RU2588133C2 - Niacin mimetics and method for use thereof - Google Patents

Abstract

FIELD: pharmaceutics.

SUBSTANCE: in the general formula (I) R represents hydrogen, C_1-6alkyl, fused bicyclic or arylalkenylaryl.

EFFECT: pharmaceutical composition based on compounds of formula (I); a method of treating hyperlipidaemia and hypercholesterolaemia, as well as a method of increasing serum level of high density lipoprotein (HDL) and a method of reducing low density lipoprotein (LDL) using same.

14 cl, 23 dwg, 8 tbl, 8 ex

Description

RELATED APPLICATIONS

This application claims the priority of United States provisional patent application 61/358264, filed June 24, 2010, the contents of which are incorporated herein by reference.

KNOWN LEVEL OF TECHNOLOGY

Hyperlipidemia and hypercholesterolemia are conditions that are characterized by a well-established correlation with an increased risk of other conditions, such as heart attacks, atherosclerosis, and other worsened unhealthy conditions. There are numerous agents available to lower cholesterol and lipids, including gemfibrizol, probucol, and not so long ago “statins” (for example, lovastatin).

Niacin (nicotinic acid), a water-soluble vitamin B complex, is used orally to treat hyperlipidemia. Niacin has been shown to be effective in lowering total plasma cholesterol (C), low density LDL-C lipoproteins and very low density lipoprotein triglycerides (VLDL triglycerides), all of which are associated with health risks. At the same time, niacin raises serum levels of high density lipoproteins (HDL-C), which are considered “healthy” lipoproteins, in patients with type II, III, IV, and hypercholesterolemia.

Although the mechanism by which niacin alters lipid patterns has not been well defined, its mechanisms of action have been shown to inhibit the release of free fatty acid from adipose tissue (see Carlson, LA, Froberg, SO and Nye, ER, Nicotinic acid in the rat 11. 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). Over 30 million Americans have elevated blood LDL-C levels. HMG-CoA reductase inhibitors (statins) are the most widely used class of drugs for treating patients with elevated LDL-C levels. Niacin, however, is the only drug recommended by the American Heart Association for improving HDL in primary prevention of cardiovascular disease in addition to lowering LDL-C. Niacin therapy is not only cost effective as monotherapy, but it is also beneficial as combination therapy because it complements the actions of other classes of lipid-lowering drugs. However, for isolated hypercholesterolemia, niacin is a second or third order choice due to the high incidence of side effects associated with oral niacin therapy. However, it has a therapeutic advantage as monotherapy when it is desirable to reduce both LDL-C and triglycerides, such as for patients with severe combined hyperlipidemia.

Niacin can also be used in combination with other cholesterol lowering agents, such as “statins,” to maximize lipid lowering activity. One study found that niacin / lovastatin was highly effective in lowering LDL-C, triglycerides and lipoprotein (a) (Lp (a)) while maintaining the strength of niacin in raising 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 is widely used to lower serum cholesterol because it is considered cost effective therapy. Daily oral doses of 2-3 g of niacin in humans reduce total-C and LDL-C levels by an average of 20% -30%, lower triglyceride levels by 35% -55%, increase HDL-C by 20% -35%, and reduce Lp (a). Niacin also reduces overall mortality, as well as mortality from coronary artery disease (see The Coronary Drug Project Research Group, LAMA 231: 360-381, 1975; and Canner, PL, Berge, KG, Wenger, N. K., 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 down or reverse the progression of atherosclerosis (see Blankenhorn, DH, Nessim, SA, Johnson, RL, Samnarco, ME, Azen, SP and Cashin-Hemphill, L., Beneficial effects of combined colestipoliac therapy on coronary atherosclerosis and coronary venous bypass grafts, JAMA 257: 3233-3240, 1987; and Cashin-Hemphill L .; Mack, WJ, Pogoda, JM, Samnarco, MT, Azen, SP and Blankenhorn, DH, Beneficial effects of colestipol-niac in on coronary atherosclerosis. A 4-year follow-up, JAMA 264: 3013-3017, 1990).

Unfortunately, oral niacin therapy has side effects that limit its usefulness. Although niacin is a vitamin, it should be used in therapeutic doses to lower cholesterol. At these doses, both immediate release and sustained release of niacin can have some side effects. The most common side effect of niacin is a rush of blood, a sensation of warmth on the skin, usually associated with redness and sometimes itching. A rush of blood is not dangerous, but most patients find it very uncomfortable, which severely limits the patient’s consent to niacin therapy. The rush of blood caused by niacin can be significantly mitigated by prior treatment with cyclooxygenase inhibitors, suggesting that vasodilation is caused by a prostaglandin-mediated mechanism (see Carlson, L.A., Nicotinic acid and inhibition of fat mobilizing lipolysis. Present status, of effects on lipid metabolism, Adv Exp Med Biol 109: 225-238, 1978).

Liver function tests are always monitored in patients taking niacin, since increased serum transaminase levels are associated with niacin treatment, and prolonged niacin release is associated with more serious liver problems (see McKenney, JM, Proctor, JD, Harris, S., and Chinchili, VM, A comparison of the efficacy and toxic effects of substained- 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 ulcers and impaired diabetes control. Accordingly, the safety and effectiveness of oral niacin therapy is undermined by the need for careful clinical monitoring and the profile of side effects of the compound.

SUMMARY

One aspect of the present invention relates to 6- (morpholinoalkyl) -substituted pyridines and their pharmaceutically acceptable salts, which are active against a number of mammalian diseases. In some embodiments, said pyridines or salts thereof include a functional group that is substantially anionic at physiological pH.

Another aspect of the invention relates to a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient. Another aspect of the invention relates to a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt thereof; niacin; and a pharmaceutically acceptable excipient.

Another aspect of the invention relates to a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt thereof; a statin selected from the group consisting of atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin; and a pharmaceutically acceptable excipient. The present invention also relates to a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt thereof; niacin; a statin selected from the group consisting of atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin; and a pharmaceutically acceptable excipient. Additional therapeutic agents that may be administered in conjunction with the compounds of the invention are discussed below.

Niacin or nicotinic acid has been shown to be effective in treating dyslipidemia, but the clinical use of niacin is limited to a cutaneous rush of blood, which is known to be associated with a side effect. The rush of blood, which is estimated by the predominance of such a high rate as 25% -40%, is indicated as the main reason for interrupting niacin therapy. A number of studies have found that moderate doses of prostaglandin inhibitors reduce the response expressed in cutaneous flushing due to the administration of niacin. Other approaches to lowering the flushing include regular, consistent dosing, use of sustained or sustained release formulations, patient education, dosing with food or while going to bed, and avoiding alcohol, hot drinks, spicy foods, and hot baths or showers close to time or after administration of a dose of the drug. In some embodiments, the compounds of the present invention may have a reduced incidence of a flushing or the severity of a flushing when they are administered to an animal, especially a human.

For example, the compounds of the present invention do not cause a rush of blood in male C57BL / 6 mouse models, as determined by laser Doppler flow or stock measurements, when administered in doses up to 100 mg / kg, and even more preferably when administered in doses up to 200, 300 or even 500 mg / kg.

In some embodiments, the compounds of the present invention may be characterized by causing a lower rush of blood when administered orally compared to an amount equivalent to a molar amount of NIASPAN® (niacin sustained release tablets, Abbott Laboratories). In some embodiments, the compounds of the present invention, when administered orally, populations of ordinary patients show a decrease in the number of patients with the manifestation of hot flashes greater than or equal to 5 on the visual analogue scale for oral administration compared to an equivalent molar amount of NIASPAN®.

The present invention also relates to a method for treating diseases, disorders or conditions selected from the group consisting of hyperlipidemia, hypercholesterolemia, hypodystrophy, dyslipidemia, atherosclerosis and coronary artery disease, comprising the step of administering to a mammal in need thereof a therapeutically effective amount of a compound or pharmaceutical composition of the present inventions.

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

Another aspect of the present invention relates to a method for raising serum high density lipoprotein (HDL) levels, comprising the step of administering to a mammal in need of a therapeutically effective amount of a compound or pharmaceutical composition of the present invention.

Another aspect of the present invention relates to a method for decreasing low density lipoprotein (LDL) levels or reducing serum lipoprotein (a) levels, comprising the step of administering to a mammal in need thereof a therapeutically effective amount of a compound or pharmaceutical composition of the present invention.

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

Another aspect of the present invention relates to a method for treating a disease, disorder or condition selected from the group consisting of congestive heart failure, cardiovascular disease, hypertension, coronary heart disease, angina pellagra, Hartnup syndrome, carcinoid syndrome, arterial occlusive disease, hypothyroidism, narrowing of blood vessels, osteoarthritis, rheumatoid arthritis, Alzheimer's disease, disorders of the peripheral and central nervous system, hematological diseases, cancer, inflammation, respiratory diseases and gastrointestinal diseases, comprising the step of administering to a mammal in need thereof a therapeutically effective amount of a compound or pharmaceutical composition of the present invention.

Additional aspects, embodiments, and advantages of the invention are discussed in detail below.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1. Traces of liquid chromatography mass spectroscopy (LC-MS) for ARI-001 obtained from Shanghai SpeedChem (Shanghai, China). To determine the purity, UV absorption at 215 nm was used. The peak region at 3.59 min represents 98.9% of the total peak region of the tracks.

Figure 2. Relative stability of the ARI-001 under storage conditions as determined in the test. The total area representing the peak for ARI-001 was calculated, and then normalized to the total peak area identified by the LC-MS traces. This was expressed as% of total peaks. The upper graph, the powder composition of the drug; (■) standard conditions: 50 ° C, no marked humidity. The lower graph, the liquid form of the drug; (◊) room temperature (ct); (■) 4 ° C; (▲) 20 ° C.

Figure 3. FPLC-coated traces of pooled plasma from hamsters contained in either normal food (bold line) or high fat food + high sugar (HF / HS) (dashed line).

Figure 4. FPLC traces of pooled plasma from hamsters receiving a vehicle (bold line), 1200 mg / kg (mpk) niacin (dashed line), or 2240 mg / kg ARI-001 (less bold line).

Figure 5. Changes in the lipid parameter as a function of the dose of ARI-001 (presented in mmol / kg / d). ARI-001 (■ and the connecting line) shows a dose-dependent effect on lipid values in HF / HS hamsters. Niacin (◊) showed significance with respect to changes in total cholesterol (TS), high density lipoprotein (HDL), and only low density lipoprotein (LDL).

Figures 6 and 7. Correlation between lipid parameters and plasma concentration of ARI-001. Each lipid parameter achieved statistically significant correlations with ARI-001 concentrations, with the exception of HDL, which was statistically significant and positive. A linear correlation line is drawn (bold line), as well as a zone of 95% confidence of the correlation line (less bold curves). For each series of data, Pearson correlation coefficients are given, with a 95% confidence interval in parentheses. P-values are the results of two-sample unpaired t-tests.

Figure 8 (Left graph). Correlation between concentrations in the liver and plasma of ARI-001 in HF / HS hamsters with doses over 18 days. The values for each tissue are transformed using the logarithm, and therefore, the axes are dimensionless. (Right graph) Correlation between concentrations in adipose tissue and plasma in the same animals. Adipose concentrations are transformed using the “logarithm + 1” function, which makes any values between -1 and 0 positive. This is done for clarity and does not in any way distort the distribution of the data series.

Figures 9-11. Correlation between concentrations in the liver of ARI-001 in HF / HS hamsters and the values of various lipid parameters; also, correlations between concentrations in adipose tissue ARI-001 in HF / HS hamsters and the values of various lipid parameters. All values are the logarithm of lipid values versus the logarithm of tissue concentrations. Correlations are presented between tissue concentration and lipid values in the same animals. Adipose concentrations are transformed using the “logarithm + 1” function, which makes any values between -1 and 0 positive. This is done for clarity and does not in any way distort the distribution of the data series.

Figures 12A and B. Parameters for testing liver function from hamsters fed a high fat diet and dosed orally with vehicle, niacin or ARI-001 for 18 days. Percentage changes are relative to the bulking agent. P-values are reported from two-sample unpaired t-tests compared to a vehicle. Figure 12A, aspartate aminotransferase (AST). Figure 12B, alanine aminotransferase (ALT).

Figure 13. Glucose values measured in plasma from an 18-day study of HF / HS hamsters, which were given a daily dose of excipient, niacin or ARI-001. Percentage changes are reported as compared to those in the bulking group. P-value is determined from a two-sample unpaired t-test.

Figure 14. Concentrations of ARI-001 in plasma in mice dosed with a single administration of ARI-001 either orally (PO) or intraperitoneally (intraperitoneally) (IP).

Figures 15A-15D. Plasma concentrations of ARI-001 in mice dosed with multiple daily doses of ARI-001 for 30 consecutive days. Four different doses were used. Each mouse received the same indicated dose of ARI-001 every day for 30 days.

Figures 16A and 16B. Summary parameters C _max and AUC for ARI-001 from a 30-day study with multiple administration to wild-type mice. Values are given on the graph as an average with standard error. There was no significant change in any parameter as a function of time (○) 996 mg / kg / day; (□) 1493 mg / kg / day; (∆) 2240 mg / kg / day; (◊) 3360 mg / kg / day.

Figure 17. Plasma concentrations of ARI-001 in Golden Syrian hamsters in a high fat / high sugar diet after a single administration of ARI-001 at 5.9 mmol / kg.

Figure 18. The concentration of ARI-001 in plasma in fasting monkeys after a single injection of ARI-001 or (♦) 96 mg / kg intravenously (IV), or (○) 288 mg / kg (mpk) orally (PO). The y-axis represents a logarithmic scale for clarity. (Insert): The same data, and the y-axis in a linear scale.

Figure 19. Plasma concentrations of ARI-001 after a single administration of 288 mg / kg orally in (♦) fed monkeys or (○) starving monkeys. Values are averages with standard error.

Figure 20. The concentration of ARI-001 in plasma after repeated daily administration of 288 mg / kg orally in fasting monkeys. Values are averages with standard error. (♦) Samples shown for 1 day. (○) Samples shown on day 7.

Figure 21. ARI-001 does not replenish with beta-arrestin the cell membrane of cells expressing the niacin receptor GPR109A. The ligand refers to niacin or ARI-001, as indicated. RLUs, relatively small units, as measured by chemiluminescent reading in the assay for receptor activity in combination with G-protein.

Figure 22. Dose response to lower triglyceride with single oral doses of ARI-001 in human patients. The percentage change is the average change in percent triglycerides 4 hours after the dose.

Figure 23. The concentration of ARI-001 in serum over time after a single oral administration of the indicated amounts of ARI-001 to humans.

DETAILED DESCRIPTION

One aspect of the invention relates to niacin analogues for use in increasing serum HDL levels in mammals. In some embodiments, the compounds of the invention have an ability to increase HDL equal to or greater than niacin, while having less or no tendency to cause flushing, an undesirable side effect of niacin itself when used in doses sufficient to raise serum HDL levels. Some non-flushing analogues of niacin are described in US Patent Application Publication No. 2009/0312355, which is incorporated herein by reference in its entirety. In some embodiments, the key structural formulas of the compounds described herein explicitly include the presence of a heterocyclylalkyl or heteroaralkyl group of a steam to a carboxyl group in niacin.

DEFINITIONS

For convenience, some terms used in the description, examples and appended claims are collected here. All definitions, data, and used herein replace vocabulary definitions, definitions in documents included by reference to them, and / or the usual meanings of defined terms.

The indefinite articles “a” and “an” are used here to refer to one or more than one (ie, at least one) grammatical object. For example, the English word “element” (with indefinite article) means one element or more than one element.

The phrase “and / or” as used herein in the description and in the claims should be understood as meaning “one of two or both” of the elements, in combination, i.e. elements that are present in combination in some cases and characteristically present in other cases. In the same way, multiple elements enumerated with “and / or”, i.e. thus “one or more of the elements” in combination. Other elements may optionally be present other than those specified specifically using the words “and / or”, whether or not they relate to elements specifically specified. Thus, as a non-limiting example, a reference to “A and / or B” used in conjunction with a non-limiting word such as “including” may refer in one embodiment to only A (optionally including elements other than B); in yet another embodiment, only to B (optionally including elements other than A); in yet another embodiment to both A and B (optionally including other elements); etc.

Used here in the description and in the claims, the word “or” should be understood as having the same meaning as in the case of “and / or”, as defined above. For example, when separate words or paragraphs are indicated in the list, “or” or “and / or” should be understood as indicating inclusively, i.e. the inclusion of at least one, but also including more than one, from a number or list of elements, and, optionally, additional elements not listed. Only terms clearly indicated in the opposite sense, such as “only one of” or “exactly one of”, or, used in the claims, “consisting of”, will refer to the inclusion of exactly one element from a row or list of elements. In general, the term “or,” as used herein, should be understood only to include exceptional alternatives (ie, “one or the other, but not both”) when it is preceded by terms of exclusivity, such as “one of two,” “one of ”,“ only one of ”, or“ exactly one of ”. “Consisting essentially of” as used in the claims is to be understood in its ordinary sense as used in the field of patent law.

The phrase “at least one”, as used herein in the description and claims, in reference to a list of one or more elements, is to be understood as meaning at least one element selected from any one or more elements in the list of elements, but not necessarily including at least one of each and any element listed specifically in the list of elements, and not excluding any combination of elements in the list of elements. This definition also assumes that elements other than elements specifically indicated in the list of elements to which the phrase “at least one” refers may or may not be present, whether or not it refers to those specifically specified 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”) may refer to one an embodiment of at least one, optionally including more than one, A, without any B present (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, without any A present (and optionally including elements other than A); in yet another embodiment, to at least one, optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other elements); etc.

It should also be understood that unless the exact opposite is indicated, in any methods claimed herein that include more than one step or step, the order of the steps or steps of the process is not necessarily limited to the order in which the steps or steps of the method are listed.

In the claims, as well as in the above description, all intermediate phrases, such as “including” (English “comprising” and “including”), “bearing”, “having”, “containing”, “involving or affecting ”,“ Possessing ”,“ composed of ”, and similar ones, should not be understood in a restrictive sense, i.e. as meaning inclusion, but not as a limitation to the indicated. Only the intermediate phrases “consisting of” and “consisting essentially of” must be closed or half-closed intermediate phrases, respectively, as set forth in Manual of Patent Examining Procedures, Section 2111.03 of the United States Patent Office.

The terms “co-administration” and “co-administration” refer both to the simultaneous administration (administration of two or more therapeutic agents at the same time) and to the administration at different times (administration of two or more therapeutic agents at a time other than the time of administration additionally therapeutic agent or agents), while therapeutic agents at the same time are present to some extent in the patient's body.

The term “solvate” refers to a pharmaceutically acceptable form of said compound, with one or more solvent molecules, which retains the biological effectiveness of such a compound. Examples of solvates include compounds of the invention in combination with solvents such as, for example, water (forming a hydrate), isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, ethanolamine or acetone. Solvate mixtures are also included, such as a compound of the invention in combination with two or more solvents.

It is understood that the definition of each expression, for example, alkyl, m, n and the like, when it occurs more than once, in any structure, is independent of the definition elsewhere in the same structure.

Obviously, it is understood that “substitution” or “substituted by something” includes the implied condition that such substitution is in accordance with the permissible valency of the substituted atom and substituent, and that the substitution results in a stable compound, for example, a compound that does not spontaneously undergo a transformation such as rearrangement, cyclization, elimination, or other reaction.

The term “substituted” is also intended to include all valid substituents of organic compounds. In a broad aspect, acceptable substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. Illustrative substituents include, for example, the substituents described herein below. Permissible substituents may be one or more and the same or different for the corresponding organic compounds. For the purposes of this invention, heteroatoms, such as nitrogen, may have hydrogen substituents and / or any permissible substituents of organic compounds described herein that satisfy the valencies of the heteroatoms.

The term “lower” as applied to any of the groups listed below indicates that the group contains less than seven carbon atoms (i.e., six carbons or less). For example, “lower alkyl” refers to an alkyl group containing 1-6 carbon atoms, and “lower alkenyl” refers to an alkenyl group containing 2-6 carbon atoms.

The term “unsaturated”, as used herein, refers to compounds and / or groups that have at least one carbon-carbon double bond or carbon-carbon triple bond.

The term “aliphatic”, as used here, refers to compounds and / or groups that are linear or branched, but not cyclic (also called “acyclic” or “open chain” groups).

The term “cyclic” as used herein refers to compounds and / or groups that have one ring, two or more rings (eg, spiro, fused, bridged). “Monocyclic” refers to compounds and / or groups with one ring; and “bicyclic” refers to compounds and / or groups with two rings.

The term “aromatic” refers to a planar or polycyclic structure characterized by a cyclically conjugated molecular moiety containing 4n + 2 electrons, where n is the absolute value of an integer. Aromatic molecules containing fused or linked rings are also called bicyclic aromatic rings. For example, bicyclic aromatic rings containing heteroatoms in a hydrocarbon ring structure are also called bicyclic heteroaryl rings.

The term “hydrocarbon,” as used herein, refers to an organic compound consisting entirely of hydrogen and carbon.

For the purposes of this invention, chemical elements are identified or determined in accordance with the Periodic Table of Elements, CAS version, Handbook of Chemistry and Physics, 67 ^th Ed., 1986-87, inner binding cover.

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

The term “alkyl” means an aliphatic or cyclic hydrocarbon radical 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, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 2-methylcyclopentyl, 1- (1-ethylcyclopropyl) ethyl and 1-cyclohexylethyl.

The term “cycloalkyl” represents a subgroup of alkyl, which refers to a cyclic hydrocarbon radical containing from 3 to 15, 3-10 or 3-7 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 radical containing from 2 to 10 carbon atoms 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-heptenyl, 2-methyl-1-heptenyl and 3- decentralized.

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

The term “alkylene” is recognized in the art 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 here, means a monocyclic or polycyclic (for example, bicyclic, tricyclic, etc.) hydrocarbon radical containing from 3 to 12 carbon atoms, i.e. fully saturated, or has one or more unsaturated bonds, and to avoid doubt, the degree of unsaturation is not the result in an aromatic ring system (e.g. phenyl). Examples of carbocyclyl groups include 1-cyclopropyl, 1-cyclobutyl, 2-cyclopentyl, 1-cyclopentenyl, 3-cyclohexyl, 1-cyclohexenyl and 2-cyclopentenylmethyl.

The term “heterocyclyl” as used herein refers to a radical of a non-aromatic ring system including, but not limited to, monocyclic, bicyclic and tricyclic rings that may be fully saturated or which may contain one or more unsaturation units, to avoid doubt, the degree of unsaturation is not a result in an aromatic ring system, and have 3-12 atoms including at least one heteroatom, such as a nitrogen, oxygen or sulfur atom. For purposes of illustration, by examples, which should not be construed as limiting the scope of the invention, the following are examples of heterocyclic rings: aziridinyl, azirinyl, oxiranyl, thiranyl, thiurenyl, dioxiranyl, diazirinyl, azetyl, oxetanyl, oxetyl, thietanyl, thiethyl, diazetidinyl, dioxethenyl, , dithietanyl, dithiethyl, furyl, dioxalanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, triazinyl, isothiazolyl, isoxazolyl, thiophenyl, pyrazolyl, tetrazolyl, pyridinyl, pyridyl, p pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, pyridopyrazine, benzoxazolyl, benzothiophenyl, benzimidazolyl, benzothiazolyl, benzoxadiazolyl, benztiadiazolil, indolyl, benztriazolyl, naphthyridinyl, azepines, azetidinyl, morpholinyl, oxopiperidinyl, oxopyrrolidinyl, piperazinyl, piperidinyl, pyrrolidinyl, chinicludinyl, thiomorpholinyl, tetrahydropyranyl and tetrahydrofuranyl. The heterocyclyl groups of the invention are substituted with 0, 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, haloalkyl, fluoroalkyl, hydroxy, alkoxy, alkynyloxy, alkynyloxy, carbocycloxy, heterocyclyloxy, haloalkoxy, fluoroalkyloxy, sulfhydryl, alkylthio, haloalkylthio, fluoroalkylthio, alkienylthio, alkynylthio, sulfonic acid, alkylsulfonyl, haloalkylsulfonyl, fluoroalkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, alkoxy sulfenyl Nile ftoralkoksisulfonila, alkeniloksisulfonila, alkiniloksisulfonila, aminosulfonyl, sulfinic acid, alkylsulfinyl, haloalkylsulfinyl, ftoralkilsulfinila, alkenylsulfinyl, alkinilsulfinila, alkoksisulfinila, galogenalkoksisulfinila, ftoralkoksisulfinila, alkeniloksisulfinila, alkiniloksisulfinila, aminosulfinila, formyl, alkylcarbonyl, haloalkylcarbonyl, ftoralkilkarbonila, alkenylcarbonyl, alkynylcarbonyl, carboxyl, alkoxycarbonyl , haloalkoxycarbonyl, fluoroalkoxycarbonyl, al keniloksikarbonila, alkynyloxycarbonyl, alkylcarbonyloxy, galogenalkilkarboniloksi, ftoralkilkarboniloksi, alkenylcarbonyloxy, alkynylcarbonyloxy, alkylsulfonyloxy galogenalkilsulfoniloksi, ftoralkilsulfoniloksi, alkenilsulfoniloksi, alkinilsulfoniloksi, galogenalkoksisulfoniloksi, ftoralkoksisulfoniloksi, alkeniloksisulfoniloksi, alkiniloksisulfoniloksi, alkilsulfiniloksi, galodialkilsulfiniloksi, ftoralkilsulfiniloksi, alkenilsulfiniloksi, alkinilsulfiniloksi, alkoksisulfiniloksi, galogenalkok sisulfinyloxy, fluoroalkoxy-sulfonyloxy, alkenyloxy-sulfonyloxy, alkynyloxy-sulfyloxy, amino-sulfonyloxy, amino, amido, amino-sulfonyl, aminosulfinyl, cyano, nitro, azido, phosphinyl, phosphoryl, silyl, silyloxy, alkyl-substituted methylene groups, for example .

The term “aryl” as used herein means a phenyl, naphthyl, phenanthrenyl or anthracenyl group. The aryl groups 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, halogen, haloalkyl, fluoroalkyl, hydroxy, alkoxy, alkynyloxy, alkynyloxy, carbocyclyloxy, heterocyclyloxy, haloalkoxy, fluoroalkyloxy, sulfhydryl, alkylthio, haloalkylthio, fluoroalkylthio, alkienylthio, alkynylthio, sulfonic acid, alkylsulfonyl, haloalkylsulfonyl, fluoroalkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, alkynylsulfonyl fonila, galogenalkoksisulfonila, ftoralkoksisulfonila, alkeniloksisulfonila, alkiniloksisulfonila, aminosulfonyl, sulfinic acid, alkylsulfinyl, haloalkylsulfinyl, ftoralkilsulfinila, alkenylsulfinyl, alkinilsulfinila, alkoksisulfinila, galogenalkoksisulfinila, ftoralkoksisulfinila, alkeniloksisulfinila, alkiniloksisulfinila, aminosulfinila, formyl, alkylcarbonyl, haloalkylcarbonyl, ftoralkilkarbonila, alkenylcarbonyl, alkynylcarbonyl, carboxyl , alkoxycarbonyl, haloalkyloxycar Onila, ftoralkiloksikarbonila, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxy, galogenalkilkarboniloksi, ftoralkilkarboniloksi, alkenylcarbonyloxy, alkynylcarbonyloxy, alkylsulfonyloxy galogenalkilsulfoniloksi, ftoralkilsulfoniloksi, alkenilsulfoniloksi, alkinilsulfoniloksi, galogenalkoksisulfoniloksi, ftoralkoksisulfoniloksi, alkeniloksisulfoniloksi, alkiniloksisulfoniloksi, alkilsulfiniloksi, galogenalkilsulfiniloksi, ftoralkilsulfiniloksi, alkenilsulfiniloksi, alkinilsulfiniloksi, alkoxy-sulfonyloxy, haloalkoxy-sulfonyloxy, fluoroalkoxy-sulfonyloxy, alkenyloxy-sulfonyloxy, alkynyloxy-sulfyloxy, amino-sulfonyloxy, amino, amido, aminosulfonyl, aminosulfinyl, cyano, nitro, azido, phosphinyl, alkyl, silyl, silyl, methylene).

The term “arylene” is recognized in the art 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, coupled to the parent molecular moiety through an alkyl group as defined herein. Representative examples of aralkyl include, but are not limited to, benzyl, 2-phenylethyl, 3-phenylpropyl, and 2-naphth-2-yl-ethyl.

The term “biaryl” as used herein means an aryl-substituted aryl, an aryl-substituted heteroaryl, heteroaryl-substituted aryl, or heteroaryl-substituted heteroaryl, in which aryl and heteroaryl are as defined herein. Representative examples include 4- (pheni) phenyl and 4- (4-methoxyphenyl) pyridinyl.

The term “heteroaryl” as used herein includes radicals of aromatic ring systems, including, but not limited to, monocyclic, bicyclic and tricyclic rings, which have 3-12 atoms, including at least one heteroatom, such as nitrogen, oxygen or sulfur. For purposes of illustration, examples which should not be construed as limiting the scope of the present invention are: aminobenzimidazole, benzimidazole, azaindolyl, benzo (b) thienyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzoxadiazolyl, furanylindiolindamide , indazolyl, isoindolinyl, isoxazolyl, isothiazolyl, isoquinolinyl, oxadiazolyl, oxazolyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrrolyl, pyrrolo [2,3-d] pyrimidinyl, pyrazolo [ 3,4-d] pyrimidinyl, quinolinyl, quinazolinyl, triazolyl, thiazolyl, thiophenyl, tetrahydroindolyl, tetrazolyl, thiadiazolyl, thienyl, thiomorpholinyl, triazolyl or tropanil. The heteroaryl groups of the invention are substituted with 0, 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, haloalkyl, fluoroalkyl, hydroxy, alkoxy, alkenyloxy, alkynyloxy, carbocyclyloxy, heterocyclyloxy, haloalkoxy, fluoroalkyloxy, sulfhydryl, alkylthio, haloalkylthio, fluoroalkylthio, alkenylthio, alkynylthio, sulfonic acid, alkylsulfonyl, haloalkylsulfonyl, fluoroalkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, alkoxyisulfonyl a, ftoralkoksisulfonila, alkeniloksisulfonila, alkiniloksisulfonila, aminosulfonyl, sulfinic acid, alkylsulfinyl, haloalkylsulfinyl, ftoralkilsulfinila, alkenylsulfinyl, alkinilsulfinila, alkoksisulfinila, galogenalkoksisulfinila, ftoralkoksisulfinila, alkeniloksisulfinila, alkiniloksisulfinila, aminosulfinila, formyl, alkylcarbonyl, haloalkylcarbonyl, ftoralkilkarbonila, alkenylcarbonyl, alkynylcarbonyl, carboxyl, alkoxycarbonyl , haloalkoxycarbonyl, fluoroalkoxycarbonyl, alkene yloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxy, galogenalkilkarboniloksi, ftoralkilkarboniloksi, alkenylcarbonyloxy, alkynylcarbonyloxy, alkylsulfonyloxy galogenalkilsulfoniloksi, ftoralkilsulfoniloksi, alkenilsulfoniloksi, alkinilsulfoniloksi, galogenalkoksisulfoniloksi, ftoralkoksisulfoniloksi, alkeniloksisulfoniloksi, alkiniloksisulfoniloksi, alkilsulfiniloksi, galogenalkilsulfiniloksi, ftoralkilsulfiniloksi, alkenilsulfiniloksi, alkinilsulfiniloksi, alkoksisulfiniloksi, haloalkoxy sulfonyloxy, fluoroalkoxy-sulfonyloxy, alkenyloxy-sulfyloxy, alkynyloxy-sulfyloxy, amino-sulfonyloxy, amino, amido, aminosulfonyl, aminosulfinyl, cyano, nitro, azido, phosphinyl, phosphoryl, silyl, silyloxy, and an alkylene-group-substituted hetero group .

The term “heteroarylene” is recognized in the art 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 heteroaryl, as defined herein, coupled 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 radical of a bicyclic ring system in which two rings are ortho-fused and each ring contains a total of four, five, six or seven atoms (i.e., carbon atoms and heteroatoms), including two fusion atom, and each ring may be fully saturated, may contain one or more unsaturation units, or may be completely unsaturated (for example, in some cases aromatic). For the avoidance of doubt, the degree of unsaturation in the fused bicyclyl does not result in an aryl or heteroaryl moiety.

The term “halogen” means —Cl, —Br, —I, or —F.

The term “haloalkyl” means an alkyl group as defined herein in which at least one hydrogen 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 an alkyl group, as defined herein, in which some or all of the hydrogen atoms are replaced by fluorine atoms.

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 an alkyl group, as defined herein, coupled 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 alkenyloxy, alkynyloxy, carbocyclyloxy, and heterocyclyloxy are defined similarly.

The term “haloalkoxy” as used herein means an alkoxy group as defined herein in which at least one hydrogen 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” has specific meanings.

The term “aryloxy,” as used herein, means an aryl group, as defined herein, coupled to the parent molecular moiety through oxygen. The term “heteroaryloxy” as used herein means a heteroaryl group, as defined herein, coupled to the parent molecular moiety through oxygen. The term “heteroaryloxy” has the meanings defined previously.

The term “arylalkoxy” or “arylalkyloxy,” as used herein, means an arylalkyl group, as defined herein, coupled to the parent molecular moiety through oxygen. The term “heteroarylalkoxy” has the meanings defined previously. Representative examples of aryloxy and heteroarylalkoxy include, but are not limited to, 2-chlorophenylmethoxy, 3-trifluoromethylphenylethoxy and 2,3-dimethylpyridinylmethoxy.

The term “sulfhydryl” or “thio” as used herein means an —SH group.

The term “alkylthio,” as used herein, means an alkyl group, as defined herein, coupled to the parent molecular moiety through sulfur. Representative examples of alkylthio include, but are not limited to, methylthio, ethylthio, tert-butylthio and hexylthio. The terms “haloalkylthio”, “fluoroalkylthio”, “alkynylthio”, “alkynylthio”, “carbocyclylthio” and “heterocyclylthio” have previously defined meanings.

The term “arylthio,” as used herein, means an aryl group, as defined herein, coupled to the parent molecular moiety through sulfur. The term “heteroarylthio” has previously defined meanings.

The term “arylalkylthio” or “aralkylthio,” as used herein, means an arylalkyl group, as defined herein, coupled to the parent molecular moiety through sulfur. The term “heteroarylalkylthio” has the meanings defined in a similar manner.

The term “sulfonyl,” as used herein, refers to an —S (= O) ₂ - group.

The term “sulfonic acid” as used herein refers to —S (= O) ₂ OH.

The term “alkylsulfonyl,” as used herein, means an alkyl group, as defined herein, coupled to the parent molecular moiety through a sulfonyl, as defined herein. Representative examples of alkylsulfonyl include, but are not limited to, methylsulfonyl and ethylsulfonyl. The terms “haloalkylsulfonyl”, “fluoroalkylsulfonyl”, “alkenylsulfonyl”, “alkynylsulfonyl”, “carbocyclylsulfonyl”, “heterocyclylsulfonyl”, “arylsulfonyl”, “aralkylsulfonyl”, “heteroarylsulfonyl” have the same meanings as heteroarylsulfonyl.

The term “alkoxysulfonyl” as used herein means an alkoxy group, as defined herein, coupled 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 “haloalkoxy sulphonyl”, “fluoroalkoxy sulphonyl”, “alkenyloxy sulphonyl”, “alkynyloxy sulphonyl”, “carbocyclyloxy sulphonyl”, “heterocyclyloxy sulphonyl”, “aryloxy sulphonyl”, aryloxy-sulfonyl-aryloyl, are defined as

The terms “triflil”, “tosyl”, “mesyl” and “nonaflil” are recognized in the art and refer to trifluoromethanesulfonyl, p-toluenesulfonyl, methanesulfonyl and nonafluorobutanesulfonyl groups, respectively. The terms “triflate”, “tosylate”, “mesylate” and “nonaflat” are recognized in this field and refer to trifluoromethanesulfonate ester, p-toluenesulfonate, methanesulfonate ester and nonafluorobutanesulfonate ester functional groups, which respectively contain the indicated groups.

The term “aminosulfonyl,” as used herein, means an amino group, as defined herein, coupled to the parent molecular moiety through a sulfonyl group.

The term “sulfinyl,” as used herein, refers to the group —S (= O) -. Sulfinyl groups have the meanings given above for sulfonyl groups. The term “sulfinic acid,” as used herein, refers to the group —S (= O) OH.

The term “hydroxy” refers to an —O— group.

The term “carbonyl,” as used herein, refers to a —C (═O) - group.

The term “thiocarbonyl” as used herein refers to 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 or radical of the form —C (═O) R, where R is an organic group. An example of an acyl group is the acetyl group (—C (═O) CH ₃ ).

The term “alkylcarbonyl” as used herein means an alkyl group, as defined herein, coupled to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of alkylcarbonyl include, but are not limited to, acetyl, 1-oxopropyl, 2,2-dimethyl-1-oxopropyl, 1-oxobutyl and 1-oxopentyl. The terms “haloalkylcarbonyl,” “fluoroalkylcarbonyl,” “alkenylcarbonyl,” “alkynylcarbonyl,” “carbocyclylcarbonyl,” “heterocyclylcarbonyl,” “arylcarbonyl,” “aralkylcarbonyl,” “heteroarylcarbonyl,” and “heteroalkyl” mean the same.

The term “carboxyl” as used herein means a —CO ₂ H group.

An “isoster carboxyl group” as used herein refers to a group that is isosteric to a carboxyl group. Examples of the isosteres of the carboxyl group include tetrazolyl, oxazolidinonyl, 3-isoxazolyl, hydroxyisoxazolyl, sulfonic acid, sulfinic acid, acylsulfonamide, phosphonic acid, phosphinic acid, hydantoin, pyrrolidionyl, boronic acid, hydroxamic acid azonamide and acyanediamide.

The term “alkoxycarbonyl” as used herein means an alkoxy group, as defined herein, coupled 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, carbocyclyloxycarbonyl, heterocyclyloxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl, heteroaryloxycarbonyl have the same meaning.

The term “alkylcarbonyloxy” as used herein means an alkylcarbonyl group, as defined herein, coupled to the parent molecular moiety through an oxygen atom. Representative examples of alkylcarbonyloxy include, but are not limited to, acetyloxy, ethylcarbonyloxy and tert-butylcarbonyloxy. The terms “haloalkylcarbonyloxy,” “fluoroalkylcarbonyloxy,” “alkenylcarbonyloxy,” “alkynylcarbonyloxy, carbocyclylcarbonyloxy,” “heterocyclylcarbonyloxy,” “arylcarbonyloxy,” “aralkylcarbonyloxy,” “heteroarylcarbonyloxy,” mean “heteroarylcarbonyloxy.”

The term “alkylsulfonyloxy” as used herein means an alkylsulfonyl group as defined herein, connected to the parent molecular moiety through an oxygen atom. The terms "galogenalkilsulfoniloksi", "ftoralkilsulfoniloksi", "alkenilsulfoniloksi", "alkinilsulfoniloksi" karbotsiklilsulfoniloksi "," geterotsiklilsulfoniloksi "," arylsulfonyloxy "," aralkilsulfoniloksi "," geteroarilsulfoniloksi "," geteroaralkilsulfoniloksi "," galogenalkoksisulfoniloksi "," ftoralkoksisulfoniloksi "," alkeniloksisulfoniloksi ”,“ Alkynyloxy sulphonyloxy ”, carbocyclyloxy sulphonyloxy”, “heterocyclyloxy sulphonyloxy”, “aryloxy sulphonyloxy”, “aralkyloxy sulphonyloxy”, geteroariloksisulfoniloksi "and" geteroaralkiloksisulfoniloksi "have the meanings defined similarly.

The term “amino” or “amine” as used herein refers to —NH ₂ and its substituted derivative, wherein one or both of the hydrogen is independently replaced by substituents selected from the group consisting of alkyl, haloalkyl, fluoroalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl , aryl, aralkyl, heteroaryl, heteroalkyl, alkylcarbonyl, haloalkylcarbonyl, fluoroalkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, carbocyclylcarbonyl, heterocyclylcarbonyl, arylcarbonyl, aralkylcarbonyl, heteroarylcarbonyl sulfonyl and sulfinyl groups defined above; or when both hydrogen atoms are together replaced by an alkylene group (forming a ring that contains nitrogen). Representative examples include, but are not limited to, methylamino, acetylamino, and dimethylamino.

The term “amido,” as used herein, means an amino group, as defined herein, coupled to the parent molecular moiety through a carbonyl.

The term “cyano” as used herein means a —C≡N group.

The term “nitro” as used herein means an —NO ₂ group.

The term “azido” as used herein means an —N ₃ group.

The term “phosphinyl” or “phosphino” as used herein includes —PH ₃ and its substituted derivatives in which one, two or three hydrogen atoms are independently replaced with substituents selected from the group consisting of alkyl, haloalkyl, fluoroalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, aralkyl, heteroaryl, heteroalkyl, alkoxy, haloalkoxy, fluoroalkyloxy, alkenyloxy, alkynyloxy, carbocyclyloxy, heterocyclyloxy, aryloxy, aralkyloxy, heteroaryloxy, heteroaraloxy and

The term “phosphoryl” as used herein refers to the group —P (═O) OH ₂ and its substituted derivative, wherein one or both hydroxyls is independently replaced by substituents selected from the group consisting of alkyl, haloalkyl, fluoroalkyl, alkenyl, alkynyl, carbocyclyl , heterocyclyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkoxy, haloalkoxy, fluoroalkyloxy, alkenyloxy, alkynyloxy, carbocyclyloxy, heterocyclyloxy, aryloxy, aralkyloxy, heteroaryloxy, heteroaralkyloxy and amino.

The term “silyl” as used herein includes H ₃ Si and its substituted derivatives in which one, two or three hydrogen atoms are independently replaced by substituents selected from alkyl, haloalkyl, fluoroalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, aralkyl heteroaryl and heteroalkyl. Representative examples include trimethylsilyl (TMS), tert-butyldiphenylsilyl (TBDPS), tert-butyldimethylsilyl (TBS / TBDMS), triisopropylsilyl (TIPS) and [2- (trimethylsilyl) ethoxy] methyl (SEM).

The term “silyloxy” as used herein means a silyl group, as defined herein, attached to the parent molecule by an oxygen atom.

The abbreviations Me, Et, Ph, Tf, Nf, Ts, and Ms are methyl, ethyl, phenyl, trifluoromethanesulfonyl, nonafluorobutanesulfonyl, p-toluenesulfonyl, and methanesulfonyl, respectively. A more extensive list of abbreviations used by ordinary specialists in organic chemistry is in the first issue of each volume of the Journal of Organic Chemistry; this list is symbolically represented in the table entitled Standard List of Abbreviations.

The term “treatment” as used herein encompasses the administration and / or use of one or more of the compounds described herein to a subject for prophylaxis or the ability to cope with a patient and / or cure a disease state. “Treatment” for this invention may, but should not, provide a course of treatment; rather, “treatment” may be in the form of coping with the condition. When the compounds described herein are used to treat unwanted proliferating cells, including cancer, “treatment” includes the partial or complete destruction of unwanted proliferating cells with minimal destructive effects in relation to normal cells. Apoptosis is the desired mechanism for treating unwanted rapidly proliferating cells, including cancer cells, at the cellular level.

The term “treat,” as used herein, encompasses not only healing but also slowing the progression and / or reducing the severity of the disease, disorder or condition. In one embodiment, “treatment” may encompass “prevention” (or prevention).

The term “prevention” as used herein includes either the prophylaxis or delay in the onset of the clinically apparent development of the disease as a whole or the prevention or delay in the onset of the obvious stage prior to the onset of the disease in patients at risk of becoming ill. This includes preventive treatment for patients at risk of developing the disease.

The term “subject” for treatment purposes includes any person or animal who is diagnosed, or who has symptoms, or who risks developing a disease. For prevention methods, the subject is any human or animal.

The term “optionally deuterated”, as used herein, refers to any radical described above in which one or more hydrogens is replaced by deuterium. Examples of deuterated alkyl include —CD ₂ H and —CD ₃ .

The term “polyol” as used herein refers to small molecules and polymers that have more than one hydroxyl.

The “carbohydrate” (or, equivalently, “sugar”) used here is a saccharide (including monosaccharides, oligosaccharides and polysaccharides) and / or a molecule (including oligomers and polymers) produced from one or more monosaccharides, for example, reduction of carbonyl groups, oxidation of one or more terminal groups of carboxylic acids, substitution of one or more hydroxy groups by a hydrogen atom, an amino group, a thiol group or similar heteroaromatic groups, etc. The term “carbohydrate” also includes derivatives of these soy İnönü. In some cases, the carbohydrate may be pentose (i.e., having 5 carbons) or hexose (i.e., having 6 carbons); and in some cases, the carbohydrate may be an oligosaccharide comprising pentose and / or hexose units, for example, including those described above.

“Carbohydrate” and “sugar” as used herein also include sugar mimetics and sugar-like moieties. Sugar mimetics are well known to those skilled in the art and include those described in Essentials of Glycobiology Edited by Varki, A., et al, Cold Spring Harbor Laboratory Press. Cold Spring Harbor, N.Y. 2002. For example, sugar-like groups covered by the present invention include cyclites, such as cycloalkane containing one hydroxyl group on each of three or more ring atoms, as defined by the IUPAC convention. In other embodiments, such cyclic fragments include inositol, such as scylo-inositol. Suitable sugar-like moieties include acyclic sugar moieties. Such groups include linear alkites and erythrites, only a few are named. It is obviously understood that sugar groups exist in either cyclic or acyclic form. Accordingly, acyclic forms of sugar groups are encompassed by the present invention as suitable sugar-like moieties.

The term “polythiol” as used herein refers to small molecules and polymers that have more than one thiol.

COMPOUNDS

Niacin, also known as nicotinic acid, has the structure

One aspect of the invention relates to compounds represented by structure I, or their pharmaceutically acceptable salts:

wherein

R represents hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, condensed bicyclyl, carboxyalkyl or arylalkenylaryl;

R ^{4 is} independently selected for each case from the group consisting of deuterium, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, halogen, nitro, cyano, sulfonic acid, alkyl sulfoxyl, arylsulfoxyl, heteroarylsulfoxyl, aralkylsulfoxylalkylalkyl, heteroalkylsulfoxyl, hetero , alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aralkylsulfonyl, heteroaralkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, hydroxyl, alkoxyl, aryloxyl, heteroaryloxyl, aralkyl and, heteroaralkyloxy, alkenyloxy, alkynyloxy, thiol, alkylthio, arylthio, aralkylthio, heteroaralkylthio, alkenylthio, alkynylthio, formyl, acyl, formyloxy, acyloxy, formylthio, acylthio, amine, alkylamine, arylamino, aryl aryl, aryl aryl aryl aryl aryl aryl formylamine, acylamine, carboxyl, alkyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, aralkyloxycarbonyl, heteroaralkyloxycarbonyl, amido, alkylaminecarbonyl, arylaminecarbonyl, heteroarylaminecarbonyl, aralkylaminecarbonyl and heteroaralkylaminecarbonyl;

n represents 0, 1, 2, 3, 4, 5, 6, 7, or 8; and

m represents 1, 2, 3 or 4.

In some embodiments, the invention relates to any one of the above compounds in which n is 0.

In some embodiments, the invention relates to any one of the above compounds in which n is 1.

In some embodiments, the invention relates to any one of the above compounds in which n is 2.

In some embodiments, the invention relates to any one of the above compounds in which n is 3.

In some embodiments, the invention relates to any one of the above compounds in which n is 1, 2 or 3; and R ^{4 is} substituted with a substituent independently selected from the group consisting of lower alkyl, halogen, nitro, cyano, sulfonic acid, hydroxyl, alkoxyl, thiol, alkylthio, formyl, acyl, formyloxy, acyloxy, formylthio, acylthio, amine, alkylamine, formylamine , acylamine and carboxyl.

In some embodiments, the invention relates to any one of the above compounds in which n represents 1; and R ^{4 is} selected from the group consisting of lower alkyl, halogen, nitro, cyano, sulfonic acid, hydroxyl, alkoxyl, thiol, alkylthio, formyl, acyl, formyloxy, acyloxy, formylthio, acylthio, amine, alkylamine, formylamine, acylamine and carboxyl .

In some embodiments, the invention relates to any one of the above compounds in which m is 1.

In some embodiments, the invention relates to any one of the above compounds in which m is 2.

In some embodiments, the invention relates to any one of the above compounds in which m is 3.

In some embodiments, the invention relates to any one of the above compounds in which m is 4.

In some embodiments, the invention relates to any one of the above compounds in which R is hydrogen.

In some embodiments, the invention relates to any one of the aforementioned compounds in which R is lower alkyl.

In some embodiments, the invention relates to any one of the above compounds in which R is

In some embodiments, the invention relates to any one of the above compounds in which R is an aliphatic group that hydrolyzes to carboxyl under physiological conditions.

Another aspect of the invention relates to a compound or a pharmaceutically acceptable salt thereof, selected from the group consisting of

Another aspect of the invention relates to the connection

or a pharmaceutically acceptable salt thereof.

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

in which independently for each case

W represents a polyol or polythiol;

p represents 2-500 inclusive;

R ¹ represents

and is either attached to the polyol through the oxygen atom of the polyol, or attached to the polythiol through the sulfur atom of the polythiol;

R represents hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, condensed bicyclyl, carboxyalkyl or arylalkenylaryl;

R ^{4 is} independently selected for each case from the group consisting of deuterium, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, halogen, nitro, cyano, sulfonic acid, alkyl sulfoxyl, arylsulfoxyl, heteroarylsulfoxyl, aralkylsulfoxylalkylalkyl, heteroalkylsulfoxyl, hetero , alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aralkylsulfonyl, heteroaralkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, hydroxyl, alkoxyl, aryloxyl, heteroaryloxyl, aralkyl and, heteroaralkyloxy, alkenyloxy, alkynyloxy, thiol, alkylthio, arylthio, aralkylthio, heteroaralkylthio, alkenylthio, alkynylthio, formyl, acyl, formyloxy, acyloxy, formylthio, acylthio, amine, alkylamine, arylamino, aryl aryl, aryl aryl aryl aryl aryl aryl formylamine, acylamine, carboxyl, alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, aralkyloxycarbonyl, heteroaralkyloxycarbonyl, amido, alkylaminecarbonyl, arylaminecarbonyl, heteroarylaminecarbonyl, aralkylaminecarbonyl and etroaralkilaminkarbonila;

R ⁵ for each case is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, halogen, nitro, cyano, sulfonic acid, alkyl sulfoxyl, arylsulfoxyl, heteroarylsulfoxyl, aralkyl sulfoxylalkyl, heteroalkyl, hetero , alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aralkylsulfonyl, heteroaralkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, hydroxyl, alkoxyl, aryloxyl, heteroaryloxyl, aralkyl and, heteroaralkyloxy, alkenyloxy, alkynyloxy, thiol, alkylthio, arylthio, aralkylthio, heteroaralkylthio, alkenylthio, alkynylthio, formyl, acyl, formyloxy, acyloxy, formylthio, acylthio, amine, alkylamine, arylamino, aryl aryl, aryl aryl aryl aryl aryl aryl formylamine, acylamine, carboxyl, alkyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, aralkyloxycarbonyl, heteroaralkyloxycarbonyl, amido, alkylaminecarbonyl, arylaminecarbonyl, heteroarylaminecarbonyl, aralkylaminecarbonyl and heteroaralkylaminecarbonyl;

R ⁶ represents hydrogen or lower alkyl;

n represents 0, 1, 2, 3, 4, 5, 6, 7, or 8; and

m represents 1, 2, 3 or 4.

In some embodiments, the invention relates to any one of the above compounds in which W is polythiol.

In some embodiments, the invention relates to any one of the above compounds in which W is a polyol.

In some embodiments, the invention relates to any one of the above compounds in which said polyol is carbohydrate.

In some embodiments, the invention relates to any one of the above compounds in which said polyol is maltitol, sorbitol, xylitol and isomalt.

In some embodiments, the invention relates to any one of the above compounds in which said polyol is sorbitol.

In some embodiments, the invention relates to any one of the above compounds in which said polyol is inositol.

In some embodiments, the invention relates to any one of the above compounds in which said polyol is cis-1,2,3,5-trans-4,6-cyclohexanehexol.

In some embodiments, the invention relates to any one of the above compounds in which p is 2, 3, 4, 5, or 6.

In some embodiments, the invention relates to any one of the above compounds, in which p is 2-100 inclusive. In some embodiments, the invention relates to any one of the above compounds in which p is 2-50 inclusive. In some embodiments, the invention relates to any one of the above compounds in which p is 2-10 inclusive.

In some embodiments, the invention relates to any one of the above compounds in which said p is 2. In some embodiments, the invention relates to any one of the above compounds in which p is 3. In some embodiments, the invention relates to any one of the above compounds in which p is 4. In some embodiments, the invention relates to any one of the above compounds in which p is 5. In some embodiments of acquisition refers to any one of the above compounds in which p is 6.

Another aspect of the invention relates to a compound or a pharmaceutically acceptable salt thereof, selected from the group consisting of

It has been found that at least some of the compounds of the invention possess the desired physiological properties of niacin, with reduced unwanted side effects of niacin. For example, the compounds of the invention have the ability to modulate at least one lipid in a desired manner, without limiting side effects, or without a degree of limitation of side effects characteristic of niacin.

Additionally, it was found that at least some of the compounds of the invention did not seem to involve a niacin receptor with a high affinity for GPR109A in a niacin-like manner. GPR109A, also called PUMA-G and HM74A, is a member of the G-protein-coupled receptor (GPCR) family of nicotinic acid receptors. 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 effects of niacin on both lipids and flushing are eliminated. The flushing effect, but not lipid-modifying effects, niacin is attributed to activation with GPR109A ERK ½ MAP kinase, arrestin-mediated beta 1 (beta (β) -restin). It was reported that in mice knocked out by arrestin beta 1, the effect of niacin on the rush of blood is significantly reduced, while the lipid-modifying effects are preserved. Walters RW et al. (2009) J Clin Invest 119: 1312-21. It is important that at least some of the compounds of the invention greatly reduce the ability to induce β-arrestin to the membrane of cells expressing GPR109A compared to niacin, while still maintaining the clinically important lipid-modifying effects.

Many of the compounds of the invention may be provided as salts with pharmaceutically acceptable counterions (i.e., as pharmaceutically acceptable salts). “Pharmaceutically acceptable salt” means a non-toxic salt which, after administration to a recipient, is capable of producing either directly or indirectly a compound or prodrug of a compound of the present invention. A “pharmaceutically acceptable salt” is the ionic portion of a salt that is not toxic when released from the salt after administration to the recipient. Pharmaceutically acceptable salts can be formed with many acids, including, but not limited to, hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc. 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 bisulfide, hydrochloric, hydrobromic, hydroiodic, sulfuric and phosphoric acids, as well as organic acids such as para-toluenesulfonic, salicylic, tartaric, bitartaric, ascorbic, maleic, besilic, fumaric, gluconic, glucuronic, formic, glutamic, methanesulfonic, ethanesulfonic, benzenesulfonic, milk, oxalic, para-bromophenyl sulfonic, coal succinic, succinic, citric, benzoic and acetic acids, and related inorganic and organic acids. Such pharmaceutically acceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, mono-acid phosphate, di-acid phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate , formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suerate, subacate, fumarate, maleate, butyn-1,4-dioate, hexin-1,6-dioate, benzoate, chlorobenzoate, methyl benzoate, dinitrobenzoate, hydroxyb , methoxybenzoate, phthalate, terephthalate, sulfonate, xylene sulfonate, phenylacetate, fe ilpropionat, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycollate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate and similar salts. Examples of pharmaceutically acceptable acid addition salts include salts formed with mineral acids such as hydrochloric and hydrobromic acids, and especially salts formed with organic acids such as maleic acid.

Suitable bases for the formation of pharmaceutically acceptable salts with acidic functional groups include, but are not limited to, alkali metal hydroxides such as sodium, potassium and lithium; alkaline earth metal hydroxides such as calcium and magnesium; hydroxides of other metals such as aluminum and zinc; ammonia and organic amines, such as unsubstituted or hydroxy substituted mono, di or trialkylamines; dicyclohexylamine; tributylamine; pyridine; N-methyl, N-ethylamine; diethylamine; triethylamine; mono-, bis- or tris- (2-hydroxy-lower alkyl amines) such as mono-, bis- or tris- (2-hydroxyethyl) amine, 2-hydroxy-tert-butylamine or tris (hydroxymethyl) methylamine, N , N-di-lower alkyl-N- (hydroxy lower alkyl) amines such as N, N-dimethyl-N- (2-hydroxyethyl) amine or tri- (2-hydroxyethyl) amine; N-methyl-D-glucamine; and amino acids such as arginine, lysine and the like.

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

Certain compounds of the invention and their salts may also exist in the form of solvates, for example hydrates, and the present invention includes each solvate and mixtures thereof.

Some compounds of the invention may contain one or more chiral centers and exist in various optically active forms. When the compounds of the invention contain one chiral center, the compounds exist in two enantiomeric forms, and the present invention includes both enantiomers and mixtures of enantiomers, such as racemic mixtures. Enantiomers may be resolved by methods known to those skilled in the art, for example, by the formation of diastereoisomeric salts, which can be resolved, for example, by crystallization; the formation of diastereoisomeric derivatives or complexes that can be separated, for example by crystallization, gas-liquid or liquid chromatography; selective reaction of one enantiomer with an enantiomer-specific reagent, for example, enzymatic complex esterification; or gas-liquid or liquid chromatography in a chiral environment, for example, on a chiral substrate, for example, silicon dioxide, with a linked chiral ligand or in the presence of a chiral solvent. Obviously, it is understood that when the desired enantiomer is converted to some other chemical integrity using one of the separation procedures described above, a further step can be used to liberate 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 conversion.

When a compound of the invention contains more than one chiral center, it can exist in diastereoisomeric forms. Diastereoisomeric compounds can be separated using methods known to those skilled in the art, for example, chromatography or crystallization, and individual enantiomers can be separated as described above. The present invention includes each diastereoisomer of the compounds of the present invention and mixtures thereof.

Some compounds of the invention may exist in various tautomeric forms or in the form of various geometric isomers, and the present invention includes each tautomer and / or geometric isomer of the compounds of the invention and mixtures thereof.

Some compounds of the invention may exist in various stable conformational forms, which may be separable. Separation of the various conformers can result in torsional asymmetry due to limited rotation around an asymmetric single bond, for example, due to spatial obstruction or ring stress. The present invention includes each conformational isomer of the compounds of the invention and mixtures thereof.

Some compounds of the invention may exist in zwitterionic form, and the present invention includes a zwitterionic form of the compounds of the invention and mixtures thereof.

The present invention also includes prodrugs. As used herein, the term “prodrugs” refers to an agent that is converted to the parent drug in vivo using some physiological chemical process (for example, a prodrug brought to a physiological pH is converted to the desired dosage form). Prodrugs are often useful, in some situations, they may be easier to administer than the original drug. They may, for example, be bioavailable when administered orally, whereas the parent drug is not. A prodrug may also have improved solubility in pharmaceutical compositions compared to the parent drug. Without limitation, an example of a prodrug can be a compound of the present invention when it is administered as an ester (“prodrug”) to facilitate passage through a cell membrane where the solubility in water is not favorable, but then it is metabolically hydrolyzed to a carboxylic acid immediately inside the cell, where solubility in water is favorable. Prodrugs have many beneficial properties. For example, the prodrug may be more water soluble than the final drug, whereby intravenous administration of the drug is facilitated. A prodrug may also have a higher level of oral bioavailability than the final drug. After administration, the prodrug is enzymatically or chemically cleaved, delivering the final drug to the blood or tissue.

Exemplary prodrugs after cleavage release the corresponding free acid, and such hydrolyzable ester-forming residues of the compounds of this invention include, but are not limited to, carboxylic substituents (for example, —C (O) ₂ H or a moiety that contains carboxylic acid), where free hydrogen substituted with (C ₁ -C ₄ ) alkyl, (C ₂ -C ₁₂ ) alkanoyloxymethyl, (C ₄ -C ₉ ) -1- (alkanoyloxy) ethyl, 1-methyl-1- (alkanoyloxy) ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having 3 to 6 carbon atoms yes, 1- (alkoxycarbonyloxy) ethyl having 4 to 7 carbon atoms, 1-methyl-1- (alkoxycarbonyloxy) ethyl having 5 to 8 carbon atoms, N- (alkoxycarbonyl) aminomethyl having 3 to 9 carbon atoms , 1- (N- (alkoxycarbonyl) amino) ethyl having 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolactone-4-yl, di-N, N- (C ₁ -C ₂ ) alkylamino (C ₂ -C ₃ ) alkyl (such as β-dimethylaminoethyl), carbamoyl- (C ₁ -C ₂ ) alkyl, N, N-di (C ₁ -C ₂ ) alkylcarbamoyl- (C ₁ -C ₂ ) alkyl and piperidino, pyrrolidino or morpholino (C ₂ -C ₃ ) alkyl.

Other exemplary prodrugs liberate the alcohol or amine of a compound of the invention in which the free hydrogen of the hydroxyl or amine substituent is substituted with (C ₁ -C ₆ ) alkanoyloxymethyl, 1 - ((C ₁ -C ₆ ) alkanoyloxy) ethyl, 1-methyl-1 - (( C ₁ -C ₆ ) alkanoyloxy) ethyl, (C ₁ -C ₆ ) alkoxycarbonyl-hydroxymethyl, N- (C ₁ -C ₆ ) alkoxycarbonylaminomethyl, succinoyl, (C ₁ -C ₆ ) alkanoyl, α-amino (C ₁ - With ₄ ) alkanoyl, arylactyl and α-aminoacyl, or α-aminoacyl-α-aminoacyl, in which the indicated α-aminoalkyl moieties are independently any of of naturally occurring L-amino acids found in proteins, -P (O) (OH) ₂ , -P (O) (O (C ₁ -C ₆ ) alkyl) ₂ or glycosyl (a radical resulting from the removal of the hydroxyl of the hemi-acetal carbohydrate )

The phrase “protecting group” as used herein means temporary substituents that protect a potentially reactive functional group from undesired chemical transformations. Examples of such protecting groups include esters of carboxylic acids, silyl ethers of alcohols, and acetals and ketals of aldehydes and ketones, respectively. A review of the field of chemistry of protective groups is given in (Greene, TW; Wuts, PGM. Protective Groups in Organic Synthesis, 2 ^nd ed .; Wiley: New York, 1991). Protected forms of the compounds of the invention are included within the scope of this invention.

The term “chemically protected form” as used herein refers to a compound in which one or more reactive functional groups are protected from undesirable chemical reactions, that is, in the form of a protective or protecting group (also known as a masking or masking group). It may be convenient or desirable to obtain, purify and / or handle the active compound in a chemically protected form.

By protecting the reactive functional group, reactions involving other unprotected reactive functional groups without affecting the protected group may be carried out; the protecting group can be removed, usually in a subsequent step, without affecting substantially the rest of the molecule. See, e.g., Protective Groups in Organic Synthesis (T. Green and P. Wuts, Wiley, 1991) and Protective Groups in Organic Synthesis. (T. Green and P. Wuts; 3 ^rd Edition; John Wiley and Sons, 1999).

For example, the hydroxy group may be protected as an ether (-OR) or an ester (-OC (= O) R), for example, as t-butyl ether; benzyl, benzhydryl (diphenylmethyl) or trityl (triphenylmethyl) ether; trimethylsilyl or t-butyldimethylsilyl ether; or acetyl ether (-OC (= O) CH _3, -OAc).

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

For example, an amine group can be protected, for example, as an amide NRC (= O) R) or urethane (-NRC (= O) OR), for example, as methylamide (-NHC (= O) CH ₃ ); benzyloxyamide (-NHC (= O) OCH ₂ C ₆ H ₅ NH (Cbz); t-butoxyamide (-NHC = (O =) OC (CH ₃ ) ₃ , -NHBoc); 2-biphenyl-2-propoxyamide (- NHC (= O) OC (CH ₃ ) ₂ C ₆ H ₄ C ₆ H ₅ NHBoc) as 9-fluorenylmethoxyamide (-NHFmoc) as 6-nitroveratryloxyamide (NHNvoc) as 2-trimethylsilylethyloxyamide (-NHTeoc) as 2 , 2,2-trichlorethyloxyamide (NHTroc) as allyloxyamide (= NHAlloc), as 2- (phenylsulfonyl) ethyloxyamide (= NHPsec; or in suitable cases (e.g. cyclic amines), as nitroxide radical.

For example, a carboxylic acid group may be protected as an ester or amide, for example, as: benzyl ether; t-butyl ether; methyl ether or methylamide.

For example, a thiol group may be protected as a thioether (-SR), for example, as: benzyl thioether; or acetamidomethyl ether (SCH ₂ NHC (= O) CH ₃ ).

PHARMACEUTICAL COMPOSITIONS

The invention provides pharmaceutical compositions comprising one or more of the compounds referred to above. In one aspect, the present invention provides pharmaceutically acceptable compositions that comprise a therapeutically effective amount of one or more of the compounds described above formulated together with one or more pharmaceutically acceptable carriers (additives) and / or diluents.

Alternatively or in addition, the invention provides pharmaceutical compositions characterized by having one desired therapeutic effect of niacin and a decrease or absence of at least one undesirable side effect of niacin.

In one embodiment, the pharmaceutical composition is formulated for oral administration; when administered to a person by mouth, it lowers serum or plasma levels of at least one lipid selected from the group consisting of total cholesterol, low density lipoprotein (LDL) cholesterol, triglycerides and lipoprotein (a); and oral administration of the composition is characterized by a reduced rush of blood and a decrease in hepatocellular damage compared with the administration of an equimolar oral dose of niacin.

When administered orally to a human, the pharmaceutical composition lowers serum or plasma levels of at least one lipid selected from the group consisting of total cholesterol, low density lipoprotein cholesterol (LDL), triglycerides and lipoprotein (a). Said composition reduces the level of at least one lipid in serum or plasma when such a level in serum or plasma decreases in a measurable amount compared to pretreatment, baseline or control level. In one embodiment, the composition lowers the level of at least one lipid in serum or plasma when that level in serum or plasma decreases by at least 5 percent pretreatment, baseline, or control; that is, serum or plasma levels are reduced to no more than 95 percent of the pretreatment, baseline, or control level. In one embodiment, the composition reduces the level of at least one lipid in serum or plasma when that level in serum or plasma decreases by at least 10 percent of the pretreatment, baseline, or control level. In one embodiment, the composition reduces the level of at least one lipid in serum or plasma when that level in serum or plasma decreases by at least 15 percent of the pretreatment, baseline, or control level. In one embodiment, the composition lowers the level of at least one lipid in serum or plasma when that level in serum or plasma decreases by at least 20 percent of the pretreatment, baseline, or control level.

As used herein, the term “rush of blood” refers to an objective cutaneous vasodilation, often accompanied by redness, and / or a subjective experience of feeling warm on the skin, the latter with or without itching. The rush of blood can be objectively measured using objective measurements, such as Doppler measurements of capillary blood flow. Alternatively or additionally, a rush of blood can be measured using a so-called visual analogue scale (VAS), which can be either based on an observer or based on a subject. VAS usually provides for marking signs or symptoms on a scale of zero (0) to ten (10), where zero corresponds to the complete absence of the marked sign or symptom, and ten corresponds to the unbearable or maximum amount or degree of the sign or symptom.

The term “hepatocellular damage” as used herein refers to toxic damage to parenchymal liver cells. Hepatocellular damage can be assessed using any suitable method. In one embodiment, hepatocellular damage is assessed by measuring one or more serum liver enzymes. In one embodiment, one such liver enzyme is aminotransferase (AST, also called SGOT). In one embodiment, one such liver enzyme is alanine aminotransferase (ALT, also called SGPT). Serum AST and ALT levels are usually measured in clinical practice, and there is no need to describe methods for measuring them here. Normal levels of both of AST and ALT are usually 0-35 u / L. In contrast to AST, which is primarily found in the liver, AST is found in other tissues, including the heart, skeletal muscle, kidneys and brain, and is thus somewhat less specific as an indicator of liver dysfunction. Although elevated levels of AST or ALT can occur in a variety of non-hepatic conditions, including myocardial infarction, these conditions are usually clinically different from liver disease. In liver disease, elevations in serum AST and ALT reflect liver necrosis, a severe form of hepatocellular disorder.

Oral administration of the composition is characterized by reduced blood flow and reduced damage to liver cells compared to the administration of an equimolar oral dose of niacin. In this context, it is said that the rush of blood decreases when it decreases by a measurable amount or degree compared to the corresponding degree of rush of blood associated with the administration of an equimolar oral dose of niacin. In one embodiment, the rush of blood is said to decrease when the maximum degree or amount of the rush of blood decreases by a measurable degree or amount compared to the maximum degree or amount of the rush of blood associated with the administration of an equimolar oral dose of niacin.

In one embodiment, said rush of blood is reduced when the Doppler capillary blood flow is reduced by at least 2 percent compared to the Doppler capillary blood flow in the corresponding tissue associated with the administration of an equimolar oral dose of niacin, i.e. the flow decreases to no more than 98 percent of the Doppler capillary blood flow in the corresponding tissue associated with the administration of an equimolar oral dose of niacin. In one embodiment, this rush of blood is reduced when the Doppler capillary blood flow is reduced by at least 5 percent compared to the Doppler capillary blood flow in the corresponding tissue associated with the administration of an equimolar oral dose of niacin. In one embodiment, this rush of blood is reduced when the Doppler capillary blood flow is reduced by at least 10 percent compared to the Doppler capillary blood flow in the corresponding tissue associated with the administration of an equimolar oral dose of niacin.

In one embodiment, the flow of blood decreases when the VAS mark for the corresponding tissue decreases by at least one (1) (on a scale from 0 to 10) compared to the VAS mark for the corresponding tissue associated with the administration of an equimolar oral dose of niacin; those. the VAS mark is reduced to no more than one less than the VAS mark for the corresponding tissue associated with the administration of an equimolar oral dose of niacin. For example, in one embodiment, this rush of blood decreases when the maximum VAS mark is 5, while the maximum VAS mark for the corresponding tissue associated with the administration of an equimolar oral dose of niacin is 6-10.

Of course, any of the previous comparisons are primarily based on population. For example, average AST, ALT, or VAS can be compared. Similarly, the average values of the maximum elevation ALT, AST or VAS can be compared.

A comparison is made with respect to an equimolar oral dose of niacin. An equimolar oral dose of niacin refers to an equimolar oral dose of niacin in any form, including, for example, immediate, extended, sustained and extended release niacin formulations. In one embodiment, an equimolar oral dose is formulated in a similar manner, for example, in the form of tablets in which each individual tablet contains the same or substantially the same molar amount of active agent. Thus, in one embodiment, a comparison can be made between oral doses given in the form of single tablets, each of which contains 8.2 mmol of active agent (for example, 1 g of niacin). As an alternative example, in yet another embodiment, a comparison may be made between oral doses given in two tablet form, each tablet containing 4.1 mmol of active agent (e.g., 0.5 g of niacin).

Except, possibly noted otherwise, all pharmacokinetic comparisons with respect to “niacin” are comparisons with the composition of the so-called immediate release niacin.

In some embodiments, the invention relates to any one of the above compositions in which the peak concentration in serum or plasma (C _max ) for the compound is 40 percent or less C _max equimolar oral dose of niacin. In one embodiment, the peak serum or plasma concentration (C _max ) for the compound is 35 percent or less of the C _max equimolar oral dose of niacin. In one embodiment, the peak serum or plasma concentration (C _max ) for the compound is 30 percent or less (C _max ) of an equimolar oral dose of niacin. In one embodiment, the peak serum or plasma concentration (C _max ) for the compound is 25 percent or less of the C _max equimolar oral dose of niacin. In one embodiment, the peak serum or plasma concentration (C _max ) for the compound is 20 percent or less of the C _max equimolar oral dose of niacin. In one embodiment, the peak concentration in serum or plasma (C _max ) for the compound is 15 percent or less C _max equimolar oral dose of niacin. In one embodiment, the peak concentration in serum or plasma (C _max ) for the compound is 10 percent or less C _max equimolar oral dose of niacin. In one embodiment, the peak concentration in serum or plasma (C _max ) for the compound is 5 percent or less C _max equimolar oral dose of niacin. In one embodiment, the peak concentration in serum or plasma (C _max ) for the compound is 1 percent or less C _max equimolar oral dose of niacin. For each of the preceding embodiments, it should be understood that a comparison is made with the immediate release niacin composition. Methods useful for measuring concentration are described in detail below.

In some embodiments, the invention relates to any one of the above compositions in which the peak concentration in serum or plasma (C _max ) for the compound is 1-40 percent (C _max ) of an equimolar oral dose of niacin. In one embodiment, the peak serum or plasma concentration (C _max ) for the compound is 1-35 percent of the C _max equimolar oral dose of niacin. In one embodiment, the peak concentration in serum or plasma (C _max ) for the compound is 1-30 percent of the C _max equimolar oral dose of niacin. In one embodiment, the peak serum or plasma concentration (C _max ) for the compound is 1-25 percent of the C _max equimolar oral dose of niacin. In one embodiment, the peak concentration in serum or plasma (C _max ) for the compound is 1-20 percent C _max equimolar oral dose of niacin. In one embodiment, the peak concentration in serum or plasma (C _max ) for the compound is 1-15 percent C _max equimolar oral dose of niacin. In one embodiment, the peak serum or plasma concentration (C _max ) for the compound is 1-10 percent of the C _max equimolar oral dose of niacin. For each of the preceding embodiments, it should be understood that a comparison is made with the immediate release niacin composition. Methods useful for measuring concentration are described in detail below.

In some embodiments, the invention relates to any one of the above compositions in which the ratio of the peak concentration in serum or plasma (C _max ) to the area under the curve for 24 hours (AUC _0-24 ) (i.e., the ratio C _max / AUC _{0 -24} ) for the compound is 0.35 h ^-1 or less. In one embodiment, the ratio of peak concentration to area under the curve for 24 hours (C _max / AUC _0-24 ) for the compound is 0.30 h ^-1 or less. In one embodiment, the ratio of peak concentration to area under the curve for 24 hours (C _max / AUC _0-24 ) for the compound is 0.25 h ^-1 or less. In one embodiment, the ratio of peak concentration to area under the curve for 24 hours (C _max / AUC _0-24 ) for the compound is 0.20 h ^-1 or less. In one embodiment, the ratio of peak concentration to area under the curve for 24 hours (C _max / AUC _0-24 ) for the compound is 0.15 h ^-1 or less. In one embodiment, the ratio of peak concentration to area under the curve for 24 hours (C _max / AUC _0-24 ) for the compound is 0.10 h ^-1 or less. In one embodiment, the ratio of peak concentration to area under the curve for 24 hours (C _max / AUC _0-24 ) for the compound is 0.05 h ^-1 or less. In one embodiment, the ratio of peak concentration to area under the curve for 24 hours (C _max / AUC _0-24 ) for the compound is 0.01 h ^-1 or less.

In some embodiments, the invention relates to any one of the above compositions in which the ratio of the peak concentration in serum or plasma (C _max ) to the area under the curve for 24 hours (AUC _0-24 ) (i.e., the ratio C _max / AUC _{0 -24} ) for the compound is 0.10 h ^-1 - 0.35 h ^-1 . In one embodiment, the ratio of peak concentration to area under the curve for 24 hours (C _max / AUC _0-24 ) for the compound is 0.10 h ^-1 - 0.30 h ^-1 . In one embodiment, the ratio of concentration peak to area under the curve for 24 hours (C _max / AUC _0-24 ) for the compound is 0.10 h ^-1 - 0.25 h ^-1 . In one embodiment, the ratio of peak concentration to area under the curve for 24 hours (C _max / AUC _0-24 ) for the compound is 0.10 h ^-1 - 0.20 h ^-1 .

In some embodiments, the invention relates to any one of the above compositions in which the time to peak concentration in serum or plasma (t _max ) for the compound is in the range of 30 minutes to 5 hours. In one embodiment, the time to peak concentration (t _max ) for the compound is in the range of 1-5 hours. In one embodiment, the time to peak concentration (t _max ) for the compound is in the range of 1-4 hours. In one embodiment, the time to peak concentration (t _max ) for the compound is in the range of 1-3 hours. In one embodiment, the time to peak concentration (t _max ) for the compound is in the range of 1-2 hours.

In some embodiments, the invention relates to any one of the above compositions in which the compound has an EC ₅₀ with respect to β-arrestin-mediated function GPR109A, which is at least 10 times greater than EC _{50 of} niacin with respect to β-arrestin-mediated function GPR109A. EC ₅₀ refers to a concentration at which a particular effect reaches 50 percent of its maximum. The function of β-arrestin-mediated GPR109A is described hereinafter. In one embodiment, the compound has an EC ₅₀ with respect to β-arrestin-mediated function of GPR109A, which is at least 20 times greater than EC _{50 of} niacin with respect to β-arrestin-mediated function of GPR109A. In one embodiment, the compound has an EC ₅₀ with respect to β-arrestin-mediated function of GPR109A, which is at least 30 times greater than EC _{50 of} niacin with respect to β-arrestin-mediated function of GPR109A. In one embodiment, the compound has an EC ₅₀ with respect to β-arrestin-mediated function of GPR109A, which is at least 40 times greater than EC _{50 of} niacin with respect to β-arrestin-mediated function of GPR109A. In one embodiment, the compound has an EC ₅₀ with respect to β-arrestin-mediated function of GPR109A, which is at least 50 times greater than EC _{50 of} niacin with respect to β-arrestin-mediated function of GPR109A. In one embodiment, the compound has an EC ₅₀ with respect to β-arrestin-mediated function of GPR109A, which is at least 100 times greater than EC _{50 of} niacin with respect to β-arrestin-mediated function of GPR109A.

In some embodiments, the invention relates to any one of the above compositions, which, when administered orally to a human, also increases the level of high density lipoprotein (HDL) in serum or plasma. Serum or plasma HDL cholesterol levels increase by at least a measurable amount compared to a pre-treatment level, baseline, or control level. For example, in one embodiment, the serum or plasma level of HDL cholesterol is increased by at least 5 percent compared to a pre-treatment, baseline or control level. In one embodiment, the serum or plasma HDL cholesterol level is increased by at least 10 percent compared to a pre-treatment, baseline, or control level. In one embodiment, the serum or plasma HDL cholesterol level is increased by at least 15 percent compared to a pre-treatment, baseline, or control level. In one embodiment, the serum or plasma HDL cholesterol level is increased by at least 20 percent compared to a pre-treatment, baseline, or control level. In one embodiment, the serum or plasma HDL cholesterol level is increased by at least 25 percent compared to a pre-treatment, baseline, or control level.

In some embodiments, the invention relates to any one of the above compositions, which, when administered orally to a human, does not substantially induce any increase in the levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), or both. In one embodiment, “substantially no increase” in this context means less than 20 percent increase over a preposition, baseline, or reference level. In one embodiment, “substantially no increase” in this context means less than 10 percent increase over a preposition, baseline, or reference level.

In some embodiments, the invention relates to any one of the above compositions, which, when administered orally to a human, does not cause substantially any increase in serum levels of uric acid, glucose, or both. Normal serum uric acid levels are 1.5-8.0 mg / dl. In one embodiment, “substantially no increase in serum uric acid” means less than a 10 percent increase compared with pre-treatment, baseline, or control. Normal fasting plasma glucose levels are approximately 75-115 mg / dl. Normal randomly selected plasma glucose levels (2 hours after a meal) are approximately <140 mg / dl. In one embodiment, “substantially no increase in serum glucose” means less than a 20 percent increase over pre-treatment, baseline, or control. In one embodiment, “substantially no increase in serum glucose” means less than a 15 percent increase over pre-treatment, baseline, or control. In one embodiment, “substantially no increase in serum glucose” means less than a 10 percent increase over pre-treatment, baseline, or control.

In yet another aspect, the agents of the invention may be administered as such, or may be administered in mixtures with pharmaceutically acceptable carriers, and may also be administered in combination with other agents. The therapy in combination with something involves the sequential, simultaneous and separate or joint administration of one or more compounds of the invention, in which the therapeutic effects of the first agent administered are not completely gone when the next compound is administered. In other words, the term “coadministration” as used herein refers to concurrent administration (administration of two or more therapeutic agents at the same time) and time-varying administration (administration of one or more therapeutic agents at a time different from the administration time optionally therapeutic agent or agents), while therapeutic agents are present in the patient at the same time.

As described in detail below, the pharmaceutical compositions of the present invention can be specially formulated for administration in solid or liquid form, including forms selected for the following: (1) oral administration, for example, liquid forms (aqueous or non-aqueous solutions or suspensions), tablets, for example, tablets for cheek, sublingual and systemic absorption or absorption, capsules, boluses, powders, granules, pastes for use in the tongue; (2) parenteral administration, for example, by intravenous, intramuscular, intraperitoneal, subcutaneous or epidural injection or infusion, for example, in the form of a sterile solution or suspension, or a sustained or continuous release formulation; (3) topical or topical application, for example, in the form of a cream, ointment, or slices of a controlled release patch applied to the skin; (4) intrauterine or intrarectal administration, for example, in the form of pessaries, creams or foams; (5) sublingual; (6) ocularly; (7) transdermally; (8) nasal; (9) pulmonary; or (10) intrathecal.

The phrase “therapeutically effective amount” as used herein means an amount of a compound, material or composition comprising a compound of the present invention that is effective to achieve some desired effect, at least in a subpopulation of cells in animals with an acceptable benefit / risk ratio for any medical treatment .

The phrase “pharmaceutically acceptable” is used herein to refer to compounds, materials, compositions and / or dosage forms which, in the scope of sound medical judgment, are suitable for use in contact with tissues of humans and animals without excessive toxicity, irritation, allergic reaction or other problems or complications commensurate with an acceptable benefit / risk ratio.

The phrase “pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition, or excipient, such as a liquid or solid excipient, diluent, excipient, derivative auxiliary agent (eg, lubricant, talc, magnesium, calcium or zinc stearate, or stearic acid ) or an encapsulating solvent material involved in transferring or transporting a compound in a subject from one organ or part of an organism to another organ or part of an organism. Each carrier must be “acceptable”, in the sense of being compatible with other ingredients of the composition, and harmless to 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 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 waxes; (9) oils, such as peanut oil, cottonseed oil, sunflower, sesame, olive, corn 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-agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) pH buffers; (21) polyesters, polycarbonates and / or polyanhydrides; and (22) other non-toxic compatible substances used in the pharmaceutical compositions.

As noted above, in some embodiments, the present compounds may contain a basic functional group, such as amino or alkylamino, and are thus capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable acids. The term “pharmaceutically acceptable salts” as used herein refers to the relatively non-toxic, inorganic and organic acid addition salts of the present invention. These salts can be prepared in situ by the administration of an excipient or during the production of dosage forms, or separately by reacting the purified compound of the invention in the form of a free base with a suitable organic or inorganic acid, and separating the salt thus formed during subsequent purification. Typical salts include hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, mesylate , lactobionate and lauryl sulfonate salts and the like (see, for example, Berge et al. (1977) “Pharmaceutical Salts”, J. Pharm. Sci. 66: 1-19).

Pharmaceutically acceptable salts of the disclosed compounds include conventional non-toxic salts or quaternary ammonium salts of compounds, for example, from non-toxic organic or inorganic acids. For example, such conventional non-toxic salts include salts derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and salts produced from organic acids, such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, palmitic, maleic, hydroxy maleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilibenzoic, 2 fumaric, toluenesulfonic, methanesulfonic, ethanedisulfonic, oxalic, isothionic and the like.

In other cases, the compounds of the present invention may contain one or more acid functional groups and, thus, are capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases. The term “pharmaceutically acceptable salts” in these cases refers to the relatively non-toxic inorganic and organic base addition salts of the compounds of the present invention. These salts can likewise be prepared in situ by administration of an excipient or during the manufacturing of a dosage form, or separately by reacting the purified compound in free form with a suitable base such as a pharmaceutically acceptable metal cation hydroxide, carbonate or bicarbonate, with ammonia or with 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 the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like (see, for example, Berge et al., Above).

Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweeteners, flavoring and flavoring agents, preservatives and antioxidants may also be present in the compositions.

Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol and the like; and (3) metal chelating agents such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

The compositions of the compositions of the present invention include forms suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal and / or parenteral administration. The compositions may conveniently be presented in unit dosage form and may be prepared by any method well known in the pharmaceutical art. The amount of active ingredient that can be combined with the material of the carrier to obtain one dosage form varies depending on the subject to be treated, the particular route of administration. The amount of active ingredient that can be combined with the material of the carrier to obtain a single dosage form is usually the amount of a compound that gives a therapeutic effect. Typically, based on one hundred percent, this amount will be from about 0.1 percent to about ninety-nine percent of the active ingredient, preferably from about 5 to 70 percent, most preferably from about 10 percent to about 30 percent.

In some embodiments, the composition of the composition of the present invention includes an excipient selected from the group consisting of cyclodextrins, celluloses, liposomes, micelle forming agents, for example, bile acids, and polymeric carriers, for example, polyesters and polyanhydrides; and a compound of the present invention. In some embodiments, the aforementioned composition makes a compound of the present invention orally bioavailable.

Methods for preparing these forms or compositions include the step of combining a compound of the present invention with a carrier and, optionally, one or more accessory ingredients. Typically, compositions are prepared by uniformly and thoroughly mixing the compounds of the present invention with liquid carriers, or finely divided solid carriers, or both, and, when necessary, molding the product.

Compositions of the invention suitable for oral administration may be in the form of capsules, wafers, pills, tablets, troches (using a base, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil emulsion, or an elixir or syrup, or as lozenges (using an inert base such as gelatin and glycerin, or sucrose and Arabian gum) and / or as a rinse for mouth and similar, each of which contains a given th number of compounds of the present invention as an active ingredient. The compound of the present invention may also be administered as boluses, electuary or pastes.

In solid dosage forms of the invention for oral administration (capsules, tablets, pills, dragees, powders, granules, troches and the like), the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or diluents, such as starches, lactose, sucrose, glucose, mannitol and / or silicic acid; (2) binders such as carboxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and / or gum arabic; (3) humectants, such as glycerin; (4) disintegrating agents such as agar agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain silicates and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators such as quaternary ammonium compounds and surfactants such as poloxamer and sodium lauryl sulfate; (7) wetting agents such as cetyl alcohol, glycerol monostearate and non-ionic surfactants; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, zinc stearate, sodium stearate, stearic acid and mixtures thereof; (10) coloring agents; and (11) release control agents, such as crospovidone or ethyl cellulose. In the case of capsules, tablets and pills, the pharmaceutical compositions may also include buffering agents. Solid compositions of a similar type can also be used as fillers in soft and hard shell gelatine capsules using excipients such as lactose or milk, as well as high molecular weight polyethylene glycols, and the like.

Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be made using a binder (e.g. gelatin or hydroxypropyl methyl cellulose), a lubricant, an inert diluent, a preservative, a disintegrating agent (e.g. sodium starch glycolate or cross-linked carboxymethyl cellulose), a surface-active or dispersing agent. Molded tablets may be made by molding in a suitable device a mixture of the powdered compound moistened with an inert liquid diluent.

Tablets and other solid dosage forms of the pharmaceutical compositions of the present invention, such as dragees, capsules, pills and granules, may optionally be labeled or coated and coated, such as enteric coatings and other coatings well known in the pharmaceutical formulations field. They can also be in the form of compositions in order to slowly or in a controlled manner release the active ingredient using, for example, hydroxypropyl methylcellulose in varying proportions to provide the desired release profile for other polymer matrices, liposomes and / or microspheres. They can be formulated for quick release, for example, by freeze-dried. They can be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in them in the form of sterile solid compositions that can be dissolved in water or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents, and may be such that they release the active ingredient (s) only, or preferably, in a certain part of the gastrointestinal tract, not necessarily in a delayed manner. Examples of compositions that can be used include polymeric substances and waxes. The active ingredient may also be in microencapsulated form, if appropriate, with one or more of the excipients described above.

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, liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate , propylene glycol, 1,3-butylene glycol, oils (in particular cottonseed, peanut, corn, germ, olive, castor and sesame oils), glycerin, tetrahydrofuryl alcohol, polyethylene glycols and sorbitol New fatty acid esters, and mixtures thereof.

In addition to inert diluents, oral compositions may also include auxiliary agents, such as wetting, emulsifying and suspending agents, sweetening, flavoring, coloring, flavoring and preserving agents.

Suspensions, in addition to the active compounds, may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar agar and tragacanth, and mixtures thereof.

Formulations of the pharmaceutical compositions of the invention for rectal or vaginal administration can be presented in the form of medical suppositories, which can be obtained by mixing one or more compounds of the invention with one or more suitable non-irritating excipients or carriers, including, for example, cocoa butter, polyethylene glycol, suppository wax or salicylate, and which are solid at room temperature but liquid at body temperature and therefore will soften in the rectum or in the water galische and release the active compound.

Formulations of compositions of the present invention that are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or sprays containing such carriers that are known in the art and are suitable for this purpose.

Dosage forms for topical or transdermal administration of the compounds of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, plasters and inhalers. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier and with any preservatives, buffers or propellants that may be required.

Ointments, pastes, creams and gels may contain, in addition to the active compound of this invention, fillers such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and oxide zinc, or mixtures thereof.

Powders and sprays may contain, in addition to the compound of the present invention, fillers such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays may further comprise conventional propellants, such as chlorofluorocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

Transdermal plaques have the added benefit of providing controlled release of a compound of the present invention to the body. Such dosage forms may be prepared by dissolving and dispersing the compound in an appropriate medium. Absorption enhancers can also be used to increase the movement of the compound through the skin. The speed of such movement can be controlled either by providing a rate of regulation of the membrane, or by dispersing the compound in a polymer matrix or gel.

Ophthalmic compositions, ophthalmic ointments, powders, solutions and the like are also covered by the scope of this invention.

Pharmaceutical compositions of the invention suitable for parenteral administration include one or more compounds of the invention in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders that can be converted into sterile injectable solutions before use. or dispersions that may contain sugars, alcohols, antioxidants, buffers, bacteriostatic agents, dissolved substances that elayut form the composition isotonic with the blood of the intended recipient or suspending or thickening agents.

Examples of suitable aqueous and non-aqueous vehicles that can be used in the pharmaceutical compositions of the invention include water, ethanol, polyols (such as glycerin, 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. Proper fluidity can be achieved, for example, by using coating materials such as lecithin, maintaining the required particle size in the case of dispersions, and using surfactants.

These compositions may also contain adjuvants, such as preservatives, wetting, emulsifying and dispersing agents. Prevention of the action of microorganisms on the compounds in question can be guaranteed by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenolsorbic acid and the like. It may also be desirable to include isotonic agents in the composition, such as sugars, sodium chloride and the like. Additionally, prolonged absorption of the injectable pharmaceutical form can be achieved by the inclusion of agents that delay absorption, 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 from subcutaneous or intramuscular injection. This result can be achieved by using a liquid suspension of crystalline or amorphous material having poor solubility in water. The absorption rate of the drug then depends on the dissolution rate, which in turn may depend on the size of the crystals and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is achieved by dissolving or suspending the drug in an oil vehicle.

Injectable spare forms are made by forming microcapsule matrices of the compounds in question in biodegradable polymers such as polyactide-polyglycolide. Depending on the ratio of drug to polymer and the nature of the particular polymer used, the rate of release of the drug can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Spare injectable forms of the compositions are also prepared by enclosing the drug in liposomes or microemulsions that are compatible with body tissue.

When the compounds of the present invention are administered to humans and animals as pharmaceuticals, they can be used alone or in the form of a pharmaceutical composition containing, for example, 0.1-99% (more preferably 10-30%) of the active ingredient in combination with a pharmaceutically acceptable carrier.

The preparations of the present invention can be given orally, parenterally, topically or rectally. They are of course used in forms suitable for each route of administration. For example, they are administered in the form of tablets or capsules, by injection, by inhalation, in the form of an eye lotion, ointment, suppository, by injection, infusion or inhalation, topically as a lotion or ointment; and rectally, by suppository.

The phrases “parenteral administration” and “administered or administered parenterally” as used herein indicate methods of administration other than enteral (into the digestive tract) and local administration, usually by injection, and include, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intraarticular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrathoracic th injection and infusion.

The phrases “systemic administration”, “systemically administered”, “peripheral administration” and “peripheral administration” as used herein mean the administration of a compound, drug or other material in a way other than directly into the central nervous system so that it enters the patient’s system and thus undergoes metabolism and other similar processes, for example, subcutaneous administration.

The compounds can be administered to humans and animals for therapy by any suitable route of administration, including by mouth, through the nose, such as, for example, in the form of a spray, rectally, intravaginally, parenterally, intracisternally and topically, in the form of powders, ointments or drops, including by chewing and sublingually.

Whatever the chosen route of administration, the compounds of the present invention that can be used in a suitable hydrated form and / or the pharmaceutical compositions of the present invention are converted into pharmaceutically acceptable dosage forms by convenient methods known to those skilled in the art.

Actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention may vary so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition and route of administration that is not toxic to the patient.

The dose level chosen will depend on many factors, including the activity of the particular compound of the present invention used, or its ester, salt or amide, route of administration, time of administration, rate of excretion or metabolism of the particular compound used, rate and extent of absorption, duration of treatment, other drugs means, compounds and / or materials used in combination with the particular compound used, age, gender, weight, condition, general health status and medical history dvergaemogo treated patient, and like factors well known in the medical technology industry.

A doctor or veterinarian having ordinary knowledge in this field will be able to easily determine and prescribe an effective amount of the required pharmaceutical composition. For example, a doctor or veterinarian could start with doses of the compounds of the invention used in pharmaceutical compositions at levels lower than those required in order to achieve the desired therapeutic effect and gradually increase the dose until the desired effect is achieved.

Usually a suitable daily dose of a compound of the invention is the amount of compound that is the smallest dose effective to produce a therapeutic effect. Such an effective dose will depend on the factors described above. Typically, the oral, intravenous, intraventricular, and subcutaneous doses of the compounds of this invention to a patient, used for these effects, will be from about 0.0001 to about 100 mg per kilogram of body weight per day.

The invention in particular considers oral administration in humans. The oral dosage in adults is usually on the order of 0.05 grams (50 mg) to 10 grams per day, given as a single dose or in divided doses. In one embodiment, the oral dosage for adults is 0.5 grams (500 mg) to 10 grams per day, given as a single dose or in divided doses. In one embodiment, the oral dosage for adults is 0.5-8 grams per day, given as a single dose or in divided doses. In one embodiment, the oral dosage for adults is 0.5-6 grams per day, given as a single dose or in divided doses. In one embodiment, the oral dosage for adults is 0.5-4 grams per day, given as a single dose or in divided doses. In one embodiment, the oral dosage for adults is 0.5-2 grams per day, given as a single dose or in divided doses. In one embodiment, the oral dosage for adults is 0.5-1 grams per day, given as a single dose or in divided doses.

If desired, an effective daily dose of the active compound may be administered in the form of two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally in unit dosage forms. An example of a dosage administration is one administration per day.

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

The compounds of the invention may be formulated in any convenient manner for use in human or veterinary medicine, by analogy with other pharmaceutical agents.

In yet another aspect, the present invention provides pharmaceutically acceptable compositions that comprise a therapeutically effective amount of one or more of the compounds discussed above, together with one or more pharmaceutically acceptable carriers (additives) and / or diluents. As described in detail below, the pharmaceutical compositions of the present invention can be specifically formulated for administration in solid or liquid form, including forms adapted for the following: (1) oral administration, for example, in the form of doses of an animal medicine (aqueous or non-aqueous solutions or suspensions) tablets, boluses, powders, granules, pastes for use in the tongue; (2) parenteral administration, for example, by subcutaneous, intramuscular or intravenous injection, such as, for example, 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) intravaginally or intrarectally, for example, in the form of pessaries, creams or foams; (5) sublingual or buccal; (6) ocularly; (7) transdermally; or (8) nasal.

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

The compound of the invention may be administered as such or in mixtures with pharmaceutically acceptable carriers, and may also be administered in combination with at least one other active compound. The combination therapy, therefore, includes the sequential, simultaneous or separate administration of the active compound so that the therapeutic effects of the first administration compound do not completely disappear when the subsequent compound is administered.

Micelles. Microemulsification technology improves the bioavailability of certain lipophilic (water insoluble) pharmaceutical agents. Examples include trimethrin (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). Among other things, microemulsification represents increased bioavailability, directing mainly absorption to the lymphatic system instead of the circulatory system, which thereby bypasses the liver, and prevents the destruction of compounds during hepatic-bile circulation.

Although all suitable amphiphilic carriers are contemplated, representative examples of carriers are usually those that are commonly Recognized as Safe (GRAS) and which can both solubilize the compound of the present invention and microemulsify it at a later stage when the solution comes into contact with the complex aqueous phase (such as located in the human gastrointestinal tract). Typically, amphiphilic ingredients that satisfy these requirements have an HLB (hydrophilic-lipophilic balance) of 2-20, and their structures contain straight chain aliphatic radicals within the range of C-6 - C-20. Examples are polyethylene glycosylated glycerides and polyethylene glycols.

Particularly contemplated are industrially available amphiphilic carriers, including the Gelucire, Labrafil, Labrazole or Lauroglycol series (all manufactured and supplied by Gattefosse Corporation, Saint Priest, France), PEG monooleate, PEG dioleate, PEG monolaurate and dilaurate, lecithin, polysorbate 80, and so on. (manufactured and supplied by a number of US companies and worldwide).

Polymers Hydrophilic polymers suitable for use in the present invention are polymers that are freely soluble in water, can covalently attach to a bulking lipid, and which are transferred in vivo without toxic effects (i.e., are biocompatible). Suitable polymers include polyethylene glycol (PEG), polylactic acid (also called polylactide), polyglycolic acid (also called polyglycolide), polylactic-polyglycolic acid copolymer and polyvinyl alcohol. Representative examples of 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 to about 5,000 daltons. In one embodiment, the polymer is polyethylene glycol having a molecular weight of from about 100 to about 5000 daltons, and more preferably from about 300 to about 5000 daltons. In one embodiment, the polymer is 750 Daltons (PEG (750)). Polymers can also be determined by the number of monomers in them; an embodiment of the present invention uses polymers of at least about three monomers, such PEG polymers are composed of three monomers (approximately 150 daltons).

Other hydrophilic polymers that may be suitable for use in the present invention include polyvinyl pyrrolidone, polymethoxazoline, polyethyl oxazoline, polyhydroxypropylmethacrylamide, polymethacrylamide, polydimethyl acrylamide and cellulose derivatives such as hydroxymethyl cellulose or hydroxyethyl cellulose.

In some embodiments, the composition form of the present invention includes a biocompatible polymer selected from the group consisting of polyamides, polycarbonates, polyalkylenes, polymers of acrylic and methacrylic esters, polyvinyl polymers, polyglycolides, polysiloxanes, polyurethanes and their copolymers, celluloses, polypropylene, polyethylene, polystyrene, polymers of lactic and glycolic acid, polyanhydrides, poly (ortho) esters, poly (butyric acid) (eng. poly (butic acid), poly (valerianic acid), poly (lactide-co-caprolact it), polysaccharides, proteins, polygialuronic acids, polycyanoacrylates and mixtures or their copolymers.

Cyclodextrins. Cyclodextrins are cyclic oligosaccharides containing 6, 7 or 8 glucose units denoted by the Greek letters alpha, beta and gamma, respectively. Glucose units are linked by alpha-1,4-glucosidic bonds. As a result, the conformations of the sugar units, all secondary hydroxyl groups (at C-2, C-3) are located on one side of the ring, while all the primary hydroxyl groups at C-6 are on the other side. As a result, the outer faces are hydrophilic, making cyclodextrins soluble in water. In contrast, the cavities of cyclodextrins are hydrophobic because they line up with the hydrogen of C-3 and C-5 atoms and with ether-like oxygen. These matrices allow complexation with a variety of relatively hydrophobic compounds, including, for example, steroid compounds such as 17-beta-estradiol (see, for example, Uden et al., Plant Cell Tiss. Org. Cult. 38: 1-3-113 (1994)). Complexation takes place using the bath-der-Waals interactions and the formation of a hydrogen bond. For a general overview of the chemistry of cyclodextrins, see Wenz, Agnew. Chem. Int. Ed. Engl., 33: 803-822 (1994).

Physico-chemical properties of cyclodextrin derivatives are highly dependent on the type and degree of substitution. For example, their solubility in water is in the range from insoluble (for example, triacetyl-beta-cyclodextrin) to 147% soluble (weight / volume) (G-2-beta-cyclodextrin). In addition, they are soluble in many organic solvents. The properties of cyclodextrins make it possible to regulate the solubility of various components of the compositions by increasing or decreasing their solubility.

Numerous cyclodextrins and methods for their preparation are described. For example, Parmeter (I), et al. (US Patent No. 3453259; incorporated by reference) and Gramera, et al. (US patent No. 3459731) describe electrically neutral cyclodextrins. Other derivatives include cationic cyclodextrins (Parmeter (II)), US patent No. 3453257, incorporated by reference), insoluble cross-linked cyclodextrins (Solms, US patent No. 3420788, incorporated by reference), and anionic cyclodextrins (Parmeter (III) , US Patent No. 3426011, incorporated by reference). Among the derivatives of cyclodextrin with anionic properties, carboxylic acids, phosphorous, phosphinic, phosphonic, phosphoric, thiophosphonic, thiosulfinic and sulfonic acids are attached to the starting cyclodextrin (see Parmeter (III), above). In addition, sulfoalkyl ether derivatives of cyclodextrin are described by Stella et al., (US Pat. No. 5,134,127, incorporated by reference).

Liposomes. Liposomes consist of at least one lipid bilayer membrane with an enclosed aqueous internal compartment. Liposomes can be characterized by membrane type and size. Small unilamellar vesicles (SUVs) have one membrane and the diameter is usually between 0.02 and 0.05 microns; large monolamellar vesicles (LUVS) are usually larger than 0.05 microns. Oligolamellar large vesicles and multilayer vesicles have multilamellar, usually concentric, membrane layers and are usually larger than 0.1 μm. Liposomes with several non-concentric membranes, i.e. several smaller vesicles contained in a larger vesicle are called multivesicular vesicles.

One aspect of the present invention relates to compositions comprising liposomes containing a compound of the present invention, in which the liposome membrane is formed, providing a liposome with an enlarged bearing cavity. Alternatively or additionally, the compound of the present invention may be contained internally or adsorbed onto a liposome bilayer. The compound of the present invention can be assembled together with a lipid surfactant and transferred in the inner space of the liposome; in these cases, the liposome membrane is formed to withstand the damaging effects of the active agent / surfactant combination.

According to one embodiment of the present invention, the lipid bilayer of the liposome contains lipids derivatized with polyethylene glycol (PEG), so that the PEG chains extend from the inner surface of the lipid bilayer into the inner space encapsulated by the liposome and extend from the outside of the lipid bilayer into the environment.

The active agents contained in the liposomes of the present invention are in solubilized form. Combinations of a surfactant and an active agent (such as emulsions or micelles containing the active agent of interest) can be trapped in the interior of the liposomes of the present invention. The surfactant acts to disperse and solubilize the active agent, and can be selected from any aliphatic, cycloaliphatic or aromatic surfactants, including, but not limited to, biocompatible, lysophosphatidylcholines (LPCs) with varying chain lengths (e.g., approximately from C14 to about C20). Polymer-derivatized lipids, such as PEG lipids, can also be used to form micelles, since they act by inhibiting micelle / membrane fusion, and since the addition of the polymer to the surfactant molecules reduces the critical micelle concentration (CMC) of the surfactant substances and helps the formation of micelles. Examples are SMS surfactants in the micromolar range; higher SMS surfactants can be used to produce micelles enclosed within the liposomes of the present invention, however, monomers of the micelles surfactant can affect the stability of the liposome bilayer and are a factor in the design of the liposome desired stability.

Liposomes useful in the present invention can be obtained using any of a variety of techniques that are known in the art. See, for example, US patent No. 4235871; PCT published application WO 96/14057; New RRC, Liposones: 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 useful in the present invention can be obtained by diffusing a lipid derivatized with a hydrophilic polymer into preformed liposomes, such as exposing the preformed liposomes to micelles composed of lipid crosslinked polymers at lipid concentrations corresponding to the final molar percentage of the derivatized a lipid that is desired in a liposome. Liposomes containing a hydrophilic polymer can also be obtained by homogenization, hydration of the lipid region or extrusion techniques that are known in the art.

In one aspect of the present invention, liposomes are substantially homogeneous in size in a selected size range. One effective method of sorting by size involves extruding an aqueous suspension of liposomes through a series of polycarbonate membranes having a selected uniform pore size; the pore size of the membrane will roughly correspond to the largest sizes of liposomes obtained by extrusion through the membrane. See, for example, US patent No. 4737323.

Release modifiers. The release characteristics of the composition of the present invention depend on the encapsulating material, the concentration of the encapsulated drug, and the presence of release modifiers. For example, the release can be manipulated to be pH dependent using a pH sensitive coating that provides release only at a low pH, like in the stomach, or at a higher pH, like in the intestine. Enteric coating can be used to prevent release from the environment not earlier than after passing through the stomach. Numerous coatings or mixtures of cyanamide encapsulated in various materials can be used to achieve an initial release in the stomach followed by a later release in the intestine. The release can also be controlled by the incorporation of salts or pore forming agents that can increase water absorption or drug release by diffusion from the capsule. Excipients that modify 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 included. They can be added to the drug as a separate phase (i.e., in the form of particles), or they can co-dissolve in the polymer phase, depending on the compound. In all cases, the amount should be between 0.1 and thirty percent (w / w polymer). Types of breakdown or decomposition 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 and organic bases such as protamine sulfate, spermine, choline, ethanolamine, diethanolamine and triethanolamine, and surfactants such as Tween® and Pluronic®. Pore-forming agents that add a microstructure to the matrices (i.e., water-soluble compounds such as inorganic salts and sugars) are added in particulate form. The limit should be between one and thirty percent (w / w polymer).

Absorption can also be controlled by changing the residence time of the particles in the intestine. This can be achieved, for example, by coating the particles, or by choosing as the encapsulating material a mucosal adhesive polymer. Examples include most polymers with free carboxyl groups, such as chitosan, celluloses, and especially polyacrylates (the polyacrylates used here refer to polymers including acrylate groups and modified acrylate groups such as cyanoacrylates and methacrylates).

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

In some embodiments, the present invention relates to any one of the aforementioned pharmaceutical compositions, wherein the pharmaceutical preparation has an EC ₅₀ for lowering serum cholesterol, LDL and / or triglycerides, which on average in human patients is not more than 20 percent of half the maximum concentration of a pharmaceutical preparation that would cause cutaneous vasodilation (rush of blood) in a population of average patients.

In some embodiments, the present invention relates to any one of the aforementioned pharmaceutical compositions, in which the EC ₅₀ for lowering serum cholesterol, LDL and / or triglycerides is not more than 1 percent of the maximum pharmaceutical concentration that would cause skin vasodilation (flush blood) in a population of average patients.

In some embodiments, the present invention relates to any one of the above pharmaceutical compositions, in which the pharmaceutical preparation has an EC ₅₀ for lowering serum cholesterol, LDL and / or triglycerides, which on average in human patients is not more than 20 percent of half the concentration of the pharmaceutical preparation, which would cause an increase in serum levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT), requiring discontinuation of the pharmaceutical preparation.

In some embodiments, the present invention relates to any one of the aforementioned pharmaceutical compositions, among which the composition is effective in reducing serum lipid without causing treatment limiting (i) hepatotoxicity and (ii) an increase in uric acid or glucose levels, or one and the other, after administration to the indicated patient, which would require that such treatment be interrupted when the composition is taken by the patient once a day.

In some embodiments, the present invention relates to any one of the above pharmaceutical compositions formulated in combination with a statin.

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

In some embodiments, the present invention relates to any one of the aforementioned pharmaceutical compositions formulated in conjunction with at least one additional therapeutic agent selected from the group consisting of 11β HSD-1 inhibitors, 5HT carrier inhibitors, 5HT2c agonists, 5- LO or FLAP inhibitors, α-glucosidase inhibitors, ABCA1 enhancers, ACC inhibitors, acylCoA inhibitors: cholesterol-O-acyltransferase, acylestrogen, antidiabetic agents, anti-dyslipidemic agents, anti-hypertensive agents, antioxidants, Apo A1 mimetics, Aro A1 modulators, Apo E mimetics, apolipoprotein-B secretion protein / microsomal triglyceride transfer inhibitors (apo-B / MTP), appetite suppressants, aspirin, β3 agonists, bile acid reabsorption inhibitors, bile acid binding agents, bombesin agonists, BRS3 agonists, CB ₁ antagonists / inverse agonists, CCK-A agonists, cholesterol absorption inhibitors, cholesterol transport inhibitors, cholesteryl ester transfer protein inhibitors (CETP), C NTF, CNTF agonists / modulators, a combination of ezetimibe and simvastatin and / or atorvastatin, CSL-111, dehydroepiandrosterone, delipidated HDL, DGAT antisense oligo agents, DGAT1 inhibitors, DGAT2 inhibitors, receptor agonists, dicarbonetamine, dicarboxylate inhibitors, dicarboxylate inhibitors, dicarboxylate inhibitors, dicarboxylate inhibitors, dicarboxylate inhibitors, dicarboxylate inhibitors, dicarboxylate inhibitors, dicarboxyne inhibitor inhibitors, fatty acid binding protein inhibitors (FABPs), fatty acid carrier inhibitors, fatty acid carrier protein inhibitors (FATPs), tide inhibitors, FXR receptor modulators, galanin receptor antagonists а, gemcaben, ghrelin antagonists, ghrelin antibodies, GLP-1 agonists, glucagon-like peptide-1 receptor agonists, glucocorticoid agonists / antagonists, glucose transporter inhibitors, HDL mimetics, HMG CoA reductase inhibitor compounds, HMG-CoA synthetase inhibitors, sensory antagonists of HMG-CoA synthetase inhibitors hormone lipase agouti-related human proteins (AGRP), _H3 antagonists / inverse agonists, inorganic cholesterol sequestrants, L-4f, lapakvistata, leptin agonists / modulators, leptin, lipase inhibitors, inhibitors sy and lipoprotein, lorapoprant, inducers or activators of low density lipoprotein receptor, Lp (a) lowering agents, LXR receptor agonists, linkinase inhibitor, Mc3r agonists, Mc4r agonists, MCH1R antagonists, MCH2R agonists / antagonists, antagonists of melon G 5 microsomal triglyceride transport inhibitors, monoamine reuptake inhibitors, natural water-soluble fibers, NE carrier inhibitors, neuromedin U receptor agonists, neuropeptide-Y antagonists, niacin agonists or niacin receptor, nicotinic acid, noradrenergic anorectic agents, NPY1 antagonists, NPY2 agonists, NPY4 agonists, NPY5 antagonists, non-steroidal anti-inflammatory agents (NSAIDs), omega-3 fatty acids, PD opioid antagonists, opioid antagonists , phentermine, phosphate transporter inhibitors, phytopharm compounds 57, plant stanols and / or plant stanol fatty acid esters, platelet accumulation inhibitors, PPAR-α agonists, PPAR-δ agonist c, PPAR-δ partial agonists, PPAR-γ agonists, probucol, renin angiotensin inhibitors, reversed-4F, SCD-1 inhibitors, sertonin reuptake inhibitors, SGLT2 inhibitors, squalene oxidase inhibitors, squalene synthesis inhibitors, agonist biosynthesis inhibitors, biosynthesis of biosynthesis thyroid hormone β, thyromimetic agents, topiramate, triglyceride synthesis inhibitors, UCP-1 activators, UCP-2 activators, UCP-3 activators and antagonists of the urocortin binding protein.

In some embodiments, the present invention relates to a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt thereof; niacin; and a pharmaceutically acceptable excipient.

In some embodiments, the present invention relates to a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt thereof; niacin; a statin selected from the group consisting of atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin; and a pharmaceutically acceptable excipient.

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

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

In some embodiments, the present invention relates to a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt thereof; a fibrate selected from the group consisting of fenofibrate and bezafibrate; and a pharmaceutically acceptable excipient.

In some embodiments, the present invention relates to a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt thereof; niacin; a fibrate selected from the group consisting of fenofibrate and bezafibrate; and a pharmaceutically acceptable excipient.

WAYS

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

One aspect of the invention relates to a method for treating diseases, disorders or conditions selected from the group consisting of hyperlipidemia, hypercholesterolemia, hypodystrophy, dyslipidemia, atherosclerosis and coronary artery disease, comprising the step of administering to the mammal in need thereof a therapeutically effective amount of a pharmaceutical composition of the present invention. In one embodiment, the mammal is a human.

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

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

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

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

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

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

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

In some embodiments, the present invention relates to any of the above methods, further comprising co-administering a therapeutically effective amount of statin. In one such embodiment, co-administration is co-administration orally.

In some embodiments, the present invention relates to any of the above methods, further comprising co-administering a therapeutically effective amount of statin, wherein the statin is selected from the group consisting of atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin. In one such embodiment, co-administration is co-administration orally.

In some embodiments, the present invention relates to any of the methods mentioned above, further comprising co-administering a therapeutically effective amount of at least one additional therapeutic agent selected from the group consisting of 11β HSD-1 inhibitors, 5HT carrier inhibitors, 5HT2c agonists, 5 -LO or FLAP inhibitors, α-glucosidase inhibitors, ABCA1 enhancers, ACC inhibitors, acyl CoA inhibitors: cholesterol-O-acyltransferase, acyl estrogen, antidiabetic agents, anti-dyslipide chemical agents, anti-hypertensive agents, antioxidants, Apo A1 mimetics, Apo A1 modulators, Apo E mimetics, apolipoprotein-B secretion protein / microsomal triglyceride transfer inhibitors (apo-B / MTP), appetite suppressing agents, aspirin, β3 agonists, inhibitors of bile acid reabsorption, substances that bind bile acid, bombesin agonists, BRS3 agonists, _CB1 antagonists / inverse agonists, CCK-A agonists, cholesterol absorption inhibitors, cholesterol transport inhibitors, layer transfer protein inhibitors cholesteryl ester (CETP), CNTF, CNTF agonists / modulators, a combination of ezetimibe and simvastatin and / or atorvastatin, CSL-111, dehydroepiandrosterone, delipidated HDL, DGAT antisense oligo agents, DGAT1 inhibitors, DGAT1 inhibitors, DGAT1 inhibitors, DGAT1 inhibitors, DGAT1 inhibitors, DGAT1 inhibitors, DGAT1 inhibitors, DGAT1 inhibitors, DGAT1 inhibitors, DGAT1 inhibitors, DGAT1 inhibitors, DGAT1 inhibitors, DGAT1 inhibitors, DGAT1 inhibitors, DGAT1 inhibitors, DP receptor antagonists, ezetimibe, FAS inhibitors, fatty acid binding protein inhibitors (FABP), fatty acid carrier inhibitors, fatty acid carrier protein inhibitors (FATP), blood flow inhibitors, FXR receptor modulators a, galanin receptor antagonists, gemcabene, ghrelin antagonists, ghrelin antibodies, GLP-1 agonists, glucagon-like peptide-1 receptor agonists, glucocorticoid agonists / antagonists, glucose transporter inhibitors, HDL mimetics, HMG CoA HM reductase inhibitor compounds, inhibitors synthetase, hormone-sensitive lipase antagonists, agouti-related human proteins (AGRP), H ₃ antagonists / inverse agonists, inorganic cholesterol sequestrants, L-4f, lapaquist, leptin agonists / modulators, leptins, ing lipase inhibitors, lipoprotein synthesis inhibitors, lorapoprant, low density lipoprotein receptor inducers or activators, Lp (a) lowering agents, LXR receptor agonists, linkinase inhibitor, Mc3r agonists, Mc4r agonists, MCH1R antagonists, MCH2R agonist antagonists / antagonists , mGluR5 antagonists, inhibitors of microsomal triglyceride transport, monoamine reuptake inhibitors, natural water-soluble fibers, NE carrier inhibitors, neuroma receptor agonists Dyne U, neuropeptide-Y antagonists, niacin agonists or niacin receptor, nicotinic acid, noradrenergic anorectic agents, NPY1 antagonists, NPY2 agonists, NPY4 agonists, NPY5 antagonists, non-steroidal anti-inflammatory agents (NSAID 3-ohms, antagonists, orexin receptor antagonists, PDE inhibitors, phentermine, phosphate transporter inhibitors, phytopharm compounds 57, plant stanols and / or plant stanol fatty acid esters, thrombus inhibitors oocytes, PPAR-α agonists, PPAR-δ agonists, PPAR-δ partial agonists, PPAR-γ agonists, probucol, renin angiotensin inhibitors, reversed-4F, SCD-1 inhibitors, sertonin reuptake inhibitors, SGLT2 inhibitors, squalene epoxide inhibitors, inhibitors of synthesis squalene, sterol biosynthesis inhibitors, sympathomimetic agonists, thyroid hormone β agonists, thyromimetic agents, topiramate, triglyceride synthesis inhibitors, UCP-1 activators, UCP-2 activators, UCP-3 activators and protein binding antagonists tin. In one embodiment, co-administration is oral.

In some embodiments, the present invention relates to any of the above 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, aspirin, cholesteryl ester transfer protein inhibitors, NSAIDs, Fibrates, Subtilisin / Kexin Protein Convertase (PCSK9), Inorganic Cholesterol Sequestrants, AcylCoA Inhibitors: Cholesterol O-Acyltransferase, 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 modulators inhibitors, metformin niacin receptor and DPP-IV inhibitors. In one such embodiment, coadministration is oral.

In some embodiments, the present invention relates to any of the above 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, cholesteryl ester transfer protein inhibitors, aspirin, NSAIDs, fibrates, DP receptor antagonists, ezetimibe, or a combination of ezetimibe and simvastatin. In one such embodiment, coadministration is oral.

In some embodiments, the present invention relates to any of the above methods, further comprising co-administering a therapeutically effective amount of at least one HMG CoA reductase inhibitor selected from lovastatin, simvastatin, pravastatin, atorvastatin, fluvastatin, cerivastatin, rivastatin, rosuvastatin calcium and pitavastatin. In one such embodiment, coadministration is oral.

In some embodiments, the present invention relates to any of the above methods, further comprising co-administering simvastatin. In one such embodiment, coadministration is oral.

In some embodiments, the present invention relates to any of the above methods, further comprising co-administering a cholesteryl ester transfer protein inhibitor. In one such embodiment, coadministration is oral.

In some embodiments, the present invention relates to any of the above methods, further comprising co-administering ezetimibe, aspirin, ibuprofen, acetaminophen, or a combination of ezetimibe and simvastatin. In one such embodiment, coadministration is oral.

One aspect of the invention relates to a method for treating hyperlipidemia, comprising the step of co-administering to a mammal in need thereof a therapeutically effective amount of a compound of the present invention; and a therapeutically effective amount of niacin. In one embodiment, co-administration is oral. In one embodiment, the mammal is a human.

One aspect of the invention relates to a method for treating hyperlipidemia, comprising the step of co-administering to a mammal in need thereof a therapeutically effective amount of a pharmaceutical composition of the present invention; and a therapeutically effective amount of niacin. In one embodiment, co-administration is oral. In one embodiment, the mammal is a human.

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

One aspect of the invention relates to a method for increasing serum levels of high density lipoprotein (HDL) in a mammal, comprising the step of co-administering to a mammal in need thereof a therapeutically effective amount of a pharmaceutical composition of the present invention; and a therapeutically effective amount of niacin. In one embodiment, co-administration is oral. In one embodiment, the mammal is a human.

One aspect of the invention relates to a method for lowering serum levels of low density lipoprotein (LDL) in a mammal, comprising the step of co-administering to a mammal in need thereof a therapeutically effective amount of a compound of the present invention; and a therapeutically effective amount of niacin. In one embodiment, co-administration is oral. In one embodiment, the mammal is a human.

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

One aspect of the invention relates to a method for lowering serum lipoprotein (a) (Lp (a)) levels in a mammal, comprising the step of co-administering to a mammal in need thereof a therapeutically effective amount of a compound of the present invention; and a therapeutically effective amount of niacin. In one embodiment, co-administration is oral. In one embodiment, the mammal is a human.

One aspect of the invention relates to a method for lowering serum lipoprotein (a) (Lp (a)) levels in a mammal, comprising the step of co-administering to a mammal in need thereof a therapeutically effective amount of a pharmaceutical composition of the present invention; and a therapeutically effective amount of niacin. In one embodiment, co-administration is oral. In one embodiment, the mammal is a human.

One aspect of the invention relates to a method for treating hyperlipidemia, hypercholesterolemia, atherosclerosis, coronary artery disease, congestive heart failure, cardiovascular disease, hypertension, coronary heart disease, angina pellagra, Hartnup syndrome, carcinoid syndrome, arterial occlusive disease, obesity, osteoarthritis, rheumatoid arthritis, diabetes, Alzheimer's disease, hypodystrophy or dyslipidemia, including the stage of co-administration of mammals it need thereof a therapeutically effective amount of a compound of the present invention; a therapeutically effective amount of niacin; and a therapeutically effective amount of a statin selected from the group consisting of atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin. In one embodiment, co-administration is oral. In one embodiment, the mammal is a human.

One aspect of the invention relates to a method for treating hyperlipidemia, hypercholesterolemia, atherosclerosis, coronary artery disease, congestive heart failure, cardiovascular disease, hypertension, coronary heart disease, angina pellagra, Hartnup syndrome, carcinoid syndrome, arterial occlusive disease, obesity, vasoconstriction, osteoarthritis, rheumatoid arthritis, diabetes, Alzheimer's disease, hypodystrophy or dyslipidemia, including the stage of co-administration of mammals anyone in need of a therapeutically effective amount of a pharmaceutical composition of the present invention; a therapeutically effective amount of niacin; and a therapeutically effective amount of a statin selected from the group consisting of atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin. In one embodiment, co-administration is oral. In one embodiment, the mammal is a human.

One aspect of the invention relates to a method for treating hyperlipidemia, comprising the step of co-administering to a mammal in need thereof a therapeutically effective amount of a compound of the present invention; a therapeutically effective amount of niacin; and a therapeutically effective amount of a statin selected from the group consisting of atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin. In one embodiment, co-administration is oral. In one embodiment, the mammal is a human.

One aspect of the invention relates to a method for treating hyperlipidemia, comprising the step of co-administering to a mammal in need thereof a therapeutically effective amount of a pharmaceutical composition of the present invention; a therapeutically effective amount of niacin; and a therapeutically effective amount of a statin selected from the group consisting of atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin. In one embodiment, co-administration is oral. In one embodiment, the mammal is a human.

One aspect of the invention relates to a method for increasing serum levels of high density lipoprotein (HDL) in mammals, comprising the step of co-administering to a mammal in need thereof a therapeutically effective amount of a compound of the present invention; a therapeutically effective amount of niacin; and a therapeutically effective amount of a statin selected from the group consisting of atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin. In one embodiment, co-administration is oral. In one embodiment, the mammal is a human.

One aspect of the invention relates to a method for increasing serum levels of high density lipoprotein (HDL) in a mammal, comprising the step of co-administering to a mammal in need thereof a therapeutically effective amount of a pharmaceutical composition of the present invention; a therapeutically effective amount of niacin; and a therapeutically effective amount of a statin selected from the group consisting of atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin. In one embodiment, co-administration is oral. In one embodiment, the mammal is a human.

One aspect of the invention relates to a method for lowering serum levels of low density lipoprotein (LDL) in a mammal, comprising the step of co-administering to a mammal in need thereof a therapeutically effective amount of a compound of the present invention; a therapeutically effective amount of niacin; and a therapeutically effective amount of a statin selected from the group consisting of atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin. In one embodiment, co-administration is oral. In one embodiment, the mammal is a human.

One aspect of the invention relates to a method for lowering serum levels of low density lipoprotein (LDL) in a mammal, comprising the step of co-administering to a mammal in need thereof a therapeutically effective amount of a pharmaceutical composition of the present invention; a therapeutically effective amount of niacin; and a therapeutically effective amount of a statin selected from the group consisting of atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin. In one embodiment, co-administration is oral. In one embodiment, the mammal is a human.

One aspect of the invention relates to a method for lowering serum lipoprotein (a) (Lp (a)) levels in a mammal, comprising the step of co-administering to a mammal in need thereof a therapeutically effective amount of a compound of the present invention; a therapeutically effective amount of niacin; and a therapeutically effective amount of a statin selected from the group consisting of atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin. In one embodiment, co-administration is oral. In one embodiment, the mammal is a human.

One aspect of the invention relates to a method for lowering serum lipoprotein (a) (Lp (a)) levels in a mammal, comprising the step of co-administering to a mammal in need thereof a therapeutically effective amount of a pharmaceutical composition of the present invention; a therapeutically effective amount of niacin; and a therapeutically effective amount of a statin selected from the group consisting of atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin. In one embodiment, co-administration is oral. In one embodiment, the mammal is a human.

In some embodiments, the present invention relates to any of the above methods and the accompanying limitations, wherein the statin is lovastatin or atorvastatin.

One aspect of the invention relates to a method for treating diabetes in a mammal, comprising the step of 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 glitazone selected from the group consisting of troglitazone, rosiglitazone and pioglitazone. In one embodiment, co-administration is oral. In one embodiment, the mammal is a human.

One aspect of the invention relates to a method for treating diabetes in a mammal, comprising the step of co-administering to a mammal in need thereof a therapeutically effective amount of a pharmaceutical composition of the present invention; and glitazone selected from the group consisting of troglitazone, rosiglitazone and pioglitazone. In one embodiment, co-administration is oral. In one embodiment, the mammal is a human.

One aspect of the invention relates to a method for treating diabetes in a mammal, comprising the step of 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 glitazone selected from the group consisting of troglitazone, rosiglitazone and pioglitazone. In one embodiment, co-administration is oral. In one embodiment, the mammal is a human.

One aspect of the invention relates to a method for treating diabetes in a mammal, comprising the step of co-administering to a mammal in need thereof a therapeutically effective amount of a pharmaceutical composition of the present invention; niacin; and glitazone selected from the group consisting of troglitazone, rosiglitazone and pioglitazone. In one embodiment, co-administration is oral. In one embodiment, the mammal is a human.

One aspect of the invention relates to a method for treating diabetes in a mammal, comprising the step of 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 a fibrate selected from the group consisting of fenofibrate and bezafibrate. In one embodiment, co-administration is oral. In one embodiment, the mammal is a human.

One aspect of the invention relates to a method for treating diabetes in a mammal, comprising the step of co-administering to a mammal in need thereof a therapeutically effective amount of a pharmaceutical composition of the present invention; and a fibrate selected from the group consisting of fenofibrate and bezafibrate. In one embodiment, co-administration is oral. In one embodiment, the mammal is a human.

One aspect of the invention relates to a method for treating diabetes in a mammal, comprising the step of 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 fibrate selected from the group consisting of fenofibrate and bezafibrate. In one embodiment, co-administration is oral. In one embodiment, the mammal is a human.

One aspect of the invention relates to a method for treating diabetes in a mammal, comprising the step of co-administering to a mammal in need thereof a therapeutically effective amount of a pharmaceutical composition of the present invention; niacin; and a fibrate selected from the group consisting of fenofibrate and bezafibrate. In one embodiment, co-administration is oral. In one embodiment, the mammal is a human.

In some embodiments, the present invention relates to any of the above methods and the accompanying limitations, in which mammals are primates, bovine, sheep, rodents, horses, canine or feline.

In some embodiments, the present invention relates to any of the above methods and the accompanying restrictions, wherein said mammal is a human.

In some embodiments, the present invention relates to any of the above methods and the accompanying restrictions, wherein said compound, compounds or pharmaceutical composition is administered orally.

In some embodiments, the present invention relates to any of the methods mentioned above and the accompanying restrictions, wherein said compound, compounds or pharmaceutical composition is administered intravenously.

In some embodiments, the present invention relates to any of the aforementioned methods and the accompanying limitations, wherein said compound, compounds or pharmaceutical composition is administered sublingually.

In some embodiments, the present invention relates to any of the aforementioned methods and the accompanying restrictions, wherein said compound, compounds or pharmaceutical composition is administered by inhalation.

In some embodiments, the present invention relates to any of the methods mentioned above and the accompanying restrictions, wherein said compound, compounds or pharmaceutical composition is administered ocularly.

In some embodiments, the present invention relates to any of the above methods and the accompanying restrictions, wherein said compound, compounds or pharmaceutical composition is administered transdermally.

In some embodiments, the present invention relates to any of the aforementioned methods and the accompanying restrictions, wherein said compound, compounds or pharmaceutical composition is administered rectally.

In some embodiments, the present invention relates to any of the aforementioned methods and the accompanying limitations, wherein said compound, compounds or pharmaceutical composition is administered vaginally.

In some embodiments, the present invention relates to any of the methods mentioned above and the accompanying restrictions, wherein said compound, compounds or pharmaceutical composition is administered.

In some embodiments, the present invention relates to any of the methods mentioned above and the accompanying restrictions, wherein said compound, compounds or pharmaceutical composition is administered intramuscularly.

In some embodiments, the present invention relates to any of the above methods and the accompanying restrictions, wherein said compound, compounds or pharmaceutical composition is administered subcutaneously.

In some embodiments, the present invention relates to any of the above methods and the accompanying restrictions, wherein said compound, compounds or pharmaceutical composition is administered buccally.

In some embodiments, the present invention relates to any of the methods mentioned above and the accompanying restrictions, wherein said compound, compounds or pharmaceutical composition is administered nasally.

ACKNOWLEDGMENT BY EXAMPLES

The invention is now described in General, it will be more easily understood with reference to the following description, which is included only for the purpose of illustrating some aspects and embodiments of the present invention, and is not intended to limit the invention.

Example 1: Synthesis Schemes

A. Compound ARI-001

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

6-Methyl nicotinic acid methyl ester (4.5 g, 30 mmol), morpholine hydrochloride (1.85 g, 15 mmol), n-PrOH (18 ml) and formaldehyde solution (in water 37%) (1.2 g, 15 mmol) was added to a 50 ml flask equipped with a refrigerator. The reaction mixture was heated under reflux with an oil bath preheated to 100 ° C for 2.5 hours under argon. The mixture was then left to stand at room temperature overnight and yellow needle crystals precipitated (if precipitation did not occur at room temperature, a cold room (4 ° C) or even -10 ° C freezing was recommended). The crystals isolated by filtration and washed with a small amount of ethyl ether gave the crude product of stage 1 as an HCl salt (1.5 g, yield 35%; purity about 95%; Mannich double addition by-product was about 3%). This crude product was further purified by one-time recrystallization from n-PrOH and MeOH to give the purer product of step 1 as an off-white or pale yellow powder (1.2 g, 28% yield; 99.1% purity, double by-product joining according to Mannich made 0.9%).

The product of stage 1 (1.5 g, 5 mmol) was dissolved in MeOH (20 ml) and water (10 ml) was added, 1N. LiOH (15 ml) while cooling with ice water. The resulting mixture was stirred at room temperature overnight, and then adjusted to pH 2-3 with 2N. HCl. After cooling in vaacum, the residue was further purified by preparative HPLC, eluting with acetonitrile and water (with 5 mM HCl) to give 1.2 g of the target compound ARI-001 as a white powder (HCl salt, overall yield was about 30% for two stages when the crude product of stage 1) was used.

B. Compound ARI-002

Reaction conditions: i. HCHO, Morpholine.HCl

C. Compound ARI-001D

Reaction conditions: i. HCHO, Morpholine-d8.HCl; ii. NaOH, then HCl.

D. Compound ARI-005

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

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

Reaction conditions: i. imio-inositol, 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 studies

ARI-001 was synthesized as described above. Purity was determined independently before use in experiments using liquid chromatography mass spectroscopy (LC-MS). A sample of the material was dissolved in water / acetonitrile and injected onto a reverse phase Discovery C-18 column. The mobile phase began as a mixture of 2%: 98% acetonitrile: water, which was held for three minutes, after which a linear gradient began, which remained in effect for 6 minutes, increasing the percentage of acetonitrile until a final ratio of 98% was reached: 2% acetonitrile: water. This final ratio was maintained for 3 minutes. UV detection was carried out at 215 nm, as shown in figure 1. The main peak was identified as ARI-001.

Purity was determined by the ratio of the region of the main peak (3.59 minutes) to the sum of the regions of all peaks. According to the determination, the purity was 98.9%. Minor peaks were not identified.

Stability was determined during storage of ARI-001 at 50 ° C without special moisture requirements. At various points in time for 3 months (90 days), a small sample (<5 mg) of ARI-001 was collected for analysis using LC-MS under the same conditions as used to determine purity (see above). Figure 2 shows the stability time of ARI-001 under such conditions.

Under standard conditions (50 ° C, uncontrolled humidity), ARI-001 remained 98.9% pure for a period of 65 days. Only at 90 days at 50 ° C did ARI-001 begin to show any decomposition. After 90 days, it was found that the compound was 95.9% pure.

Example 3: in vivo studies

To study the effect of ARI-001 on lipid modulation, a hamster model was developed and used to prescribe chronic administration of the compound. This model, its development, and the effects of ARI-001 are described here.

The effect of food modification on the lipid profile in hamsters. Like other rodents, the Golden Syrian hamster lipid profile consists of HDL, with negligible LDL or VLDL cholesterol. However, in high-fat feed, hamsters experience an increase in cholesterol accumulation, including triglycerides and free fatty acids. Adding sugar, such as 10% fructose, to a drinking water source greatly increases triglyceride accumulation, including VLDL. At this feed, hamsters become a useful model for investigating the role of modulators on triglycerides and VLDL, and on LDL cholesterol. Indeed, literature has used this model to study modulating triglycerides and free fatty acids compounds such as fenofibrate.

We tested the effect of feed modification on the lipid profile in male Syrian Golden hamsters. The hamsters were ordered from Charles River Labs (Wilmington, MA), and were asked to weigh 111-120 g (respectively 56-61 days old). The hamsters were kept in cages at 4-5 per cage, and kept on a standard light cycle for 12 hours with the light on / 12 hours. All feed was obtained from Dyets, Inc. (Bethlehem, RA). The “normal food” was rodent standard food, catalog # 5001, made in balls. Water and this standard food were available to this group of hamsters without restrictions. Food was fed into the cells as necessary, but no less often than twice a week. The “high-fat feed" was the same standard rodent meal with the addition of the following: 11.5% corn oil, 11.5% coconut oil, 0.5% cholesterol, and 0.25% deoxycholate. It is also available from Dyets, Inc., as catalog number # 611201. Both feeds were ordered in batches of 10 kg and stored at 4 ° C for the duration of the experiments (4-8 weeks), and at -20 ° C for longer storage (up to six months). Water and this high-fat food were available to this group of hamsters without restrictions. The “high fat + fructose” group was fed the same fat supplement as the high fat group (# 611201), but fructose was added to water to a final concentration of 10%. Fructose was supplied by Now Foods (catalog # 6931), and sold by Lucky Vitamine (catalog # 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 given to hamsters, fructose water was kept in water bottles in hamster cages at room temperature, in the same as standard water. Fructose water and high-fat food gave this group of hamsters without restriction. All animals remained on their respective diets for 21 days.

To begin this experiment, hamsters were randomly assigned to groups defined by the above diet modifications. After a fixed time, blood was collected from hamsters (N = 3-4) to determine the plasma lipid content. Due to limitations in the ability to adequately collect blood from hamsters, all blood samples were obtained using final cardiac puncture, which was preceded by carbon dioxide asphyxiation. Blood (approximately 2 ml) was collected with a 22G needle in a 5 ml syringe and transferred to a hollow cylinder with K ₂ EDTA. Samples were stored on ice until centrifuged (14,000 rpm for 10 minutes at 4 ° C) to separate the plasma. Plasma was then aliquoted into cylinders for storage at -80 ° C until analysis.

Lipid parameters were then determined using commercially available kits from Wako USA (Richmond, VA) according to the manufacturer's instructions.

Lipid values from control animals (zero days on any of the three diets described above) were essentially indistinguishable (see Table 1). By day 21, both diet modifications had a significant effect on the lipid profiles of these hamsters when compared with animals kept on a diet with a normal meal. All parameters significantly increased from the control (p <0.05 in all groups), with the exception of HDL. As predicted, the addition of fructose to a high-fat diet further increased the concentration of triglyceride and free fatty acid to a greater extent than with a single high-fat diet. HDL was unchanged when compared with the normal diet group, despite diet modification.

Table 1
Hamster lipid values on one of three different diets for 21 days. The hamsters were killed and their plasma was analyzed as described above. Values are the average of the measurements of each parameter (N = 3), with a standard deviation. TS: total cholesterol; HDL: high density lipoprotein cholesterol; LDL: low density lipoprotein cholesterol; TG: triglycerides; FFA: free fatty acids. Day 21 TC (± STD) (mg / dl) HDL (± STD) (mg / dl) LDL (± STD) (mg / dl) TG (± standard off) (mg / dl) FFA (± standard off) (mEq / L) Normal diet 115 ± 8 63 ± 6 17 ± 3 325 ± 89 0.76 ± 0.02 High fat diet 680 ± 82 *** 130 ± 16 384 ± 20 *** 1129 ± 123 ** 1.65 ± 0.42 * High Fat + Fructose 654 ± 135 ** 97 ± 41 282 ± 85 ** 1658 ± 673 * 2.17 ± 0.43 ** * p <0.05 compared with a normal diet in the same parameter
** p <0.01 compared with a normal diet in the same parameter
*** p <0.001 compared with a normal diet in the same parameter

Fast protein liquid chromatography (FPLC) was used to separate the various cholesterol subpopulations from hamster plasma samples. Briefly, plasma from each animal within a given group was poured together and applied to an AKTA fluid control system with a Superose 6 10/300 GL column (product 14-5172-01, GE Life Sciences). 250 μl of the 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), applied to the column and eluted with 23.5 ml of buffer at a flow rate of 1.0 ml / min. , fractions of 0.24 ml. In each fraction, the cholesterol concentration was separately measured using the Wako total cholesterol kit, as described above, with the following modification: the sample volume was increased to 30 μl, and the reagent volume was reduced to 60 μl.

Traces of FPLC gave continuous curves with three distinct peaks representing each of the subgroups of cholesterol: VLDL, LDL and HDL. Since the column used in this experiment is a column with the exception of size, the largest particles appear first, while the smallest appear last. From here, VLDL is the first peak in the wake, followed by LDL, with HDL appearing last. Assuming that each of these peaks accepts a Gaussian distribution, we can expand the FPLC trace into each of these three components to determine the contribution that each component makes to the entire curve.

Figure 3 illustrates FPLC traces of plasma combined from hamsters contained in two different diets for three weeks. The VLDL curve is extremely stretched on a high-fat + fructose diet. LDL peak is also much higher. Interestingly, there is a very slight difference in the HDL peak, indicating that diet modification has a much stronger effect on the non-HDL cholesterol population. This model then behaves towards being a useful tool by which to measure the effects of ARI-001 on VLDL and LDL cholesterol.

ARI-001 lowers LDL levels of cholesterol, triglycerides and free fatty acid in HF / HS hamsters. Golden Syrian male hamsters were purchased from Charles River Labs (111-120 g, 56-61 days) and acclimated to a high fat + fructose diet (referred to herein as “HF / HS”) as described above for two weeks. Hamsters were divided into groups according to body weight after two weeks of acclimatization to the diet. Twelve hamsters were assigned to a filler group, 9 to receiving niacin at a dose of 1200 mg / kg, 10 to receiving ARI-001 at a dose of 1120 mg / kg, and 10 to receiving ARI-001 at a dose of 2240 mg / kg. At the end of this period of acclimatization (addiction) to the diet of hamsters, 1 ml of a solution of filler (water), niacin, or ARI-001 was administered orally through a gastric tube in one of two doses. Hamsters were dosed once a day for a total of 18 days. Throughout the dosing period, all animals remained on the HF / HS diet described above. Dosage solutions for each group were prepared for 7 days at a time, although they were prepared enough to last for 8 days. Each solution was stored between administrations at room temperature. Groups were determined according to table 2 below. Due to the difference in molecular weight between niacin and ARI-001, doses were given in both mg / kg and mmol / kg. Note that 1200 mg / kg niacin is equivalent to 2240 mg / kg ARI-001 on a molar basis.

table 2
Grouping for 18-day dose administration studies in HF / HS hamsters Compound Dose (mg / kg) Dose (mmol / kg) Animals Days Filler 0 0 12 eighteen Niacin 1200 9.75 10 eighteen ARI-001 1120 4.88 10 eighteen ARI-001 2240 9.75 10 eighteen

As shown in Table 3, ARI-001 given orally through a gastric tube for 18 days at 2240 mg / kg lowered LDL cholesterol and total cholesterol levels in hamsters of the HF / HS model. ARI-001 also lowered triglyceride and free fatty acid levels with very little difference between animals, as illustrated by a small standard deviation. At a molar equivalent dose of 1200 mg / kg, niacin was not able to give these effects on this animal model, which suggests that ARI-001 is at least 1.67 times more effective than niacin as regards the LDL parameter cholesterol, and at least 1.54 times more effective than niacin, in relation to the parameter of total cholesterol. The values of triglycerides and free fatty acids are shown, which indicates the response of the environment of all animals in the ARI-001 group treated with 2240 mg / kg. The fact that there is a very slight standard deviation among these data reflects an impressive response rate among these animals. The HDL / TC ratio was calculated by dividing the HDL cholesterol of each individual hamster by its total cholesterol level. The proportion that results is the HDL / TC ratio. This parameter was higher than in the group with the filler, with impressive statistical significance (p <0.001). This probably does not represent a strong increase in HDL, since the absolute HDL value increased by only 33% in the 2240 mg / kg ARI-001 group compared to the bulking group. Rather, a very large change in the HDL / TC ratio probably represents a system-wide decrease in cholesterol populations, with the exception of HDL, which not only got rid of such decreases, but also possibly increased.

Table 3
Lipid parameters from HF / HS hamsters given an oral dose of vehicle, niacin or ARI-001 for 18 days. TS, total cholesterol. These values are mean ± standard deviation. P-values are reported from two-sample unpaired t-tests in comparison with the processed filler in the same parameter. Group TC (mg / dl) HDL
(mg / dl) LDL (mg / dl) TG (mg / dl) FFA (mEq / L) HDL / TC ± stand. off ± stand. off ± stand. off ± stand. off ± stand. off ± stand. off Filler 857 ± 422 139 ± 32 253 ± 82 1065 ± 465 1.95 ± 0.53 0.21 ± 0.11 Niacin: 1200 mg / kg 552 * ± 183 79 ± 26 *** 170 ± 52 * 1555 ± 808 1.82 ± 0.69 0.17 ± 0.11 ARI-001: 1120 mg / kg 653 ± 194 142 ± 34 253 ± 91 957 ± 550 1.39 ± 0.65 * 0.24 ± 0.14 ARI-001: 2240 mg / kg 343 ± 104 ** 186 ± 74 * 114 ± 33 *** 138 ± 80 *** 0.75 ± 0.15 *** 0.48 ± 0.07 *** * p <0.05 compared with the filler in the same parameter
** p <0.01 compared to the filler in the same parameter
*** p <0.001 compared with the filler in the same parameter

The measured HDL values were borderline significant (p = 0.06) between the 2240 mg / kg ARI-001 group and vehicle. There was a significant increase in value when considering the calculated HDL / TC values. FPLC traces also showed a significant difference in lipid profile between these two groups. FPLC was performed as described above. The curves were transformed as described above. VLDL and LDL peaks not only decreased significantly compared to the filler, but the HDL curve was noticeably larger along the ARI-001 trace. See Figure 4.

With respect to the change in lipid level, Golden Syrian male hamsters from the previous experiment described showed a dose-dependent ARI-001. 2240 mg / kg is an effective dose for 18 days of daily treatment in almost all respects: total cholesterol, LDL cholesterol, triglycerides and free fatty acids. However, 1120 mg / kg shows only moderate effects according to these parameters, and only the results on free fatty acids show a statistically significant effect compared to the excipient. However, the trend is clear between doses for all lipid parameters studied, as shown in Figure 5. Moreover, with a molar equivalent dose, ARI-001 elicits a stronger response than niacin for all measured lipid parameters.

ARI-001 lowers LDL cholesterol, triglycerides and free fatty acids in a time-dependent manner. Thirty-two males of Golden Syrian hamsters were given the opportunity to get used to the HF / HS diet for two weeks, as described above. After a two-week induction period, the animals were divided into groups for an 18-day study in terms of action or excipient or ARI-001 (1120 mg / kg), or in groups for a 28-day study in terms of action or excipient or ARI-001 (1120 mg / kg). In each of the four groups, there were 8 hamsters. Solutions were prepared and stored as described above. Animals were given a dose of 1 ml per day for either 18 or 28 consecutive days, as previously described. At the end of the study, the hamsters were killed, their blood was collected in K ₂ EDTA tubes, the plasma was centrifuged and frozen until analysis. All lipids were analyzed using a commercially available kit (Wako USA) as described above. In Table 4 below, vehicle-injected animals studied both for 18 days and 28 days were combined into one group with vehicle (N = 16).

Table 4
Lipid parameters from HF / HS hamsters given an oral dose of vehicle or ARI-001 for 18 or 28 days. The values shown are mean ± standard deviation. P-values from two-sample unpaired t-tests are given in comparison with filler treatment in the same parameter. Group TC (mg / dl) HDL (mg / dl) LDL (mg / dl) TG (mg / dl) FFA (mEq / L) HDL / TC ± Art. off ± Art. off ± Art. off ± Art. off ± Art. off ± Art. off Filler 796 ± 253 135 ± 40 363 ± 85 1023 ± 630 1.30 ± 0.45 0.19 ± 0.09 ARI-001:
1120 mg / kg
18 days 668 ± 239 153 ± 30 346 ± 121 833 ± 410 1.06 ± 0.56 0.27 ± 0.15 ARI-001:
1120 mg / kg
28 days 420 ± 85 *** 138 ± 26 175 ± 80 *** 388 ± 82 ** 0.56 ± 0.12 *** 0.34 ± 0.09 *** ** p <0.01 compared to the filler in the same parameter
*** p <0.001 compared with the filler in the same parameter

ARI-001 showed beneficial effects on lipids when a dose of 1120 mg / kg was administered for up to 28 days. When hamsters were dosed for 28 days instead of 18 days, all measured lipid parameters achieved a statistically significant difference compared to the excipient, with the exception of HDL, which showed no difference compared to the excipient. The observed decrease with the introduction of 1120 mg / kg for 28 days was greater than after an 18-day dose. However, these reductions were almost not as impressive as those observed with 18-day administration at a higher dose of 2240 mg / kg.

Correlation between plasma lipid biomarkers and plasma concentrations of ARI-001. Plasma from 19 hamsters administered a dose of ARI-001 in the 18-day study described above was analyzed for ARI-001 concentration. Concentrations were determined for those samples that were collected 24 hours after the final dose. Briefly, plasma drug concentrations for non-GLP pharmacokinetic experiments were determined using LC-MS using an Applied Biosystems 4000Qtrap electrospray ionization spectrometer. Samples for analysis were prepared by precipitation of proteins in plasma with cold methanol. HPLC samples were performed using an Agilent Eclipse C18 column and a methanol / water gradient containing 0.1% formic acid and 5 mM ammonium acetate. ARI-001 was detected using a multiple monitoring reaction (MRM) using the positive ion method. For quantitative analysis, a standard curve was measured by adding known amounts of ARI-001 to plasma from untreated animals and preparing by a method identical to samples from treated animals. All plasma samples were labeled with 10 nm / ml isotope-enriched ARI-001, which served as internal standards for LC-MS measurements. All concentrations are given in μM. For correlation analysis, plasma concentrations of ARI-001 in a given animal were combined with the same lipid parameter of the animal. The analysis included all animals from both groups with the administered dose (1120 mg / kg and 2240 mg / kg). The correlation data is graphically shown in Figure 6 and Figure 7. The Pearson correlation values were determined using all the data, as in the case of a two-sample P-value for the data series.

Changes in the lipid parameter correlated well with plasma levels of the drug, measured 24 hours after the last dose. Indeed, levels of total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides and free fatty acids all reached statistically significant levels of correlation (p <0.01). The correlation with triglycerides was especially noticeable by the presence of a very high degree of statistical significance, p <0.001. These significant correlations confirm that ARI-001 is directly responsible for modulating lipid values. Moreover, these data confirm the effects of the dose response shown in Figure 5.

Concentrations of ARI-001 in tissue correlate with plasma lipid levels. Tissue samples were collected from hamsters in the 18-day experiment described above to determine the concentration of ARI-001 in both the liver and adipose tissue. Briefly, liver and adipose tissue samples were collected at the end of the experiment; samples were instantly frozen in liquid nitrogen and then stored at -80 ° C until used for analysis. To prepare for analysis, liver samples were excised from the frozen mass, weighed and homogenized with a tissue grinder, followed by ultrasonic treatment in buffer. Solid materials were then removed by centrifugation. To prepare for LC-MS analysis, the homogenate was then processed using the same technology as described for plasma preparation (see above). A sample of adipose tissue was excised from the frozen mass and transferred to a mortar and pestle, cooled with liquid nitrogen. During grinding, liquid nitrogen was added so that the adipose tissue sample remained solid. The ground sample was transferred to a pre-weighed tube to weigh the entire sample. This ground sample was extracted with methanol, and this methanol containing the compound was separated from the lipid by cooling to -20 ° C. After drying, the methanol sample was dissolved in water; then the samples were prepared for LC-MS analysis in the same manner as in the case of liver and plasma (see above).

Concentrations in the liver are given as ng ARI-001 per ml of a homogenized tissue sample extracted with buffer. Concentrations in adipose tissue are given in ng ARI-001 per mg of tissue isolated from the grinding process. Due to the distribution of tissue concentrations and lipid parameters, the transformation of the logarithm was used to determine the correlation for all samples in the liver. In addition, concentrations in adipose tissue were transformed as logarithm + 1, since transformation of the logarithm yielded negative values for these tissue samples. The transformation data made it possible to show the data on the graph more clearly, more conveniently. Finally, these transformations are justified, because the character of the Pearson correlation coefficient is invariant for both the transformation of the logarithm and the permutation.

Figure 8 graphically shows the correlation between the concentrations of ARI-001 in plasma and in the liver (left) and plasma and adipose tissue (right). Both correlation data were highly statistically significant, with p <0.01 for each pair of parameters. Figures 9-11 show graphically the correlations between the concentrations of ARI-001 in each tissue sample and the lipid parameters TC, HDL, LDL, TG and FFA. All concentration measurements and all lipid parameters were transformed using a logarithm. Pearson's correlation coefficient was determined using all illustrated data. P-value was determined for a two-sample t-test using all the illustrated data.

ARI-001 increases ABCA1, ApoAI, SR-BI, CETP and adiponectin mRNA in HF / HS hamsters. Investigation of a possible mechanism that could lead to an increase in HDL cholesterol, focused on changes in mRNA levels of several genes associated with the regulation of HDL. Hamster liver and adipose tissue were prepared by a method similar to that described for determining the concentration of ARI-001. Briefly, for preparation for analysis, a liver sample was cut from a frozen mass, weighed and homogenized using a tissue grinder, followed by ultrasonic treatment in a buffer. Solid materials were then removed by centrifugation. The resulting lysate was used in qPCR analysis to quantify the specific mRNA measured (see above) using primers designed for specific sequences of interest. All mRNA amounts were normalized to vehicle-treated animals, and mRNA levels were expressed as a fold increase or decrease relative to vehicle-treated animals. Adipose tissue was treated in a similar manner to the liver: a sample of adipose tissue was excised from the frozen mass and transferred to a mortar and pestle, cooled with liquid nitrogen. During grinding, liquid nitrogen was added to allow the sample to remain solid. The ground sample was transferred to a pre-weighed tube to weigh the entire sample. This ground sample was buffered and prepared for qPCR to quantify specific mRNA.

Table 5
Relative concentrations of ABCA1, ApoAI, SR-BI, CETP mRNA per mg of liver tissue, and similarly, CETP of adipose tissue and adiponectin mRNA per mg of adipose tissue from high-fat food hamsters in bulking, niacin or ARI-001 groups. Values are given in the form of a multiple change compared to the average values in the group with the filler. Message Filler Niacin: 1200 mg / kg ARI-001: 2240 mg / kg ABCA1 liver 1.02 ± 0.18 0.80 ± 0.18 1.54 ± 0.48 ** ApoAI of the liver 1.04 ± 0.28 1.17 ± 0.19 1.72 ± 0.24 *** SR-BI liver 1.00 ± 0.25 0.79 ± 0.18 1.50 ± 0.33 ** Liver cetp 1.00 ± 0.45 1.03 ± 0.55 2.05 ± 0.38 *** CETP adipose tissue 1.00 ± 0.46 1.12 ± 0.33 1.72 ± 0.70 * Adiponectin adiponectin 1.00 ± 0.43 1.67 ± 0.32 *** 2.00 ± 0.23 ***

Both ABCA1 and ApoAI mRNA levels were higher in the group of animals treated with ARI-001 relative to control animals with vehicle. Indeed, a statistically significant correlation was between HDL and ApoAI mRNA levels. This suggests a possible mechanism by which ARI-001 can increase HDL in this model of hamsters.

Table 6
Correlations between ABCA1, ApoAI, SR-BI, and CETP mRNA per mg of liver tissue versus HDL levels, and similarly between CETP and adiponectin mRNA per mg adipose tissue versus HDL levels from hamsters fed high-fat foods in groups treated with vehicle, niacin or ARI-001. Correlation Filler Niacin: 1200 mg / kg ARI-001: 2240 mg / kg [HDL] against liver ABCA1 -0.007 (-0.60 ... 0.60) -0.40 (-0.84 ... 0.36) 0.49 (-0.33 ... 0.89) [HDL] against ApoAI of the liver 0.32 (-0.34 ... 0.77) 0.19 (-0.54 ... 0.76) 0.80 (0.21 ... 0.96) * [HDL] against SR-BI liver 0.46 (-0.19 ... 0.83) 0.46 (-0.29 ... 0.86) -0.10 (-0.75 ... 0.65) [HDL] against liver CETP 0.18 (-0.47 ... 0.70) -0.13 (-0.73 ... 0.58) 0.30 (-0.52 ... 0.83) [HDL] anti-adipose tissue CETP -0.03 (-0.62 ... 0.58) 0.54 (-0.19 ... 0.89) 0.85 (0.28 ... 0.98) * [HDL] against adipose tissue adiponectin 0.43 (-0.22 ... 0.82) 0.31 (-0.48 ... 0.81) -0.22 (-0.83 ... 0.64)

Example 4: Pharmacological Safety Studies (Non-GLP Preliminary Studies)

Due to the notoriety that niacin is associated with liver toxicity and glucose intolerance in chronic dosing, we tested whether ARI-001, a niacin mimetic, could be related in a similar way. In order to study this, we tested the usual functional liver enzymes AST and ALT in hamster plasma from the experiment described in Example 3. These animals were given a dose of the test substances for 18 consecutive days, and the animals were on an HF / HS diet for a total of about 5 weeks. We also tested the plasma glucose levels of these animals. For pharmacokinetic studies, we used wild-type mice to study both single and repeated administration. Finally, pharmacokinetic studies were supported by data from single and repeated administration to monkeys.

A. Effect on liver function

ARI-001 improves liver function in trials of chronic dosing to hamsters fed high-fat foods. Some niacin formulations are known to cause hepatotoxicity in humans. This led to a study in liver function tests (AST, ALT) from plasma of hamsters that had been given a dose of ARI-001 for 18 days. AST and ALT were measured using commercially available kits (Bio-Quant Diagnostic Kits, San Diego, CA). As expected, the AST and ALT values of untreated hamsters (group with a filler) were very high, since a diet with a high fat content leads to hepatomegaly and fatty liver. This disease is reflected in elevated levels of AST and ALT. In contrast, AST and ALT levels in animals treated with ARI-001 were significantly lower than in the vehicle group. Indeed, AST decreased sharply at a dose of 2240 mg / kg, and even decreased significantly at a dose of 1120 mg / kg. ALT scores were likewise reduced in a dose-dependent manner. See Figure 12A and Figure 12B.

B. Actions on glucose tolerance

ARI-001 has no effect on glucose levels among hamsters fed high-fat foods. Niacin is known to have a negative effect on glucose levels in diabetic patients. The hamster model used in this experiment yielded populations with elevated glucose levels, as demonstrated by the excipient group in Figure 13. Consistent with the actions shown in humans, glucose in animals treated with niacin increased relative to the excipient group. However, not a single dose of ARI-001 produced any significant change in glucose levels compared to the bulking group.

Example 5: Pharmacokinetic Studies

A. In vivo mouse studies

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

Administration of a single dose of ARI-001 orally through a gastric tube and using intraperitoneal injection gave pharmacokinetic curves with the parameters described in Table 7. By the end of 24 hours of the time period, the remaining concentration of ARI-001 was not detected.

Table 7
Pharmacokinetic parameters of a single administration of ARI-001 in mice of this type ARI-001 C _max (μm) t _1/2 (h) t _max (h) AUC (μm * h) PO 289 1,5 0.5 1096 IP 450 0.5 0.25 439

Pharmacokinetic study of ARI-001 in wild-type mice with multiple administration. Wild type C57BL / 6 mice were dosed with ARI-001 in solution orally through a gastric tube daily for 30 consecutive days. After a course of five 24-hour periods, blood was collected and the resulting plasma was analyzed for ARI-001 concentration. Four doses were used: 996 mg / kg, 1493 mg / kg, 2240 mg / kg and 3360 mg / kg. As expected, C _max levels and total 24-hour exposure (AUC) were dose dependent. However, these values were time-dependent, since no tendency was observed between these parameters and the days of administration. See Figures 15A-15D and Figures 16A-16B.

B. Additional in vivo mouse studies

Single-dose pharmacokinetic studies in wild-type mice. Wild-type mice C57BL / 6 were dosed with a single dose of niacin, ARI-001, or compound 2230C (disclosed in U.S. Patent Application Publication No. 2009/0312355 A1, incorporated herein by reference), in solution, orally through a gastric tube as a single bolus (PO ) Compound 2230C has the structure

Then, blood samples were collected at various points in time over a 24-hour period; then plasma was analyzed for the concentration of niacin, ARI-001 and 2230C, as described previously. The results are shown in Table 8.

C. In vivo studies on Golden Syrian hamsters

Single-dose ARI-001 pharmacokinetic study on Golden Syrian hamsters. The pharmacokinetic profile of ARI-001 was evaluated on HF / HS Golden Syrian hamsters given a single oral dose of 5.9 mmol / kg ARI-001. Plasma samples were collected using cardiac puncture in five animals at each time point to measure plasma concentrations of ARI-001 for 24 hours. The results are shown in Figure 17.

D. In vivo studies on monkeys

Pharmacokinetic study of ARI-001 in monkeys with single dose macaques. Starving monkeys were given a single administration of ARI-001 in solution, either orally through a gastric tube (PO), or via intravenous injection (IV). Blood samples were collected at various time points over a 24-hour period; then plasma was analyzed at a concentration of ARI-001. ARI-001 was administered either at a dose of 288 mg / kg as a single bolus orally through a gastric tube, or at a dose of 96 mg / kg as a single bolus with an IV injection. The results are shown in Figure 18.

Pharmacokinetic study of a single dose of ARI-001 in feeding or starving monkeys. The feeding monkeys were fed and allowed to digest for some time before ARI-001 was administered as a solution orally through a gastric tube, as described previously. The results are shown in Figure 19.

Pharmacokinetics of multiple administration of ARI-001 on starving monkeys. ARI-001 was administered to the monkeys orally through a gastric tube once a day for seven days. After the first and after the last administration, blood samples were collected to measure the plasma concentration of ARI-001. There was a very slight difference between plasma concentrations on day 1 versus day 7. The largest discrepancy was in the C _max index, which was higher on day 7 than on day 1. Concentrations 24 hours after or after the first or after the last dose were essentially identical. See Figure 20.

Example 6: ARI-001 does not replenish β-arrestin cell membrane of cells expressing high affinity niacin receptor GRP109A

It has been demonstrated that niacin-induced skin flushes are mediated by activation of the niacin receptor, GRP109A, in a β-arrestin-dependent manner. Walters RW et al. (2009) J Clin Invest 119: 1312-21. Β-arrestin cells expressing GRP109A ready for PathHunter eXpress analysis were placed on a 96-well plate at 10,000 cells / well and stimulated with either niacin or ARI-001, each in the concentration range, for 90 minutes. Conjugate receptor G-protein activity (GPCR) was determined by measuring the interaction of β-arrestin with activated GPCR using complementation of a fragment of the β-galactosadis enzyme. After stimulation with either niacin or ARI-001, a signal was detected using chemiluminescent PathHunter detection reagents. Typical results are shown in Figure 21.

Unlike niacin, stimulation of GPR109A with ARI-001 at concentrations up to 10 mM did not replenish β-arrestin cell membrane expressing GRP109A. Since niacin-induced hot flashes are known to be mediated by activation of GRP109A in a β-arrestin-dependent manner, this finding is consistent with the observation that ARI-001 significantly reduced the side effect of hot flashes compared to niacin.

Example 7: Summary of Pharmacological Studies of ARI-001 in Animal Models

In relation to ARI-001, a series of studies of pharmacokinetics, safety, and efficacy have been conducted in a variety of animals, including mice, rats, Golden Surian hamsters, dogs, and monkeys. The general results of these studies established the following.

ARI-001 decreased plasma levels of total cholesterol, LDL-C, TG and FFA with an increase in total HDL-C and HDL-C / TC ratios. The effects of lipid changes from a single dose per day of ARI-001 were more pronounced, lipid effects observed with an almost 2-fold higher dose of niacin given once a day.

ARI-001, which was given to animals once daily for 28 days, resulted in large changes in plasma lipid levels compared to the same dose of ARI-001 given once daily for 18 days.

ARI-001, given once a day daily, led to very significant changes in plasma lipids, to greater than or equal effects of changes in lipid levels compared to the same total dose of ARI-001 given twice a day. In addition, ARI-001 at a single dose per day was stronger than niacin in achieving the desired lipid changes.

Plasma change levels of TC, HDL-C, TG, LDL-C, and FFA correlated with the concentrations of ARI-001 present in plasma.

Plasma and liver concentrations of ARI-001 are proportionally related.

The concentration of ARI-001 in the liver correlated with decreases in plasma TC, LDL-C, TG and FFA and increases in plasma HDL-C.

ARI-001 showed no evidence of capillary vasodilation or hyperemia (close to high tide) in experiments in mice using Doppler measurements of capillary blood flow. In addition, in rats or dogs, no clinical symptoms of “flushing” were observed for 28 days.

Example 8: Clinical trial of ARI-001 in humans

Conduct a random or random, double-blind, placebo-controlled study with successive increasing doses with observations within 30 hours after administration of the dose and a return examination on the 8th day. The subjects of the study are healthy adult male and female volunteers, 18-60 years old, with LDL-C> 130 mg / dl and weight <85 kg. Subjects were randomly assigned to receive the study drug or placebo.

Five periods of increasing a single dose, with 8 subjects per group (6 with drug: 2 with placebo), involved a total of 40 people. A placebo appropriately assigned blindly was provided. Group 1 receives 500 mg of ARI-001, formulated as a single oral tablet, plus 11 placebo tablets; Group 2 - 1000 mg, taken in the form of two 500 mg tablets ARI-001, plus ten placebo tablets; Group 3 - 2000 mg, taken in the form of four 500 mg tablets ARI-001, plus eight placebo tablets; Group 4 - 4000 mg taken in the form of eight 500 mg ARI-001 tablets, plus four placebo tablets; Group 5 - 6000 mg, taken in the form of twelve 500 mg tablets ARI-001. Subjects with placebo alone take twelve placebo tablets. Each tablet is a compressed, film-coated tablet suitable for oral administration.

The primary objectives of the study are to evaluate the safety and ability to tolerate single doses of ARI-001 by healthy adult volunteers at doses from 500 mg to 6000 mg.

The secondary goals of the study are to establish the pharmacokinetic profile of ARI-001 in the blood after a single dose in healthy volunteers; observation of changes in fasting triglycerides, free fatty acids and other lipid biomarkers; correlation of the dose level and the time of exposure to the drug in plasma over time with any changes in fasting triglycerides, free fatty acids and other lipid biomarkers; and establishing the effect of ARI-001 on symptoms of flushing on a visual analogue scale (VAS).

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

Each time a sample is taken, 3 ml of blood is taken into a Vacutainer cylinder containing EDTA (purple top) and cooled immediately. Within 30 minutes of collection, the plasma fraction is separated by centrifugation at 2000 rpm for 15 minutes at 4 ° C. All samples are analyzed in a central laboratory.

On day 1, before the dose, the following procedures are 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 LPA and ApoA-1)

- 12-wire ECG

- vital signs

- VAS

- Baseline plasma plasma RK

- Urine collection for the baseline of the Republic of Kazakhstan between midnight and 0 hours (dose)

After administration of the test drug, the following procedures are performed.

- Clinical laboratory tests, including liver function (ALT, AST, serum bilirubin), CK, hematology and APTT, PT 6, 12 and 24 hours after the dose

- Lipid chemistry (LDL-C, HDL-C, free fatty acids, triglycerides, Lp (a) and ApoA-1) 4, 12 and 24 hours after the dose

- 12-ECG electrical connection at 1, 2, 4, 6, 8, 12 and 24 hours after the dose

- Urinalysis 24 hours after the dose

- Vital signs 6, 12, 24 and 30 hours after the dose

- VAS 0.25, 0.5, 1, 2, 4, 8, 12, and 24 hours after the dose

- Physical examination 24 hours after the dose and a brief clinical examination 30 hours after the dose

- Taking blood samples for RK after 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24 and 30 hours after the dose

- Taking a blood sample for troponin 4 hours after the dose

- Urine collection in the Republic of Kazakhstan at 6-hour intervals after 0-6, 6-12, 12-18, 18-24 and 24-30 hours after the dose

The preliminary results of this clinical trial in humans include the surprising observation that no patient showed any signs of flushing at any dose of ARI-001, up to and including a dose of 6000 mg.

Additional preliminary results are shown in Figure 22, which illustrates the dose response in relation to lowering human triglycerides at single oral doses of ARI-001 according to data measured 4 hours after the dose.

Additional preliminary results are shown in Figure 23, which illustrates the concentration of ARI-001 in serum, measured over 24 hours in humans after single oral doses, ranging from 500 mg to 6000 mg of ARI-001. The C _max for the 2000 mg ARI-001 dose was about 7500 ng / ml (7.5 mg / ml); With a _max for 1500 mg of niacin (roughly equimolar dose) was 30,000 ng / ml (30 mg / ml).

INCLUSION IN THE DESCRIPTION BY REFERENCE

All publications and patents referred to herein are incorporated by reference in their entirety, as if each individual publication or patent were specifically and individually incorporated by reference. In case of disagreement, this application, including any definitions in it, will serve as a control.

EQUIVALENTS

Although specific embodiments of the discussed invention are disclosed in the description, the above description is illustrative and not limiting. Many modifications of the invention will become apparent to experts in this field after reading this description. The accompanying claims do not mean to state that all such embodiments and modifications, and the full scope of the invention should be determined by referring to the claims along with the full scope of equivalents and descriptions together with such variations or modifications.

Claims (14)

1. The compound represented by formula

or a pharmaceutically acceptable salt thereof,
wherein
R represents hydrogen, C _1-6 alkyl, fused bicyclyl or arylalkenylaryl. 2. The compound according to claim 1, in which R represents hydrogen. 3. The compound of claim 1, wherein R is C _1-6 alkyl. 4. The compound of claim 1, wherein R is fused bicyclyl. 5. The compound of claim 1, wherein R is arylalkenylaryl. 6. The compound or its pharmaceutically acceptable salt selected from the group consisting of

,

,

,

and

. 7. The compound or its pharmaceutically acceptable salt selected from the group consisting of

and

. 8. A pharmaceutical composition for treating a condition selected from the group consisting of hyperlipidemia, hypercholesterolemia, and a combination thereof, comprising a compound according to any one of claims. 1-6, and a pharmaceutically acceptable excipient. 9. The pharmaceutical composition according to claim 8, in which the ratio of the peak concentration to the area under the curve for 24 hours (C _max / AUC _0-24 ) for the compound is 0.35 h ^-1 or less. 10. The pharmaceutical composition of claim 8 or 9, in which the time to peak concentration (t _max ) for the compound is in the range of 30 minutes to 5 hours. 11. The pharmaceutical composition according to any one of paragraphs. 8-10, in which the compound has an EC ₅₀ in relation to the function of the mediated β-arrestin GPR109A, at least 10 times higher than the EU ₅₀ in relation to the function of the mediated β-arrestin GPR109A. 12. A method of treating a disease of a condition selected from the group consisting of hyperlipidemia, hypercholesterolemia and a combination thereof, comprising the step of administering to the mammal in need of a therapeutically effective amount of a compound according to any one of claims. 1-6, or a pharmaceutical composition according to any one of paragraphs. 8-11. 13. A method of increasing serum levels of high density lipoprotein (HDL), comprising the step of administering to a mammal in need thereof a therapeutically effective amount of a compound according to any one of claims. 1-6, or a pharmaceutical composition according to any one of paragraphs. 8-11. 14. A method of lowering serum levels of low density lipoprotein (LDL), comprising the step of administering to a mammal in need thereof a therapeutically effective amount of a compound according to any one of claims. 1-6, or a pharmaceutical composition according to any one of paragraphs. 8-11.

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