocyclic group optionally containing 5 to 12 ring atoms including X and N. Or a heteroaryl group, which is optionally substituted with from 1 to 3 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, hetero Aralkyl, halogen, nitro, cyano, sulfonic acid, alkyl thiooxy, aryl thiooxy, heteroaryl thiooxy, aralkyl thiooxy, heteroaralkyl thiooxy, alkene Thioryloxy, alkynylthiooxy, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aralkylsulfonyl, heteroaralkylsulfonyl, alkenylsulfonyl , alkynylsulfonyl, hydroxy, alkoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, alkenyloxy, alkynyloxy, thiol, alkylthio, aryl Sulfur, aralkylthio, heteroaralkylthio, alkylthio, alkynylthio, decyl, decyl, methyloxy, decyloxy, methylthio, sulfonyl, amine, alkane Amine, arylamine, heteroarylamine, aralkylamine Heteroarylalkylamine, alkenylamine, alkynylamine, formamylamine, mercaptoamine, carboxyl, alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, aralkoxycarbonyl, heteroaralkyl oxycarbonyl group, acyl group, alkyl aminocarbonyl, aryl aminocarbonyl, heteroaryl aminocarbonyl, arylalkyl aminocarbonyl and heteroaralkyl aminocarbonyl; X is O, S, N or N (R ⁶⁾ X ¹ is O or S; R is hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, Heteroaralkyl, fused bicyclic, carboxyalkyl or arylalkenylaryl; R ² is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, halogen, hydroxy, amine, carboxyl, ring Alkyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, cyano or nitro; R ³ is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, halogen, hydroxy, amine a carboxy, cycloalkyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, cyano or nitro group; each occurrence of R ⁵ is independently selected from the group consisting of hydrogen, Alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, Aralkyl, halogen, nitro, cyano, sulfonic acid, alkyl thiooxy, aryl thiooxy, heteroaryl thiooxy, aralkyl thiooxy, heteroaralkyl thiooxy, alkene Thioryloxy, alkynylthiooxy, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aralkylsulfonyl, heteroaralkylsulfonyl, alkenylsulfonyl , alkynylsulfonyl, hydroxy, alkoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, alkenyloxy, alkynyloxy, thiol, alkylthio, aryl Sulfur, aralkylthio, heteroaralkylthio, alkylthio, alkynylthio, decyl, decyl, methyloxy, decyloxy, methylthio, sulfonyl, amine, alkane Amine, arylamine, heteroarylamine, aralkylamine, heteroarylalkylamine, alkenylamine, alkynylamine, formamylamine, mercaptoamine, carboxyl, alkoxycarbonyl, aryloxy Carbonyl, heteroaryloxycarbonyl, aralkoxycarbonyl, heteroaralkyloxycarbonyl, decylamino, alkylaminecarbonyl, arylaminecarbonyl, heteroarylaminecarbonyl, aralkylaminecarbonyl and heteroaralkyl Alkylcarbonyl; R ⁶ is hydrogen or lower alkyl; and M is 1, 2, 3 or 4 .

In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein W is a polythiol.

In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein W is a polyol.

In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein the polyol is a carbohydrate.

In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein the polyol is maltitol, sorbitol, xylitol or isomalt.

In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein the polyol is sorbitol.

In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein the polyol is inositol.

In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein p is 2, 3, 4, 5 or 6.

In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein p is 2-100, including 2 and 100. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein p is 2-50, inclusive. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein p is 2-10, inclusive.

In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein p is 2. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein p is 3. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein p is 4. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein p is 5. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein p is 6.

It has been discovered that at least some of the compounds of the invention have desirable physiological properties of niacin, with undesirable physiological side effects of niacin being reduced. For example, the compounds of the invention have the ability to modulate at least one lipid in a desired manner, with the limiting side effects of the characteristics of the anthraquinone acid or the extent that the limiting side effects are not achieved.

Additionally, it has been found that at least some of the compounds of the invention do not appear to engage the high affinity nicotinic acid receptor GPR109A in a manner similar to niacin. GPR109A, also known as PUMA-G and HM74A, is a member of the niacin receptor family of G protein-coupled redeptors (GPCRs). Wise A, et al, (2003) J Biol Chem 278: 99-74; Soga T et al, (2003) Biochem Biophys Res Comm 303: 364-9. In GPR109A knockout mice, the effect of niacin on lipid and flushing was removed. The flushing effect of nicotinic acid has been attributed to the inhibition of protein β1 (β-arrestin)-mediated activation of GPR109A by ERK 1/2 MAP kinase, whereas lipid modification is not. In the inhibitory protein β1 knockout mice, it has been reported that the effect of nicotinic acid on flushing is greatly reduced, and the lipid reforming effect is maintained. Walters RW et al. (2009) J Clin Invest 119: 1312-21. Significantly, at least some of the compounds of the invention induce a greatly reduced ability of β-arrestin to recruit to membranes of cells expressing GPR109A, greatly reduce the flushing effect compared to nicotinic acid, and still maintain clinically significant desired lipid modifications. effect.

Many of the compounds of the invention may be provided in the form of a pharmaceutically compatible salt of a relative ion (i.e., a pharmaceutically acceptable salt). "Pharmaceutically acceptable salt" means any non-toxic salt of a compound of the present invention or a compound of the present invention which can be directly or indirectly provided after administration to a recipient. "Pharmaceutically acceptable counterion" is the non-toxic ionic moiety of a salt when released from a salt after administration to a recipient. Pharmaceutically compatible salts can be formed with a wide variety of acids including, but not limited to, hydrochloric acid, sulfuric acid, acetic acid, lactic acid, tartaric acid, malic acid, succinic acid, and the like. Salts tend to be more soluble in aqueous or other protic solvents than the corresponding free base forms.

Acids commonly used to form pharmaceutically acceptable salts include inorganic acids such as hydrogen disulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and phosphoric acid, and organic acids such as p-toluenesulfonic acid, salicylic acid, tartaric acid. , heavy tartaric acid, ascorbic acid, maleic acid, benzenesulfonic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, Lactic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid and acetic acid, and related inorganic and organic acids. Such pharmaceutically acceptable salts thus include sulfates, pyrosulfates, hydrogen sulfates, sulfites, bisulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates. Salt, chloride, bromide, iodide, acetate, propionate, citrate, octoate, acrylate, formate, isobutyrate, decanoate, heptanoate, propiolate, Oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-diate, Alkyne-1,6-diacid salt, benzoate, chlorobenzoate, methyl benzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, Phthalate, terephthalate, sulfonate, xylene sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, beta-hydroxy Butyrate, glycolate, maleate, tartrate, methanesulfonate, propane sulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate and the like salt. Exemplary pharmaceutically acceptable acid addition salts include those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and especially with organic acids such as maleic acid.

Bases suitable for forming pharmaceutically acceptable salts with acidic functional groups include, but are not limited to, hydroxides of alkali metals such as sodium, potassium and lithium; hydroxides of alkaline earth metals such as calcium and magnesium; such as aluminum and zinc Other metal hydroxides; ammonia and organic amines, such as unsubstituted or hydroxy substituted mono-, di- or trialkylamines; dicyclohexylamine; tributylamine; pyridine; N-methylamine, N- Ethylamine; diethylamine; triethylamine; mono-, di- or para-(2-hydroxy lower alkylamine), such as mono-, di- or para-(2-hydroxyethyl)amine, 2-hydroxy- Tributylamine or cis-(hydroxymethyl)methylamine, N,N-di-lower alkyl-N-(hydroxyl lower alkyl)-amine, such as N,N-dimethyl-N- (2-hydroxyethyl)amine or cis-(2-hydroxyethyl)amine; N-methyl-D-reduced glucosamine; and amino acids such as arginine, lysine and the like.

Certain compounds of the invention and salts thereof may exist in more than one crystalline form, and the invention includes each crystalline form and mixtures thereof.

Certain compounds of the invention and salts thereof may also be in the form of a solvate, such as a hydrate, and the invention includes each solvate and mixtures thereof.

Certain compounds of the invention may contain one or more chiral centers and may be in different optically active forms. When a compound of the invention contains a chiral center, the compound is in two enantiomeric forms, and the invention includes both enantiomers and mixtures of enantiomers, such as racemic mixtures. The enantiomers can be resolved by methods known to those skilled in the art, for example to form diastereomeric salts which can be separated, for example, by crystallization; to form diastereomeric derivatives or complexes which may For example, separation by crystallization, gas-liquid or liquid chromatography; selective reaction of one enantiomer with an enantiomer-specific reagent, such as enzymatic esterification; or in a chiral environment (eg in Gas-liquid or liquid chromatography coupled to a chiral ligand such as a chiral support such as cerium oxide or in the presence of a chiral solvent. It will be appreciated that when one of the above separation procedures is used to convert a desired enantiomer to another chemical entity, another step may be used to release the desired enantiomeric form. Alternatively, specific enantiomers can be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents or by converting one enantiomer to another using asymmetric transformation.

When a compound of the invention contains more than one chiral center, it may be in the form of a diastereomer. Diastereomeric compounds can be separated by methods known to those skilled in the art, such as chromatography or crystallization, and the individual enantiomers can be separated as described above. The invention includes the individual diastereomers of the compounds of the invention and mixtures thereof.

Certain compounds of the invention may be in different tautomeric forms or different geometric isomers, and the invention includes each tautomer and/or geometric isomer of the compounds of the invention and mixtures thereof.

Certain compounds of the invention may be in different separable stable conformational forms. Torsional asymmetry due to limited rotation about asymmetric single bonds, for example due to steric hindrance or ring stress, may allow separation of different conformers. The present invention includes each conformational isomer of the compound of the present invention and mixtures thereof.

Certain compounds of the invention may exist in zwitterionic form, and the invention includes each zwitterionic form of the compounds of the invention and mixtures thereof.

The invention also includes prodrugs. The term "prodrug" as used herein refers to an agent that is converted in vivo to a parent drug by some physiological chemical process (eg, the prodrug is converted to the desired drug form under physiological pH conditions). Prodrugs are generally suitable because, in some cases, they are easier to administer than the parent drug. It can be utilized for oral administration, for example, via oral administration, while the parent drug is not. Prodrugs may also have improved solubility in the pharmacological composition over the parent drug. A non-limiting example of a prodrug would be a compound of the invention wherein it is administered in the form of an ester ("prodrug") to aid in the transport across the cell membrane (where water solubility is unfavorable), but then once it is in the cell ( Where water solubility is advantageous) that is, metabolic hydrolysis to a carboxylic acid. Prodrugs have many suitable properties. For example, a prodrug can be more water soluble than the final drug, thereby facilitating intravenous administration of the drug. Prodrugs can also have higher oral bioavailability than the final drug. After administration, the prodrug is enzymatically or chemically cleaved to deliver the final drug in the blood or tissue.

Exemplary prodrugs release the corresponding free acid after cleavage, and such ester-forming hydrolyzable residues of the compounds of the invention include, but are not limited to, carboxylic acid substituents (eg, -C(O) ₂ H or a moiety containing a carboxylic acid) Wherein free hydrogen is replaced by (C ₁ -C ₄ )alkyl, (C ₂ -C ₁₂ )alkylnonyloxymethyl, (C ₄ -C ₉ )1-(alkylindolyloxy)B a 1-methyl-1-(alkylindenyloxy)-ethyl group having 5 to 10 carbon atoms, an alkoxycarbonyloxymethyl group having 3 to 6 carbon atoms, having 4 to 7 a 1-(alkoxycarbonyloxy)ethyl group having 1 to 9 carbon atoms and having 1 to 9 carbon atoms; N-(alkoxycarbonyl)aminomethyl, 1-(N-(alkoxycarbonyl)amino)ethyl, 4-indolyl, 4-crotonyl lactone having 4 to 10 carbon atoms , γ-butyrolactone-4-yl, di-N,N-(C ₁ -C ₂ )alkylamino (C ₂ -C ₃ )alkyl (such as β-dimethylaminoethyl), Aminomethylindenyl-(C ₁ -C ₂ )alkyl, N,N-di(C ₁ -C ₂ )-alkylaminemethylindenyl-(C ₁ -C ₂ )alkyl and piperidinyl (C ₂ -C ₃₎ alkyl, pyrrolidinyl (C ₂ -C ₃₎ alkyl or morpholinyl (C ₂ -C ₃₎ alkyl

Other exemplary prodrugs release an alcohol or an amine of a compound of the invention wherein the free hydrogen of the hydroxy or amine substituent is replaced by (C ₁ -C ₆ ) alkoxymethyl, 1-((C ₁ -C _{6 )} Alkyloxy)ethyl, 1-methyl-1-((C ₁ -C ₆ )alkyloxy)ethyl, (C ₁ -C ₆ )alkoxycarbonyloxymethyl, N- (C ₁ -C ₆ ) alkoxycarbonylamino-methyl, butyl decyl, (C ₁ -C ₆ )alkyl fluorenyl, α-amino (C ₁ -C ₄ ) alkanoyl, aryl Mercapto and α-aminoindenyl or α-aminoindenyl-α-aminoindenyl, wherein the α-aminoindenyl moiety is independently any naturally occurring L-amine group visible in the protein Acid, -P(O)(OH) ₂ , -P(O)(O(C ₁ -C ₆ )alkyl) ₂ or a glycosyl group (a group derived from the hydroxyl group of a hemiacetal separating a carbohydrate) .

The term "protecting group" as used herein, refers to a temporary substituent that protects a potentially reactive functional group from unwanted chemical transformation. Examples of such protecting groups include carboxylic acid esters, decyl alcohol ethers, and acetals and ketals corresponding to aldehydes and ketones. The field of protecting group chemistry has been reviewed (Greene, TW; Wuts, PGM Protective Groups in Organic Synthesis , 2nd ed.; Wiley: New York, 1991). Protected forms of the compounds of the invention are included within the scope of the invention.

The term "chemically protected form" as used herein means that one or more reactive functional groups in a compound are protected against unwanted chemical reactions, ie, as protecting groups (also known as masking groups). form. It may be convenient or desirable to prepare, purify and/or treat the active compound in a chemically protected form.

By protecting the reactive functional groups, reactions involving other unprotected reactive functional groups can be carried out without affecting the protecting groups; the protecting groups can generally be removed in subsequent steps without substantially affecting the remainder of the molecule. See, for example, Protective Groups in Organic Synthesis (T. Green and P. Wuts, Wiley, 1991) and Protective Groups in Organic Synthesis (T. Green and P. Wuts). ; 3rd edition; John Wiley and Sons, 1999).

For example, the hydroxy group can be protected as an ether (-OR) or an ester (-OC(=O)R), such as a third butyl ether; a benzyl ether; a benzhydryl/diphenylmethyl ether or a trisole Trityl/triphenylmethyl ether; trimethyldecyl or tert-butyldimethyl decyl ether; or ethoxylated (-OC(=O)CH ₃ , -OAc).

For example, an aldehyde or a ketone group can be protected as an acetal or a ketal, respectively, wherein the carbonyl group (C(=O)) is converted to a diether (C(OR) ₂ ) by reaction with, for example, a primary alcohol. The aldehyde or ketone group can be readily regenerated by hydrolysis using a large excess of water in the presence of an acid.

For example, an amine group can be protected, for example, as a guanamine (-NRC(=O)R) or a urethane (-NRC(=O)OR), such as formamide (-NHC(=O)CH) ₃ ) benzyloxyguanamine (-NHC(=O)OCH ₂ C ₆ H ₅ NHCbz), third butoxy decylamine (-NHC=(=O)OC(CH ₃ ) ₃ , -NHBoc), 2-biphenyl-2-propoxydecylamine (-NHC(=O)OC(CH ₃ ) ₂ C ₆ H ₄ C ₆ H ₅ NHBoc), 9-fluorenylmethoxy decylamine (-NHFmoc), 6-nitrovaleryl decylamine (-NHNvoc), 2-trimethyldecyl ethoxy decylamine (-NHTeoc), 2,2,2-trichloroethoxy decylamine (-NHTroc), Allyloxyguanamine (NHAlloc), 2-(phenylsulfonyl)ethoxyguanamine (-NHPsec); or in a suitable base, protected as an oxynitride group.

For example, a carboxylic acid group can be protected as an ester or a guanamine such as benzyl, tert-butyl, methyl or formamide.

For example, a thiol group can be protected as a thioether (-SR), such as benzyl sulfide or acetaminomethyl ether (-SCH ₂ NHC(=O)CH ₃ ).

Pharmaceutical composition

The invention provides a pharmaceutical composition comprising one or more of the compounds mentioned above. In one aspect, the invention provides a pharmaceutically acceptable composition comprising a therapeutically effective amount of one or more of the above compounds in association with one or more pharmaceutically acceptable carriers (additives) and/or diluents Together.

Alternatively or additionally, the invention provides a pharmaceutical composition characterized by having at least one desired therapeutic effect of niacin and at least one undesirable side effect of reducing or lacking niacin.

In one aspect, the invention provides a pharmaceutical composition comprising a nicotinic acid analog or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient; wherein the composition is formulated for use in Oral administration; a nicotinic acid analog reduces at least one member selected from the group consisting of total cholesterol, low density lipoprotein (LDL) cholesterol, triglyceride, and lipoprotein (a) when administered orally to a human. The serum or plasma content of the lipid; and the oral administration of the composition is characterized by reducing flushing and reducing hepatocyte damage as compared to administration of a molar oral dose of niacin.

As used herein, "niacin analog" is a structural analog of nicotinic acid other than nicotinic acid (nicotinic acid). When administered orally to an individual, at least one is administered orally. A lipid-regulating effect characteristic of nicotinic acid. Niacinic acid analogs are similar in structure to nicotinic acid but differ from nicotinic acid in at least one atom, functional group, substituent or substructure, which is displaced by other atoms, groups, substituents or substructures. The nicotinic acid analogs of the invention specifically exclude chrono-release, sustained release and extended release formulations of niacin, including polymers such as polyethylene glycol or hydroxypropyl methylcellulose (hypromellose) Nicotinic acid blended together.

In one embodiment, the nicotinic acid analog is a pyridine containing compound.

In a specific example, the nicotinic acid analog is not

In one embodiment, the nicotinic acid analog specifically excludes 6-[2-(pyrrolidin-1-yl)ethyl]pyridine and 4-pyridine- disclosed in US Patent Application Publication No. US 2009/0312355 A1. 3-yl-but-3-enoic acid.

In one embodiment, the nicotinic acid analog specifically excludes any one or more of the following: , ,

In a specific example, the nicotinic acid analog specifically excludes the compound represented by structure A or a pharmaceutically acceptable salt thereof:

Wherein R, at each occurrence, independently represents H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, fluoro, chloro, bromo, iodo, nitro, cyano , sulfonic acid, alkyl thiooxy, aryl thiooxy, heteroaryl thiooxy, aralkyl thiooxy, heteroaralkyl thiooxy, alkenyl thiooxy, alkynyl thiooxy, Alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aralkylsulfonyl, heteroaralkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, hydroxy, alkoxy Base, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, alkenyloxy, alkynyloxy, thiol, alkylthio, arylthio, aralkylthio, heteroaralkyl Sulfuryl, olefinylthio, alkynylthio, decyl, decyl, methyl methoxy, decyloxy, methylthio, thiol, amine, alkylamino, arylamine, hetero Arylamino, aralkylamino, heteroarylalkylamine, alkenylamino, alkynylamino, decylamino, decylamino, carboxylate, alkoxycarbonyl, aryl Oxycarbonyl, heteroaryloxycarbonyl, aralkoxycarbonyl, heteroaralkyloxycarbonyl, A Amino, alkylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, aralkylaminocarbonyl or heteroarylalkylaminocarbonyl; R' independently represents H, alkane at each occurrence Base, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aralkylsulfonyl, Heteroaralkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, hydroxy, alkoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, alkenyloxy, Alkynyloxy, indenyl, fluorenyl, amine, alkylamino, arylamino, heteroarylamino, aralkylamino, heteroarylalkyl, alkenylamino, alkynyl Amino, decylamino, decylamino, alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, aralkyloxycarbonyl, heteroaralkyloxycarbonyl, alkylaminocarbonyl, aromatic Alkylcarbonyl, heteroarylaminocarbonyl, aralkylaminocarbonyl or heteroarylalkylaminocarbonyl; or two R' together represent -(CH ₂ ) ₂ -, -(CH ₂ ) ₃ -, _{- (CH 2) 4 -,} - (CH 2) 5 - or _{- (CH 2) 6 -;} R " in each occurrence, Independently represent H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl or heteroaralkyl; and N is 2, 3 or 4.

A nicotinic acid analog reduces at least one serum or plasma selected from the group consisting of total cholesterol, low density lipoprotein (LDL) cholesterol, triglyceride, and lipoprotein (a) when administered orally to a human. content. A nicotinic acid analog is believed to reduce the serum or plasma content when the serum or plasma content of at least one lipid is reduced by a measurable amount compared to the pre-treatment, baseline or control levels. In one embodiment, when the serum or plasma level of the at least one lipid is reduced by at least 5% of the pre-treatment, baseline or control content, ie, the serum or plasma content is reduced to no more than 95 pre-treatment, baseline or control levels. At %, the nicotinic acid analog is considered to reduce the serum or plasma content. In one embodiment, the nicotinic acid analog is believed to reduce the serum or plasma content when the serum or plasma content of at least one lipid is reduced by at least 10% of the pre-treatment, baseline or control levels. In one embodiment, the nicotinic acid analog is believed to reduce the serum or plasma content when the serum or plasma level of at least one lipid is reduced by at least 15% of the pre-treatment, baseline or control content. In one embodiment, the nicotinic acid analog is believed to reduce the serum or plasma content when the serum or plasma level of at least one lipid is reduced by at least 20% of the pre-treatment, baseline or control content.

As used herein, "flushing" refers to the vasodilation of a target skin, usually accompanied by a reddened, and/or subjective experience of the warmth of the skin, which may or may not be accompanied by itching. Flushing can be objectively measured using an objective measurement such as Doppler capillary blood flow measurement. Alternatively or additionally, flushing may be measured using an observer-based or individual-based so-called visual analog scale (VAS). VAS typically involves scoring signs or symptoms according to a scale ranging from zero (0) to ten (10), where zero corresponds to a sign or symptom that is completely ungradable, and ten corresponds to the sign or symptom of the score. Tolerate or maximize the amount or degree.

As used herein, "hepatocellular damage" refers to a toxic injury to a liver's substantial cells. Hepatocyte damage can be assessed using any suitable method. In one embodiment, hepatocyte damage is assessed by measuring one or more serum liver enzymes. In one embodiment, one such liver enzyme is aspartate aminotransferase (AST, also known as SGOT). In one embodiment, one such liver enzyme is alanine aminotransferase (ALT, also known as SGPT). Serum levels of AST and ALT are typically measured in clinical practice and their measurement methods need not be described herein. The normal serum levels of AST and ALT are generally 0-35 U/L. In contrast to ALT, which is primarily found in the liver, AST is also found in other tissues, including the heart, skeletal muscle, kidney, and brain, and thus has a slightly lower specificity as an indicator of liver dysfunction. Although high serum levels of AST or ALT can be observed in a variety of non-hepatic conditions including myocardial infarction, such conditions are often easily distinguished clinically from liver disease. In liver disease, elevated serum AST and ALT reflect hepatic necrosis, a form of severe hepatocyte damage.

Oral administration of the composition is characterized by reducing flushing and reducing hepatocyte damage as compared to administration of a molar oral dose of niacin. In this connection, it is considered to reduce flushing when the amount or degree of measurability is reduced as compared to the corresponding degree of flushing caused by the oral oral dose of nicotinic acid. In one embodiment, the reduction in flushing is considered to be reduced when the maximum extent or amount of flushing is reduced to a measurable extent or amount compared to the maximum or amount of flushing caused by the oral oral dose of nicotinic acid. .

In one embodiment, the Doppler capillary blood flow of the associated tissue is reduced by at least 2 compared to the Doppler capillary blood flow of the corresponding tissue caused by administration of a molar oral dose of nicotinic acid. At the time of %, that is, when the flow rate is reduced to not more than 98% of the Doppler capillary blood flow of the corresponding tissue caused by the oral oral dose of nicotinic acid, it is considered to reduce the flushing. In one embodiment, the Doppler capillary blood flow of the associated tissue is reduced by at least 5 compared to the Doppler capillary blood flow of the tissue associated with administration of a molar oral dose of niacin. When it is %, it is considered to reduce the flushing. In one embodiment, the Doppler capillary blood flow of the associated tissue is reduced by at least 10 compared to the Doppler capillary blood flow of the tissue associated with administration of a molar oral dose of niacin. When it is %, it is considered to reduce the flushing.

In one embodiment, the VAS score of the relevant tissue is reduced by at least one (1) (by 0 to 10) compared to the VAS score of the corresponding tissue caused by administration of a molar oral dose of nicotinic acid. At the time of the table, that is, when the VAS score was reduced to not exceed the VAS score of the corresponding related tissue caused by the administration of the oral oral dose of nicotinic acid minus 1, it was considered that the flushing was reduced. For example, in one specific example, flushing is considered to be reduced when the maximum VAS score is 5 and the maximum VAS score of the corresponding tissue associated with administration of a meager oral dose of niacin is 6-10.

Of course, any of the above comparisons can advantageously be based on groups. For example, the average or median of AST, ALT, or VAS scores can be compared. Similarly, the average or median of the AST max, ALT max, or VAS score maxima can be compared.

The comparison was performed with an oral dose of nicotinic acid. An oral oral dose of nicotinic acid refers to any form of niacin that is administered in an oral dosage form, including, for example, immediate release, timed release, sustained release, and extended release formulations of niacin. In one embodiment, the oral oral dose is formulated in a similar manner, for example, in the form of a troche, wherein each troche comprises the same or substantially the same molar amount of active agent. Thus, for example, in one embodiment, the comparison can be made between oral doses administered in a single lozenge, each lozenge containing 8.2 mmol of active agent (eg, 1 g of nicotinic acid). As an alternative example, in another embodiment, the comparison can be made between oral doses administered in two single lozenges, each lozenge containing 4.1 mmol of active agent (e.g., 0.5 g of nicotinic acid).

All pharmacokinetic comparisons to "niacin" are compared to so-called immediate release formulations of niacin, unless otherwise indicated herein.

In certain embodiments, the invention relates to any one of the aforementioned compositions, wherein the peak serum or plasma concentration ( _Cmax ) of the nicotinic acid analog is 40% of the _Cmax of the oleic acid of the oral molar dose or smaller. In one embodiment, the peak serum or plasma concentration ( _Cmax ) of the niacin analog is 35% or less of the _Cmax of the oleic acid of the oral molar dose. In one embodiment, the peak serum or plasma concentration ( _Cmax ) of the niacin analog is 30% or less of the _Cmax of the oleic acid of the oral molar dose. In one embodiment, the peak serum or plasma concentration ( _Cmax ) of the niacin analog is 25% or less of the _Cmax of the oleic acid of the oral molar dose. In one embodiment, the peak serum or plasma concentration ( _Cmax ) of the niacin analog is 20% or less of the _Cmax of the oleic acid of the oral molar dose. In one embodiment, the peak serum or plasma concentration ( _Cmax ) of the niacin analog is 15% or less of the _Cmax of the oleic acid of the oral molar dose. In one embodiment, the peak serum or plasma concentration ( _Cmax ) of the niacin analog is 10% or less of the _Cmax of the oleic acid of the oral molar dose. In one embodiment, the peak serum or plasma concentration ( _Cmax ) of the niacin analog is 5% or less of the _Cmax of the oleic acid of the oral molar dose. In one embodiment, the peak serum or plasma concentration ( _Cmax ) of the niacin analog is 1% or less of the _Cmax of the oleic acid of the oral molar dose. For each of the foregoing specific examples, it is understood that comparison is made with an immediate release formulation of niacin. Methods suitable for measuring concentrations are disclosed in detail below.

In certain embodiments, the invention relates to any of the foregoing compositions, wherein the peak serum or plasma concentration ( _Cmax ) of the compound is from 1 to 40% of the _Cmax of the oleic acid of the oral molar dose. In one embodiment, the peak serum or plasma concentration ( _Cmax ) of the compound is 1-35% of the _Cmax of the oleic acid of the oral molar dose. In one embodiment, the peak serum or plasma concentration ( _Cmax ) of the compound is from 1 to 30% of the _Cmax of the oleic acid of the oral molar dose. In one embodiment, the peak serum or plasma concentration ( _Cmax ) of the compound is 1-25% of the _Cmax of the oleic acid of the oral molar dose. In one embodiment, the peak serum or plasma concentration ( _Cmax ) of the compound is 1-20% of the _Cmax of the oleic acid of the oral molar dose. In one embodiment, the peak serum or plasma concentration ( _Cmax ) of the compound is 1-15% of the _Cmax of the oleic acid of the oral molar dose. In one embodiment, the peak serum or plasma concentration ( _Cmax ) of the compound is 1-10% of the _Cmax of the oleic acid of the oral molar dose. For each of the foregoing specific examples, it is understood that comparison is made with an immediate release formulation of niacin. Methods suitable for measuring concentrations are disclosed in detail below.

In certain embodiments, the invention relates to any of the foregoing compositions, wherein the ratio of peak serum or plasma concentration ( _Cmax ) of the nicotinic acid analog to the area under the curve at 24 hours (AUC _0-24 ) (also That is, the ratio C _max /AUC _0-24 ) is 0.35 h ^-1 or less. In one particular example, the ratio of the area under the curve (C _max / AUC _0-24) was 0.30 h ^-1 or less at the peak concentration and niacin analogs for 24 hours. In one particular example, the ratio of the area under the curve (C _max / AUC _0-24) was 0.25 h ^-1 or less at the peak concentration and niacin analogs for 24 hours. In one particular example, the ratio of the area under the curve (C _max / AUC _0-24) was 0.20 h ^-1 or less at the peak concentration and niacin analogs for 24 hours. In one particular example, the ratio of the area under the curve (C _max / AUC _0-24) was 0.15 h ^-1 or less at the peak concentration and niacin analogs for 24 hours. In one particular example, the ratio of the area under the curve (C _max / AUC _0-24) was 0.10 h ^-1 or less at the peak concentration and niacin analogs for 24 hours. In one particular example, the ratio of the area under the curve (C _max / AUC _0-24) was 0.05 h ^-1 or less at the peak concentration and niacin analogs for 24 hours. In one embodiment, the ratio of the peak concentration of the nicotinic acid analog to the area under the curve at 24 hours (Cm _ax /AUC _0-24 ) is 0.01 h ^-1 or less.

In certain instances, a ratio of about any one of the foregoing composition, wherein the area under the curve peak serum or plasma concentration of the compound (C _max) and 24 hours (AUC _0-24) of the present invention is based (i.e., the ratio of C _max /AUC _0-24 ) is 0.10 h ^-1 to 0.35 h ^-1 . In one embodiment, the ratio of the peak concentration of the compound to the area under the curve at 24 hours ( _Cmax / AUC _0-24 ) is from 0.10 h ^-1 to 0.30 h ^-1 . In one embodiment, the ratio of the peak concentration of the compound to the area under the curve at 24 hours ( _Cmax / AUC _0-24 ) is from 0.10 h ^-1 to 0.25 h ^-1 . In one embodiment, the ratio of the peak concentration of the compound to the area under the curve at 24 hours ( _Cmax / AUC _0-24 ) is from 0.10 h ^-1 to 0.20 h ^-1 .

In certain embodiments, the invention relates to any of the foregoing compositions, wherein the time ( _tmax ) at which the nicotinic acid analog reaches a peak serum or plasma concentration is in the range of 30 minutes to 5 hours. In one embodiment, the time ( _tmax ) at which the nicotinic acid analog reaches a peak concentration is in the range of 1 to 5 hours. In one embodiment, the time ( _tmax ) at which the nicotinic acid analog reaches a peak concentration is in the range of 1 to 4 hours. In one embodiment, the time ( _tmax ) at which the nicotinic acid analog reaches a peak concentration is in the range of 1 to 3 hours. In one embodiment, the time ( _tmax ) at which the nicotinic acid analog reaches a peak concentration is in the range of 1 to 2 hours.

In certain instances, any one of the preceding EC regarding composition, wherein the nicotinic acid analogs of β- mediated inhibition of protein function GPR109A ₅₀ of the present invention is based on nicotinic acid β- mediated inhibition of protein function GPR109A The EC _{50 is} at least 10 times larger. EC ₅₀ refers to the concentration at which a particular effect reaches 50% of its maximum value. Beta-arrestin-mediated GPR109A function is described elsewhere herein. In one particular example, nicotinic acid analogs of β- mediated inhibition of protein function GPR109A EC ₅₀ of niacin to ₅₀ β- least 20 times greater inhibition of protein mediated functions at GPR109A EC. In one particular example, nicotinic acid analogs of β- mediated inhibition of protein function GPR109A EC ₅₀ of niacin-mediated inhibition of β- GPR109A function of the EC ₅₀ is at least 30 times. In one particular example, nicotinic acid analogs of β- mediated inhibition of protein function GPR109A EC ₅₀ of niacin β- inhibition of ₅₀ times is at least 40 GPR109A protein mediated functions at EC. In one particular example, nicotinic acid analogs of β- mediated inhibition of protein function GPR109A EC ₅₀ of niacin inhibition of ₅₀ β- least 50 times greater protein mediated functions at GPR109A EC. In one particular example, nicotinic acid analogs of β- mediated inhibition of protein function GPR109A EC ₅₀ of niacin-mediated inhibition of β- GPR109A functions at EC ₅₀ of at least 100-fold.

In certain embodiments, the invention relates to any of the foregoing compositions, wherein the nicotinic acid analog also increases the serum or plasma content of high density lipoprotein (HDL) cholesterol when administered orally to a human. The serum or plasma content of HDL cholesterol is increased by at least a measurable amount compared to pre-treatment, baseline or control levels. For example, in one embodiment, the serum or plasma content of HDL cholesterol is increased by at least 5% compared to pre-treatment, baseline or control levels. In one embodiment, the serum or plasma content of HDL cholesterol is increased by at least 10% compared to pre-treatment, baseline or control levels. In one embodiment, the serum or plasma content of HDL cholesterol is increased by at least 15% compared to pre-treatment, baseline or control levels. In one embodiment, the serum or plasma content of HDL cholesterol is increased by at least 20% compared to pre-treatment, baseline or control levels. In one embodiment, the serum or plasma content of HDL cholesterol is increased by at least 25% compared to pre-treatment, baseline or control levels.

In certain embodiments, the present invention relates to any of the foregoing compositions, wherein the nicotinic acid analog substantially does not cause aspartate aminotransferase (AST), alanine amino group when orally administered to a human. There is any increase in serum levels of transferase (ALT) or both. In one specific example, "substantially no increase" means less than 20% increase in pre-treatment, baseline or control levels. In one specific example, "substantially no increase" means an increase of less than 10% over pre-treatment, baseline or control levels.

In certain embodiments, the invention relates to any of the foregoing compositions, wherein the nicotinic acid analog does not substantially increase the serum content of uric acid, glucose or both when administered orally to a human. The normal serum level of uric acid is 1.5-8.0 mg/dL. In one embodiment, "substantially no increase in serum level of uric acid" means an increase of less than 10% over pre-treatment, baseline or control levels. The normal fasting plasma level of glucose is about 75-115 mg/dL. The normal plasma glucose (2 hours postprandial) plasma content is about <140 mg/dL. In one embodiment, "substantially no increase in serum level of glucose" means an increase of less than 20% over pre-treatment, baseline or control levels. In one embodiment, "the serum content of glucose is substantially no increase" means an increase of less than 15% over pre-treatment, baseline or control levels. In one embodiment, "the serum content of glucose is substantially no increase" means an increase of less than 10% over pre-treatment, baseline or control levels.

In certain embodiments, the invention relates to any of the foregoing compositions, wherein the nicotinic acid analog is represented by structure I :

Wherein A is a heterocyclic or heteroaryl group optionally having 5 to 12 ring atoms including X and N, optionally substituted by 1 to 3 groups selected from the group consisting of: Base substitution: alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, halogen, nitro, cyano, sulfonic acid, alkyl thiooxy, aryl thiooxy ,heteroarylthiooxy, aralkylthiooxy, heteroaralkylthiooxy, alkenylthiooxy, alkynylthiooxy, alkylsulfonyl, arylsulfonyl, heteroaryl Sulfonyl, aralkylsulfonyl, heteroaralkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, hydroxy, alkoxy, aryloxy, heteroaryloxy, aralkyloxy , heteroaralkyloxy, alkenyloxy, alkynyloxy, thiol, alkylthio, arylthio, aralkylthio, heteroaralkylthio, alkylthio, alkynylthio, decyl, Sulfhydryl, methyl methoxy, decyloxy, methylthio, thiol, amine, alkylamine, arylamine, heteroarylamine, aralkylamine, heteroarylalkylamine, alkenylamine , alkynylamine, formamylamine, mercaptoamine, carboxyl, alkoxycarbonyl, Oxycarbonyl, heteroaryloxycarbonyl, aralkyloxycarbonyl, heteroaralkyloxycarbonyl, decylamino, alkylaminecarbonyl, arylaminecarbonyl, heteroarylaminecarbonyl, aralkylaminecarbonyl and hetero Aralkylamine carbonyl; X is O, S, N or N(R ⁶ ); Z is Or a homo-electron arrangement of carboxyl groups; X ¹ is O or S; X ² is O or S; R is hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, heterocyclyl An alkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, fused bicyclic, carboxyalkyl or arylalkenylaryl; R ² is hydrogen, lower alkyl, lower carboxy, Lower alkynyl, halogen, hydroxy, amine, carboxyl, cycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cyano or nitro; R ³ is hydrogen, lower alkyl, lower carbon alkenyl, lower alkynyl, halogen, hydroxyl, amine, carboxyl, cycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cyano or nitro; R ⁵ at each occurrence when Independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, halogen, nitro, cyano, sulfonic acid, Alkylthiooxy, arylthiooxy, heteroarylthiooxy, aralkylthiooxy, heteroaralkylthiooxy, alkenylthiooxy, alkynylthiooxy, alkylsulfonyl Base, arylsulfonyl, heteroarylsulfonyl, aralkylsulfonyl, heteroaryl Sulfosyl, alkenylsulfonyl, alkynylsulfonyl, hydroxy, alkoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, alkenyloxy, alkynyloxy , mercaptan, alkylthio, arylthio, aralkylthio, heteroaralkylthio, alkylthio, alkynylthio, decyl, decyl, methyl methoxy, decyloxy, formazan Thio group, sulfonylthio group, amine, alkylamine, arylamine, heteroarylamine, aralkylamine, heteroarylalkylamine, alkenylamine, alkynylamine, formamylamine, mercaptoamine, Carboxyl, alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, aralkoxycarbonyl, heteroaralkyloxycarbonyl, decylamino, alkylaminecarbonyl, arylaminecarbonyl, heteroarylaminecarbonyl An aralkylamine carbonyl group and a heteroarylalkylamine carbonyl group; R ⁶ is hydrogen or a lower alkyl group; and m is 1, 2, 3 or 4.

In certain embodiments, the invention relates to any of the foregoing compositions, wherein A represents a heterocyclic group.

In certain embodiments, the invention relates to any of the foregoing compositions, wherein A represents a heteroaryl group.

In certain embodiments, the invention relates to any of the foregoing compositions, wherein A is a monocyclic group having 5, 6 or 7 ring atoms.

In certain embodiments, the invention relates to any of the foregoing compositions, wherein A is a bicyclic group having 9, 10, 11 or 12 ring atoms.

In certain embodiments, the invention relates to any of the foregoing compositions, wherein X is O.

In certain embodiments, the invention relates to any of the foregoing compositions, wherein X is S.

In certain embodiments, the invention relates to any of the foregoing compositions, wherein X is N.

In certain instances, the present invention is based on any one of the aforementioned composition, wherein X is N (R ^6).

In certain embodiments, the invention relates to any of the aforementioned compositions, wherein X is N(H).

In certain embodiments, the invention relates to any one of the aforementioned compositions, wherein A is pyrrolidinyl, imidazolidinyl, thiazolidinyl, isothiazolidinyl, Azolidinyl, Diazolidinyl, piperidinyl, piperid Base, thiomorpholinyl or morpholinyl.

In certain embodiments, the invention relates to any one of the aforementioned compositions, wherein A is imidazolyl, pyrazolyl, isomeric Azolyl, Azyl, isothiazolyl, thiazolyl, Base, furfuryl, Diazolyl, thiadiazolyl, triazolyl, dithiazolyl, di base, Base Base, three Base, four Base, diazepine or thiazolidine.

In certain embodiments, the invention relates to any one of the preceding compositions, wherein A is substituted with from 1 to 3 substituents independently selected from the group consisting of lower alkyl, halo, nitro , cyano, sulfonic acid, hydroxy, alkoxy, thiol, alkylthio, decyl, decyl, methyl methoxy, decyloxy, methylthio, thiol, amine, alkylamine , mercaptoamine, mercaptoamine and carboxyl.

In certain embodiments, the invention relates to any one of the preceding compositions, wherein A is substituted with one substituent independently selected from the group consisting of lower alkyl, halo, nitro, cyanide Base, sulfonic acid, hydroxy, alkoxy, thiol, alkylthio, decyl, decyl, methyl methoxy, decyloxy, methylthio, thiol, amine, alkylamine, A Mercaptoamine, mercaptoamine and carboxyl.

In certain embodiments, the invention relates to any of the foregoing compositions, wherein A is unsubstituted.

In certain embodiments, the invention relates to any of the aforementioned compositions, wherein R ² is hydrogen or lower alkyl.

In certain embodiments, the invention relates to any one of the aforementioned compositions, wherein R ² is hydrogen.

In certain instances, the present invention relates to any one of the aforementioned composition, wherein R ³ is hydrogen or lower alkyl.

In certain instances, the present invention relates to any one of the aforementioned composition, wherein R ³ is hydrogen.

In certain embodiments, the invention relates to any one of the aforementioned compositions, wherein R ² is hydrogen; and R ³ is lower alkyl.

In certain embodiments, the invention relates to any one of the aforementioned compositions, wherein R ² is lower alkyl; and R ³ is hydrogen.

In certain embodiments, the invention relates to any one of the aforementioned compositions, wherein R ² is hydrogen; and R ³ is hydrogen.

In certain embodiments, the invention relates to any of the foregoing compositions, wherein m is one.

In certain embodiments, the invention relates to any of the foregoing compositions, wherein m is 2.

In certain embodiments, the invention relates to any of the foregoing compositions, wherein m is 3.

In certain embodiments, the invention relates to any of the foregoing compositions, wherein m is 4.

In certain embodiments, the invention relates to any one of the aforementioned compositions, wherein each occurrence of R ⁵ is independently selected from the group consisting of hydrogen, lower alkyl, halogen, nitro, cyanide Base, sulfonic acid, hydroxy, alkoxy, thiol, alkylthio, decyl, decyl, methyl methoxy, decyloxy, methylthio, thiol, amine, alkylamine, A Mercaptoamine, mercaptoamine and carboxyl.

In certain instances, the present invention relates to any one of the aforementioned composition, wherein R ⁵ is hydrogen.

In certain embodiments, the invention relates to any of the foregoing compositions, wherein Z is a carboxyl group.

In certain embodiments, the invention relates to any of the foregoing compositions, wherein Z is a carboxy-isomeric alignment.

In certain embodiments, the invention relates to any one of the aforementioned compositions, wherein Z is tetrazolyl, Zyridinone, sulfonic acid, sulfinic acid, decylsulfonamide, phosphonic acid, phosphinic acid, beta-urea, pyrrolidone, 3-iso Azolyl or boric acid.

In certain embodiments, the invention relates to any of the foregoing compositions, wherein Z is .

In certain embodiments, the invention relates to any of the aforementioned compositions, wherein X ¹ is O.

In certain embodiments, the invention relates to any of the foregoing compositions, wherein X ¹ is S.

In certain embodiments, the invention relates to any of the aforementioned compositions, wherein X ² is O.

In certain embodiments, the invention relates to any of the aforementioned compositions, wherein X ² is S.

In certain embodiments, the invention relates to any one of the aforementioned compositions, wherein X ¹ is O; and X ² is O.

In certain embodiments, the invention relates to any of the foregoing compositions, wherein R is lower alkyl.

In certain embodiments, the invention relates to any of the foregoing compositions, wherein R is hydrogen.

In certain embodiments, the invention relates to any one of the aforementioned compositions, wherein R is

In certain embodiments, the invention relates to any of the foregoing compositions, wherein R represents an aliphatic group which can be hydrolyzed to a carboxyl group under physiological conditions.

In some embodiments, the invention relates to any one of the aforementioned compositions, wherein the nicotinic acid analog is a compound represented by structure II or a pharmaceutically acceptable salt thereof,

Wherein, at each occurrence, independently, W is a polyol or a polythiol; p is from 2 to 500, including 2 and 500; R ¹ is And attached to the polyhydric alcohol via a oxygen atom of the polyol or via a sulfur atom of the polythiol; A is a heterocyclic ring containing 5 to 12 ring atoms including X and N Or a heteroaryl group, which is optionally substituted with from 1 to 3 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, Heteroarylalkyl, halogen, nitro, cyano, sulfonic acid, alkylthiooxy, arylthiooxy, heteroarylthiooxy, aralkylthiooxy, heteroaralkylthiol, Alkenylthiooxy, alkynylthiooxy, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aralkylsulfonyl, heteroaralkylsulfonyl, alkenylsulfonyl , alkynylsulfonyl, hydroxy, alkoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, alkenyloxy, alkynyloxy, thiol, alkylthio, aromatic Thiothio, aralkylthio, heteroaralkylthio, alkylthio, alkynylthio, decyl, decyl, methyloxy, decyloxy, methylthio, thiol, amine, Alkylamine, arylamine, heteroarylamine, aralkyl , heteroarylalkylamine, alkenylamine, alkynylamine, formylamine, mercaptoamine, carboxyl, alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, aralkoxycarbonyl, heteroaryl Alkoxycarbonyl, decylamino, alkylaminecarbonyl, arylaminecarbonyl, heteroarylaminecarbonyl, aralkylaminecarbonyl and heteroaralkylaminecarbonyl; X is O, S, N or N (R ⁶ X ¹ is O or S; R is hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl , heteroarylalkyl, fused bicyclic, carboxyalkyl or arylalkenylaryl; R ² is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, halogen, hydroxy, amine, carboxy, a cycloalkyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, cyano or nitro group; R ³ is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, halogen, hydroxy, An amine, a carboxyl group, a cycloalkyl group, an aryl group, a heteroaryl group, an aralkyl group, a heteroarylalkyl group, a cyano group or a nitro group; each occurrence of R ⁵ is independently selected from the group consisting of hydrogen: , alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl Heteroarylalkyl, halogen, nitro, cyano, sulfonic acid, alkylthiooxy, arylthiooxy, heteroarylthiooxy, aralkylthiooxy, heteroaralkylthiol, Alkenylthiooxy, alkynylthiooxy, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aralkylsulfonyl, heteroaralkylsulfonyl, alkenylsulfonyl , alkynylsulfonyl, hydroxy, alkoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, alkenyloxy, alkynyloxy, thiol, alkylthio, aromatic Thiothio, aralkylthio, heteroaralkylthio, alkylthio, alkynylthio, decyl, decyl, methyloxy, decyloxy, methylthio, thiol, amine, Alkylamine, arylamine, heteroarylamine, aralkylamine, heteroarylalkylamine, alkenylamine, alkynylamine, formamylamine, mercaptoamine, carboxyl, alkoxycarbonyl, aryloxy Alkylcarbonyl, heteroaryloxycarbonyl, aralkoxycarbonyl, heteroaralkyloxycarbonyl, decylamino, alkylaminecarbonyl, arylaminecarbonyl, heteroarylaminecarbonyl, aralkylaminecarbonyl and heteroaryl alkylamine carbonyl group; R ⁶ is hydrogen or lower alkyl; and m is 1, 2 4.

In certain embodiments, the invention relates to any of the foregoing compositions, wherein W is a polythiol.

In certain embodiments, the invention relates to any of the foregoing compositions, wherein W is a polyol.

In certain embodiments, the invention relates to any of the foregoing compositions, wherein the polyol is a carbohydrate.

In certain embodiments, the invention relates to any of the foregoing compositions, wherein the polyol is maltitol, sorbitol, xylitol or isomalt.

In certain embodiments, the invention relates to any of the foregoing compositions, wherein the polyol is sorbitol.

In certain embodiments, the invention relates to any of the foregoing compositions, wherein the polyol is inositol.

In certain embodiments, the invention relates to any of the foregoing compositions, wherein p is 2, 3, 4, 5 or 6.

In certain embodiments, the invention relates to any of the foregoing compositions, wherein p is 2-100, including 2 and 100. In certain embodiments, the invention is directed to any of the foregoing compositions, wherein p is from 2 to 50, including 2 and 50. In certain embodiments, the invention is directed to any of the foregoing compositions, wherein p is 2-10, including 2 and 10.

In certain embodiments, the invention relates to any of the foregoing compositions, wherein p is 2. In certain embodiments, the invention relates to any of the foregoing compositions, wherein p is 3. In certain embodiments, the invention relates to any of the foregoing compositions, wherein p is 4. In certain embodiments, the invention relates to any of the foregoing compositions, wherein p is 5. In certain embodiments, the invention relates to any of the foregoing compositions, wherein p is 6.

In another aspect, the agents of the invention may be administered as such or in a mixture with a pharmaceutically acceptable carrier, and may also be administered in combination with other agents. Combination therapies thus include the sequential, simultaneous, and separate or co-administration of one or more compounds of the invention wherein the therapeutic effect of the first agent has not completely disappeared upon administration of the subsequent compound. In other words, the term "co-administration/co-administering" as used herein refers to simultaneous administration (simultaneous administration of two or more therapeutic agents) and simultaneous administration (in combination with administration) The therapeutic agent may be administered to the patient at a different time, as long as the therapeutic agent is present in the patient at a different time.

As described in detail below, the pharmaceutical compositions of the present invention may be specially formulated to be administered in solid or liquid form, including those suitable for: (1) oral administration, such as a potting agent (aqueous or non-aqueous solution or Suspensions, lozenges, for example, lozenges targeted for buccal, sublingual, and systemic absorption, capsules, boluses, powders, granules, pastes applied to the tongue; (2) parenteral administration, For example, by intravenous, intramuscular, intraperitoneal, subcutaneous or intradural injection or infusion, for example in the form of a sterile solution or suspension or a sustained release formulation; (3) topical application, for example, as a cream or ointment applied to the skin. Or controlled release patch or spray form; (4) intravaginal or rectal administration, for example in the form of a pessary, cream or foam; (5) sublingual administration; (6) administration via the eye; (7) transdermal administration; (8) nasal administration; (9) administration via the lung; or (10) intrathecal administration.

The term "therapeutically effective amount" as used herein means the amount of a compound, substance or composition comprising a compound of the invention in at least a cell of an animal at a reasonable benefit/risk ratio applicable to any medical treatment. The subgroup effectively produces some of the desired therapeutic effects.

"Pharmaceutically acceptable" as used herein to mean that a compound, substance, composition and/or dosage form is suitable for use in contact with human and animal tissues without reasonable toxicity and irritation in the context of sound medical judgment. , an allergic reaction or other problem or complication, in accordance with a reasonable benefit/hazard ratio.

As used herein, the term "pharmaceutically-acceptable carrier" means a pharmaceutically acceptable substance, composition or vehicle, such as a liquid or solid filler, diluent, Agent, manufacturing aid (such as lubricant, talc, calcium stearate or zinc stearate or stearic acid) or solvent encapsulating material, involving carrying or transporting a compound of the invention from one organ or part of the body to another An organ or part of the body. Each carrier must be "acceptable", meaning that it is compatible with the other ingredients of the formulation and does not harm the patient. Some examples of materials that can serve as pharmaceutically acceptable carriers include: (1) sugars such as lactose, glucose, and sucrose; (2) starches such as corn starch and potato starch; (3) cellulose and its derivatives , such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, Such as cocoa butter and suppository wax; (9) oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols such as propylene glycol; (11) polyols, such as Glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers such as magnesium hydroxide and aluminum hydroxide (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethanol; (20) pH buffer solution; (21) polyester, polycarbonate and/or polyanhydride; and (22) other non-toxic compatible materials used in pharmaceutical formulations.

As mentioned above, certain specific examples of the compounds of the invention may contain basic functional groups, such as amine or alkylamine groups, and are therefore capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable acids. The term "pharmaceutically-acceptable salt" as used herein, refers to relatively non-toxic, inorganic and organic acid addition salts of the compounds of this invention. Such salts may be prepared on the spot during the manufacture of the vehicle or dosage form, or by separately reacting the pure compound of the invention in a free base form with a suitable organic or inorganic acid and isolating during subsequent purification. Salt is prepared. Representative salts include hydrobromide, hydrochloride, sulfate, hydrogen sulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, Benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, nail Sulfonic acid salts, glucoheptonates, galactoates, and lauryl sulfonates and the like. See, for example, Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci . 66: 1-19.

The pharmaceutically acceptable salts of the compounds of the invention include the conventional non-toxic salts or quaternary ammonium salts of such compounds, for example those formed from non-toxic organic or inorganic acids. For example, such conventional non-toxic salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, aminosulfonic acid, phosphoric acid, nitric acid, and the like; and from organic acids. a salt to be prepared, such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxybutene Ammonium diamine, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, p-aminobenzenesulfonic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, B Alkanedisulfonic acid, oxalic acid, isosulfuric acid and the like.

In other instances, the compounds of the invention may contain one or more acidic functional groups and are therefore capable of forming a pharmaceutically acceptable salt with a pharmaceutically acceptable base. The term "pharmaceutically acceptable salts" in this context refers to the relatively non-toxic, inorganic and organic base addition salts of the compounds of this invention. These salts can likewise be prepared on the spot during the manufacture of the vehicle or dosage form, or by separately reacting the pure compound in free acid form with a suitable base such as a hydroxide of a pharmaceutically acceptable metal cation. Prepared by reacting with a carbonate, or bicarbonate, ammonia or a pharmaceutically acceptable organic primary, secondary or tertiary amine. Representative alkali or alkaline earth metal salts include lithium, sodium, potassium, calcium, magnesium and aluminum salts and the like. Representative organic amines suitable for use in the formation of base addition salts include ethylamine, diethylamine, ethylidene diamine, ethanolamine, diethanolamine, piperazine And its analogues. (See, for example, Berge et al., supra)

Wetting agents, emulsifiers and lubricants (such as sodium lauryl sulfate and magnesium stearate) as well as coloring agents, release agents, coating agents, sweeteners, flavoring and fragrances, preservatives and antioxidants may also be present In the composition.

Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants such as ascorbic acid, cysteamine hydrochloride, sodium hydrogen sulfate, sodium metabisulfite, sodium sulfite, and the like; (2) Oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxymethoxybenzene (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol and the like; And (3) a metal chelating agent such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

Formulations of the invention include formulations suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal and/or parenteral administration. Formulations are conveniently presented in unit dosage form and may be prepared by any methods known in the art of pharmacy. The amount of active ingredient which may be combined with the carrier materials to produce a single dosage form will vary depending upon the host being treated and the particular mode of administration. The amount of active ingredient which may be combined with the carrier materials to produce a single dosage form will generally be such that the compound will produce a therapeutic effect. The amount will generally range from about 0.1% to about 99% active ingredient, preferably from about 5% to about 70%, most preferably from about 10% to about 30%, based on 100%.

In certain embodiments, the formulations of the invention comprise an excipient selected from the group consisting of cyclodextrins, cellulose, liposomes, micromicelle formers (eg, cholic acid), and polymeric carriers. (e.g., polyesters and polyanhydrides); and the compounds of the invention. In certain embodiments, the foregoing formulations allow the compounds of the invention to be utilized as a living organism.

Methods of preparing such formulations or compositions include the step of bringing into association a compound of the invention with a carrier and optionally one or more accessory ingredients. Formulations are generally prepared by uniformly and intimately bringing into association a compound of the present invention with a liquid carrier or a finely divided solid carrier or both, and, if necessary, shaping the product.

Formulations of the invention suitable for oral administration may be in the form of capsules, cachets, pills, troches, lozenges (using a flavoring base, usually sucrose and gum arabic or tragacanth), powders, granules, Or in the form of a solution or suspension in an aqueous or non-aqueous liquid, in the form of an oil-in-water or water-in-oil liquid emulsion, or in the form of an elixir or syrup, or in the form of a tablet (using an inert matrix) For example, gelatin and glycerin, or sucrose and gum arabic, and/or in the form of mouthwashes and the like, each containing a predetermined amount of a compound of the invention as an active ingredient. The compounds of the invention may also be administered in the form of a bolus, elixirs or paste.

In the solid dosage form (capsules, lozenges, pills, dragees, powders, granules, buccal tablets and the like) for oral administration of the present invention, the active ingredient is one or more pharmaceutically acceptable a carrier such as sodium citrate or dibasic calcium phosphate and/or any combination of the following: (1) a filler or extender such as starch, lactose, sucrose, glucose, mannitol and/or citric acid; a binder such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and/or gum arabic; (3) a humectant such as glycerin; (4) a disintegrant such as agar, carbonic acid Calcium, potato or tapioca starch, alginic acid, certain citrates and sodium carbonate; (5) dissolution delaying agents, such as paraffin wax; (6) absorption enhancers, such as quaternary ammonium compounds and surfactants, such as poloxa (poloxamer) and sodium lauryl sulfate; (7) wetting agents such as cetyl alcohol, glyceryl monostearate and nonionic surfactants; (8) absorbents such as kaolin and bentonite; (9) Lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, lauryl Sodium, zinc stearate, sodium stearate, stearic acid and mixtures thereof; (10) a colorant; and (11) a controlled release agent, such as cross-linked povidone (crospovidone) or ethyl cellulose. In the case of capsules, lozenges and pills, the pharmaceutical compositions may also contain buffering agents. In soft shell and hard shell gelatin capsules using excipients such as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like, solid compositions of a similar type may also be employed as fillers.

Tablets can be prepared by compression or molding, as appropriate, with one or more accessory ingredients. Compressed tablets may use a binder (such as gelatin or hydroxypropyl methylcellulose), a lubricant, an inert diluent, a preservative, a disintegrant (such as sodium carboxymethyl starch or croscarmellose sodium), Surface active or dispersant preparation. Molded lozenges can be prepared by molding in a suitable machine a mixture of a wet powder compound and an inert liquid diluent.

Tablets of the pharmaceutical compositions of the present invention and other solid dosage forms such as sugar-coated pills, capsules, pills, and granules may optionally be scored or coated with other coatings such as enteric coatings and pharmaceutical formulation techniques. preparation. It may also be formulated with, for example, hydroxypropyl methylcellulose, other polymeric matrices, liposomes and/or microspheres in varying proportions to provide the desired release profile to slow or control release of the active ingredient therein. It can be formulated for quick release, such as freeze drying. It can be sterilized by, for example, filtration through a bacterial retention filter or by incorporation of a bactericidal agent in the form of a sterile solid composition that can be dissolved in sterile water or some other sterile injectable medium immediately prior to use. Such compositions may also contain opacifying agents, as appropriate, and may, in a delayed manner, only or preferentially release the active ingredient in a portion of the gastrointestinal tract. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient may also be in microencapsulated form with one or more of the above-mentioned excipients, as appropriate.

Liquid dosage forms for oral administration of the compounds of the invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage form may contain inert diluents such as water or other solvents commonly employed in the art; solubilizers and emulsifiers such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, Benzoyl benzoate, propylene glycol, 1,3-butanediol, oils (especially cottonseed oil, groundnut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerin, tetrahydrofuryl alcohol , fatty acid esters of polyethylene glycol and sorbitan and mixtures thereof.

Besides the inert diluent, the oral composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents, coloring agents, perfuming agents, and preservatives.

In addition to the active compound, the suspension may also contain suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, expanded soil, agar And tragacanth and its mixture.

The formulation of the pharmaceutical composition of the present invention for rectal or vaginal administration may be in the form of a suppository by mixing one or more compounds of the present invention with one or more suitable non-irritating excipients or carriers (including, for example It is prepared from cocoa butter, polyethylene glycol, suppository wax or salicylate, and is solid at room temperature, but liquid at body temperature, and thus will melt and release the active compound in the rectum or vaginal cavity.

Formulations of the invention suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing suitable carriers known in the art. Things.

Dosage forms for topical or transdermal administration of a compound of the invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound can be mixed under sterile conditions with apharmaceutically acceptable carrier and any preservative, buffer or propellant which may be required.

Ointments, pastes, creams and gels may contain excipients, such as animal and vegetable fats, oils, waxes, waxes, starches, tragacanth, cellulose derivatives, poly, in addition to the active compounds of the present invention. Ethylene glycol, polyfluorene oxide, bentonite, citric acid, talc, and zinc oxide or a mixture thereof.

Powders and sprays can contain, in addition to a compound of the invention, excipients such as lactose, talc, decanoic acid, aluminum hydroxide, calcium citrate and polyamide powder or mixtures thereof. Sprays may additionally contain conventional propellants such as chlorofluorocarbons; and volatile unsubstituted hydrocarbons such as butane and propane.

Transdermal patches have the added advantage of providing controlled delivery of the compounds of the invention to the body. Such dosage forms can be prepared by dissolving or dispersing the compound in a suitable medium. Absorption enhancers can also be used to increase the flux of the compound throughout the skin. The rate of flow can be controlled by providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

Ophthalmic formulations, ophthalmic ointments, powders, solutions and the like are also encompassed within the scope of the invention.

The pharmaceutical composition of the present invention suitable for parenteral administration comprises one or more compounds of the invention and one or more of the sugars, alcohols, antioxidants, buffers, bacteriostatic agents, blood of the formulation and the intended recipient, etc. A pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solution, dispersion, suspension or emulsion of a solute or suspending or thickening agent or a sterile powder which can be reconstituted into a sterile injectable solution or dispersion before use. combination.

Examples of suitable aqueous and non-aqueous vehicles which may be employed in the pharmaceutical compositions of the present invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like) and suitable mixtures thereof; vegetable oils, such as Olive oil; and injectable organic esters such as ethyl oleate. The proper fluidity can be maintained, for example, by the use of a coating material such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.

These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms on the compounds of the present invention can be ensured by including various antibacterial or antifungal agents (e.g., parabens, chlorobutanol, phenol sorbic acid, and the like). It is also desirable to include an isotonic agent such as sugar, sodium chloride, and the like in the composition. In addition, prolonged absorption of the injectable pharmaceutical form can be brought about by the inclusion of a delayed absorbent such as aluminum monostearate and gelatin.

In some cases, in order to prolong the effect of the drug, it is desirable to slow the absorption of the drug by subcutaneous or intramuscular injection. This result can be achieved by using a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug depends on its rate of dissolution, which in turn depends on the crystal size and crystalline form. Alternatively, delayed absorption of the parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.

Injectable long-acting forms are prepared by forming a microcapsule matrix of a compound of the invention in a biodegradable polymer such as polylactide-polyglycolide. The rate of drug release can be controlled by the ratio of drug to polymer and the nature of the particular polymer employed. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Long acting injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.

When the compound of the present invention is administered to humans and animals as a medicine, it may be administered by itself or in the form of a pharmaceutical composition containing, for example, 0.1 to 99% (more preferably 10 to 30%) of the active ingredient in combination with a pharmaceutically acceptable carrier. give.

The formulations of the invention may be administered orally, parenterally, topically or rectally. It is of course given in a form suitable for each route of administration. For example, it is administered in the form of a tablet or capsule, by injection, inhalation, eye wash, ointment, suppository, by injection, infusion or inhalation; topically by lotion or ointment; and by suppository Rectal administration.

As used herein, the term "parenteral administration/administered parenterally" means a mode of administration other than enteral and topical administration, usually by injection, and includes but is not limited to intravenous , intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, intratracheal, subcutaneous, subepidermal, intra-articular, subcapsular, subarachnoid, intraspinal and Intrasternal injection and infusion.

As used herein, the terms "systemic administration/administered systemically" and "peripheral administration/administered peripherally" mean the addition of compounds, drugs or other substances directly to the central nervous system. To allow it to enter the patient's system, and thus undergo metabolic and other similar processes, such as subcutaneous administration.

The compound can be administered to humans and other animals for treatment by any suitable route of administration, including oral, nasal (in the form of, for example, a spray), rectal, intrathecal, parenteral, intracellular, and topical (eg, as a powder). , ointment or drops), including buccal and sublingual.

The compound of the present invention and/or the pharmaceutical composition of the present invention which can be used in a suitable hydrated form is formulated into a pharmaceutically acceptable dosage form by conventional methods known to those skilled in the art, regardless of the route of administration selected.

The actual dosage of the active ingredient in the pharmaceutical compositions of the present invention can be varied to achieve an amount of active ingredient that is effective for a particular patient, composition, and mode of administration to achieve a desired therapeutic response without toxicity to the patient.

The selected dosage will depend on a number of factors, including the activity of the particular compound of the invention or its ester, salt or guanamine, the route of administration, the time of administration, the rate of secretion or metabolism of the particular compound employed, the rate of absorption, and Degree, duration of treatment, other drugs, compounds and/or substances used in combination with the particular compound employed, age, sex, weight, condition, general health and prior medical history of the patient being treated, and similar factors well known in the medical field .

An effective amount of the desired pharmaceutical composition can be readily determined and prescribed by a physician or veterinarian skilled in the art. For example, a physician or veterinarian can dose less than the amount of the compound of the invention employed in the starting pharmaceutical composition to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.

A suitable daily dose of a compound of the invention will generally be the amount of the compound which is the lowest dose effective to produce a therapeutic effect. The effective dose will generally depend on the above factors. The oral, intravenous, intraventricular, and subcutaneous doses of the compounds of the invention for use in a patient will generally range from about 0.0001 mg to about 100 mg per kilogram of body weight per day when used to achieve an indicated effect.

The invention specifically encompasses oral administration in humans. Oral administration to an adult is typically from about 0.05 g (50 mg) to 10 g per day, administered in a single dose or in divided doses. In one embodiment, oral administration to an adult is from about 0.5 g (500 mg) to 10 g per day, administered in a single dose or in divided doses. In one embodiment, oral administration to an adult is from about 0.5 g to 8 g per day, administered in a single dose or in divided doses. In one embodiment, oral administration to an adult is from about 0.5 g to 6 g per day, administered in a single dose or in divided doses. In one embodiment, oral administration to an adult is from about 0.5 g to 4 g per day, administered in a single dose or in divided doses. In one embodiment, oral administration to an adult is from about 0.5 g to 2 g per day, administered in a single dose or in divided doses. In one embodiment, oral administration to an adult is from about 0.5 g to 1 g per day, administered in a single dose or in divided doses.

If necessary, an effective daily dose of the active compound may be administered in divided doses in divided doses of 2, 3, 4, 5, 6 or more times at appropriate intervals throughout the day, as appropriate, in unit dosage form. An exemplary administration is once a day.

Although the compound of the present invention can be administered alone, it is preferred to administer the compound in the form of a pharmaceutical formulation (composition).

The compounds of the invention may be formulated for administration in any manner convenient for human or veterinary use by other pharmaceuticals.

In another aspect, the invention provides a pharmaceutically acceptable composition comprising a therapeutically effective amount of one or more of the compounds of the invention and one or more pharmaceutically acceptable carriers (additives) as described above. And / or thinner blended together. As described in detail below, the pharmaceutical compositions of the present invention may be specially formulated to be suitable for administration in solid or liquid form, including those suitable for: (1) oral administration, such as administration (aqueous or non-aqueous solutions or Suspensions, lozenges, boluses, powders, granules, pastes applied to the tongue; (2) parenteral administration, for example, subcutaneous, intramuscular or intravenous injection, for example in the form of a sterile solution or suspension (3) topical application, for example in the form of a cream, ointment or spray applied to the skin, lungs or mucous membranes; or (4) in the sheath or in the rectum, for example in the form of a pessary, cream or foam; 5) sublingual or buccal; (6) transocular; (7) percutaneous; or (8) nasal.

The patient receiving the treatment is any animal in need, generally including primates, especially humans, and other mammals such as horses, cows, pigs and sheep; and poultry and pets.

The compounds of the invention may be administered as such or in a mixture with a pharmaceutically acceptable carrier, and may also be administered in combination with at least one other active compound. Combination therapies thus include sequential, simultaneous and separate administration of the active compound in a manner that is administered to the subsequent ones when the therapeutic effect of the first responder has not completely disappeared.

Micro micelles. Microemulsification technology improves the bioavailability of some lipophilic (water insoluble) pharmaceutical agents. Examples include Trimetrine (Dordunoo, SK et al, Drug Development and Industrial Pharmacy, 17 (12), 1685-1713, 1991) and REV 5901 (Sheen, PC et al, J Pharm Sci 80 (7), 712-714, 1991 ). Microemulsification, especially by preferentially guiding the lymphatic system rather than the circulatory system, thereby bypassing the liver provides enhanced bioavailability and prevents the compound from being destroyed in the hepatobiliary circulation.

While encompassing all suitable amphiphilic vehicle carriers, exemplary carriers are generally in a generally-recognized-as-safe (GRAS) state and are soluble in the compounds of the invention and as a solution with complex water (such as A carrier which is microemulsified at a later stage when it is contacted by the aqueous phase visible in the human gastrointestinal tract. Typically, the two parental components that meet these requirements have an HLB (hydrophilic and lipophilic balance) value of 2-20 and a structure containing a linear aliphatic group in the range of C-6 to C-20. Examples are polyethylene-glycolated fatty acid glycerides and polyethylene glycols.

In particular, it covers commercially available amphiphilic carriers, including the Gelucire series, Labrafil, Labrasol or Lauroglycol (all manufactured and distributed by Gattefosse Corporation, Saint Priest, France), PEG-monooleate, PEG-dioleate, PEG-monolaurate and dilaurate, lecithin, polysorbate 80, etc. (produced and distributed by USA and many companies worldwide).

polymer. Hydrophilic polymers suitable for use in the present invention are those which are readily water soluble, are covalently attachable to lipids which form vesicles, and are tolerated in vivo without toxic effects (i.e., biocompatible). Suitable polymers include polyethylene glycol (PEG), polylactic acid (also known as polylactide), polyglycolic acid (also known as polyglycolide), polylactic acid-polyglycolic acid copolymer And polyvinyl alcohol. Exemplary polymers are polymers having a molecular weight of from about 100 or 120 Daltons to about 5,000 or 10,000 Daltons and more preferably from about 300 Daltons to about 5,000 Daltons. In one embodiment, the polymer is a polyethylene glycol having a molecular weight of from about 100 to about 5,000 Daltons and more preferably from about 300 to about 5,000 Daltons. In one embodiment, the polymer is 750 Dalton polyethylene glycol (PEG (750)). The polymer may also be defined by the number of monomers therein; one embodiment of the invention utilizes a polymer of at least about three monomers, such as a PEG polymer (about 150 Daltons) composed of three monomers.

Other hydrophilic polymers that may be suitable for use in the present invention include polyvinylpyrrolidone, polymethyl Oxazoline, polyethyl Oxazoline, polyhydroxypropylmethacrylamide, polymethacrylamide, polydimethylacrylamide, and derivatized cellulose such as hydroxymethylcellulose or hydroxyethylcellulose.

In certain embodiments, the formulations of the present invention comprise a biocompatible polymer selected from the group consisting of polyamines, polycarbonates, polyalkylenes, acrylates, and methacrylates. Polymers, polyethylene polymers, polyglycolides, polyoxyalkylenes, polyurethanes and copolymers thereof, polymers of cellulose, polypropylene, polyethylene, polystyrene, lactic acid and glycolic acid, Polyanhydride, poly(orthoacid) ester, poly(butyric acid), poly(valeric acid), poly(lactide-co-caprolactone), polysaccharide, protein, polyhyaluronic acid, polycyanoacrylate and their blending , a mixture or a copolymer.

Cyclodextrin. Cyclodextrin is a cyclic oligosaccharide consisting of 6, 7 or 8 glucose units, named by the Greek letters α, β and γ, respectively. The glucose unit is linked by an alpha-1,4-glycosidic bond. Due to the chair configuration of the sugar unit, all of the secondary hydroxyl groups (at C-2, C-3) are on one side of the ring, while all of the hydroxyl groups at the C-6 are located on the other side. Therefore, the outer surface is hydrophilic, making the cyclodextrin water soluble. In contrast, the cyclodextrin cavity is hydrophobic because it is lined by C-3 and C-5 hydrogen atoms and ether-like oxygen. Such matrices allow for mismatching with a variety of relatively hydrophobic compounds, including, for example, steroid compounds such as 17-beta-estradiol (see, for example, van Uden et al, Plant Cell Tiss. Org. Cult. 38:1-3-113 ( 1994)). This misalignment occurs by the interaction of Van der Waals and hydrogen bond formation. For a review of the chemistry of cyclodextrins, see Wenz, Agnew. Chem. Int. Ed. Engl., 33: 803-822 (1994).

The physicochemical properties of cyclodextrin derivatives depend closely on the type and extent of substitution. For example, its solubility in water ranges from insoluble (eg, triethylsulfonyl-beta-cyclodextrin) to 147% soluble (w/v) (G-2-beta-cyclodextrin). In addition, it is soluble in many organic solvents. The nature of the cyclodextrin can be controlled by increasing or decreasing the solubility of the various formulation components.

A number of cyclodextrins and methods for their preparation have been described. For example, Parmeter (I), et al. (U.S. Patent No. 3,453,259, incorporated herein by reference), and the entire disclosure of U.S. Patent No. 3,459,731, the disclosure of fine. Other derivatives include cyclodextrins having cationic properties (Parmeter (II), U.S. Patent No. 3,453,257; incorporated herein by reference), in the in in in in in in in in in in in in in in in in in in in in in in in in in in in in in in in in in in in in Incorporated herein) and cyclodextrin having anionic properties (Parmeter (III), U.S. Patent No. 3,426,011; herein incorporated by reference). Among the cyclodextrin derivatives having anionic properties, carboxylic acid, phosphorous acid, phosphinous acid, phosphonic acid, phosphoric acid, thiophosphonic acid, thiosulphinic acid and sulfonic acid have been used. Attached to the parent cyclodextrin (see Parmeter (III), supra). In addition, sulfoalkyl ether cyclodextrin derivatives have been described by Stella et al. (U.S. Patent No. 5,134,127; incorporated herein by reference).

Liposomes . The liposome consists of at least one lipid bilayer membrane enclosed in an aqueous internal compartment. Liposomes can be characterized by membrane type and size. A single layer of small vesicles (SUV) has a single membrane and typically has a diameter between 0.02 and 0.05 [mu]m; a single layer of large vesicles (LUVS) is typically greater than 0.05 [mu]m. The oligo-layered large vesicles and multi-layered vesicles have a plurality of, typically concentric, layers, and are typically greater than 0.1 [mu]m. Liposomes with several non-concentric membranes, that is, larger vesicles contain several smaller vesicles called polylipid granules.

One aspect of the invention pertains to formulations comprising liposomes comprising a compound of the invention wherein the liposomal membrane is formulated to provide liposomes with increased load carrying capacity. Alternatively or additionally, the compounds of the invention may be contained within or adsorbed to the liposomes of the liposomes. The compounds of the invention may be aggregated with the lipid surfactant and carried within the interior of the liposome; in such cases, the liposomal membrane is formulated to resist the destructive effects of the active agent-surfactant aggregate.

According to an embodiment of the present invention, the lipid bilayer of the liposome contains a polyethylene glycol (PEG)-derived lipid such that the PEG chain extends from the inner surface of the lipid bilayer into the inner space of the liposome encapsulation, and Extending from the outside of the lipid bilayer to the surrounding environment.

The active agent contained in the liposome of the present invention is in a dissolved form. Aggregates of surfactant and active agent, such as emulsions or micromicelles containing the relevant active agent, can be trapped within the interior space of the liposomes of the present invention. The surfactant is used to disperse and dissolve the active agent, and may be selected from any suitable aliphatic, cycloaliphatic or aromatic surfactant, including but not limited to biological phases having different chain lengths (eg, from about C14 to about C20). Capacitive lysophosphatidylcholine (LPC). Micromicelle formation can also be performed using polymer-derived lipids such as PEG-lipids as it will be used to inhibit micromicelle/membrane fusion and reduce the criticality of surfactants by adding polymers to the surfactant molecules Micromicelle concentration (CMC) and contribute to micromicelle formation. Examples are surfactants containing CMC in the micromolar concentration range; microcelles trapped in the liposomes of the invention can be prepared using higher CMC surfactants, whereas micromicelle surfactant monomers can affect the liposomal bilayer Stability and will be a factor in designing liposomes with desirable stability.

Liposomes suitable for use in the present invention can be prepared by any of a variety of techniques known in the art. See, e.g., U.S. Patent No. 4,235,871; PCT Published Application WO 96/14057; New RRC, Liposomes: A practical approach, IRL Press, Oxford (1990), pp. 33-104; Lasic DD, Liposomes from physics to applications, Elsevier Science Publishers BV, Amsterdam, 1993.

For example, liposomes suitable for use in the present invention can be prepared by diffusing a lipid derivatized with a hydrophilic polymer into a preformed liposome, such as by exposing the preformed liposome to a lipid-containing graft polymer. The micromicelle, lipid concentration corresponds to the final molar percentage of the desired derivatized lipid in the liposome. Liposomes containing a hydrophilic polymer can also be formed by homogenization, lipid field hydration or extrusion techniques known in the art.

In one aspect of the invention, the liposomes have a substantially homogeneous size within a selected size range. One effective screening method involves extruding an aqueous suspension of liposomes via a series of polycarbonate membranes having a selected uniform pore size; the pore size of the membrane will generally be consistent with the largest dimension of liposomes produced by extrusion through the membrane. See, e.g., U.S. Patent No. 4,737,323.

Release the modifier. The release profile of the formulations of the invention will depend on the encapsulating material, the concentration of the encapsulated drug, and the presence of the release modifying agent. For example, release can be pH-dependent using a pH sensitive coating that is only released at low pH (such as in the stomach) or at a higher pH (such as in the intestine). An enteric coating can be used to prevent release from occurring before delivery to the stomach. The initial release in the stomach can be achieved using a multi-layer coating or a mixture of cyanamide encapsulated in different materials, followed by subsequent release in the intestine. Release can also be manipulated by including a salt or pore former that can increase water absorption or drug release by diffusion from the capsule. Excipients that alter the solubility of the drug can also be used to control the rate of release. Agents that enhance matrix degradation or release from the matrix may also be combined. Depending on the compound, it may be added to the drug, added as a separate phase (i.e., as a particle), or may be co-dissolved in the polymer phase. In all cases, the amount should be between 0.1% and 30% (w/w polymer). Types of degradation enhancers include inorganic salts such as ammonium sulfate and ammonium chloride; organic acids such as citric acid, benzoic acid and ascorbic acid; inorganic bases such as sodium carbonate, potassium carbonate, calcium carbonate, zinc carbonate and zinc hydroxide; Organic bases such as protamine sulfate, spermine, choline, ethanolamine, diethanolamine and triethanolamine; and surfactants such as Tween And Pluronic . A porogen (i.e., a water-soluble compound such as an inorganic salt and a sugar) to which a microstructure is added to the matrix is added in the form of particles. The range should be between 1% and 30% (w/w polymer).

Absorption can also be manipulated by altering the residence time of the particles in the intestine. This can be achieved, for example, by coating the particles with a mucoadhesive polymer or by selecting a mucoadhesive polymer as the encapsulating material. Examples include most polymers having free carboxyl groups, such as polyglucosamine, cellulose, and especially polyacrylates (as used herein, polyacrylate refers to polymerizations comprising acrylate groups and modified acrylate groups) Such as cyanoacrylate and methacrylate).

One aspect of the invention pertains to a pharmaceutical composition comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

In certain instances, the present invention relates to any one of the aforementioned pharmaceutical composition, wherein the pharmaceutical formulation of reducing serum cholesterol in a human patient population average, LDL and / or triglyceride EC ₅₀ of the pharmaceutical preparation does not exceed the average human 20% of the half-maximal concentration of skin vasodilation (flushing) in the patient population.

In certain instances, the present invention relates to any one of the aforementioned pharmaceutical composition, wherein the reducing serum cholesterol, LDL and / or triglyceride of EC ₅₀ will cause the pharmaceutical preparation does not exceed the average population of human patients skin vasodilation ( 1% of the maximum concentration of the flushing).

In certain instances, the present invention relates to any one of the aforementioned pharmaceutical composition, wherein the pharmaceutical formulation of reducing serum cholesterol in a human patient population average, LDL and / or triglyceride of EC ₅₀ will cause the pharmaceutical preparation does not exceed asparagine The amino acid aminotransferase (AST) and alanine (ALT) serum levels are increased to require 20% of the concentration of the pharmaceutical preparation to be discontinued.

In some embodiments, the present invention relates to any one of the aforementioned pharmaceutical compositions, wherein when the composition is ingested once a day by the patient, the composition is effective to lower serum lipids without causing the following after administration to the patient Limit treatment events: (i) liver toxicity and (ii) an increase in uric acid or glucose levels or both, or the treatment will need to be discontinued.

In certain embodiments, the invention relates to any of the foregoing pharmaceutical compositions, which are formulated in combination with a statin.

In some embodiments, the invention relates to any one of the aforementioned pharmaceutical compositions, wherein the statin is selected from the group consisting of atorvastatin, cerivastatin, fluvastatin, lovastatin, Mevastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin.

In certain embodiments, the invention relates to any one of the aforementioned pharmaceutical compositions formulated in combination with at least one other therapeutic agent selected from the group consisting of: 11β HSD-1 inhibitor, 5HT transporter inhibitor , 5HT2c agonist, 5-LO or FLAP inhibitor, alpha-glucosidase inhibitor, ABCA1 enhancer, ACC inhibitor, sulfhydryl-based CoA: cholesterol O-thiotransferase inhibitor, thiol-estrogen, Antidiabetic agents, anti-lipid drugs, antihypertensive agents, antioxidants, Apo A1 mimetic, Apo A1 modulator, Apo E mimetic, apolipoprotein-B secretion/microsomal triglyceride transfer protein (apo- B/MTP) inhibitors, appetite suppressants, aspirin, beta 3 agonists, bile acid reuptake inhibitors, bile acid chelators, campesin agonists, BRS3 agonists, CB ₁ antagonists / Reverse agonist, CCK-A agonist, cholesterol absorption inhibitor, cholesterol transport inhibitor, cholesterol ester transfer protein (CETP) inhibitor, CNTF, CNTF agonist/regulator, ezetimibe and sim Combination of statin and/or atorvastatin, CSL-111, dehydroepiandrosterone, delipidated HDL DGAT antisense oligomer, DGAT1 inhibitor, DGAT2 inhibitor, dicarboxylate transporter inhibitor, dopamine agonist, DP receptor antagonist, ezetimibe, FAS inhibitor, fatty acid binding protein (FABP) Inhibitors, fatty acid transporter inhibitors, fatty acid transporter protein (FATP) inhibitors, flushing inhibitors, FXR receptor modulators, galanin receptor antagonists, gemcabene, brain gut peptide antagonists, brain gut peptides Antibody, GLP-1 agonist, glycopeptide-like peptide-1 receptor agonist, glucocorticoid agonist/antagonist, glucose transporter inhibitor, HDL mimetic, HMG CoA reductase inhibitor compound, HMG-CoA synthetase inhibitor, hormone sensitive lipase antagonist, human hamster color related protein (AGRP), H ₃ antagonist/reverse agonist, inorganic cholesterol chelating agent, L-4f, lapastat, thin Agonists/modulators, leptin, lipase inhibitors, lipoprotein synthesis inhibitors, lopavirin, low-density lipoprotein receptor inducer or activator, Lp(a) reducing agent, LXR receptor agonist Agent, lyn kinase inhibitor, Mc3r agonist, Mc4r agonist, MCH1R antagonist, MCH2R agonist/antagonist, melanin-concentrating hormone antagonist, mGluR5 antagonist, microsomal triglyceride transport inhibitor, monoamine reuptake inhibitor, natural water-soluble fiber, NE transporter inhibitor, neuromodulin U receptor agonist, neuropeptide-Y antagonist, nicotinic acid or nicotinic acid receptor agonist, niacin, norepinephrine-induced appetite suppressant, NPY1 antagonist, NPY2 agonist, NPY4 agonist, NPY5 antagonist, non-steroidal anti-inflammatory agent (NSAID), omega-3 fatty acid, opioid antagonist, orexin receptor antagonist, PDE inhibitor, phentermine, phosphate transporter inhibitor, plant Pharmaceutical compound 57, fatty acid ester of plant stanol and/or plant stanol, platelet aggregation inhibitor, PPAR-α agonist, PPAR-δ agonist, PPAR-δ partial agonist, PPAR-γ Agonists, probucol, renin angiotensin inhibitors, reverse-4F, SCD-1 inhibitors, serotonin reuptake inhibitors, SGLT2 inhibitors, squalene epoxidase inhibitors, squalene Synthetic inhibitors, sterol biosynthesis inhibitors, sympathomimetic agonists, thyroid stimulating A beta agonist, a thyroxine, a topiramate, a triglyceride synthesis inhibitor, a UCP-1 activator, a UCP-2 activator, a UCP-3 activator, and a urocortin-binding protein antagonist.

In certain embodiments, the invention relates to a pharmaceutical composition comprising a compound of the invention or a pharmaceutically acceptable salt thereof; nicotinic acid; and a pharmaceutically acceptable excipient.

In certain embodiments, the invention relates to any pharmaceutical composition comprising a compound of the invention or a pharmaceutically acceptable salt thereof; nicotinic acid; a group of statin selected from the group consisting of: Ato Ruvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin; and pharmaceutically acceptable excipients.

In certain embodiments, the invention relates to a pharmaceutical composition comprising a compound of the invention or a pharmaceutically acceptable salt thereof; selected from the group consisting of troglitazone, rosiglitazone, and pioglitazone a ketone; and a pharmaceutically acceptable excipient.

In certain embodiments, the invention relates to a pharmaceutical composition comprising a compound of the invention or a pharmaceutically acceptable salt thereof; nicotinic acid; selected from the group consisting of troglitazone, rosiglitazone and pioglitazone Group of glitazone; and pharmaceutically acceptable excipients.

In certain embodiments, the invention relates to a pharmaceutical composition comprising a compound of the invention or a pharmaceutically acceptable salt thereof; a fiber ester selected from the group consisting of fenofibrate and bezafibrate (fibrate); and pharmaceutically acceptable excipients.

In certain embodiments, the invention relates to a pharmaceutical composition comprising a compound of the invention or a pharmaceutically acceptable salt thereof; nicotinic acid; selected from the group consisting of fenofibrate and bezafibrate a fibrous ester; and a pharmaceutically acceptable excipient.

method

One aspect of the invention relates to a method of treating a disease, disorder or condition selected from the group consisting of hyperlipidemia, hypercholesterolemia, lipid dystrophy, dyslipidemia, atherosclerosis, and coronary artery disease. A step comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof. In one embodiment, the mammal is a human.

One aspect of the invention relates to a method of treating a disease, disorder or condition selected from the group consisting of hyperlipidemia, hypercholesterolemia, lipid dystrophy, dyslipidemia, atherosclerosis, and coronary artery disease. A step comprising administering to a mammal in need thereof a therapeutically effective amount of a pharmaceutical composition of the invention. In one embodiment, the mammal is a human.

One aspect of the invention relates to a method of treating a disease, disorder or condition selected from the group consisting of metabolic syndrome, obesity, fatty liver disease, and diabetes, comprising administering a therapeutically effective amount to a mammal in need thereof A step of inventing a compound or a pharmaceutically acceptable salt thereof. In one embodiment, the mammal is a human.

One aspect of the invention relates to a method of treating a disease, disorder or condition selected from the group consisting of metabolic syndrome, obesity, fatty liver disease, and diabetes, comprising administering a therapeutically effective amount to a mammal in need thereof The step of inventing a pharmaceutical composition. In one embodiment, the mammal is a human.

One aspect of the invention relates to a method of raising serum high density lipoprotein (HDL) levels comprising the step of administering to a mammal in need thereof a therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof. In one embodiment, the mammal is a human.

One aspect of the invention pertains to a method of raising serum high density lipoprotein (HDL) levels comprising the step of administering to a mammal in need thereof a therapeutically effective amount of a pharmaceutical composition of the invention. In one embodiment, the mammal is a human.

One aspect of the invention relates to a method of lowering serum low density lipoprotein (LDL) levels or lowering serum lipoprotein (a) levels, comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of the invention or a pharmaceutical thereof The step of accepting the salt. In one embodiment, the mammal is a human.

One aspect of the invention relates to a method for lowering serum low density lipoprotein (LDL) levels or lowering serum lipoprotein (a) levels, comprising the step of administering to a mammal in need thereof a therapeutically effective amount of a pharmaceutical composition of the invention . In one embodiment, the mammal is a human.

One aspect of the invention relates to a method of treating a disease, disorder or condition selected from the group consisting of: congestive heart failure, cardiovascular disease, hypertension, coronary heart disease, colic, pellagra, Hartnap syndrome, carcinoid tumor syndrome, arterial obstructive disease, hypothyroidism, vasoconstriction, osteoarthritis, rheumatoid arthritis, Alzheimer's disease, peripheral and central nervous system disorders, hematological diseases , cancer, inflammation, respiratory disease and gastrointestinal disease, comprising the step of administering a compound of the invention or a pharmaceutically acceptable salt thereof to a mammal in need thereof. In one embodiment, the mammal is a human.

One aspect of the invention relates to a method of treating a disease, disorder or condition selected from the group consisting of: congestive heart failure, cardiovascular disease, hypertension, coronary heart disease, colic, pellagra, Hartnap syndrome, carcinoid tumor syndrome, arterial obstructive disease, hypothyroidism, vasoconstriction, osteoarthritis, rheumatoid arthritis, Alzheimer's disease, peripheral and central nervous system disorders, hematological diseases , cancer, inflammation, respiratory diseases and gastrointestinal diseases, comprising the step of administering a pharmaceutical composition of the invention to a mammal in need thereof. In one embodiment, the mammal is a human.

In certain embodiments, the invention relates to any of the foregoing methods, further comprising co-administering a therapeutically effective amount of a statin. In one such specific example, a total of administrations are administered orally.

In certain embodiments, the invention relates to any one of the aforementioned methods, further comprising co-administering a therapeutically effective amount of a statin; wherein the statin is selected from the group consisting of atorvastatin, west Rivarstatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin. In one such specific example, a total of administrations are administered orally.

In certain embodiments, the invention relates to any one of the aforementioned methods, further comprising co-administering a therapeutically effective amount of at least one additional therapeutic agent selected from the group consisting of: 11β HSD-1 inhibitor, 5HT transporter Inhibitor, 5HT2c agonist, 5-LO or FLAP inhibitor, alpha-glucosidase inhibitor, ABCA1 enhancer, ACC inhibitor, sulfhydryl-based CoA: cholesterol O-thiotransferase inhibitor, thiol- Estrogen, Antidiabetic Agent, Antilipid Abnormal Agent, Antihypertensive Agent, Antioxidant, Apo A1 Simulator, Apo A1 Modulator, Apo E Simulator, Apolipoprotein-B Secretion/Microsomal Triglyceride Transfer Protein (apo-B/MTP) inhibitor, appetite suppressant, aspirin, β3 agonist, cholic acid reuptake inhibitor, bile acid chelating agent, valerin agonist, BRS3 agonist, CB ₁ Antagonist/reverse agonist, CCK-A agonist, cholesterol absorption inhibitor, cholesterol transport inhibitor, cholesterol ester transfer protein (CETP) inhibitor, CNTF, CNTF agonist/modulator, ezetimidate Combination of shellfish with simvastatin and/or atorvastatin, CSL-111, dehydroepiandrosterone, go HDL, DGAT antisense oligomer, DGAT1 inhibitor, DGAT2 inhibitor, dicarboxylate transporter inhibitor, dopamine agonist, DP receptor antagonist, ezetimibe, FAS inhibitor, fatty acid binding Protein (FABP) inhibitors, fatty acid transporter inhibitors, fatty acid transporter protein (FATP) inhibitors, flushing inhibitors, FXR receptor modulators, galanin receptor antagonists, gemcabene, brain gut peptide antagonists, Brain gut peptide antibody, GLP-1 agonist, glycosidin-like peptide-1 receptor agonist, glucocorticoid agonist/antagonist, glucose transporter inhibitor, HDL mimetic, HMG CoA reductase inhibition Compound, HMG-CoA synthetase inhibitor, hormone sensitive lipase antagonist, human hamster color related protein (AGRP), H ₃ antagonist/reverse agonist, inorganic cholesterol chelating agent, L-4f, Lapas He, leptin agonist/modulator, leptin, lipase inhibitor, lipoprotein synthesis inhibitor, lopavirin, low-density lipoprotein receptor inducer or activator, Lp(a) reducing agent, LXR Somatostatin, lyn kinase inhibitor, Mc3r agonist, Mc4r agonist, MCH1R antagonist Anti-agents, MCH2R agonists/antagonists, melanin-concentrating hormone antagonists, mGluR5 antagonists, microsomal triglyceride transport inhibitors, monoamine reuptake inhibitors, natural water-soluble fibers, NE transporter inhibitors, Neuromodulin U receptor agonist, neuropeptide-Y antagonist, nicotinic acid or nicotinic acid receptor agonist, nicotinic acid, norepinephrine-induced appetite suppressant, NPY1 antagonist, NPY2 Agent, NPY4 agonist, NPY5 antagonist, non-steroidal anti-inflammatory agent (NSAID), omega-3 fatty acid, opioid antagonist, orexin receptor antagonist, PDE inhibitor, phentermine, phosphate transporter inhibition Agent, botanical compound 57, fatty acid ester of plant stanol and/or plant stanol, platelet aggregation inhibitor, PPAR-α agonist, PPAR-δ agonist, PPAR-δ partial agonist, PPAR-γ agonist, probucol, renin angiotensin inhibitor, reverse-4F, SCD-1 inhibitor, serotonin reuptake inhibitor, SGLT2 inhibitor, squalene epoxidase inhibitor, Squalene synthesis inhibitor, sterol biosynthesis inhibitor, sympathomimetic agonist, A Gonadotropin beta agonist, thyroxine, and care. Specific esters, triglyceride synthesis inhibitors, UCP-1 activators, UCP-2 activators, UCP-3 activators, and urocortin-binding protein antagonists. In one such specific example, a total of administrations are administered orally.

In certain embodiments, the invention relates to any one of the aforementioned methods, further comprising co-administering a therapeutically effective amount of at least one additional therapeutic agent selected from the group consisting of: HMG CoA reductase inhibitor, Aspirin Pilling, cholesterol ester transfer protein inhibitor, NSAID, fiber ester, proprotein convertase subtilisin/kexin type (PCSK9), inorganic cholesterol clamp, thiol CoA: cholesterol O-thiol transferase inhibitor, CETP Inhibitors, PPARα agonists, PPARγ agonists, bile acid reuptake inhibitors, triglyceride synthesis inhibitors, lipoprotein receptor activators, DGAT1 inhibitors, SCD-1 inhibitors, lipase inhibitors, DP receptor antagonists, apo A1 modulators, cholesterol transport inhibitors, metformin, nicotinic acid receptor agonists, and DPP-IV inhibitors. In one such specific example, a total of administrations are administered orally.

In certain embodiments, the invention relates to any one of the aforementioned methods, further comprising co-administering a therapeutically effective amount of at least one additional therapeutic agent selected from the group consisting of HMG CoA reductase inhibitors, cholesterol esters Combination of transfer protein inhibitor, aspirin, NSAID, fiber ester, DP receptor antagonist, ezetimibe or ezetimibe with simvastatin. In one such specific example, a total of administrations are administered orally.

In certain embodiments, the invention relates to any one of the aforementioned methods, further comprising co-administering a therapeutically effective amount of at least one HMG CoA reductase inhibitor selected from the group consisting of: lovastatin, simvastatin, pravastatin, Atorvastatin, fluvastatin, cerivastatin, revastatin, rosuvastatin calcium, and pitavastatin. In one such specific example, a total of administrations are administered orally.

In certain embodiments, the invention relates to any of the foregoing methods, further comprising co-administering simvastatin. In one such specific example, a total of administrations are administered orally.

In certain embodiments, the invention relates to any of the foregoing methods, further comprising co-administering a cholesterol ester transfer protein inhibitor. In one such specific example, a total of administrations are administered orally.

In certain embodiments, the invention relates to any of the foregoing methods, further comprising co-administering ezetimibe, aspirin, ibuprofen, ethametol or ezetimibe with A combination of simvastatin. In one such specific example, a total of administrations are administered orally.

One aspect of the invention pertains to a method of treating hyperlipidemia comprising the step of co-administering to a mammal in need thereof a therapeutically effective amount of a compound of the invention and a therapeutically effective amount of niacin. In one specific example, a total co-administration is administered orally. In one embodiment, the mammal is a human.

One aspect of the invention relates to a method of treating hyperlipidemia comprising the step of co-administering to a mammal in need thereof a therapeutically effective amount of a pharmaceutical composition of the invention and a therapeutically effective amount of niacin. In one specific example, a total co-administration is administered orally. In one embodiment, the mammal is a human.

One aspect of the invention relates to a method for increasing serum high density lipoprotein (HDL) levels in a mammal comprising co-administering to a mammal in need thereof a therapeutically effective amount of a compound of the invention and a therapeutically effective amount of niacin A step of. In one specific example, a total co-administration is administered orally. In one embodiment, the mammal is a human.

One aspect of the invention relates to a method for increasing serum high density lipoprotein (HDL) levels in a mammal comprising co-administering to a mammal in need thereof a therapeutically effective amount of a pharmaceutical composition of the invention and a therapeutically effective amount of a medicament The step of alkali acid. In one specific example, a total co-administration is administered orally. In one embodiment, the mammal is a human.

One aspect of the invention relates to a method of reducing serum low density lipoprotein (LDL) levels in a mammal comprising co-administering to a mammal in need thereof a therapeutically effective amount of a compound of the invention and a therapeutically effective amount of nicotinic acid. step. In one specific example, a total co-administration is administered orally. In one embodiment, the mammal is a human.

One aspect of the invention relates to a method of reducing serum low density lipoprotein (LDL) levels in a mammal comprising co-administering to a mammal in need thereof a therapeutically effective amount of a pharmaceutical composition of the invention and a therapeutically effective amount of nicotine The acid step. In one specific example, a total co-administration is administered orally. In one embodiment, the mammal is a human.

One aspect of the invention relates to a method of reducing serum lipoprotein (a) (Lp(a)) levels in a mammal comprising co-administering to a mammal in need thereof a therapeutically effective amount of a compound of the invention and a therapeutically effective amount thereof The step of nicotinic acid. In one specific example, a total co-administration is administered orally. In one embodiment, the mammal is a human.

One aspect of the invention relates to a method for reducing serum lipoprotein (a) (Lp(a)) levels in a mammal comprising co-administering to a mammal in need thereof a therapeutically effective amount of a pharmaceutical composition of the invention and therapeutically effective The step of measuring nicotinic acid. In one specific example, a total co-administration is administered orally. In one embodiment, the mammal is a human.

One aspect of the present invention relates to the treatment of hyperlipidemia, hypercholesterolemia, atherosclerosis, coronary artery disease, congestive heart failure, cardiovascular disease, hypertension, coronary heart disease, colic, pellagra, Hartnap syndrome, carcinoid tumor syndrome, arterial obstructive disease, obesity, hypothyroidism, vasoconstriction, osteoarthritis, rheumatoid arthritis, diabetes, Alzheimer's disease, lipid dystrophy or blood lipids An aberrant method comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of the invention, a therapeutically effective amount of niacin, and a therapeutically effective amount selected from the group consisting of atorvastatin, cerivastatin, fluvastatin, A step of group statin consisting of lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin. In one specific example, a total co-administration is administered orally. In one embodiment, the mammal is a human.

One aspect of the present invention relates to the treatment of hyperlipidemia, hypercholesterolemia, atherosclerosis, coronary artery disease, congestive heart failure, cardiovascular disease, hypertension, coronary heart disease, colic, pellagra, Hartnap syndrome, carcinoid tumor syndrome, arterial obstructive disease, obesity, hypothyroidism, vasoconstriction, osteoarthritis, rheumatoid arthritis, diabetes, Alzheimer's disease, lipid dystrophy or blood lipids An aberrant method comprising administering to a mammal in need thereof a therapeutically effective amount of a pharmaceutical composition of the invention, a therapeutically effective amount of niacin, and a therapeutically effective amount selected from the group consisting of atorvastatin, cerivastatin, and fluvastatin A step of a group of statins consisting of statins, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin. In one specific example, a total co-administration is administered orally. In one embodiment, the mammal is a human.

One aspect of the invention relates to a method of treating hyperlipidemia comprising co-administering to a mammal in need thereof a therapeutically effective amount of a compound of the invention, a therapeutically effective amount of nicotinic acid, and a therapeutically effective amount selected from the group consisting of Ato A step of the group of staclistatins consisting of statin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, russatin and simvastatin. In one specific example, a total co-administration is administered orally. In one embodiment, the mammal is a human.

One aspect of the invention relates to a method of treating hyperlipidemia comprising co-administering to a mammal in need thereof a therapeutically effective amount of a pharmaceutical composition of the invention, a therapeutically effective amount of nicotinic acid, and a therapeutically effective amount selected from the group consisting of A step of group statin consisting of atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin. In one specific example, a total co-administration is administered orally. In one embodiment, the mammal is a human.

One aspect of the invention relates to a method of increasing serum high density lipoprotein (HDL) levels in a mammal comprising co-administering to a mammal in need thereof a therapeutically effective amount of a compound of the invention, a therapeutically effective amount of niacin And a therapeutically effective amount selected from the group consisting of atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin The steps of the statin. In one specific example, a total co-administration is administered orally. In one embodiment, the mammal is a human.

One aspect of the invention relates to a method for increasing serum high density lipoprotein (HDL) levels in a mammal comprising co-administering to a mammal in need thereof a therapeutically effective amount of a pharmaceutical composition of the invention, a therapeutically effective amount of a smoke. Alkali acid and a therapeutically effective amount selected from the group consisting of atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin The steps of the statin. In one specific example, a total co-administration is administered orally. In one embodiment, the mammal is a human.

One aspect of the invention relates to a method of reducing serum low density lipoprotein (LDL) levels in a mammal comprising co-administering to a mammal in need thereof a therapeutically effective amount of a compound of the invention, a therapeutically effective amount of nicotinic acid, and A therapeutically effective amount selected from the group consisting of atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin A step of. In one specific example, a total co-administration is administered orally. In one embodiment, the mammal is a human.

One aspect of the invention relates to a method of reducing serum low density lipoprotein (LDL) levels in a mammal comprising co-administering to a mammal in need thereof a therapeutically effective amount of a pharmaceutical composition of the invention, a therapeutically effective amount of nicotine An acid and a therapeutically effective amount selected from the group consisting of atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin The steps of statin. In one specific example, a total co-administration is administered orally. In one embodiment, the mammal is a human.

One aspect of the invention relates to a method of reducing serum lipoprotein (a) (Lp(a)) levels in a mammal comprising co-administering to a mammal in need thereof a therapeutically effective amount of a compound of the invention, a therapeutically effective amount thereof Niacin and a therapeutically effective amount selected from the group consisting of atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin The steps of the group of statins. In one specific example, a total co-administration is administered orally. In one embodiment, the mammal is a human.

One aspect of the invention relates to a method for reducing serum lipoprotein (a) (Lp(a)) content in a mammal comprising co-administering to a mammal in need thereof a therapeutically effective amount of a pharmaceutical composition of the invention, therapeutically effective A quantity of nicotinic acid and a therapeutically effective amount selected from the group consisting of atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin The steps of the group of statins. In one specific example, a total co-administration is administered orally. In one embodiment, the mammal is a human.

In certain embodiments, the invention relates to any of the foregoing methods and the attendant limitations, wherein the statin is lovastatin or atorvastatin.

One aspect of the present invention relates to a method of treating diabetes in a mammal comprising co-administering to a mammal in need thereof a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof and selected from troglitazone ( The step of glitazone, a group consisting of troglitazone), rosiglitazone, and pioglitazone. In one specific example, a total co-administration is administered orally. In one embodiment, the mammal is a human.

One aspect of the invention relates to a method of treating diabetes in a mammal comprising co-administering to a mammal in need thereof a therapeutically effective amount of a pharmaceutical composition of the invention and selected from the group consisting of troglitazone, rosiglitazone and pioglitazone The steps of the group consisting of glitazone. In one specific example, a total co-administration is administered orally. In one embodiment, the mammal is a human.

One aspect of the present invention relates to a method of treating diabetes in a mammal comprising co-administering to a mammal in need thereof a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, niacin, and a selected from the group consisting of The step of glitazone consisting of a group consisting of glitazone, rosiglitazone and pioglitazone. In one specific example, a total co-administration is administered orally. In one embodiment, the mammal is a human.

One aspect of the invention relates to a method of treating diabetes in a mammal comprising co-administering to a mammal in need thereof a therapeutically effective amount of a pharmaceutical composition of the invention, nicotinic acid, and selected from the group consisting of troglitazone and roggliin a step of a ketone of a group consisting of a ketone and pioglitazone. In one specific example, a total co-administration is administered orally. In one embodiment, the mammal is a human.

One aspect of the invention relates to a method of treating diabetes in a mammal comprising co-administering to a mammal in need thereof a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, and selected from fenofibrate ( The step of a fiber ester of a group consisting of fenofibrate) and bezafibrate. In one specific example, a total co-administration is administered orally. In one embodiment, the mammal is a human.

One aspect of the invention relates to a method of treating diabetes in a mammal comprising co-administering to a mammal in need thereof a therapeutically effective amount of a pharmaceutical composition of the invention and a composition selected from the group consisting of fenofibrate and bezafibrate. The step of grouping the cellulose esters. In one specific example, a total co-administration is administered orally. In one embodiment, the mammal is a human.

One aspect of the invention relates to a method of treating diabetes in a mammal comprising co-administering to a mammal in need thereof a therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof, niacin, and a non-selective A step of a fiber ester of a group consisting of Norbert and bezafibrate. In one specific example, a total co-administration is administered orally. In one embodiment, the mammal is a human.

One aspect of the invention relates to a method of treating diabetes in a mammal comprising co-administering to a mammal in need thereof a therapeutically effective amount of a pharmaceutical composition of the invention, nicotinic acid, and selected from the group consisting of fenofibrate and benzalbe The step of specifically forming a group of fiber esters. In one specific example, a total co-administration is administered orally. In one embodiment, the mammal is a human.

In certain embodiments, the invention relates to any one of the aforementioned methods and the attendant limitations, wherein the mammal is a primate, a cow, a sheep, a rodent, a horse, a dog or a cat.

In certain embodiments, the invention relates to any one of the aforementioned methods and the attendant limitations, wherein the mammal is a human.

In certain embodiments, the invention relates to any one of the aforementioned methods and the attendant limitations, wherein the (or equivalent) compound or pharmaceutical composition is administered orally.

In certain embodiments, the invention relates to any one of the aforementioned methods and the attendant limitations, wherein the (or equivalent) compound or pharmaceutical composition is administered intravenously.

In certain embodiments, the invention relates to any one of the aforementioned methods and the attendant limitations, wherein the (or other) compound or pharmaceutical composition is administered sublingually.

In certain embodiments, the invention relates to any of the foregoing methods and attendant limitations, wherein the (or equivalent) compound or pharmaceutical composition is administered by inhalation.

In certain embodiments, the invention relates to any one of the aforementioned methods and the attendant limitations, wherein the (or equivalent) compound or pharmaceutical composition is administered ocularly.

In certain embodiments, the invention relates to any one of the aforementioned methods and the attendant limitations, wherein the compound or pharmaceutical composition is administered transdermally.

In certain embodiments, the invention relates to any of the foregoing methods and concomitant limitations, wherein the (or equivalent) compound or pharmaceutical composition is administered rectally.

In certain embodiments, the invention relates to any one of the aforementioned methods and the attendant limitations, wherein the (or other) compound or pharmaceutical composition is administered vaginally.

In certain embodiments, the invention relates to any one of the aforementioned methods and concomitant limitations, wherein the (etc.) compound or pharmaceutical composition is administered topically.

In certain embodiments, the invention relates to any one of the aforementioned methods and the attendant limitations, wherein the (or equivalent) compound or pharmaceutical composition is administered intramuscularly.

In certain embodiments, the invention relates to any one of the aforementioned methods and the attendant limitations, wherein the (etc.) compound or pharmaceutical composition is administered subcutaneously.

In certain embodiments, the invention relates to any one of the aforementioned methods and the attendant limitations, wherein the compound or pharmaceutical composition is administered buccally.

In certain embodiments, the invention relates to any one of the aforementioned methods and the attendant limitations, wherein the compound or pharmaceutical composition is administered nasally.

illustration

The present invention is generally described, and the present invention is to be understood by the following description of the invention.

Example 1: Synthesis scheme

A. Compound ARI-001

Reaction conditions: i. HCHO, morpholine hydrochloride, n-PrOH, 100 ° C; ii. NaOH, then HCl.

To a 50 mL flask equipped with a condenser was added 6-methyl-nicotinate (4.5 g, 30 mmol), morpholine hydrochloride (1.85 g, 15 mmol), n-PrOH (18 mL) and formaldehyde Solution (aqueous solution, 37%) (1.2 g, 15 mmol). The reaction mixture was refluxed for 2.5 hours under argon using a preheated 100 ° C oil bath. Subsequently, the mixture was allowed to stand at room temperature overnight, and yellow needle crystals were precipitated (if no precipitate formed at room temperature, a cold room (4 ° C) or even a -10 ° C refrigerator would be recommended). The crystals were isolated by filtration and washed with a little diethyl ether to give the crude product of step 1 as a hydrochloride salt (1.5 g, 35% yield; purity about 95%, double Mannich addition by-product It is about 3%). This crude product was further purified by recrystallization from n-PrOH and MeOH to afford a purified product of step 1 as an off-white or pale yellow powder (1.2 g, 28% yield; purity 99.1%, double The Mannich addition by-product was 0.9%).

The product of Step 1 (1.5 g, 5 mmol) was dissolved in MeOH (20 mL) and water (10 mL). The resulting mixture was stirred at room temperature overnight, then the pH was adjusted to 2-3 using 2N HCl. After condensing under vacuum, the residue was further purified by preparative HPLC eluting with solvent acetonitrile and water (5 mM HCl) to give the title compound ARI-001 (sal. When the crude product of step 1 was used, the total yield of the two steps was about 30%).

B. Compound ARI-002

Reaction conditions: i. HCHO, morpholine hydrochloride

C. Compound ARI-001D

Reaction conditions: i. HCHO, morpholine-d8 hydrochloride; ii. NaOH, followed by HCl.

D. Compound ARI-005

Reaction conditions: i. 5-indanol, EDAC, DMAP.

E. Compound ARI-006 (six ARI-001 inositol)

Reaction conditions: i. Myocardial alcohol, EDCI, DMAP.

F. Compound ARI-008

Reaction conditions: i. D-sorbitol, EDAC, DMAP.

G. Compound ARI-010

Reaction conditions: i. ARI-001, EDAC, DMAP; ii. Bu ₄ NI, BCl ₃ .

Example 2: In vitro study

ARI-001 was synthesized as described above. Purity was independently determined by liquid chromatography-mass spectrometry (LC-MS) examination before use in experiments. The material sample was dissolved in water/acetonitrile and injected onto a Discovery C-18 reverse phase column. The mobile phase started at 2%: 98% acetonitrile: water for 3 minutes, after which a linear gradient was initiated, operating for 6 minutes, increasing the percentage of acetonitrile until a final ratio of 98% was reached: 2% acetonitrile: water. This final ratio is maintained for 3 minutes. UV detection was collected at 215 nm as shown in Figure 1. The main peak was identified as ARI-001.

Purity was determined from the ratio of the main peak (3.59 minutes) area to the sum of all peak areas. The purity was determined to be 98.9%. No small peaks were identified.

Stability was determined by storing ARI-001 at 50 ° C with no specified humidity requirements. A small sample of ARI-001 (<5 mg) was collected at various time points over a period of 3 months (90 days) for analysis by LC-MS under the same conditions as used for the purity determination (see above). Figure 2 shows the time course of ARI-001 stability under these conditions.

Under standard conditions (50 ° C, no humidity adjustment), ARI-001 remained 98.9% pure for 65 days. At 90 ° C for only 90 days, ARI-001 began to show degradation. After 90 days, the compound was found to be 95.9% pure.

Example 3: In vivo study

To investigate the effects of ARI-001 on lipid regulation, a hamster model was developed and used in the case of long-term administration of compounds. This model, its development, and the impact of ARI-001 are described herein.

The effect of food adjustment on hamster lipid profiles . Like other rodents, the lipid characteristics of the Golden Syrian hamster are mainly composed of HDL and a small amount of LDL or VLDL cholesterol. However, in accepting high-fat foods, hamsters experienced an increase in the cholesterol pool including triglycerides and free fatty acids. The addition of sugars (such as 10% fructose) to the drinking water source significantly expands the triglyceride pool, including VLDL. With this food, hamsters became models for studying the effects of modulators on triglycerides, VLDL and LDL cholesterol. In fact, literature resources have used this model to study triglycerides and free fatty acid modulating compounds such as fenofibrate.

We examined the effects of food regulation on the lipid profile of male Syrian gold hamsters. Hamsters are ordered from Charles River Labs (Wilmington, MA) and are required to weigh 111-120 g (corresponding to 56-61 days). The hamsters were housed in cages, 4-5 per cage, and maintained for 12 hours of light/12 hours of standard light cycle. All food was obtained from Dyets (Bethlehem, PA). "Normal Diet" is a standard rodent food, catalog number 5001, which is made into a granular food. Water and this standard food are available for free consumption by this group of hamsters. Although food is added to the cage when needed, the frequency is not less than twice a week. "High Fat Diet" is a rodent food supplemented with the same criteria as: 11.5% corn oil, 11.5% coconut oil, 0.5% cholesterol, and 0.25% deoxycholate. This is also available directly from Dyets under catalog number 611201. Both foods were ordered in 10 kg batches and stored at 4 °C during the duration of the experiment (4-8 weeks) and stored at -20 °C for longer storage (up to 6 months). Water and this high-fat food can be used by this group of hamsters. The "High Fat + Fructose" group fed the same fat-rich food (#611201) as the "high fat diet" group, but the fruit was supplemented with fructose at a final concentration of 10%. Fructose was supplied by Now Foods (catalog number 6931) and sold by Lucky Vitamin (catalog number WB48432). Fructose water was prepared by adding 400 g of fructose to 4 L of water and stirring at room temperature until dissolved. Fructose water was stored at 4 ° C until use. When supplied to hamsters, fructose water is maintained in a water bottle in a hamster cage at room temperature, exactly as standard water. Fructose water and high-fat foods can be used by this group of hamsters. All animals maintained their respective food for 21 days.

To begin this experiment, hamsters were randomly assigned to the group defined by the above food adjustments. After a fixed time, blood was collected from hamsters (N = 3-4) to determine the lipid content of the plasma. Due to the ability to properly collect blood from hamsters, all blood samples were obtained via end cardiac puncture after asphyxiation with carbon dioxide. Blood (approximately 2 mL volume) was collected with a 22G needle into a 5 mL syringe and transferred to a K ₂ EDTA tube. The sample was kept on ice until centrifugation (14,000 rpm, 10 minutes at 4 °C) to separate the plasma. Plasma was then aliquoted into tubes and stored at -80 °C until analysis.

Lipid parameters were determined using a commercial kit from Wako USA (Richmond, VA) according to the manufacturer's instructions.

Control animals (receiving food of any one of the three one day zero) of the lipid values substantially indistinguishable (see Table 1). By day 21, both food adjustments had a significant effect on the lipid profile of these hamsters when compared to animals receiving normal food. All parameters were significantly higher than the control group (p<0.05 for all groups), with the exception of HDL. As predicted, the addition of fructose to high-fat foods further increased the concentration of triglycerides and free fatty acids to a greater extent than the high-fat diet alone. Regardless of the food adjustment, there was no change in HDL compared to the normal food group.

Table 1. Lipid values of hamsters receiving one of three different foods for 21 days. Hamsters were sacrificed and analyzed for plasma as described. The value is the average of the measured values of each parameter (N=3) and the standard deviation. TC: total cholesterol; HDL: high density lipoprotein cholesterol; LDL: low density lipoprotein cholesterol; TG: triglyceride; FFA: free fatty acid.

Different cholesterol subpopulations were isolated from hamster plasma samples using fast protein liquid chromatography (FPLC). Briefly, the plasma of each animal in a given group was mixed together and applied to an AKTA liquid handling system (Product No. 14-5172-01, GE Life Sciences) with a Superose 6 10/300 GL column. 250 μL of sample was applied to the injection system, diluted with 5 mL of buffer (100 mM Na ₂ HPO ₄ , 100 mM NaCl, pH 7.5), loaded onto the column, and flowed at a flow rate of 1.0 mL/min with 23.5 mL of buffer. Stripped to 0.24 mL size elution. The cholesterol concentrations of each of the eluted fractions were individually measured using Wako's total cholesterol set as described above, with the following modifications being made: the sample volume was increased to 30 μL and the reagent volume was reduced to 60 μL.

The FPLC trace produces a continuous curve with three distinct peaks representing each of the cholesterol subpopulations: VLDL, LDL, and HDL. Because the column used in this experiment is a size exclusion column, the largest particle appears first and the smallest particle appears last. Therefore, VLDL is the first peak on the trace, followed by LDL, and HDL finally appears. If it is assumed that these peaks each exhibit a Gaussian distribution, the FPLC trace can be deconvoluted into each of the three components to determine the contribution of each component to the overall curve.

Figure 3 shows FPLC traces of confluent plasma of hamsters receiving two different foods for three weeks. The VLDL curve broadly expanded when receiving high fat + fructose foods. The LDL peak is also extremely high. Interestingly, there is a small difference in HDL peaks, suggesting that this food adjustment has a considerable impact on non-HDL cholesterol populations. This model thus makes it a suitable means of measuring the effects of ARI-001 on VLDL and LDL cholesterol.

ARI-001 reduces LDL cholesterol, triglycerides and free fatty acids in HF/HS hamsters. Male gold Syrian hamsters were purchased from Charles River Labs (111-120 g, 56-61 days) and adapted to the high fat + fructose (herein referred to as "HF/HS") food as described above for two weeks. Two weeks after the food was adapted, the hamsters were grouped according to their body weight. Twelve hamsters were assigned to the vehicle group, 9 were assigned to receive 1200 mg/kg niacin, 10 were assigned to 1120 mg/kg ARI-001, and 10 were assigned to receive 2240 mg/kg ARI- 001. At the end of this food acclimation period, hamsters were orally gavaged with 1 mL of vehicle (water), niacin or ARI-001 (one of two doses). The hamsters were administered once a day for a total of 18 days. All animals maintained the above HF/HS food throughout the administration period. The dosing solutions of each group were prepared for 7 days at a time, but sufficient amounts were also prepared for 8 days. Each solution was stored at room temperature between administrations. Groups are defined according to Table 2 below . Since there is a molecular weight difference between nicotinic acid and ARI-001, the dose is expressed in mg/kg and mmol/kg. Note that 1200 mg/kg nicotinic acid is equivalent to 2240 mg/kg ARI-001 in terms of molar concentration.

Table 2. Group assignments for 18 day dosing studies in HF/HS hamsters

As shown in Table 3 , LD-001 administered by oral gavage for 2 days at 2240 mg/kg reduced the LDL cholesterol and total cholesterol content of the HF/HS hamster model. ARI-001 also reduces triglyceride and free fatty acid content, as indicated by small standard deviations, with minimal changes between animals. At an equimolar dose of 1200 mg/kg, nicotinic acid did not confer this effect on the animal model, indicating that the effectiveness of ARI-001 on LDL cholesterol parameters is at least 1.67 times that of nicotinic acid, and the total cholesterol parameter The effectiveness is at least 1.54 times that of niacin. Note the triglyceride and free fatty acid values, which were shown to be responsive in all animals of the 2240 mg/kg ARI-001 group. The standard deviation between these data points is extremely small, reflecting the extremely high response rate between these animals. The HDL/TC ratio is calculated by dividing the HDL cholesterol content of each individual hamster by its total cholesterol content. The score obtained is the HDL/TC ratio. This parameter was higher than the vehicle group and was statistically significant (p < 0.001). This is unlikely to indicate a significant increase in HDL because the absolute HDL value measured in the 2240 mg/kg ARI-001 group increased by only 33% compared to the vehicle. Rather, a large change in the HDL/TC ratio is likely to indicate a systemic reduction in the cholesterol population, with the exception of HDL, which not only does not exhibit such a decrease, but may also increase.

Table 3. Lipid parameters of HF/HS hamsters administered orally, niacin or ARI-001 for 18 days. TC, total cholesterol. The values given are mean ± standard deviation. The P value is reported as compared to the vehicle treated in the same parameter according to the two-tailed unpaired t test.

The measured HDL values were significant at 2240 mg/kg between the ARI-001 group and the vehicle group (p=0.06). When considering the calculated HDL/TC value, the significance is greatly increased. FPLC traces also demonstrated significant differences in lipid profiles between the two groups. FPLC was carried out as described above. The curve is deconvolved as described above. In the ARI-001 trace, not only the VLDL and LDL peaks were significantly reduced compared to the vehicle, but also the HDL curve was significantly larger. See Figure 4 .

The male gold Syrian hamster from the previously described experiment demonstrated a dose-dependent ARI-001 for lipid changes. 2240 mg/kg is an effective dose that lasts for 18 days per day for almost all parameters: total cholesterol, LDL cholesterol, triglycerides, and free fatty acids. However, 1120 mg/kg showed only modest effects on these parameters, with only the free fatty acid parameters showing statistically significant effects compared to vehicle. Nevertheless, the trend of the lipid parameters between all doses of study it was clear, as shown in FIG. Furthermore, at the molar equivalent dose, ARI-001 produced a stronger reaction than nicotinic acid in all of the measured lipid parameters.

ARI-001 reduces LDL cholesterol, triglycerides and free fatty acids in a time-dependent manner. Thirty-two male golden Syrian hamsters were acclimated to HF/HS food as described above for two weeks. After a two-week induction period, animals were assigned to a cohort of 18-day studies for vehicle or ARI-001 (1120 mg/kg) or for vehicle or ARI-001 (1120 mg/kg) Group of 28-day studies. There are 8 hamsters in each of the four groups. The solution was prepared and stored as described above. Animals were dosed 1 mL daily for 18 or 28 consecutive days as previously described. At the end of the study, hamsters were sacrificed and their blood was collected in K ₂ EDTA tubes, plasma was separated by centrifugation and frozen until analysis. All lipids were analyzed using a commercial kit (Wako USA) as described above. In Table 4 below, 18 day and 28 day vehicle animals were combined into a single vehicle group (N=16).

Table 4. Lipid parameters of HF/HS hamsters administered orally or ARI-001 for 18 or 28 days. The values given are mean ± standard deviation. The P value is reported as compared to the vehicle treated in the same parameter according to the two-tailed unpaired t test.

When the 1120 mg/kg dose was administered to 28 days, ARI-001 showed a beneficial effect on lipids. When hamsters were administered for 28 days instead of 18 days, all measured lipid parameters achieved statistically significant differences compared to vehicle, with the exception of HDL, which showed no difference compared to vehicle. At 28 days, the reduction seen at 1120 mg/kg was greater than after 18 days of dosing. However, at the higher doses of 2240 mg/kg, these reductions were much less pronounced than in the 18-day situation.

Correlation between plasma lipid biomarkers and ARI-001 plasma concentrations . The ARI-001 concentration of the plasma of 19 ARI-001 hamsters in the 18-day study was analyzed. The concentrations of these samples were determined and these samples were collected 24 hours after the final dose was administered. Briefly, plasma drug concentrations in non-GLP pharmacokinetic experiments were determined by electrospray ionization using LC-MS using an Applied Biosystems 4000 Qtrap spectrometer. Samples were prepared for analysis by precipitation of plasma proteins with cold methanol. HPLC of the samples was carried out using an Agilent Eclipse C18 column and a methanol/water gradient containing 0.1% formic acid and 5 mM ammonium acetate. ARI-001 uses multiple reaction monitoring (MRM) to detect in cation mode. When quantified, the standard curve was measured by adding a known amount of ARI-001 to the untreated animal plasma and formulating it in the same manner as the treated animal sample. All plasma samples were spiked with 10 ng/mL isotope-rich ARI-001 that served as an internal standard for LC-MS measurements. All compound concentrations are reported in μM. In the correlation analysis, the plasma concentration of ARI-001 of a given animal was paired with the lipid parameters of the same animal. All animals in the two administration groups (1120 mg/kg and 2240 mg/kg) were included in the analysis. These correlation diagrams are shown in Figures 6 and 7 . The Pearson correlation coefficient value is determined using all data points, just like the two-tailed P value of the data set.

Changes in lipid parameters were closely related to the plasma levels of the drug measured 24 hours after the last dose. In fact, total cholesterol, HDL cholesterol, LDL cholesterol, triglyceride, and free fatty acid content all reached a statistically significant correlation (p < 0.01). The correlation with triglycerides is particularly noteworthy because of the extremely high degree of statistical significance, p < 0.001. These significant correlations support the notion that ARI-001 is directly responsible for lipid value regulation. In addition, these data confirm the dose-response effect seen in Figure 5 .

The concentration of ARI-001 in the tissue correlates with plasma lipid content. Tissue samples were collected from hamsters in the above 18-day experiment to determine the concentration of ARI-001 in liver and adipose tissue. Briefly, liver and fat samples were collected at the end of the experiment; samples were snap frozen in liquid nitrogen and subsequently stored at -80 °C until analysis. For analysis, liver samples were excised from the frozen block, weighed and homogenized with a tissue grinder, and then sonicated in buffer. The solid matter is then removed by centrifugation. To be ready for LC-MS analysis, the tissue homogenate was then treated with the same preparative techniques described above for plasma preparation (see above). A fat sample was cut from the frozen block and transferred to a mortar and mortar cooled with liquid nitrogen. During the milling, liquid nitrogen was added to ensure that the fat sample remained solid. The ground sample was transferred to a tube that was weighed to weigh the total sample. The ground sample was extracted with methanol, and the methanol and lipid containing the compound were separated by cooling to -20 °C. After drying, the methanol sample was dissolved in water; the sample was then prepared in the same manner as the liver and plasma for LC-MS analysis (see above).

Liver concentrations are reported as the Nike number of ARI-001 per milliliter of homogenized tissue sample extracted in buffer. The concentration in the fat is reported in nanograms of ARI-001 per milligram of tissue recovered from the milling process. Due to tissue concentration and distribution of lipid parameters, logarithmic transformations were used for all liver samples when correlation was determined. In addition, the fat concentration is converted logarithmically +1 because the logarithmic transformation of these tissue samples produces a negative value. These transformations make the data more convenient to display graphically. Finally, these transformations are based on the fact that the properties of the Pearson coefficient correlation coefficients are invariant under logarithmic transformations and shift terms.

Figure 8 illustrates the correlation between plasma versus liver (left panel) and plasma versus fat (right panel) ARI-001 concentration. Both correlations were statistically significant, with each pair of parameters being p < 0.01. Figures 9 to 11 illustrate the correlation between ARI-001 concentration in each tissue sample versus lipid parameters TC, HDL, LDL, TG and FFA. All concentration measurements and all lipid parameters were transformed by logarithm. Pearson r is determined using all of the data points shown. The P values for the two-tailed t-test were determined using all of the data points shown.

ARI-001 increased ABCA1, ApoAI, SR-BI, CETP and adiponectin mRNA in HF/HS hamsters. Studies of possible mechanisms for increasing HDL cholesterol have focused on changes in the mRNA content of several genes associated with HDL regulation. Hamster liver and fat were prepared in a manner similar to that described for the ARI-001 concentration assay. Briefly, in order to be ready for analysis, liver samples were excised from the frozen block, weighed and homogenized with a tissue grinder, and then sonicated in buffer. The solid matter is then removed by centrifugation. The resulting lysate was used in qPCR analysis to quantify the specific mRNA measured using primers designed for the relevant specific sequences (see below). All mRNA amounts were corrected for vehicle treated animals and the mRNA content is expressed as an increase or decrease in fold relative to the vehicle treated group. The fat is treated in a similar manner to the liver: the fat sample is cut from the frozen block and transferred to a mortar and pestle cooled with liquid nitrogen. During the milling, liquid nitrogen was added to ensure that the fat sample remained solid. The ground sample was transferred to a tube that was weighed to weigh the total sample. This ground sample was treated with buffer and prepared for qPCR to quantify the specific amount of mRNA.

Table 5. ABCA1, ApoAI, SR-BI, CETP mRNA per mg of liver tissue and fat CETP per mg of adipose tissue in high fat fed hamsters treated with vehicle, niacin or ARI-001 The relative concentration of adiponectin mRNA. Values are expressed as a multiple of the change from the average of the media values.

The ABCA1 and ApoAI mRNA levels were higher in the ARI-001 treated group relative to the vehicle control animals. In fact, a statistically significant correlation can be seen between HDL and ApoAI mRNA levels. This indicates the possible mechanism by which ARI-001 can increase HDL in this hamster model.

Table 6. ABCA1, ApoAI, SR-BI, and CETP mRNA per mg of liver tissue in high fat fed hamsters compared to HDL levels and equally per milligram of adipose tissue in a group treated with vehicle, nicotinic acid, or ARI-001 Correlation between CETP and adiponectin mRNA versus HDL content.

Example 4: Safety Pharmacology Study (non-GLP Preliminary Study)

Since niacin is known to cause liver toxicity and glucose intolerance in the case of long-term administration, we have examined whether ARI-001 (i.e., a nicotinic acid mimetic) causes similar problems. For this study, we examined the common liver function enzymes AST and ALT in the plasma of hamsters as tested in Example 3 above. Animals were dosed for 18 consecutive days while receiving HF/HS food for a total of approximately 5 weeks. We also test the glucose content in the plasma of these animals. In pharmacokinetic studies, we used wild-type mice for single and repeated dosing studies. Finally, pharmacokinetic studies were confirmed by single and repeated administration of monkey data.

A. Effect on liver function

ARI-001 Improves liver function testing of high fat fed hamsters for long-term administration. Certain nicotinic acid formulations are known to cause liver toxicity in humans. This led to a study of liver function tests (AST, ALT) of plasma administered to ARI-00118 days of hamsters. AST and ALT were measured using a commercially available kit (Bio-Quant Diagnostic Kits, San Diego, CA). As expected, the AST and ALT values of untreated hamsters (vehicle group) were extremely high because high fat foods caused hepatomegaly and fatty liver. This disease state is reflected by high AST and ALT levels. In contrast, animals treated with ARI-001 had significantly lower AST and ALT levels than vehicle. In fact, AST was significantly reduced at the 2240 mg/kg dose and was significantly reduced even at the 1120 mg/kg dose. The ALT values were similarly reduced, again in a dose dependent manner. See Figures 12A and 12B .

B. Effect on glucose tolerance

ARI-001 had no effect on glucose content in high fat feeding hamsters. Niacin is known to adversely affect the glucose content of diabetic patients. The hamster model used in this experiment produced a high glucose content population as evidenced by the vehicle group in Figure 13 . Consistent with the effects seen in humans, the glucose of animals treated with niacin increased relative to the vehicle. However, both doses of ARI-001 did not produce any significant change in glucose content compared to the vehicle group.

Example 5: Pharmacokinetic Study

A. In vivo study of mice

Single-dose pharmacokinetic study of ARI-001 in wild-type mice. Wild type C57BL/6 mice were administered by oral gavage (PO) or by intraperitoneal injection (IP) in a single dose of ARI-001 in solution form. Blood samples were then collected at various time points over a 24 hour period; the plasma ARI-001 concentration was then analyzed as previously described. ARI-001 was administered as a single bolus via oral gavage at a dose of 2240 mg/kg, or as a single bolus via intraperitoneal injection at a dose of 448 mg/kg. See Figure 14 .

A pharmacokinetic profile of the parameters as shown in Table 7 was generated by a single dose of ARI-001 via oral gavage and intraperitoneal injection. At the 24 hour time point, the remaining concentration of ARI-001 is undetectable.

Table 7. Pharmacokinetic parameters of a single administration of ARI-001 in wild-type mice

Multi-drug pharmacokinetic study of ARI-001 in wild-type mice. Wild type C57BL/6 mice were administered by daily oral gavage with ARI-001 in solution for 30 consecutive days. Blood was collected over 5 24 hour periods and the ARI-001 concentration of the resulting plasma was analyzed. Four doses were used: 996 mg/kg, 1493 mg/kg, 2240 mg/kg, and 3360 mg/kg. As expected, _Cmax content and total 24 hour exposure (AUC) were dose dependent. However, this value does not change over time as no trend is observed between these parameters and the number of days cast. See Figures 15A-15D and Figures 16A-16B .

B. Further in vivo study in mice

Single dose pharmacokinetic study in wild type mice. A single dose of niacin, ARI-001 or Compound 2230C in solution in a single bolus via oral gavage (PO) is disclosed in US Patent Application Publication No. 2009/0312355 A1, the disclosure of which is incorporated herein by reference. Modes are incorporated herein) Administration of wild-type C57BL/6 mice. Compound 2230C has the following structure:

Blood samples were then collected at various time points over a 24 hour period; plasma nicotinic acid, ARI-001 and 2230C concentrations were subsequently analyzed as previously described. The results are shown in Table 8 .

Table 8. Comparison of pharmacokinetic parameters of single oral administration of niacin, ARI-001 and 2230C in wild-type mice

C. Gold Syrian hamster in vivo study

Single-dose pharmacokinetic study of ARI-001 in gold Syrian hamsters. The pharmacokinetic profile of ARI-001 was assessed in HF/HS gold Syrian hamsters given a single oral dose of 5.9 mmol/kg ARI-001. Plasma samples were collected from 5 animals via cardiac puncture at various time points to measure the plasma concentration of ARI-001 within 24 hours. The results are shown in Figure 17 .

D. Monkey in vivo study

Single-dose pharmacokinetic study of ARI-001 in Macaque Monkey. The fasted monkeys were administered ARI-001 as a solution via oral gavage (PO) or via intraperitoneal injection (IP). Blood samples were collected at various time points over a 24 hour period; the plasma ARI-001 concentration was subsequently analyzed. ARI-001 was administered as a single bolus via oral gavage at a dose of 288 mg/kg or as a single bolus via intravenous injection at a dose of 96 mg/kg. The results are shown in Figure 18 .

Single-dose pharmacokinetic study of ARI-001 in fed or fasted monkeys. The feeding monkeys were fed and allowed to digest for a period of time prior to administration of ARI-001 in solution form by oral gavage as previously described. The results are shown in Figure 19 .

The pharmacokinetics of ARI-001 was administered to fasting monkeys multiple times. Monkey ARI-001 was administered once daily by oral gavage for a total of 7 days. Blood samples were collected after the first administration and after the last administration to measure the ARI-001 plasma concentration. There was a very small difference between the plasma concentrations on Day 1 and Day 7. The biggest divergence point is the C _max value, which is higher than day 1 on day 7. The concentration was substantially the same 24 hours after the first dose or the last dose. See Figure 20 .

Example 6: ARI-001 failed to recruit β-arrestin to the cell membrane of cells exhibiting high affinity nicotinic acid receptor GPR109A

Niacin-induced skin flushing has been shown to be mediated by activation of the nicotinic acid receptor GPR109A in a β-arrestin-dependent manner. Walters RW et al. (2009) J Clin Invest 119: 1312-21. PathHunter eXpress β-arrestin cells expressing GPR109A assay were plated in 96-well plates at 10,000 cells per well and stimulated with niacin or ARI-001 for a certain concentration range for 90 minutes. G protein coupled receptor (GPCR) activity was detected by complementarily measuring the interaction of β-arrestin with an activated GPCR using a β-galactosidase fragment. After stimulation with niacin or ARI-001, the signal was detected using a chemiluminescent PathHunter detection reagent. Representative results are shown in Figure 21 .

Unlike nicotinic acid, stimulation of GPR109A by ARI-001 reaching a concentration of 10 mM failed to recruit β-arrestin to the membrane of cells expressing GPR109A. Since nicotinic acid-induced flushing is known to be mediated by GPR109A activation in a β-arrestin-dependent manner, the results of this study are consistent with the observation that ARI-001 significantly reduces flushing side effects compared to niacin.

Example 7: Summary of pharmacological studies of ARI-001 in animal models

Many pharmacokinetic, safety and efficacy studies on ARI-001 have been done in a variety of animals including mice, rats, golden Syrian hamsters, dogs and monkeys. Taken together, the results of these studies establish the following conclusions.

ARI-001 reduced the plasma levels of total cholesterol, LDL-C, TG and FFA, while increasing the absolute content of HDL-C and the HDL-C/TC ratio. The lipid-altering effect of the once-daily dose of ARI-001 was significantly greater than that observed with a nearly twice-fold higher dose of nicotinic acid once daily.

The change in plasma lipid content produced by administering ARI-001 once daily for 28 days was greater than the change in ARI-001 administered the same dose once daily for 18 days.

Administration of ARI-001 once daily produced a highly significant change in plasma lipids greater than or equal to the lipid-altering effect observed for the same total dose of ARI-001 administered twice daily. In addition, once daily ARI-001 is more effective than nicotinic acid in achieving the desired lipid changes.

Changes in plasma levels of TC, HDL-C, TG, LDL-C, and FFA correlate with plasma concentrations of ARI-001 present in plasma.

The plasma and liver concentrations of ARI-001 are proportionally related.

Liver concentrations of ARI-001 were associated with decreased plasma TC, LDL-C, TG, and FFA and increased plasma HDL-C.

ARI-001 showed no signs of telangiectasia or hyperemia (alternation of flushing) in experiments using Doppler capillary blood flow measurements in mice. In addition, no clinical symptoms of "flushing" were observed in rats or dogs within 28 days.

Example 8: Human Clinical Trial of ARI-001

A randomized, double-blind, placebo-controlled study was performed in groups with escalating doses, observed 30 hours after dosing and reviewed on day 8. The study was conducted as healthy male and female adult volunteers, aged 18-60 years, with LDL-C > 130 mg/dL and body weight <85 kg. Individuals randomized to receive study drug or placebo.

A single dose increase of 5 times, 8 individuals per group (6 drugs: 2 placebo), involving a total of 40 individuals. Provide a suitable double-blind matching placebo. Group 1 received 500 mg ARI-001, formulated as a single oral lozenge, plus 11 placebo lozenges; Group 2, taken in two 500 mg ARI-001 lozenges, 1000 mg plus ten placebos Lozenges; Group 3, taking 2000 mg in four 500 mg ARI-001 lozenges plus 8 placebo lozenges; Group 4, taking 4000 mg in the form of eight 500 mg ARI-001 lozenges, plus 4 placebo lozenges; Group 5, taking 6000 mg in the form of twelve 500 mg ARI-001 lozenges. Individual placebo-only individuals took 12 placebo lozenges. Each tablet is a compressed film coated tablet suitable for oral administration.

The first objective of the study was to assess the safety and tolerability of a single dose of ARI-001 in healthy adult volunteers at doses ranging from 500 mg to 6000 mg.

The second objective of the study was to establish the pharmacokinetic profile of ARI-001 in the blood of healthy volunteers after a single dose; observe changes in fasting triglycerides, free fatty acids, and other lipid biomarkers; Plasma drug exposure was associated with any changes in fasting triglycerides, free fatty acids, and other lipid biomarkers; and the effect of ARI-001 on flushing symptoms was established by visual analog scale (VAS).

Pharmacokinetic samples were collected 0-45 minutes before dosing and 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 30 and 168 hours after dosing. The actual time of each plasma collection was recorded.

At each collection, 3 mL of blood was collected in a Vacutainer tube (purple top) containing EDTA and immediately refrigerated. The plasma fraction was separated by centrifugation at 2,000 rpm for 15 minutes at 4 ° C for 30 minutes. Analysis of all samples was performed in a central laboratory.

On the first day, before administration, the following procedure was performed:

‧ Clinical laboratory tests, including liver function (ALT, AST, serum bilirubin), CK, hematology, APTT, PT, urinalysis and lipid chemistry (LDL-C, HDL-C, free fatty acids, triglycerides) Ester, LPA and ApoA-1)

‧12 lead ECG

‧vital signs

‧VAS

‧ Baseline plasma PK

‧ urine collection of baseline PK between midnight and 0 hours (administration)

After the study drug is administered, the following procedure is performed.

‧ 6, 12 and 24 hours after drug delivery, clinical laboratory tests including liver function (ALT, AST, serum bilirubin), CK, hematology and APTT, PT

‧ 4, 12 and 24 hours after administration, lipid chemical group (LDL-C, HDL-C, free fatty acid, triglyceride, LP (a) and ApoA-1)

‧12-lead ECG at 1, 2, 4, 6, 8, 12 and 24 hours after administration

‧ 24 hours after administration, urine analysis

‧ Vital signs after 6, 12, 24 and 30 hours after administration

‧ 0.25, 0.5, 1, 2, 4, 8, 12 and 24 hours after administration, VAS

‧ 24 hours after dosing, physical examination, and 30 hours after dosing, brief clinical examination

‧ Blood samples were collected for PK at 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24 and 30 hours after administration

‧ Blood samples were collected for troponin 4 hours after administration

‧ Urine was collected for PK at intervals of 6 hours after 0 to 6, 6 to 12, 12 to 18, 18 to 24, and 24 to 30 hours after administration.

Preliminary results from this human clinical trial included a noteworthy observation that no patient exhibited any flushing signs at any dose of ARI-001 up to and including the 6000 mg dose.

Other preliminary results are shown in Figure 22 , which illustrates the dose response of triglyceride reduced in humans to a single oral dose of ARI-001 as measured 4 hours after administration.

Other preliminary results are shown in Figure 23 , which illustrates serum concentrations of ARI-001 measured within 24 hours after a single oral dose in humans, ranging from 500 mg to 6000 mg ARI-001. The _Cmax of the 2000 mg dose of ARI-001 is about 7500 ng/mL (7.5 mg/mL); the _Cmax of 1500 mg niacin (about equimolar dose) is about 30,000 ng/mL (30 mg/mL) .

Incorporated by reference

All publications and patents referred to herein are hereby incorporated by reference in their entirety in their entirety in the extent of the disclosure of the disclosure of the disclosures of In case of conflict, the application (including any definition herein) will prevail.

Equivalent form

The specific embodiments of the invention have been described by way of illustration and not limitation. Many variations of the invention will be apparent to those skilled in the <RTIgt; The scope of the appended claims is not intended to

Figure 1 shows liquid chromatography-mass spectrometry (LC-MS) traces from ARI-001 of Shanghai SpeedChem (Shanghai, China). The purity was determined using the UV absorbance at 215 nm. The peak area at 3.59 min accounted for 98.9% of the total peak area of the trace.

Figure 2 shows the relative stability of ARI-001 under storage conditions as defined herein. The total area of the peaks representing ARI-001 was calculated and then corrected for the total area of the peaks identified on the LC-MS trace. It is expressed as % of the total peak. Above: Powder formulation; (■) Standard conditions: 50 ° C, no specified humidity. Below: liquid formulation; ( ) room temperature (rt); (■) 4 ° C; (▲) 20 ° C.

Figure 3 shows superimposed FPLC traces of confluent plasma of hamsters receiving normal food (solid line) or high fat + high sugar (HF/HS) food (dotted line).

Figure 4 shows FPLC traces of confluent plasma of hamsters receiving vehicle (solid line), 1200 mg/kg (mpk) niacin (dotted line) or 2240 mg/kg ARI-001 (dashed line).

Figure 5 shows the change in lipid parameters as a function of ARI-001 dose (expressed in mmol/kg/d). ARI-001 (■ and the connecting line) showed a dose-dependent effect on the lipid value of HF/HS hamsters. Nicotinic acid ) shows significance only for changes in total cholesterol (TC), high density lipoprotein (HDL), and low density lipoprotein (LDL).

Figures 6 and 7 show the correlation between lipid parameters and ARI-001 plasma concentrations. Each lipid parameter achieved a statistically significant negative correlation with ARI-001 concentration, with the exception of HDL, which was statistically significant and positively correlated. Draw a linear correlation line (solid line) and a 95% confidence zone (dashed curve) of the associated line. Given the Pearson r correlation coefficient for each data set, the 95% confidence interval is in parentheses. P is the result of a 2-tailed unpaired t-test.

Figure 8 shows (left panel) the correlation between liver and plasma concentrations of ARI-001 in HF/HS hamsters administered for 18 days. The values of the organizations are logarithmically transformed, and thus the axes have no units. (Right) Correlation between fat and plasma concentrations in the same animals. The fat concentration is transformed by the function "logarithm+1", which causes any value between -1 and 0 to become a positive value. This is for clarity and does not otherwise distort the distribution of data sets.

Figure 9 to Figure 11 show the correlation between liver concentration of ARI-001 and different lipid parameter values in HF/HS hamsters; and the correlation between adipose tissue concentration of ARI-001 and different lipid parameter values in HF/HS hamsters. Sex. All values are logarithm of the lipid value versus logarithm of tissue concentration. Correlation is the correlation between tissue concentration and lipid value in the same animal. The fat concentration is transformed by the function "logarithm + 1", which causes any value between -1 and 0 to become a positive value. This is for clarity and does not otherwise distort the distribution of data sets.

Figures 12A and 12B show liver function test parameters of a high fat fed hamster administered orally, niacin or ARI-001 for 18 days. Give the percentage change relative to the vehicle. The P-value of the two-tailed unpaired t-test compared to the vehicle was reported. Figure 12A: Aspartate aminotransferase (AST). Figure 12B: Alanine aminotransferase (ALT).

Figure 13 shows the glucose values measured in plasma for an 18 day study of HF/HS hamsters administered vehicle, niacin or ARI-001 daily. The percentage of change reported relative to the mediator group value. The P value was determined from a two-tailed t test.

Figure 14 shows the plasma concentration of ARI-001 of mice administered ARI-001 in a single oral (PO) or intraperitoneal (IP) manner.

15A to 15D show plasma concentrations of ARI-001 of mice administered orally to ARI-001 for several consecutive days for 30 days. Use four different doses. Each mouse received the same indicated dose of ARI-001 daily for 30 days.

Figure 16A and Figure 16B show a summary of _Cmax and AUC parameters from ARI-001 for a 30-day multiple dosing study on wild type mice. The values are plotted as mean and standard error. There is no significant change in any of the parameters as a function of time. ( 996 mg/kg/d; (□) 1493 mg/kg/d; (σ) 2240 mg/kg/d; ) 3360 mg / kg / d.

Figure 17 shows the plasma concentration of ARI-001 after a single dose of 5.9 mmol/kg ARI-001 in a golden Syrian hamster (Golden Syrian Hamster) receiving high fat/high sugar food.

Figure 18 shows a fasting monkey in a single administration (♦) 96 mg/kg (intravenous (IV)) or ( 288 mg/kg (mpk) (oral (PO)) ARI-001 plasma concentration after ARI-001. For the sake of clarity, the Y-axis is a logarithmic scale. (Illustration): The same data, where the y-axis is a linear scale.

Figure 19 shows a single feeding (◆) feeding monkey or (by) Plasma concentration of ARI-001 after 288 mg/kg of fasting monkeys. Values are mean and standard error.

Figure 20 shows the plasma concentration of ARI-001 after repeated oral administration of 288 mg/kg of fasted monkeys daily. Values are mean and standard error. (◆) Samples taken on the first day. ( The sample taken on the 7th day.

Figure 21 shows that ARI-001 failed to recruit β-arrestin to the cell membrane of cells expressing the nicotinic acid receptor GPR109A. According to the instructions, the coordination system refers to nicotinic acid or ARI-001. RLU, relative light units, as measured by chemiluminescent readings of G protein coupled receptor activity.

Figure 22 shows the dose response of a triglyceride reduction in a human patient receiving a single oral dose of ARI-001. The percent change is the average percent change in triglyceride at 4 hours post dose.

Figure 23 shows the ARI-001 serum concentration as a function of time after a single oral administration of the human patient indicated amount of ARI-001.

Claims (165)

Use of a nicotinic acid analogue or a pharmaceutically acceptable salt thereof for the manufacture to reduce at least one selected from the group consisting of total cholesterol, low density lipoprotein (LDL) cholesterol, triglyceride, and lipoprotein (a) a serum or plasma content of a lipid of a group consisting of a pharmaceutical product which is orally administered to a human in need thereof, wherein the oral administration is characterized by oral administration and the like. The immediate release of otonic acid from the ear dose reduces flushing and reduces hepatocyte damage. The use of the first aspect of the invention, wherein the peak concentration ( _Cmax ) of the nicotinic acid analog is 40% or less of the _Cmax of the immediate release niacin of the molar oral dose. The use of the first or second aspect of the patent application, wherein the ratio of the peak concentration of the nicotinic acid analog to the area under the curve at 24 hours (C _max /AUC _0-24 ) is 0.35 h ^-1 or less. The use of the first or second aspect of the patent application, wherein the time (t _max ) at which the nicotinic acid analog reaches a peak concentration is in the range of 1 to 5 hours. The EC patent two of the scope of use or 1, wherein the nicotinic acid analogs to inhibit protein β- (β-arrestin) GPR109A mediated function ₅₀ of nicotinic acid on β- mediated inhibition of protein GPR109A The EC _{50 of the} function is at least 10 times larger. The use of the first or second aspect of the patent application, wherein the nicotinic acid analogue also increases the serum or plasma content of high density lipoprotein (HDL) cholesterol when administered orally to a human. The use of the first or second aspect of the patent application, wherein the oral administration is characterized by substantially serum content of aspartate aminotransferase (AST), alanine aminotransferase (ALT) or both No increase. The use of claim 1 or 2, wherein the pharmaceutical product further comprises statin. For example, the application of the scope of claim 8 wherein the statin is selected from the group consisting of atorvastatin, cerivastatin, fluvastatin, and lovastatin. Lastatastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin. The use of claim 1 or 2, wherein the pharmaceutical product further comprises at least one other therapeutic agent selected from the group consisting of: an 11β HSD-1 inhibitor, a 5HT transporter inhibitor, and a 5HT2c agonist. Agent, 5-LO or FLAP inhibitor, alpha-glucosidase inhibitor, ABCA1 enhancer, ACC inhibitor, sulfhydryl-based CoA: cholesterol O-thiotransferase inhibitor, thiol-estrogen, anti-diabetic agent, Anti-lipid aberrant, antihypertensive, antioxidant, Apo A1 mimetic, Apo A1 modulator, Apo E mimetic, apolipoprotein-B secreting/microsomal triglyceride transfer protein (apo-B/MTP) Inhibitors, appetite suppressants, aspirin, β3 agonists, bile acid reuptake inhibitors, bile acid chelators, campesin agonists, BRS3 agonists, CB ₁ antagonists/anti Promoter, CCK-A agonist, cholesterol absorption inhibitor, cholesterol transport inhibitor, cholesterol ester transfer protein (CETP) inhibitor, CNTF, CNTF agonist/modulator, ezetimibe Combination with simvastatin and/or atorvastatin, CSL-111, dehydroepiandrosterone, delipidated HDL, DGA T antisense oligomer, DGAT1 inhibitor, DGAT2 inhibitor, dicarboxylate transporter inhibitor, dopamine agonist, DP receptor antagonist, ezetimibe, FAS inhibitor, fatty acid binding protein (FABP) Inhibitors, fatty acid transporter inhibitors, fatty acid transporter protein (FATP) inhibitors, flushing inhibitors, FXR receptor modulators, galanin receptor antagonists, gemcabene, brain gut peptide (ghrelin) Antagonist, brain gut peptide antibody, GLP-1 agonist, glycosidin-like peptide-1 receptor agonist, glucocorticoid agonist/antagonist, glucose transporter inhibitor, HDL mimetic, HMG CoA Reductase inhibitor compound, HMG-CoA synthetase inhibitor, hormone sensitive lipase antagonist, human hamster color related protein (AGRP), H ₃ antagonist/reverse agonist, inorganic cholesterol chelating agent, L-4f, Lapaquistat, leptin agonist/modulator, leptin, lipase inhibitor, lipoprotein synthesis inhibitor, lorapoprant, low-density lipoprotein receptor inducer or activator, Lp(a) reducing agent, LXR receptor agonist, lyn kinase inhibitor, Mc3r Agent, Mc4r agonist, MCH1R antagonist, MCH2R agonist/antagonist, melanin-concentrating hormone antagonist, mGluR5 antagonist, microsomal triglyceride transport inhibitor, monoamine reuptake inhibitor, natural water solubility Fiber, NE transporter inhibitor, neuromodulin U receptor agonist, neuropeptide-Y antagonist, nicotinic acid or nicotinic acid receptor agonist, niacin, norepinephrine Sexual appetite suppressant (noradrenergic anorectic agent), NPY1 antagonist, NPY2 agonist, NPY4 agonist, NPY5 antagonist, non-steroidal anti-inflammatory agent (NSAID), omega-3 fatty acid, opioid antagonist, orexin (orexin) a receptor antagonist, a PDE inhibitor, a phentermine, a phosphate transporter inhibitor, a phytopharm compound 57, a plant stanol, and/or a fatty acid of a plant stanol Ester, platelet aggregation inhibitor, PPAR-α agonist, PPAR-δ agonist, PPAR-δ partial agonist, PPAR-γ agonist, probucol, renin angiotensin inhibitor , reverse-4F, SCD-1 inhibitor, serotonin reuptake inhibitor, SG LT2 inhibitor, squalene epoxidase inhibitor, squalene synthesis inhibitor, sterol biosynthesis inhibitor, sympathomimetic agonist, thyroid hormone beta agonist, thyroxine, topiramate , a triglyceride synthesis inhibitor, a UCP-1 activator, a UCP-2 activator, a UCP-3 activator, and a urocortin binding protein antagonist. A pharmaceutical composition comprising a nicotinic acid analog or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient; wherein the composition is formulated for oral administration; the smoke The alkali acid analog lowers serum or plasma of at least one lipid selected from the group consisting of total cholesterol, low density lipoprotein (LDL) cholesterol, triglyceride, and lipoprotein (a) when orally administered to a human. The composition; and oral administration of the composition is characterized by reducing flushing and reducing hepatocyte damage as compared to administration of a molar oral dose of niacin. The pharmaceutical composition of claim 11, wherein the peak concentration ( _Cmax ) of the nicotinic acid analog is 40% or less of the _Cmax of the oleic acid of the molar oral dose. The pharmaceutical composition of claim 11 or 12, wherein the ratio of the peak concentration of the nicotinic acid analog to the area under the curve at 24 hours (C _max /AUC _0-24 ) is 0.35 h ^-1 or less. . A pharmaceutical composition according to claim 11 or 12, wherein the time (t _max ) at which the nicotinic acid analog reaches a peak concentration is in the range of 30 minutes to 5 hours. The pharmaceutical composition of claim 11 or 12, wherein the cyanoic acid analog has an EC ₅₀ for β-arrestin-mediated GPR109A function as an EC of nicotinic acid to β-arrestin-mediated GPR109A function. _{50 is} at least 10 times larger. The pharmaceutical composition of claim 11 or 12, wherein the nicotinic acid analog also increases the serum or plasma content of high density lipoprotein (HDL) cholesterol when administered orally to a human. The pharmaceutical composition according to claim 11 or 12, wherein the nicotinic acid analog substantially does not cause aspartate aminotransferase (AST) or alanine aminotransferase when orally administered to a human. There is any increase in serum levels of (ALT) or both. The pharmaceutical composition of claim 11 or 12, wherein the nicotinic acid analog does not substantially increase the serum content of uric acid, glucose or both when administered orally to a human. The pharmaceutical composition of claim 11 or 12, wherein the nicotinic acid analog is represented by structure I : Wherein A is a heterocyclic or heteroaryl group optionally having 5 to 12 ring atoms including X and N, optionally substituted by 1 to 3 groups selected from the group consisting of: Base substitution: alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, halogen, nitro, cyano, sulfonic acid, alkyl thiooxy, aryl thiooxy ,heteroarylthiooxy, aralkylthiooxy, heteroaralkylthiooxy, alkenylthiooxy, alkynylthiooxy, alkylsulfonyl, arylsulfonyl, heteroaryl Sulfonyl, aralkylsulfonyl, heteroaralkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, hydroxy, alkoxy, aryloxy, heteroaryloxy, aralkyloxy , heteroaralkyloxy, alkenyloxy, alkynyloxy, thiol, alkylthio, arylthio, aralkylthio, heteroaralkylthio, alkylthio, alkynylthio, decyl, Sulfhydryl, methyl methoxy, decyloxy, methylthio, thiol, amine, alkylamine, arylamine, heteroarylamine, aralkylamine, heteroarylalkylamine, alkenylamine , alkynylamine, formamylamine, mercaptoamine, carboxyl, alkoxycarbonyl, Oxycarbonyl, heteroaryloxycarbonyl, aralkyloxycarbonyl, heteroaralkyloxycarbonyl, decylamino, alkylaminecarbonyl, arylaminecarbonyl, heteroarylaminecarbonyl, aralkylaminecarbonyl, and Heteroarylalkylamine carbonyl; X is O, S, N or N(R ⁶ ); Z is Or a homo-electron arrangement of carboxyl groups; X ¹ is O or S; X ² is O or S; R is hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, heterocyclyl Alkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, fused bicyclic, carboxyalkyl, or arylalkenylaryl; R ² is hydrogen, lower alkyl, lower alkenyl , lower alkynyl, halogen, hydroxy, amine, carboxyl, cycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cyano, or nitro; R ³ is hydrogen, lower alkyl , lower alkenyl, lower alkynyl, halogen, hydroxy, amine, carboxyl, cycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cyano, or nitro; R ⁵ in each The second occurrence is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, halogen, nitro, cyano, Sulfonic acid, alkylthiooxy, arylthiooxy, heteroarylthiooxy, aralkylthiooxy, heteroaralkylthiooxy, alkenylthiooxy, alkynylthiooxy, alkane Sulfosyl, arylsulfonyl, heteroarylsulfonyl, aralkylsulfonyl Heteroaralkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, hydroxy, alkoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, alkenyloxy, Alkynyloxy, thiol, alkylthio, arylthio, aralkylthio, heteroaralkylthio, alkylthio, alkynylthio, decyl, decyl, methyloxy, decyloxy , formazanyl, sulfonylthio, amine, alkylamine, arylamine, heteroarylamine, aralkylamine, heteroarylalkylamine, alkenylamine, alkynylamine, formamylamine, hydrazine Alkylamine, carboxyl group, alkoxycarbonyl group, aryloxycarbonyl group, heteroaryloxycarbonyl group, aralkyloxycarbonyl group, heteroaralkyloxycarbonyl group, decylamino group, alkylamine carbonyl group, arylamine carbonyl group, heteroaryl group a carbonyl group, an arylalkylamine carbonyl group, and a heteroarylalkylamine carbonyl group; R ⁶ is hydrogen or a lower alkyl group; and m is 1, 2, 3 or 4. A pharmaceutical composition according to claim 19, wherein A represents a heterocyclic group. A pharmaceutical composition according to claim 19, wherein A represents a heteroaryl group. A pharmaceutical composition according to claim 19, wherein A is a monocyclic group having 5, 6 or 7 ring atoms. A pharmaceutical composition according to claim 19, wherein A is a bicyclic group having 9, 10, 11 or 12 ring atoms. For example, the pharmaceutical composition of claim 19, wherein X is O. For example, the pharmaceutical composition of claim 19, wherein X is S. For example, the pharmaceutical composition of claim 19, wherein X is N. The pharmaceutical composition of claim 19, wherein X is N(R ⁶ ). The pharmaceutical composition of claim 19, wherein A is pyrrolidinyl, imidazolidinyl, thiazolidinyl, isothiazolidinyl, Azolidinyl, Diazolidinyl, piperidinyl, piperid Base, thiomorpholinyl or morpholinyl. For example, the pharmaceutical composition of claim 19, wherein A is imidazolyl, pyrazolyl, or different Azolyl, Azyl, isothiazolyl, thiazolyl, Base, furfuryl, Diazolyl, thiadiazolyl, triazolyl, dithiazolyl, di base, Base Base, three Base, four Base, diazepine or thiazolidine. The pharmaceutical composition of claim 19, wherein A is substituted with 1 to 3 substituents independently selected from the group consisting of lower alkyl, halogen, nitro, cyano, sulfonic acid , hydroxy, alkoxy, thiol, alkylthio, decyl, decyl, methyl methoxy, decyloxy, methylthio, thiol, amine, alkylamine, formamide, Mercaptoamine and carboxyl groups. The pharmaceutical composition of claim 19, wherein A is substituted with one substituent independently selected from the group consisting of lower alkyl, halogen, nitro, cyano, sulfonic acid, hydroxyl , alkoxy, thiol, alkylthio, decyl, decyl, methyl methoxy, decyloxy, methylthio, thiol, amine, alkylamine, formamide, sulfhydryl Amines and carboxyl groups. For example, the pharmaceutical composition of claim 19, wherein A is unsubstituted. A pharmaceutical composition according to claim 19, wherein R ² is hydrogen or a lower alkyl group. A pharmaceutical composition according to claim 19, wherein R ² is hydrogen. A pharmaceutical composition according to claim 19, wherein R ³ is hydrogen or a lower alkyl group. A pharmaceutical composition according to claim 19, wherein R ³ is hydrogen. The pharmaceutical composition of claim 19, wherein R ² is a lower alkyl group and R ³ is hydrogen. The pharmaceutical composition of claim 19, wherein R ² is hydrogen and R ³ is lower alkyl. The pharmaceutical composition of claim 19, wherein R ² is hydrogen and R ³ is hydrogen. For example, the pharmaceutical composition of claim 19, wherein m is 1. For example, the pharmaceutical composition of claim 19, wherein m is 2. For example, the pharmaceutical composition of claim 19, wherein m is 3. For example, the pharmaceutical composition of claim 19, wherein m is 4. The pharmaceutical composition of claim 19, wherein each occurrence of R ⁵ is independently selected from the group consisting of hydrogen, lower alkyl, halogen, nitro, cyano, sulfonic acid, Hydroxy, alkoxy, thiol, alkylthio, decyl, decyl, methyl methoxy, decyloxy, methylthio, sulfonyl, amine, alkylamine, formamide, hydrazine Base amine and carboxyl group. A pharmaceutical composition according to claim 19, wherein R ⁵ is hydrogen. A pharmaceutical composition according to claim 19, wherein Z is a carboxyl group. The pharmaceutical composition of claim 19, wherein Z is a carboxyl group and an electron alignment. For example, the pharmaceutical composition of claim 19, wherein Z is a tetrazolyl group, Azolidinone, sulfonic acid, sulfinic acid, decylsulfonamide, phosphonic acid, phosphinic acid, beta-urea, pyrrolidone, 3-iso Azolyl or boric acid. For example, the pharmaceutical composition of claim 19, wherein Z is For example, the pharmaceutical composition of claim 49, wherein X ¹ is O. For example, the pharmaceutical composition of claim 49, wherein X ¹ is S. For example, the pharmaceutical composition of claim 49, wherein X ² is O. For example, the pharmaceutical composition of claim 49, wherein X ² is S. A pharmaceutical composition according to claim 49, wherein X ¹ is O and X ² is O. For example, the pharmaceutical composition of claim 49, wherein R is hydrogen. A pharmaceutical composition according to claim 49, wherein R is a lower alkyl group. For example, the pharmaceutical composition of claim 49, wherein R is A pharmaceutical composition according to claim 49, wherein R represents an aliphatic group which can be hydrolyzed to a carboxyl group under physiological conditions. The pharmaceutical composition of claim 11 or 12, wherein the nicotinic acid analog is represented by Formula II : Wherein, at each occurrence, independently, W is a polyol or a polythiol; p is from 2 to 500, including 2 and 500; R ¹ is And attached to the polyol via an oxygen atom of the polyol or attached to the polythiol via a sulfur atom of the polythiol; A is as appropriate for 5 to 12 ring atoms including X and N. a heterocyclic or heteroaryl group optionally substituted with from 1 to 3 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, Aralkyl, heteroaralkyl, halogen, nitro, cyano, sulfonic acid, alkyl thiooxy, aryl thiooxy, heteroaryl thiooxy, aralkyl thiooxy, heteroarylalkyl Thioxy, alkenylthiooxy, alkynylthiooxy, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aralkylsulfonyl, heteroaralkylsulfonyl, Alkenylsulfonyl, alkynylsulfonyl, hydroxy, alkoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, alkenyloxy, alkynyloxy, thiol, alkane Sulfur, arylthio, aralkylthio, heteroaralkylthio, alkylthio, alkynylthio, decyl, decyl, methyloxy, decyloxy, methylthio, sulfonium Base, amine, alkylamine, arylamine, heteroarylamine Aralkylamine, heteroarylalkylamine, alkenylamine, alkynylamine, formamylamine, mercaptoamine, carboxyl, alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, aralkyloxy Carbonyl, heteroaralkyloxycarbonyl, decylamino, alkylaminecarbonyl, arylaminecarbonyl, heteroarylaminecarbonyl, aralkylaminecarbonyl, and heteroaralkylaminecarbonyl; X is O, S, N Or N(R ⁶ ); X ¹ is O or S; R is hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl a heteroaryl group, a heteroarylalkyl group, a fused bicyclic group, a carboxyalkyl group, or an arylalkenylaryl group; R ² is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, halogen, Hydroxyl, amine, carboxyl, cycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cyano, or nitro; R ³ is hydrogen, lower alkyl, lower alkenyl, lower carbon Alkynyl, halogen, hydroxy, amine, carboxy, cycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cyano, or nitro; R ⁵ is independently selected from each of the following Group consisting of: hydrogen, alkyl, alkenyl, alkynyl, aryl Heteroaryl, aralkyl, heteroaralkyl, halogen, nitro, cyano, sulfonic acid, alkylthiooxy, arylthiooxy, heteroarylthiooxy, aralkylthiooxy, Heteroaralkylthio, alkenylthio, alkynylthio, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aralkylsulfonyl, heteroarylalkyl Sulfonyl, alkenylsulfonyl, alkynylsulfonyl, hydroxy, alkoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, alkenyloxy, alkynyloxy, Mercaptan, alkylthio, arylthio, aralkylthio, heteroaralkylthio, alkylthio, alkynylthio, decyl, decyl, methyl methoxy, decyloxy, methyl sulfonium Base, sulfonylthio, amine, alkylamine, arylamine, heteroarylamine, aralkylamine, heteroarylalkylamine, alkenylamine, alkynylamine, formamylamine, mercaptoamine, carboxyl , alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, aralkoxycarbonyl, heteroaralkyloxycarbonyl, decylamino, alkylaminecarbonyl, arylaminecarbonyl, heteroarylaminecarbonyl, aminocarbonyl aralkyl, and heteroaralkyl aminocarbonyl; R ⁶ is hydrogen or lower Alkyl; and m is 2, 3, or 4. For example, the pharmaceutical composition of claim 59, wherein W is a polythiol. For example, the pharmaceutical composition of claim 59, wherein W is a polyhydric alcohol. The pharmaceutical composition of claim 61, wherein the polyol is a carbohydrate. The pharmaceutical composition of claim 61, wherein the polyol is maltitol, sorbitol, xylitol or isomalt. The pharmaceutical composition of claim 61, wherein the polyol is sorbitol. The pharmaceutical composition of claim 61, wherein the polyol is inositol. The pharmaceutical composition of claim 59, wherein p is 2, 3, 4, 5, or 6. The pharmaceutical composition of claim 11 or 12, wherein the nicotinic acid analog reduces the EC ₅₀ of serum cholesterol, LDL and/or triglyceride of the average human patient population by no more than the nicotinic acid analog A 20% of the half maximal concentration of skin vasodilation (flushing) is caused in this average human patient population. The pharmaceutical composition of claim 67, wherein the nicotinic acid analog lowers the serum ₅₀ , cholesterol, LDL and/or triglyceride EC ₅₀ does not exceed the nicotinic acid analog in the average human patient population. It causes 1% of the half-maximal concentration of skin vasodilation (flushing). The pharmaceutical composition of claim 11 or 12, wherein the nicotinic acid analog reduces the EC ₅₀ of serum cholesterol, LDL and/or triglyceride of the average human patient population by no more than the nicotinic acid analog The serum levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) are increased to require a 20% reduction in the concentration of the pharmaceutical composition to be administered. The pharmaceutical composition of claim 11 or 12, wherein the nicotinic acid analog is effective for lowering serum lipids when administered once a day without causing the following limitations of treatment: (i) liver toxicity and (ii) ) An increase in uric acid content or glucose content or both, or the treatment will need to be discontinued. For example, the pharmaceutical composition of claim 11 or 12 also includes statin. For example, the pharmaceutical composition of claim 71, wherein the statin is selected from the group consisting of atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, and pitamate. Ruvastatin, pravastatin, rosuvastatin and simvastatin. The pharmaceutical composition according to claim 11 or 12, further comprising at least one other therapeutic agent selected from the group consisting of an 11β HSD-1 inhibitor, a 5HT transporter inhibitor, a 5HT2c agonist, 5-LO or FLAP inhibitor, alpha-glucosidase inhibitor, ABCA1 enhancer, ACC inhibitor, sulfhydryl-based CoA: cholesterol O-thiol transferase inhibitor, thiol-estrogen, anti-diabetic, anti-lipid Abnormal agents, antihypertensive agents, antioxidants, Apo A1 mimetic, Apo A1 modulator, Apo E mimetic, apolipoprotein-B secreting/microsomal triglyceride transfer protein (apo-B/MTP) inhibitor , appetite suppressant, aspirin, beta 3 agonist, cholic acid reuptake inhibitor, cholic acid chelating agent, bombesin agonist, BRS3 agonist, CB ₁ antagonist / inverse agonist, CCK-A agonist, cholesterol absorption inhibitor, cholesterol transport inhibitor, cholesterol ester transfer protein (CETP) inhibitor, CNTF, CNTF agonist/modulator, ezetimibe and simvastatin and/or ar Combination of atorvastatin, CSL-111, dehydroepiandrosterone, delipidated HDL, DGAT antisense oligomer, DGAT1 Formulations, DGAT2 inhibitors, dicarboxylate transporter inhibitors, dopamine agonists, DP receptor antagonists, ezetimibe, FAS inhibitors, fatty acid binding protein (FABP) inhibitors, fatty acid transporter inhibitors , fatty acid transporter protein (FATP) inhibitor, flushing inhibitor, FXR receptor modulator, galanin receptor antagonist, gemcabene, brain gut peptide antagonist, brain gut peptide antibody, GLP-1 agonist, Glucagon-like peptide-1 receptor agonist, glucocorticoid agonist/antagonist, glucose transporter inhibitor, HDL mimetic, HMG CoA reductase inhibitor compound, HMG-CoA synthetase inhibitor, hormone Sensitive lipase antagonist, human hamster color related protein (AGRP), H ₃ antagonist/reverse agonist, inorganic cholesterol chelating agent, L-4f, lapastat, leptin agonist/regulator, thin , lipase inhibitors, lipoprotein synthesis inhibitors, lopavirin, low-density lipoprotein receptor inducer or activator, Lp(a) reducing agent, LXR receptor agonist, lyn kinase inhibitor, Mc3r Agent, Mc4r agonist, MCH1R antagonist, MCH2R agonist/antagonist, black Hormone antagonists, mGluR5 antagonists, microsomal triglyceride transport inhibitors, monoamine reuptake inhibitors, natural water soluble fibers, NE transporter inhibitors, neuromodulin U receptor agonists, nerves Peptide-Y antagonist, nicotinic acid or nicotinic acid receptor agonist, nicotinic acid, norepinephrine-induced appetite suppressant, NPY1 antagonist, NPY2 agonist, NPY4 agonist, NPY5 antagonist , non-steroidal anti-inflammatory agents (NSAID), omega-3 fatty acids, opioid antagonists, orexin receptor antagonists, PDE inhibitors, phentermine, phosphate transporter inhibitors, botanical compounds 57, plant stanols And/or fatty acid esters of plant stanols, platelet aggregation inhibitors, PPAR-α agonists, PPAR-δ agonists, PPAR-δ partial agonists, PPAR-γ agonists, probucol, Renin angiotensin inhibitor, reverse-4F, SCD-1 inhibitor, serotonin reuptake inhibitor, SGLT2 inhibitor, squalene epoxidase inhibitor, squalene synthesis inhibitor, sterol biosynthesis Inhibitor, sympathomimetic agonist, thyroid hormone beta agonist, thyroxine Agent, topiramate, triglyceride synthesis inhibitor, UCP-1 activator, UCP-2 activator, UCP-3 activator, and urocortin-binding protein antagonist. The pharmaceutical composition of claim 11, wherein the peak concentration ( _Cmax ) of the nicotinic acid analog is 40% or less of the _Cmax of the immediate release niacin of the molar oral dose. The pharmaceutical composition of claim 11 or 74, wherein the time (t _max ) at which the nicotinic acid analog reaches a peak concentration is in the range of 1 to 5 hours. A pharmaceutical composition according to claim 11 for use in the treatment of hyperlipidemia, hypercholesterolemia, lipid dystrophy, dyslipidemia, atherosclerosis or coronary artery disease. A pharmaceutical composition according to claim 11 for use in the treatment of metabolic syndrome, obesity, fatty liver disease, or diabetes. For example, the pharmaceutical composition of claim 11 is for raising serum high density lipoprotein (HDL) content. For example, the pharmaceutical composition of claim 11 is for reducing serum low density lipoprotein (LDL) content or lowering serum lipoprotein (a) content. For example, the pharmaceutical composition of claim 11 for treating congestive heart failure, cardiovascular disease, hypertension, coronary heart disease, colic, pellagra, Hartnup's syndrome, carcinoid Tumor syndrome, arterial obstructive disease, hypothyroidism, vasoconstriction, osteoarthritis, rheumatoid arthritis, Alzheimer's disease, peripheral and central nervous system disorders, hematological diseases, cancer, inflammation , respiratory diseases, or gastrointestinal diseases. The pharmaceutical composition according to any one of claims 76 to 80, further comprising a statin. For example, the pharmaceutical composition of claim 81, wherein the statin is selected from the group consisting of atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, and pitamate. Ruvastatin, pravastatin, rosuvastatin and simvastatin. The pharmaceutical composition according to any one of claims 76 to 80, further comprising at least one other therapeutic agent selected from the group consisting of 11β HSD-1 inhibitor, 5HT transporter inhibitor, 5HT2c Agonists, 5-LO or FLAP inhibitors, alpha-glucosidase inhibitors, ABCA1 enhancers, ACC inhibitors, sulfhydryl-based CoA: cholesterol O-thiotransferase inhibitors, thiol-estrogen, anti-diabetes Agent, anti-lipid aberrant, antihypertensive agent, antioxidant, Apo A1 mimetic, Apo A1 modulator, Apo E mimetic, apolipoprotein-B secretion/microsomal triglyceride transfer protein (apo-B/ MTP) inhibitors, appetite suppressants, aspirin, beta 3 agonists, cholic acid reuptake inhibitors, cholic acid chelators, campesin agonists, BRS3 agonists, CB ₁ antagonists / reverse Agonists, CCK-A agonists, cholesterol absorption inhibitors, cholesterol transport inhibitors, cholesterol ester transfer protein (CETP) inhibitors, CNTF, CNTF agonists/modulators, ezetimibe and simvastatin And/or combination of atorvastatin, CSL-111, dehydroepiandrosterone, delipidated HDL, DGAT antisense oligomerization , DGAT1 inhibitor, DGAT2 inhibitor, dicarboxylate transporter inhibitor, dopamine agonist, DP receptor antagonist, ezetimibe, FAS inhibitor, fatty acid binding protein (FABP) inhibitor, fatty acid transport Inhibitors, fatty acid transporter protein (FATP) inhibitors, flushing inhibitors, FXR receptor modulators, galanin receptor antagonists, gemcabene, brain gut peptide antagonists, brain gut peptide antibodies, GLP-1 Agent, glycoside-like peptide-1 receptor agonist, glucocorticoid agonist/antagonist, glucose transporter inhibitor, HDL mimetic, HMG CoA reductase inhibitor compound, HMG-CoA synthetase inhibition Agent, hormone sensitive lipase antagonist, human wild mouse color related protein (AGRP), H ₃ antagonist / inverse agonist, inorganic cholesterol clamp, L-4f, lapastat, leptin agonist / regulation Agent, leptin, lipase inhibitor, lipoprotein synthesis inhibitor, lopavirin, low-density lipoprotein receptor inducer or activator, Lp(a) reducing agent, LXR receptor agonist, lyn kinase inhibitor , Mc3r agonist, Mc4r agonist, MCH1R antagonist, MCH2R agonist / antagonist Agent, melanin-concentrating hormone antagonist, mGluR5 antagonist, microsomal triglyceride transport inhibitor, monoamine reuptake inhibitor, natural water-soluble fiber, NE transporter inhibitor, neuromodulin U receptor agonist , neuropeptide-Y antagonist, nicotinic acid or nicotinic acid receptor agonist, nicotinic acid, norepinephrine-induced appetite suppressant, NPY1 antagonist, NPY2 agonist, NPY4 agonist, NPY5 Antagonists, non-steroidal anti-inflammatory agents (NSAIDs), omega-3 fatty acids, opioid antagonists, orexin receptor antagonists, PDE inhibitors, phentermine, phosphate transporter inhibitors, botanical compounds 57, plant solids Fatty acid esters of alkanols and/or plant stanols, platelet aggregation inhibitors, PPAR-α agonists, PPAR-δ agonists, PPAR-δ partial agonists, PPAR-γ agonists, probu , renin-angiotensin inhibitor, reverse-4F, SCD-1 inhibitor, serotonin reuptake inhibitor, SGLT2 inhibitor, squalene epoxidase inhibitor, squalene synthesis inhibitor, sterol Biosynthesis inhibitor, sympathomimetic agonist, thyroid hormone β agonist, Thyroxine, topiramate, triglyceride synthesis inhibitor, UCP-1 activator, UCP-2 activator, UCP-3 activator, and urocortin-binding protein antagonist. The pharmaceutical composition of claim 83, wherein the at least one other therapeutic agent is selected from the group consisting of HMG-CoA reductase inhibitor, aspirin, cholesterol ester transfer protein (CETP) Inhibitor, NSAID, fibrate, proprotein convertase subtilisin/kexin type (PCSK9), inorganic cholesterol chelating agent, sulfhydryl-based CoA: cholesterol O-thiol transferase inhibitor, PPAR-α agonist Agent, PPAR-γ agonist, bile acid reuptake inhibitor, triglyceride synthesis inhibitor, lipoprotein receptor activator, DGAT1 inhibitor, SCD-1 inhibitor, lipase inhibitor, DP receptor antagonist Agent, apo A1 modulator, cholesterol transport inhibitor, metformin, nicotinic acid receptor agonist, and DPP-IV inhibitor. The pharmaceutical composition of claim 83, wherein the at least one other therapeutic agent is selected from the group consisting of: HMG-CoA reductase inhibitor, cholesterol ester transfer protein inhibitor, aspirin, Combination of NSAID, fiber ester, DP receptor antagonist, ezetimibe, and ezetimibe with simvastatin and/or atorvastatin. The pharmaceutical composition of claim 84, wherein the at least one other therapeutic agent is an HMG-CoA reductase inhibitor selected from the group consisting of atorvastatin, cerivastatin, and fluvastatin Statins, lovastatin, pitavastatin, pravastatin, rivastatin, rosuvastatin, and simvastatin. The pharmaceutical composition of claim 86, wherein the HMG CoA reductase inhibitor is simvastatin or atorvastatin. The pharmaceutical composition of claim 86, wherein the at least one other therapeutic agent is a cholesterol ester transfer protein inhibitor. The pharmaceutical composition of claim 86, wherein the at least one other therapeutic agent is ezetimibe, aspirin, ibuprofen, acetaminophen, or ezetimibe. A combination of simvastatin and/or atorvastatin. A compound represented by structure I or a pharmaceutically acceptable salt thereof, Wherein A is a heterocyclic or heteroaryl group optionally having 5 to 12 ring atoms including X and N, optionally substituted by 1 to 3 groups selected from the group consisting of: Base substitution: alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, halogen, nitro, cyano, sulfonic acid, alkyl thiooxy, aryl thiooxy ,heteroarylthiooxy, aralkylthiooxy, heteroaralkylthiooxy, alkenylthiooxy, alkynylthiooxy, alkylsulfonyl, arylsulfonyl, heteroaryl Sulfonyl, aralkylsulfonyl, heteroaralkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, hydroxy, alkoxy, aryloxy, heteroaryloxy, aralkyloxy , heteroaralkyloxy, alkenyloxy, alkynyloxy, thiol, alkylthio, arylthio, aralkylthio, heteroaralkylthio, alkylthio, alkynylthio, decyl, Sulfhydryl, methyl methoxy, decyloxy, methylthio, thiol, amine, alkylamine, arylamine, heteroarylamine, aralkylamine, heteroarylalkylamine, alkenylamine , alkynylamine, formamylamine, mercaptoamine, carboxyl, alkoxycarbonyl, Oxycarbonyl, heteroaryloxycarbonyl, aralkyloxycarbonyl, heteroaralkyloxycarbonyl, decylamino, alkylaminecarbonyl, arylaminecarbonyl, heteroarylaminecarbonyl, aralkylaminecarbonyl, and Heteroarylalkylamine carbonyl; X is O, S, N or N(R ⁶ ); Z is Or a homo-electron arrangement of carboxyl groups; X ¹ is O or S; X ² is O or S; R is hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, heterocyclyl Alkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, fused bicyclic, carboxyalkyl, or arylalkenylaryl; R ² is hydrogen, lower alkyl, lower alkenyl , lower alkynyl, halogen, hydroxy, amine, carboxyl, cycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cyano, or nitro; R ³ is hydrogen, lower alkyl , lower alkenyl, lower alkynyl, halogen, hydroxy, amine, carboxyl, cycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cyano, or nitro; R ⁵ in each The second occurrence is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, halogen, nitro, cyano, Sulfonic acid, alkylthiooxy, arylthiooxy, heteroarylthiooxy, aralkylthiooxy, heteroaralkylthiooxy, alkenylthiooxy, alkynylthiooxy, alkane Sulfosyl, arylsulfonyl, heteroarylsulfonyl, aralkylsulfonyl Heteroaralkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, hydroxy, alkoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, alkenyloxy, Alkynyloxy, thiol, alkylthio, arylthio, aralkylthio, heteroaralkylthio, alkylthio, alkynylthio, decyl, decyl, methyloxy, decyloxy , formazanyl, sulfonylthio, amine, alkylamine, arylamine, heteroarylamine, aralkylamine, heteroarylalkylamine, alkenylamine, alkynylamine, formamylamine, hydrazine Alkylamine, carboxyl group, alkoxycarbonyl group, aryloxycarbonyl group, heteroaryloxycarbonyl group, aralkyloxycarbonyl group, heteroaralkyloxycarbonyl group, decylamino group, alkylamine carbonyl group, arylamine carbonyl group, heteroaryl group a carbonyl group, an arylalkylamine carbonyl group, and a heteroarylalkylamine carbonyl group; R ⁶ is hydrogen or a lower alkyl group; and m is 1, 2, 3, or 4. A compound according to claim 90, wherein A represents a heterocyclic group. A compound of claim 90, wherein A represents a heteroaryl group. The compound of any one of claims 90 to 92, wherein A is a monocyclic group having 5, 6 or 7 ring atoms. The compound of any one of claims 90 to 92, wherein A is a bicyclic group having 9, 10, 11 or 12 ring atoms. The compound of any one of claims 90 to 92, wherein X is O. The compound of any one of claims 90 to 92, wherein X is S. The compound of any one of claims 90 to 92, wherein X is N. The compound of any one of claims 90 to 92, wherein X is N(R ⁶ ). A compound according to claim 90, wherein A is pyrrolidinyl, imidazolidinyl, thiazolidinyl, isothiazolidinyl, Azolidinyl, Diazolidinyl, piperidinyl, piperid Base, thiomorpholinyl or morpholinyl. Such as the compound of claim 90, wherein A is imidazolyl, pyrazolyl, iso Azolyl, Azyl, isothiazolyl, thiazolyl, Base, furfuryl, Diazolyl, thiadiazolyl, triazolyl, dithiazolyl, di base, Base Base, three Base, four Base, diazepine or thiazolidine. The compound of any one of claims 90 to 92, wherein A is substituted with 1 to 3 substituents independently selected from the group consisting of lower alkyl, halogen, nitro, cyanide Base, sulfonic acid, hydroxy, alkoxy, thiol, alkylthio, decyl, decyl, methyl methoxy, decyloxy, methylthio, thiol, amine, alkylamine, A Mercaptoamine, mercaptoamine and carboxyl. The compound of any one of claims 90 to 92, wherein A is substituted with one substituent independently selected from the group consisting of lower alkyl, halogen, nitro, cyano, Sulfonic acid, hydroxy, alkoxy, thiol, alkylthio, decyl, decyl, methyl methoxy, decyloxy, methylthio, thiol, amine, alkylamine, formazan Amine, mercaptoamine and carboxyl. The compound of any one of claims 90 to 92, wherein A is unsubstituted. The compound of any one of claims 90 to 92, wherein R ² is hydrogen or lower alkyl. The compound of any one of claims 90 to 92, wherein R ² is hydrogen. The compound of any one of claims 90 to 92, wherein R ³ is hydrogen or lower alkyl. The compound of any one of claims 90 to 92, wherein R ³ is hydrogen. The compound of any one of claims 90 to 92, wherein R ² is lower alkyl; and R ³ is hydrogen. The compound of any one of claims 90 to 92, wherein R ² is hydrogen; and R ³ is lower alkyl. The compound of any one of clauses 90 to 92, wherein R ² is hydrogen; and R ³ is hydrogen. The compound of any one of claims 90 to 92, wherein m is 1. The compound of any one of claims 90 to 92, wherein m is 2. The compound of any one of claims 90 to 92, wherein m is 3. The compound of any one of claims 90 to 92, wherein m is 4. The compound of any one of claims 90 to 92, wherein each occurrence of R ⁵ is independently selected from the group consisting of hydrogen, lower alkyl, halogen, nitro, cyano , sulfonic acid, hydroxy, alkoxy, thiol, alkylthio, decyl, decyl, methyl methoxy, decyloxy, methylthio, thiol, amine, alkylamine, formazan Alkylamine, mercaptoamine and carboxyl group. The compound of any one of claims 90 to 92, wherein R ⁵ is hydrogen. The compound of any one of claims 90 to 92, wherein Z is a carboxyl group. The compound of any one of claims 90 to 92, wherein Z is a carboxy-isomeric alignment. The compound of any one of claims 90 to 92, wherein Z is a tetrazolyl group, Zyridinone, sulfonic acid, sulfinic acid, decylsulfonamide, phosphonic acid, phosphinic acid, beta-urea, pyrrolidone, 3-iso Azolyl or boric acid. A compound according to any one of claims 90 to 92, wherein Z is . A compound of claim 120, wherein X ¹ is O. A compound of claim 120, wherein X ¹ is S. A compound of claim 120, wherein X ² is O. A compound of claim 120, wherein X ² is S. A compound of claim 120, wherein X ¹ is O; and X ² is O. A compound of claim 120, wherein R is hydrogen. A compound of claim 120, wherein R is a lower alkyl group. For example, the compound of claim 120, wherein R is A compound according to claim 120, wherein R represents an aliphatic group which can be hydrolyzed to a carboxyl group under physiological conditions. a compound of formula II or a pharmaceutically acceptable salt thereof, Wherein, at each occurrence, independently, W is a polyol or a polythiol; p is from 2 to 500, including 2 and 500; R ¹ is And attached to the polyol via an oxygen atom of the polyol or attached to the polythiol via a sulfur atom of the polythiol; A is as appropriate for 5 to 12 ring atoms including X and N. a heterocyclic or heteroaryl group optionally substituted with from 1 to 3 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, Aralkyl, heteroaralkyl, halogen, nitro, cyano, sulfonic acid, alkyl thiooxy, aryl thiooxy, heteroaryl thiooxy, aralkyl thiooxy, heteroarylalkyl Thioxy, alkenylthiooxy, alkynylthiooxy, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aralkylsulfonyl, heteroaralkylsulfonyl, Alkenylsulfonyl, alkynylsulfonyl, hydroxy, alkoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, alkenyloxy, alkynyloxy, thiol, alkane Sulfur, arylthio, aralkylthio, heteroaralkylthio, alkylthio, alkynylthio, decyl, decyl, methyloxy, decyloxy, methylthio, sulfonium Base, amine, alkylamine, arylamine, heteroarylamine Aralkylamine, heteroarylalkylamine, alkenylamine, alkynylamine, formamylamine, mercaptoamine, carboxyl, alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, aralkyloxy Carbonyl, heteroaralkyloxycarbonyl, decylamino, alkylaminecarbonyl, arylaminecarbonyl, heteroarylaminecarbonyl, aralkylaminecarbonyl, and heteroaralkylaminecarbonyl; X is O, S, N Or N(R ⁶ ); X ¹ is O or S; R is hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl a heteroaryl group, a heteroarylalkyl group, a fused bicyclic group, a carboxyalkyl group, or an arylalkenylaryl group; R ² is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, halogen, Hydroxyl, amine, carboxyl, cycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cyano, or nitro; R ³ is hydrogen, lower alkyl, lower alkenyl, lower carbon Alkynyl, halogen, hydroxy, amine, carboxy, cycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cyano, or nitro; R ⁵ is independently selected from each of the following Group consisting of: hydrogen, alkyl, alkenyl, alkynyl, aryl Heteroaryl, aralkyl, heteroaralkyl, halogen, nitro, cyano, sulfonic acid, alkylthiooxy, arylthiooxy, heteroarylthiooxy, aralkylthiooxy, Heteroaralkylthio, alkenylthio, alkynylthio, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aralkylsulfonyl, heteroarylalkyl Sulfonyl, alkenylsulfonyl, alkynylsulfonyl, hydroxy, alkoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, alkenyloxy, alkynyloxy, Mercaptan, alkylthio, arylthio, aralkylthio, heteroaralkylthio, alkylthio, alkynylthio, decyl, decyl, methyl methoxy, decyloxy, methyl sulfonium Base, sulfonylthio, amine, alkylamine, arylamine, heteroarylamine, aralkylamine, heteroarylalkylamine, alkenylamine, alkynylamine, formamylamine, mercaptoamine, carboxyl , alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, aralkoxycarbonyl, heteroaralkyloxycarbonyl, decylamino, alkylaminecarbonyl, arylaminecarbonyl, heteroarylaminecarbonyl, aminocarbonyl aralkyl, and heteroaralkyl aminocarbonyl; R ⁶ is hydrogen or lower Alkyl; and m is 2, 3, or 4. A compound of claim 130, wherein W is a polythiol. A compound of claim 130, wherein W is a polyol. A compound of claim 132, wherein the polyol is a carbohydrate. A compound according to claim 132, wherein the polyol is maltitol, sorbitol, xylitol or isomalt. The compound of claim 132, wherein the polyol is sorbitol. A compound according to claim 132, wherein the polyol is inositol. The compound of any one of claims 130 to 132, wherein p is 2, 3, 4, 5 or 6. A use of a compound according to any one of claims 90 to 137, or a pharmaceutical composition according to any one of claims 11 to 73, for use in the manufacture of hyperlipidemia, A medicament for hypercholesterolemia, lipid dystrophy, dyslipidemia, atherosclerosis or coronary artery disease, wherein the medicament is administered orally to a patient in need thereof. A use of a compound according to any one of claims 90 to 137, or a pharmaceutical composition according to any one of claims 11 to 73, for use in the manufacture of a metabolic syndrome, obesity A pharmaceutical product for fatty liver disease or diabetes, wherein the pharmaceutical product is administered orally to a patient in need thereof. A use of a compound according to any one of claims 90 to 137, or a pharmaceutical composition according to any one of claims 11 to 73, for use in the manufacture of a serum high density lipid A protein (HDL) content drug, wherein the drug is administered orally to a patient in need thereof. A use of a compound according to any one of claims 90 to 137, or a pharmaceutical composition according to any one of claims 11 to 73, for use in the manufacture of a serum low density lipoprotein for lowering (LDL) or a pharmaceutical product which lowers the serum lipoprotein (a) content, wherein the pharmaceutical is administered orally to a patient in need thereof. A use of a compound according to any one of claims 90 to 137, or a pharmaceutical composition according to any one of claims 11 to 73, for use in the manufacture of a congestive heart failure, Cardiovascular disease, hypertension, coronary heart disease, colic, pellagra, Hartnap syndrome, carcinoid tumor syndrome, arterial obstructive disease, hypothyroidism, vasoconstriction, osteoarthritis, rheumatoid arthritis, A pharmaceutical for Alzheimer's disease, peripheral and central nervous system disorders, hematological diseases, cancer, inflammation, respiratory diseases, or gastrointestinal diseases, wherein the pharmaceutical is administered orally to a patient in need thereof. The use of any one of claims 138 to 142, wherein the pharmaceutical product further comprises a statin. For example, the application of the scope of patent application 143, wherein the statin is selected from the group consisting of atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin , pravastatin, rosuvastatin and simvastatin. The use of any one of claims 138 to 142, wherein the medicament further comprises at least one other therapeutic agent selected from the group consisting of: 11β HSD-1 inhibitor, 5HT transporter inhibitor , 5HT2c agonist, 5-LO or FLAP inhibitor, alpha-glucosidase inhibitor, ABCA1 enhancer, ACC inhibitor, sulfhydryl-based CoA: cholesterol O-thiotransferase inhibitor, thiol-estrogen, Antidiabetic agents, anti-lipid drugs, antihypertensive agents, antioxidants, Apo A1 mimetic, Apo A1 modulator, Apo E mimetic, apolipoprotein-B secretion/microsomal triglyceride transfer protein (apo- B/MTP) inhibitors, appetite suppressants, aspirin, beta 3 agonists, bile acid reuptake inhibitors, bile acid chelators, campesin agonists, BRS3 agonists, CB ₁ antagonists / Reverse agonist, CCK-A agonist, cholesterol absorption inhibitor, cholesterol transport inhibitor, cholesterol ester transfer protein (CETP) inhibitor, CNTF, CNTF agonist/regulator, ezetimibe and sim Combination of statin and/or atorvastatin, CSL-111, dehydroepiandrosterone, delipidated HDL, DGAT Yi oligomer, DGAT1 inhibitor, DGAT2 inhibitor, dicarboxylate transporter inhibitor, dopamine agonist, DP receptor antagonist, ezetimibe, FAS inhibitor, fatty acid binding protein (FABP) inhibition Agent, fatty acid transporter inhibitor, fatty acid transporter protein (FATP) inhibitor, flushing inhibitor, FXR receptor modulator, galanin receptor antagonist, gemcabene, brain gut peptide antagonist, brain gut peptide antibody, GLP-1 agonist, glycoside-like peptide-1 receptor agonist, glucocorticoid agonist/antagonist, glucose transporter inhibitor, HDL mimetic, HMG CoA reductase inhibitor compound, HMG- CoA synthetase inhibitor, hormone sensitive lipase antagonist, human hamster color related protein (AGRP), H ₃ antagonist/reverse agonist, inorganic cholesterol chelating agent, L-4f, lapastat, leptin Agent/modulator, leptin, lipase inhibitor, lipoprotein synthesis inhibitor, lopavirin, low-density lipoprotein receptor inducer or activator, Lp(a) reducing agent, LXR receptor agonist, Lyn kinase inhibitor, Mc3r agonist, Mc4r agonist, MCH1R antagonist, MCH2R Agent/antagonist, melanin-concentrating hormone antagonist, mGluR5 antagonist, microsomal triglyceride transport inhibitor, monoamine reuptake inhibitor, natural water-soluble fiber, NE transporter inhibitor, neuromodulin U receptor Agonists, neuropeptide-Y antagonists, nicotinic acid or nicotinic acid receptor agonists, nicotinic acid, norepinephrine-induced appetite suppressant, NPY1 antagonist, NPY2 agonist, NPY4 agonist Agent, NPY5 antagonist, non-steroidal anti-inflammatory agent (NSAID), omega-3 fatty acid, opioid antagonist, orexin receptor antagonist, PDE inhibitor, phentermine, phosphate transporter inhibitor, botanical compound 57 , fatty alcohol esters of plant stanols and/or plant stanols, platelet aggregation inhibitors, PPAR-α agonists, PPAR-δ agonists, PPAR-δ partial agonists, PPAR-γ agonists , probucol, renin-angiotensin inhibitor, reverse-4F, SCD-1 inhibitor, serotonin reuptake inhibitor, SGLT2 inhibitor, squalene epoxidase inhibitor, squalene synthesis inhibitor , sterol biosynthesis inhibitor, sympathomimetic agonist, thyroid hormone β Agents, thyromimetic agents, topiramate, triglyceride synthesis inhibitors, UCP-1 activators, UCP-2 activators, UCP-3 activators, and urocortin binding protein antagonists. The use of claim 145, wherein the at least one other therapeutic agent is selected from the group consisting of: HMG-CoA reductase inhibitor, aspirin, cholesterol ester transfer protein (CETP) inhibitor , NSAID, fiber ester, proprotein convertase subtilisin/kexin type (PCSK9), inorganic cholesterol chelating agent, sulfhydryl-based CoA: cholesterol O-thiol transferase inhibitor, PPAR-α agonist, PPAR-γ Agonists, bile acid reuptake inhibitors, triglyceride synthesis inhibitors, lipoprotein receptor activators, DGAT1 inhibitors, SCD-1 inhibitors, lipase inhibitors, DP receptor antagonists, apo A1 regulation Agent, cholesterol transport inhibitor, metformin, nicotinic acid receptor agonist, and DPP-IV inhibitor. The use of claim 145, wherein the at least one other therapeutic agent is selected from the group consisting of: HMG-CoA reductase inhibitor, cholesterol ester transfer protein inhibitor, aspirin, NSAID, Combination of a cellulite, a DP receptor antagonist, ezetimibe, and ezetimibe with simvastatin and/or atorvastatin. The use of claim 146, wherein the at least one other therapeutic agent is an HMG-CoA reductase inhibitor selected from the group consisting of atorvastatin, cerivastatin, fluvastatin, Lovastatin, pitavastatin, pravastatin, rivastatin, rosuvastatin, and simvastatin. The use of claim 148, wherein the HMG CoA reductase inhibitor is simvastatin or atorvastatin. The use of claim 148, wherein the at least one other therapeutic agent is a cholesterol ester transfer protein inhibitor. The use of claim 148, wherein the at least one other therapeutic agent is ezetimibe, aspirin, ibuprofen, acetaminophen, or ezetimibe with simvastatin and/or Or a combination of atorvastatin. A pharmaceutical composition for treating hyperlipidemia, hypercholesterolemia, lipid dystrophy, dyslipidemia, atherosclerosis or coronary artery disease, comprising as claimed in any one of claims 90 to 137 A compound, wherein the pharmaceutical composition is administered orally to a patient in need thereof. A pharmaceutical composition for treating metabolic syndrome, obesity, fatty liver disease, or diabetes, comprising a compound according to any one of claims 90 to 137, wherein the pharmaceutical composition is orally administered Need patients. A pharmaceutical composition for raising serum high-density lipoprotein (HDL) content, which comprises a compound according to any one of claims 90 to 137, wherein the pharmaceutical composition is orally administered. The patient. A pharmaceutical composition for lowering serum low-density lipoprotein (LDL) content or lowering serum lipoprotein (a), which comprises a compound according to any one of claims 90 to 137, wherein the pharmaceutical composition It is administered orally to patients who need it. A method for treating congestive heart failure, cardiovascular disease, hypertension, coronary heart disease, colic, pellagra, Hartnap syndrome, carcinoid tumor syndrome, arterial obstructive disease, hypothyroidism, vasoconstriction, bone a pharmaceutical composition of arthritis, rheumatoid arthritis, Alzheimer's disease, peripheral and central nervous system disorders, hematological diseases, cancer, inflammation, respiratory diseases, or gastrointestinal diseases, including as claimed in claim 90 The compound of any one of the items 137, wherein the pharmaceutical composition is administered orally to a patient in need thereof. The pharmaceutical composition according to any one of claims 152 to 156, which further comprises a statin. For example, the pharmaceutical composition of claim 157, wherein the statin is selected from the group consisting of atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, and pitamate. Ruvastatin, pravastatin, rosuvastatin and simvastatin. The pharmaceutical composition according to any one of claims 152 to 156, further comprising at least one other therapeutic agent selected from the group consisting of 11β HSD-1 inhibitor, 5HT transporter inhibitor, 5HT2c Agonists, 5-LO or FLAP inhibitors, alpha-glucosidase inhibitors, ABCA1 enhancers, ACC inhibitors, sulfhydryl-based CoA: cholesterol O-thiotransferase inhibitors, thiol-estrogen, anti-diabetes Agent, anti-lipid aberrant, antihypertensive agent, antioxidant, Apo A1 mimetic, Apo A1 modulator, Apo E mimetic, apolipoprotein-B secretion/microsomal triglyceride transfer protein (apo-B/ MTP) inhibitors, appetite suppressants, aspirin, beta 3 agonists, cholic acid reuptake inhibitors, cholic acid chelators, campesin agonists, BRS3 agonists, CB ₁ antagonists / reverse Agonists, CCK-A agonists, cholesterol absorption inhibitors, cholesterol transport inhibitors, cholesterol ester transfer protein (CETP) inhibitors, CNTF, CNTF agonists/modulators, ezetimibe and simvastatin And/or combination of atorvastatin, CSL-111, dehydroepiandrosterone, delipidated HDL, DGAT antisense oligomerization , DGAT1 inhibitor, DGAT2 inhibitor, dicarboxylate transporter inhibitor, dopamine agonist, DP receptor antagonist, ezetimibe, FAS inhibitor, fatty acid binding protein (FABP) inhibitor, fatty acid Transporter inhibitors, fatty acid transporter protein (FATP) inhibitors, flushing inhibitors, FXR receptor modulators, galanin receptor antagonists, gemcabene, brain gut peptide antagonists, brain gut peptide antibodies, GLP-1 Agonists, glycoside-like peptide-1 receptor agonists, glucocorticoid agonists/antagonists, glucose transporter inhibitors, HDL mimics, HMG CoA reductase inhibitor compounds, HMG-CoA synthetase inhibitors, hormone sensitive lipase antagonists, human agouti coat color related proteins (AGRP), H ₃ antagonist / inverse agonist, inorganic chelating agents cholesterol, L-4f, lapaquistat, leptin agonists / Modulators, leptin, lipase inhibitors, lipoprotein synthesis inhibitors, lopavirin, low-density lipoprotein receptor inducer or activator, Lp(a) reducing agent, LXR receptor agonist, lyn kinase inhibition Agent, Mc3r agonist, Mc4r agonist, MCH1R antagonist, MCH2R agonist / antagonist Anti-agents, melanin-concentrating hormone antagonists, mGluR5 antagonists, microsomal triglyceride transport inhibitors, monoamine reuptake inhibitors, natural water-soluble fibers, NE transporter inhibitors, neuromodulin U receptors Agent, neuropeptide-Y antagonist, nicotinic acid or nicotinic acid receptor agonist, nicotinic acid, norepinephrine-induced appetite suppressant, NPY1 antagonist, NPY2 agonist, NPY4 agonist, NPY5 antagonist, non-steroidal anti-inflammatory agent (NSAID), omega-3 fatty acid, opioid antagonist, orexin receptor antagonist, PDE inhibitor, phentermine, phosphate transporter inhibitor, botanical compound 57, plant Fatty acid esters of stanols and/or plant stanols, platelet aggregation inhibitors, PPAR-α agonists, PPAR-δ agonists, PPAR-δ partial agonists, PPAR-γ agonists, Pro Cloth, renin angiotensin inhibitor, reverse-4F, SCD-1 inhibitor, serotonin reuptake inhibitor, SGLT2 inhibitor, squalene epoxidase inhibitor, squalene synthesis inhibitor, solid Alcohol biosynthesis inhibitor, sympathomimetic agonist, thyroid hormone beta agonist, Thyroid agents, topiramate, triglyceride synthesis inhibitors, UCP-1 activators, UCP-2 activators, UCP-3 activators, and urocortin binding protein antagonists. The pharmaceutical composition of claim 159, wherein the at least one other therapeutic agent is selected from the group consisting of HMG-CoA reductase inhibitor, aspirin, cholesterol ester transfer protein (CETP) Inhibitor, NSAID, fiber ester, proprotein convertase subtilisin/kexin type (PCSK9), inorganic cholesterol chelating agent, thiol CoA: cholesterol O-thiol transferase inhibitor, PPAR-α agonist, PPAR - gamma agonist, cholic acid reuptake inhibitor, triglyceride synthesis inhibitor, lipoprotein receptor activator, DGAT1 inhibitor, SCD-1 inhibitor, lipase inhibitor, DP receptor antagonist, apo A1 modulator, cholesterol transport inhibitor, metformin, nicotinic acid receptor agonist, and DPP-IV inhibitor. The pharmaceutical composition of claim 159, wherein the at least one other therapeutic agent is selected from the group consisting of: HMG-CoA reductase inhibitor, cholesterol ester transfer protein inhibitor, aspirin, Combination of NSAID, fiber ester, DP receptor antagonist, ezetimibe, and ezetimibe with simvastatin and/or atorvastatin. The pharmaceutical composition of claim 160, wherein the at least one other therapeutic agent is an HMG-CoA reductase inhibitor selected from the group consisting of atorvastatin, cerivastatin, and fluvastatin Statins, lovastatin, pitavastatin, pravastatin, rivastatin, rosuvastatin, and simvastatin. The pharmaceutical composition of claim 162, wherein the HMG CoA reductase inhibitor is simvastatin or atorvastatin. The pharmaceutical composition of claim 162, wherein the at least one other therapeutic agent is a cholesterol ester transfer protein inhibitor. The pharmaceutical composition of claim 162, wherein the at least one other therapeutic agent is ezetimibe, aspirin, ibuprofen, acetaminophen or ezetimibe with simvastatin and / or a combination of atorvastatin.