TW201016705A - Nicotinic acid receptor agonist compounds useful to treat metabolic syndromes - Google Patents

Abstract

The present invention provides compounds of the Formula I: R'-G-R I wherein R' represents a recoverable residue of a non-steroidal anti-intlammatory drug (NSAID); G represents a hydrolysable or metabolizable linker group; and R represents a recoverable residue of a nicotinic acid receptor agonist; and salts, solvates, esters and prodrugs thereof, as well as pharmaceutical compositions containing them, and methods of using them to treat metabolic syndrome, dyslipidemia, cardiovascular diseases, disorders of the peripheral and central nervous system, hematological diseases, cancer, inflammation, respiratory diseases, gastroenterological diseases, diabetes, and non-alcoholic fatty liver diseases.

Description

201016705 6. Technical Field of the Invention: The present invention relates to novel nicotinic acid receptor agonist compounds for the treatment of metabolic syndrome, dyslipidemia, cardiovascular disease, peripheral nervous system and central nervous system. Disease, blood disease, cancer, inflammation, respiratory disease, gastrointestinal disease, diabetes and non-alcoholic fatty liver disease; pharmaceutical compositions comprising the compounds; including combinations of nicotinic acid receptor agonist compounds and other therapeutic agents Pharmaceutical compositions; and methods of using such compounds and compositions to treat conditions such as metabolic syndrome, dyslipidemia, cardiovascular disease, peripheral nervous system and central nervous system disorders, blood disorders, cancer, inflammation, respiratory diseases , gastrointestinal disease, diabetes, liver steatosis and non-alcoholic fatty liver disease. This application claims the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the present disclosure. [Prior Art] Nicotinic acid (also known as niacin) and other nicotinic acid receptor (NAR) agonists are useful for the treatment of hyperlipidemia or hypercholesterolemia. Administration of NAR to hyperlipidemia or hypercholesterolemia patients can reduce total cholesterol, VLDL-cholesterol and VLDL_cholesterol residues 'LDL•cholesterol, triglycerides and apolipoprotein a, while increasing the desired HDL_ cholesterol. A disadvantage of niacin treatment and (possibly) other NAR treatments is that the treatment is usually accompanied by a redness effect on the skin. The redness effect of the skin appears to be intense redness or congestion, usually accompanied by itching, tingling, or fever, and sometimes accompanied by headache. The redness effect of the skin itself is harmless. However, it is very unpleasant that 141543.doc 201016705 niacin treatment shows a high patient non-compliance rate. Some reports indicate that the rate of non-compliance in patients with niacin treatment is as high as 30-40%. The skin redness effect is caused by the release of prostaglandins. Prostaglandins are known to cause vasodilation and a hostile perception of discomfort. The recognized role of prostaglandins in mediating skin redness effects suggests that inhibitors of prostaglandin synthesis can be used to prevent skin redness.

Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit prostaglandin synthesis by blocking prostaglandin synthetase (also known as cyclooxygenase). Therefore, nsaid (especially aspirin) is administered in combination with acid testing to reduce the redness of the skin. This combination therapy has been successful. Administration of aspirin as part of this combination has the additional benefit of administering aspirin to prevent platelet aggregation (thrombosis) due to its long-acting inhibitor of platelet cyclooxygenase and irreversible acetylation of the enzyme . Platelet cyclooxygenase cannot be restored by protein biosynthesis due to the lack of nuclei in platelets. The problem with combination therapy is that patients must take two drugs instead of one. In addition, if a patient forgets to take an NSAID, they may experience a redness effect on the skin and lose confidence in taking any of the drugs. In view of the above, there is an urgent need in the industry for a new compound that can be used to treat metabolic syndrome. SUMMARY OF THE INVENTION In many embodiments, the present invention provides a novel species of sigma complex with an alkali acid receptor agonist for the treatment of metabolic disorders, dyslipidemia, cardiovascular disease, and peripheral sensation And central nervous system disorders, blood 141543.doc 201016705 fluid disease, cancer, inflammation, respiratory diseases, intestinal alcoholic fatty liver disease; including these compounds, 2 urinary diseases and non-acid-accepting (4) animal compounds and A pharmaceutical composition comprising a combination of ϋη ^ m ^ ^ original agents, and a method of using the same, a method for treating symptoms such as the following symptoms, metabolic syndrome, dyslipidemia, and blood stasis « . ^ ., ^ S disease, peripheral nervous system and central nervous system (four) 'systemic diseases, blood diseases, cancer, inflammation 4 septic diseases, gastrointestinal diseases, diabetes, liver steatosis and non-alcoholic fatty liver disease. In the aspect, the application discloses a compound, or a pharmaceutically acceptable salt, solvate, vinegar or prodrug of the compound, which has the general structure shown in Formula I:

RG-RI wherein R' represents a recoverable residue of a non-steroidal anti-inflammatory drug (NSAID); G represents a hydrolyzable or metabolizable linking group; and R represents a recoverable residue of a nicotinic acid receptor agonist; A pharmaceutically acceptable salt, solvate, ester or prodrug thereof. The phrase "hydrolyzable or metabolizable linking group" as used herein means that the linking group is structured such that the compound of formula I or a salt, solvate, vinegar or prodrug thereof can be hydrolyzed or metabolized in vivo. Decomposition to produce the active NS AID component R'-OH or its active NSAID derivative, and the active nicotinic acid receptor agonist component R-OH or its active nicotinic acid receptor agonist derivative. The phrase "recoverable residue of NSAID" as used herein means that the R group is structured such that the compound of formula I or its salt, solvate, ester or prodrug 141543.doc 201016705 is hydrolyzed in vivo or Upon compounding, the compound, salt, solvate, vinegar or prodrug is decomposed to yield the active NSAID component R, -OH or its active NSAID derivative. The term "NSAID" as used herein means any compound capable of inhibiting cyclooxygenase. As used herein, the phrase "recoverable residue of a nicotinic acid receptor agonist" means that the R group is structured such that the compound of the formula or its salt, solvate, vinegar or prodrug is hydrolyzed in vivo. Alternatively, the compound, salt, solvent oxime, vinegar or prodrug is decomposed during metabolism to produce an active nicotinic acid receptor agonist group R OH or an active auxin receptor agonist derivative. The phrase "in acid-receptor agonist" as used herein means any compound having an affinity (or binding to nicotinic acid receptor (also referred to as "HM74A" or "GPR109A"), and When administered to a patient in a therapeutically effective amount, it will result in a beneficial change in the patient's gres characteristics, including elevated serum levels of high density lipoprotein (HDL). The compounds of formula I and their salts, solvates, esters and prodrugs are useful in the treatment of nicotinic acid receptor agonist compounds of the following diseases: metabolic syndrome, dyslipidemia, cardiovascular disease, peripheral nervous system and central nervous system Disease, 'blood disease' cancer, inflammation, taint disease, gastroenterology, diabetes and nonalcoholic fatty liver disease. In another embodiment, the invention relates to a pharmaceutical composition comprising: a therapeutically effective amount of at least one compound of the formula: or a pharmaceutical remedy thereof; a solution, ester or prodrug thereof And at least one pharmaceutically acceptable carrier. In another embodiment, the invention relates to methods of treating a disease or condition such as the following diseases 141543.doc 201016705 in a patient: metabolic syndrome, dyslipidemia, cardiovascular disease, peripheral nervous system and mesenteric nervous system disorders, blood disorders , cancer, inflammation, respiratory disease, gastrointestinal disease, diabetes and non-alcoholic fatty liver disease. The method comprises administering to the patient an effective amount of at least one human of formula t, or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof. In another embodiment, the invention relates to methods of treating a disease or condition such as a metabolic syndrome, dyslipidemia, cardiovascular disease, 'peripheral nervous system and central nervous system disorder, blood cancer, inflammation, respiratory Sexually transmitted diseases, gastrointestinal diseases, diabetes, liver steatosis and nonalcoholic fatty liver disease. The method comprises administering to a patient an effective amount of at least one compound of Formula I, or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, in combination with at least one other active ingredient selected from the group consisting of: Hydroxyl-substituted azetidinium compound, substituted indolamine compound, HMG CoA reductase inhibitor compound, HMG c〇A synthetase inhibitor, squalene synthesis inhibitor, squalene epoxidase Inhibitors, sterol biosynthesis inhibitors, nicotinic acid derivatives, bile acid sequestrants, inorganic cholesterol chelating agents, sulfhydryl-based CoA: cholesterol 〇-hydrazinotransferase inhibitors, cholesterol ester transfer protein inhibitors, ω3 fatty acids Fatty oil esters of fish oil, natural water soluble fiber, plant residual alkanol and/or plant residual alkanol (for example, from Pronova Biocare, 〇sl〇, N〇rway 〇mac〇r(g)), low density grease Protein receptor activators, antioxidants, PPAR alpha agonists, PPAR gamma-agonists, FXR receptor modulators, LXr receptor agonists, lipoprotein synthesis inhibitors, renin angiotensin inhibitors, microsomal glycerol Triacetate transporter inhibitor, bile acid reuptake inhibitor, ppAR § agonist 141543.doc 201016705 agent, triglyceride synthesis inhibitor, squalene epoxidase inhibitor, low density lipoprotein receptor inducer, Platelet aggregation inhibitor, 5-LO or FLAP inhibitor, PPAR δ partial agonist, nicotinic acid or nicotinic acid receptor agonist, 5 ΗΤ transporter inhibitor, ΝΕ transporter inhibitor, 031 antagonist/inverse agonist , ghrelin antagonist, Η3 antagonist/inverse agonist, MCH1R antagonist, MCH2R agonist/antagonist, ΝΡΥ1 antagonist, ΝΡΥ5 antagonist, ΝΡΥ2 agonist, ΝΡΥ4 agonist, mGluR5 antagonist, lipid raft Leptin, lipoprotein agonist/modulator, lipoprotein derivative, dinosaur tablet antagonist, orexin receptor antagonist, BRS3 agonist, CCK-A agonist, CNTF, CNTF Derivatives, CNTF agonists/modulators, 5HT2c agonists, Mc4r agonists, monoamine reuptake inhibitors, serotonin reuptake inhibitors, GLP-1 agonists, phentermine, 托特比比(topiramate) , botanical drug compound 57, hunger antibody, Mc3r agonist, ACC2 inhibitor, β3 agonist, DGAT1 inhibitor, DGAT2 inhibitor, FAS inhibitor, PDE inhibitor, thyroid hormone beta agonist, UCP-1 activator , UCP-2 activator, UCP-3 activator, thiol estrogen, glucocorticoid agonist/antagonist, 11β HSD-1 inhibitor, SCD-1 inhibitor, lipase inhibitor, fatty acid transporter inhibitor , two ortho-acid transporter inhibitors, glucose transporter inhibitors, acid transporter inhibitors, anti-diabetic agents, anti-hypertensive agents, anti-lipidemia agents, DP receptor antagonists, apolipoprotein-Β secretion /microsomal triglyceride transfer protein (apo-B/MTP) inhibitor, sympathomimetic agonist, dopamine agonist, melanocyte stimulating hormone receptor analogue, melanin aggregation hormone antagonist 141543.doc 201016705 Agent, leptin, galanin receptor antagonist, bombesin agonist, neuropeptide-gamma antagonist, thyroxine agent, dehydroepiandrosterone, dehydroepian Ketone Analogue, urocortin-binding protein antagonist, glucagon-like peptide-1 receptor agonist, human guinea pig-associated protein (AGRP), neurotransmitter receptor agonist, norepinephrine-induced degeneration Appetite, appetite suppressant, hormone-sensitive lipase antagonist, MSH-receptor analogue, alpha-glucosidase inhibitor, ap〇Ai milano reverse cholesterol transport inhibitor, fatty acid binding protein inhibitor (Fabp) and Fatty acid transporter inhibitor (FATP). [Embodiment] The final acid acceptor agonist compound of the present invention can be used for the treatment of conditions such as metabolic syndrome, dyslipidemia, cardiovascular disease, peripheral nervous system and central nervous system disorders, blood diseases, cancer, inflammation, Respiratory diseases, gastrointestinal diseases, diabetes, liver steatosis and nonalcoholic fatty liver disease and other diseases listed herein. The compound or compounds of the invention may be administered alone or in combination with one or more of the other therapeutic agents described herein. The present invention provides a compound of formula I:

R'-G-R wherein R, R' and G are as defined above and their salts, solvates, vinegar and prodrugs. In one embodiment, a compound, or a pharmaceutically acceptable salt, solvate thereof, '珂乐', wherein G represents a linking group of the group consisting of: 〇, 5, NR1, _〇M Alkyl 141543.doc •10· 201016705 ,-〇-alkyl-S-,-S-alkylene-s-, -ο-Exylaryl-ο-,-ο-Exylaryl-S- , -s-Exylaryl-s-, -ο-arylalkyl-o-,-o-arylalkyl-S-'-S-arylalkyl-S-, -ο-: -o-, -o-heteroaryl-S-, -S-heteroaryl-S-, polyalkylene glycol, -c(o)o-alkylene-indole-, -c (o)o-alkyl-S-, -oc(o)-alkyl-anthracene-, -oc(o)-alkylene-S-, -c(o)o-exoaryl-〇 -, -C(0)0-Exylaryl-S-, -〇-c(o)-Exoaryl-Ο-, -OC(O)-Extend-aryl-S-, -c(o)o -heteroaryl-◦-,-(:(〇)〇-extended aryl-S-, -oc(o)-extended aryl C(O)-extended aryl-S-, and - C(O)-polyalkylene glycol; and wherein R1 represents hydrogen, H. or aryl. In another embodiment, the invention relates to a compound of formula I, or a pharmaceutically acceptable salt thereof, a solvate, ester or prodrug, wherein G represents a selected from the group consisting of Joining groups of the group: 0, S, NR1, -0(CH2)n0-, -0(C(R2)2)0-, -0(CH2)nS-, -0(C(R2)2 ) S-, -S(CH2)nS-, -s(c(r2)2)s-, -o-aryl-o-, -o-aryl-s-, -s-aryl-s- , -◦-heteroaryl-Ο-, -O-heteroaryl-S-, -S-heteroaryl-S-, PEG (polyethylene glycol), and PPG (polypropylene glycol); and R1 represents hydrogen Or an alkyl or aryl group; R2 represents an alkyl group; and η represents 0-10. In still another embodiment, the invention relates to a compound of formula I, or a pharmaceutically acceptable salt, solvate, ester or Prodrug, wherein G represents a linking group selected from the group consisting of Ο, -C(0)0(CH2)n0-, -oc(o)(c(r2)2)o-, -C(0 )0(CH2)nS-, -oc(o)(c(r2)2)s-, -C(0)S(CH2)nS-, -c(o)s(c(r2)2)s- , -c(o)o-aryl-o-, -c(o)o-aryl-s-, -c(o)s-aryl-s-, -c(o)o-heteroaryl -ο-, 141543.doc • 11 - 201016705 -c(0)0-heteroaryl-s-, -C(0)s-heteroaryl-S-, -C(0)PEG-(polyethylene) Alcohol), and -C(0)PPG-(polypropylene glycol); and R1 represents hydrogen, alkyl or aryl; R2 represents alkyl; and η represents 0-10. In another embodiment, the invention relates to a compound of Formula I, or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, wherein G represents a linking group selected from the group consisting of hydrazine, 8, >^, call (:113), -〇-CH2-0_,_0_CH2CH2-0_,_0-(CH2)3-0-,-0-CH2-CH(CH3)-〇- '-〇-CH2 -C(CH3)2-〇- ' -0-CH2-S- ' -0-CH2CH2-S- ' -〇-(CH2)3-S-, -〇-CH2-CH(CH3)-S-, -〇-CH2-C(CH3)2-S-, -S-ch2-s-, -s-ch2ch2-s-, -s-(ch2)3-s-, -s_ch2-ch(ch3)_s -, -S-CH2-C(CH3)2-S-, -O·phenylene_〇_,-CM phenyl-s-, _s-phenyl-S-,-〇-extended pyridyl Pyridyl.8_ and _8_extended pyridyl-S-indole In one embodiment, the invention relates to a compound of formula I, or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, wherein R, represents a recoverable residue of NS AID in addition to acetamidine. In one embodiment, the invention relates to a compound of Formula I, or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, wherein R represents a NSAID having a structure selected from the group consisting of Restore residues:

141543.doc -12· 201016705 α Ο—Η

141543.doc -13- 201016705

F ; and

The asterisk indicates the connection point with G. In a particularly preferred embodiment, the invention relates to a compound of formula I, or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, wherein R' represents a recoverable residue of the NSAID having the structure:

The asterisk indicates the connection point with G. In another preferred embodiment, the invention relates to a compound of Formula I, or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, wherein R' represents a recoverable residue of the NSAID having the structure :

The asterisk indicates the connection point with G. In another preferred embodiment, the invention relates to a compound of formula I, or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, wherein R| represents a recoverable residue of the NSAID having the structure : 141543.doc 201016705

The asterisk indicates the connection point with G. In another embodiment, the invention relates to a compound of Formula I, or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, wherein R represents an acid-receptor agonist other than the test acid itself It can recover residues. In still another embodiment, the invention relates to a compound of Formula I, or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, wherein R represents a recoverable residue of a nicotinic acid receptor agonist, The use of an acid-receptor agonist is described in U.S. Patent Application Publication No. US 2008/001997, the entire disclosure of which is incorporated herein by reference. Among the compounds described in the above publications, a particularly preferred one is a recoverable residue of a nicotinic acid receptor agonist having the following structure:

Or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof; wherein R3 represents an alkyl group, especially an unsubstituted alkyl or haloalkyl group, or represents a cycloalkyl or heteroalkyl group; and 141543.doc -15- 201016705 R4 stands for hydrazine, alkyl or cycloalkyl; and the asterisk indicates the point of attachment to G. Also preferred are recoverable residues of the following structure of nicotinic acid receptor agonists.

Or a pharmaceutically acceptable salt, solvate, S- or prodrug thereof; wherein R5 and R6 each independently represent a haloalkyl group, especially a fluoroalkyl group; and the asterisk indicates a point of attachment to G. In still another embodiment, the invention relates to a compound of Formula I, or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, wherein R represents a recoverable residue of a nicotinic acid receptor agonist, The nicotinic acid receptor agonist is described in the following: International Patent Application Publication No. WO 2004/033431, WO 2005/044816, WO 2005/051937, WO 2006/026273, WO 2006/069242, WO 2006/052555, WO 2007/035478, WO 2007/027532, WO 2005/077950, WO 2005/016867, WO 2005/016870, WO No. 2006/085108, WO 2006/045564, WO 2006/045565, WO 2006/085113, WO 2007/017261, WO 2007/017262, WO 2007/134986, WO 2007 /015744, WO 2007/150025, WO 2007/150026, and WO 2007/134986; and US Patent Application Publication No. 141543.doc -16 - 201016705 US 2006/0281810, US 2007/ No. 0072873 and US 2007/0 161650, all contents of which are incorporated by reference The text. In another embodiment, the invention relates to a compound of Formula I, or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, wherein R represents a nicotinic acid receptor agonist having the following structure Recovering residues: 〇

The asterisk indicates the connection point with G. In still another embodiment, the invention relates to a compound of Formula I, or a pharmaceutically acceptable salt, solvate, S- or prodrug thereof, wherein R represents an acid-receptor agonist having the following structure Recoverable residues:

The asterisk indicates the connection point with G. In a particularly preferred embodiment, R' is not a residue of acetyl salicylic acid. In a second particularly preferred embodiment, R is not a residue of nicotinic acid. In a third preferred embodiment, R' is not a residue of acetamidine and at the same time R is not a residue of nicotinic acid. a compound of formula I, and pharmaceutically acceptable salts, solvates, esters thereof 141543.doc -17· 201016705 and w drug terminal acid receptor agonists, and thus useful for treating metabolic syndrome, dyslipidemia, heart Vascular disease, sinusoidal nervous system, incomplete mesenteric nervous system disorders, blood diseases, cancer, inflammation, respiratory diseases, gastrointestinal diseases, diabetes and nonalcoholic fatty liver disease, and the use of bioequivalence only for testing Acid receptor agonists may have a reduced likelihood or severity of redness. In one embodiment, the invention relates to the inclusion of at least one formula 1

A composition of a compound or a pharmaceutically acceptable salt, solvate, vinegar or prodrug thereof and a pharmaceutically acceptable carrier.

In another embodiment, the composition of the present invention further comprises at least one other therapeutic agent selected from the group consisting of: (iv) a substituted acetophenone compound, a substituted indolamine compound, hmg c〇A Reductase inhibitor compounds, HMG coA synthetase inhibitors, horn f, dilute synthesis inhibitors, horn f diluted epoxidase inhibitors, sterol biosynthesis inhibitors, acid test derivatives, bile acid sequestrants, aspirin, Nsaid pharmaceutical, Vytodn®, ezetimibe, inorganic cholesterol chelating agent, sulfhydryl c〇a: cholesterol Ο-hydrazinotransferase inhibitor, cholesterol ester transfer protein inhibitor, fish oil with omega 3 fatty acid, natural water-soluble fiber , plant residual alkanol and / side plant (tetra) alkanol fatty acid vinegar, antioxidants, ppAR α agonist, PPAR γ-agonist, FXR receptor regulation,! , Lxr receptor agonist, prion protein synthesis inhibitor, renin vascular tone female in m-jing inhibitor, microsomal triglyceride transport inhibitor, bile acid reuptake inhibitor, ppAR ^ mobilizer, triglyceride Vinegar synthesis inhibitor, horn W epoxidase inhibitor, low density catalyzed ritual agent or activator, ^, (4) (4), 5 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

FLAP inhibitor, PPAR δ partial agonist, final acid or acid receptor agonist, 5 ΗΤ transporter inhibitor, ΝΕ transporter inhibitor, CB! antagonist/inverse agonist, ghrelin antagonist, Η3 antagonism Agent/inverse agonist, MCH1R antagonist, MCH2R agonist/antagonist, ΝΡΥ1 antagonist, ΝΡΥ5 antagonist, ΝΡΥ2 agonist, ΝΡΥ4 agonist, mGluR5 antagonist, lipoprotein, lipoprotein agonist/modulator, Lipoxygenin derivatives, opioid antagonists, orexin receptor antagonists, BRS3 agonists, CCK-A agonists, CNTF, CNTF derivatives, CNTF agonists/modulators, 5HT2c agonists, Mc4r agonists, single Amine reuptake inhibitor, serotonin reuptake inhibitor, GLP-1 mimetic, phentermine, tropine vinegar, botanical drug compound 57, ghrelin antibody, Mc3r agonist, ACC2 inhibitor, β3 agonist, DGAT1 Inhibitors, DGAT2 inhibitors, FAS inhibitors, PDE inhibitors, thyroid hormone beta agonists, UCP-1 activators, UCP-2 activators, UCP-3 activators, thiol estrogens, glucocorticoid agonists/ Antagonist, 11β HSD- 1 inhibitor, SCD-1 inhibitor, lipase inhibitor, fatty acid transporter inhibitor, dicarboxylic acid transporter inhibitor, glucose transporter inhibitor, acid ester transporter inhibitor, antidiabetic agent, antihypertensive Agents, anti-lipidemia agents, DPP-IV inhibitors, apolipoprotein-Β secretion/microsomal triglyceride transfer protein (apo-B/MTP) inhibitors, sympathomimetic agonists, dopamine agonists, promotion Melanocyte hormone receptor analogue, melanin-concentrating hormone antagonist, leptin, galanin receptor antagonist, ruthenium peptide agonist, neuropeptide-Y antagonist, thyroxine agent, dehydroepiandrosterone , Dehydroepiandrosterone analogue, urocortin-binding protein antagonist, glucagon-like peptide-1 receptor 141543.doc -19- 201016705 agonist, human guinea pig-associated protein (AGRP), neurotransmitter U receptor agonist, norepinephrine-induced anorectic agent, appetite suppressant, hormone-sensitive lipase antagonist, MSH-receptor analog, alpha-glucosidase inhibitor, apo A1 milano reverse cholesterol transport Inhibitor Inhibitors of fatty acid binding protein (FABP), and fatty acid transporter protein inhibitors (FATP). In a preferred embodiment, the invention relates to a composition wherein at least one other therapeutic agent is selected from the group consisting of HMG CoA reductase inhibitors consisting of lovastatin, simvastatin ), pravastatin, atorvastatin, fluvastatin, cerivastatin, rivastatin, rosuvastatin calcium, and Pitastatin (pitavastatin). In a particularly preferred embodiment, the invention is directed to a composition wherein at least one other therapeutic agent is simvastatin. In another preferred embodiment, the invention is directed to a composition wherein at least one other therapeutic agent is a cholesterol ester transfer protein inhibitor. In another preferred embodiment, the invention relates to a composition wherein the cholesteryl ester transfer protein inhibitor is torcetrapib. In another preferred embodiment, the invention relates to a composition wherein at least one other therapeutic agent is Vytorin®, ezetimibe, aspirin, ibuprofen or acetaminophen or a combination thereof. In another preferred embodiment, the invention relates to a composition wherein at least one other therapeutic agent is a DPP-IV inhibitor or a GLP-1 mimetic. Non-limiting examples of compounds of formula I are shown in Table 1 below: 141543.doc • 20· 201016705 Table 1 Compound Number Structure 2

3

F

141543.doc -21 - 201016705

141543.doc -22- 201016705

141543.doc -23- 201016705

17 18 19 Table 1 shows the structure of representative compounds of the present invention. The tables and the compounds therein are not intended or should be construed as limiting the invention in any way. It should be understood that 'unless otherwise stated', the following terms used throughout the above and throughout this disclosure have the following meanings: "Patient j encompasses both humans and animals. "Mammalian" means humans and other mammals. The alkyl group may be a linear or branched aliphatic hydrocarbon group having from about one to about 20 carbon atoms in the chain. Preferred alkyl chains contain from about 1 to about 12 carbon atoms. More preferably, the alkyl chain contains from about one to about six carbon atoms. Branched means that one or more lower alkyl groups are attached to the straight chain alkyl group, such as methyl, ethyl or propyl. "Lower alkyl" means a group having from about 1 to about 6 carbon atoms in a straight or branched chain. "Calcinary 141543.doc •24-201016705" may be unsubstituted or substituted by one or more substituents which may be the same or different, and each substituent is independently selected from the group consisting of halogen, alkyl , aryl, cycloalkyl, cyano, hydroxy, alkoxy, alkylthio, amine, hydrazine (eg, =N_OH), -NH(alkyl), _NH(cycloalkyl), -N (burning Base) 2, -OC(O). Affiliation, _〇_c(〇)·aryl, _〇_c(〇)_cycloalkyl, carboxyl and _c(o)o-alkyl. Non-limiting examples of suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl and tert-butyl. "Alkenyl" means an aliphatic hydrocarbon group containing at least one carbon-carbon double bond and which may be straight or branched and comprising from about 2 to about 15 carbon atoms in the chain. Preferably, the alkenyl chain has from about 2 to about 12 carbon atoms; and more preferably from about 2 to about 6 carbon atoms in the bond. Branched means that the straight-chain alkenyl group is bonded to one or more lower alkyl groups such as methyl, ethyl or propyl. "Low carbon number thiol" means a group having from about 2 to about 6 carbon atoms in a straight or branched chain. "Alkenyl" may be unsubstituted or optionally substituted with one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of: i, alkyl, aryl, naphthenic Base, cyano, alkoxy and -S(alkyl). Non-limiting examples of suitable alkenyl groups include ethenyl, propenyl, n-butenyl, 3-mercaptobut-2-enyl, n-pentenyl, octenyl and decenyl. "Alkyl" means a difunctional group obtained by removing a hydrogen atom from an alkyl group as defined above. Non-limiting examples of alkylene groups include methylene, ethyl and propyl. "Alkynyl j means an aliphatic smog group containing at least one carbon-carbon triple bond and which may be straight or branched and comprising from about 2 to about 15 carbon atoms in the chain. 141543.doc -25- 201016705 Preferably, the block has from about 2 to about 12 carbon atoms in the bond; more preferably from about 2 to about 4 carbon atoms in the chain. Branched means that the bond alkynyl is attached - or a plurality of lower A C number alkyl group such as a decyl group, an ethyl group or a propyl group. A "low carbon number alkynyl group" means a group having from about 2 to about a cap carbon atom in a linear or branched chain. Non-limiting examples of alkynyl groups include an ethyl group, a propynyl group, a 2-butanyl group, and a 3-methyl-butyl group. The "alkynyl group" may be unsubstituted or optionally substituted with one or more substituents which may be the same or different, and each substituent (4) is independently selected from the group consisting of an alkyl group, an aryl group and a cycloalkyl group. "Aryl" means an aromatic monocyclic or polycyclic ring comprising from about 6 to about 14 carbon atoms, preferably from about 6 to about carbon atoms. [Aryl can be used as desired - or multiple "Ring system substituents" which are the same or different and are as defined herein are substituted. Non-limiting examples of suitable aryl groups include phenyl and naphthyl. "Heteroaryl" means an aromatic monocyclic or polycyclic ring system comprising from about 5 to about 14 ring atoms, preferably from about 5 to about 1 ring atom, wherein one or more ring atom systems An element other than carbon 'for example, only nitrogen, oxygen or sulfur or a group thereof. Preferred heteroaryl groups contain from about 5 to about 6 ring atoms. "Heteroaryl" may be substituted, if desired, with one or more ring system substituents which may be the same or different and are as defined herein. The prefix aza, oxa or thia before the heteroaryl root means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. The nitrogen atom of the heteroaryl group can be oxidized to the corresponding ruthenium oxide as needed. "Heteroaryl" may also contain a heteroaryl group as defined above fused to an aryl group as defined above. Non-limiting examples of suitable heteroaryl groups include pyridyl, pyrazinylfuranyl, thienyl, pyrimidinyl, pyridone (including fluorene-substituted pyridone), isoxazolyl, isothiazolyl, oxazolyl , thiazolyl, pyrazole 141543.doc -26· 201016705 base, furazyl, pyrrolyl, pyrazolyl, triazolyl, thiadiazolyl, "pyrazinyl, pyridazinyl, quinoxalinyl, Pyridazinyl, hydroxydecyl imidazo[1'2-aPpyridyl, imidazolium]thiazolyl, benzofurazinyl, fluorenyl, azaindolyl, benzimidazolyl, Benzothiophenyl, quinolyl, imidazolyl, thienopyridinyl, quinazolinyl, thienopyrimidinyl, "biquinazolidinyl, imidazolyl, isoquinolinyl, benzoic The term "heteroaryl-yl" also refers to a partially saturated heteroaryl moiety, such as, for example, tetrahydroisoquinoline. A phenyl group, a tetrahydroquinolyl group, and the like. "Aralkyl" or "arylalkyl" means an aryl-alkyl- group in which both an aryl group and an alkyl group are as previously described. Preferred aralkyl groups include lower alkyl groups. Non-limiting examples of suitable aralkyl groups include benzyl, 2-phenethyl and naphthylmethyl. The bond to the parent moiety is achieved via an alkyl group. "Alkylaryl" means an alkyl-aryl- group in which both an alkyl group and an aryl group are as defined above. Preferred alkylaryl groups include lower alkyl groups. A non-limiting example of a suitable alkyl aryl group is fluorenylphenyl. The bond to the parent moiety is achieved via an aryl group. -Cycloalkyl" means a non-aromatic monocyclic or polycyclic ring system comprising from about 3 to about 1 carbon atoms, preferably about 5 i about 1 G carbon atoms. Preferably, the cycloalkyl ring contains from about 5 to about 7 ring atoms. A non-limiting example of a cycloalkyl group which may be substituted by a "ring system substituent" which may be the same or different and is as defined above, and optionally a single J-like cycloalkyl group, may include a cyclopropyl group or a cyclopentyl group. Cyclohexyl, cycloheptyl and the like. Examples of non-cyclic ring alkyl groups suitable for polycyclic cycloalkyl groups include the naphthalene group, the reduced alkyl group, the gold steel base, and the like 141543.doc • 27- 201016705. "Cycloalkyl" means a cycloalkyl moiety as defined above attached to the parent core via an alkyl moiety (as defined above). Non-limiting examples of suitable cycloalkylalkyl groups include cyclohexylmethyl, gold alkyl sulfonyl and the like. "Cycloalkenyl" means a non-aromatic monocyclic or polycyclic ring comprising from about 3 to about 1 carbon atoms, preferably from about 5 to about 10 carbon atoms, containing at least one carbon-carbon double bond. Ring system. Preferred cycloalkenyl rings contain from about 5 to about 7 ring atoms. The cycloalkenyl group may be optionally substituted by one or more "ring system substituents" which may be the same or different and are as defined above. Non-limiting examples of suitable monocyclic cycloalkenyl groups include cyclopentenyl, cyclohexenyl, cycloheptadienyl and the like. A non-limiting example of a suitable polycyclic cycloalkenyl group is a norbornenyl group. "Cycloalkenylalkyl" means a cycloalkenyl moiety as defined above attached to the parent nucleus via an alkyl moiety (as defined above). Non-limiting examples of suitable cycloalkenylalkyl groups include cyclopentenyl indenyl, cyclohexenyl indenyl, and the like. "Heteroalkyl" means an alkyl moiety as defined above which is heteroatomically selected from the group consisting of ruthenium and 8 or a hetero group selected from the group consisting of NH and N-alkyl. Non-limiting examples of suitable heteroalkyl groups include ch3-o-ch2-.ch3ch2-o-ch2.. ch3-ch2.s-ch2-. CH3-CH2-NH-CH2-CH2-, CH3-CH2-N ( Et)_CH2-CH2· (where Et means CH3-CH2-) and the like. "Halogen" means fluorine, gas, bromine or iodine. Preferred are fluorine, gas and odor. "Ring system substituent" means attached to an aromatic or non-aromatic ring system and 141543.doc -28. 201016705 (for example) replaces a substituent which may utilize hydrogen on the ring system. The ring system substituents may be the same or different 'each of which is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, alkylaryl, heteroaromatic , heteroarylalkenyl, heteroarylalkynyl, alkylheteroaryl, thiol, hydroxyalkyl, alkoxy, aryloxy, aralkyloxy, fluorenyl, aryl fluorenyl, halogen, nitrate Base, cyano group, carboxyl group, alkoxycarbonyl group, aryloxycarbonyl group, aralkyloxycarbonyl group, alkylsulfonyl group, arylsulfonyl group, heteroarylsulfonyl group, _alkylthio group, arylthio group , heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkyl, heterocyclic, -oc(o)-alkyl, _〇·(:(〇)_aryl,_0 C(0 )_cycloalkyl, pendant oxy, -C(=N-CN)_NH2, -C(=NH)-NH2, -C(=NH)-NH(alkyl), (for example, =N_OH), UN., hn•院基_, YJAC^O)-, and -SC^NYJ, wherein 1 and 丫2 may be the same or different and independently selected from the group consisting of hydrogen, alkyl, aryl, ring Alkyl and aralkyl groups. "Ring system substituent" may also mean replacing a single portion of two available hydrogens (one h on each carbon) on two adjacent carbon atoms in the ring system. Examples of this moiety are formed, for example, of the following portions of a methylenedioxy group, an ethylenedioxy group, a _C(CH3)2, and the like.

"Heteroarylalkyl" means a heteroaryl moiety as defined above attached to the parent core via an alkyl moiety (as defined above). Suitable non-limiting examples include 2 "bitergic methyl, benzyl, and the like. 141543.doc -29-201016705 heterocyclyl" is meant to include from about 3 to about 1 〇 ring atoms, preferably about a non-aromatic saturated monocyclic or polycyclic ring of 5 to about 10 ring atoms, wherein one or more of the atoms in the mysterious ring system are elements other than carbon, such as only nitrogen, oxygen or sulfur or a combination thereof. . There are no adjacent oxygen and/or sulfur atoms in the ring system. Preferred heterocyclic groups contain from about 5 to about 6 ring atoms. The oxa or thia before the heterocyclyl radical means at least a nitrogen, oxygen or sulfur atom respectively. Any of the heterocyclyl rings -NH may exist in a protected form in the presence of a prefix aza or an oxygen ring atom. Such protections exist, for example, in the form of -N(Boc), _N(CBz), _N(T〇s) groups, and the like; such protections are also considered to be part of the present invention. The heterocyclyl can be substituted, if desired, with one or more "ring system substituents" which may be the same or different and are as defined herein. The nitrogen or sulfur atom of the heterocyclic group can be optionally oxidized to the corresponding N-oxide, S-oxide or 8,8-dioxide. Non-limiting examples of suitable monocyclic heterocyclyl rings include hexahydropyridyl, pyrrolidinyl, hexahydropyrazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl , tetrahydrofuranyl, tetrahydrothiophenyl, indoleamine, internal vinegar, and the like. "Heterocyclyl" may also mean the simultaneous replacement of a single moiety of two available hydrogens on the same carbon atom of the ring system (eg, a carbonyl group)

"Heterocyclylalkyl" means a heterocyclyl moiety as defined above attached to the parent nucleus via an alkyl moiety (as defined above). Suitable non-limiting examples of heterocyclyl alkane 141543.doc -30- 201016705 include hexahydro dimethyl hexyl chloride, hexachloro phthalate, and the like. Soil "heterocyclenyl" is meant to include 3 to about 1 ring atom, preferably about 5 to about H) ring atoms (wherein one or more atomic systems in the ring system are free of carbon #70, such as only nitrogen, oxygen or sulfur atoms or A combination thereof) and a non-aromatic monocyclic or polycyclic ring system containing at least one (four) carbon double bond or carbon nitrogen double bond. There are no oxygen and/or sulfur atoms in the ring system. Preferably, the heterocyclic ring of the anthracene ring contains from about (10) to about 6 ring atoms. The arsenic, oxa or thia before the hetero-base radical means that at least a nitrogen, oxygen or sulfur atom respectively exists as a ring atom. The heterocyclic dilute group may be subjected to - or a plurality of (four) substituents, wherein t. wherein the ring system substituent is as defined in the text, the nitrogen or sulfur atom of the heterocyclic group may be oxidized to the corresponding N•oxide as needed. , 1 oxide or S, S-dioxide 1 is suitable for heterocyclic alkenyl group, non-sealed tetrachloro fluorenyl group, ^ two gas ratio bite base ... · two gas 吼 bit base, two rntV:, 5, 6 - tetrahydrogen-density base, 2, lenyl, 3 - yl group, small sitting base, 2_° ratio (tetra), dihydromi. Sit-base, di(tetra)yl: - fluorenyl, hydrazino, dihydro(tetra)yl, 3,4_digas (10), decyl, dihydro oxime, fluorodihydro phlegm, 7; IMA ring [2.2.1] heptyl, -sulfurylthio, -hydrogenthiopyranyl and the like. "Miscellaneous" means simultaneously replacing two bases on the same carbon atom in the ring system. Part (for example, carbonyl). An example of this part is the single (pyrrolidinone) of the wind: & D than the Luodian network 141543.doc -31- 201016705

"Heterocyclenylalkyl" means a heterocycloalkenyl moiety as defined above attached to the parent nucleus via an alkyl moiety (as defined above). It should be noted that in the hetero atom-containing ring system of the present invention, no hydroxyl group is present on a carbon atom adjacent to n, oxime or s, and no N or S group is present on the carbon adjacent to the other hetero atom. So, for example, in the ring:

There is no _〇H on the carbon directly attached to the labels 2 and 5. It should also be noted that the tautomeric forms are considered to be, for example, the following in some embodiments of the invention:

quite. "Alkynylalkyl" means an alkynyl-thingyl- group in which both alkynyl and alkyl are as defined above. Preferably, the alkynylalkyl group contains a lower alkynyl group and a lower alkyl group. The bond to the parent moiety is achieved via an alkyl group. Non-limiting examples of suitable alkynylalkyl groups include propargylmethyl. "Heteroaralkyl" means a heteroaryl-alkyl- group in which the heteroaryl and alkyl are as defined above. Preferred heteroaralkyl groups contain a lower alkyl group. Non-limiting examples of suitable pharmaceutically acceptable bases include the dimethyl group and the quinone-3-ylmethyl group. 141543.doc 201016705 The bond to the parent moiety is achieved via an alkyl group. "Hydroxyalkyl" means an HO-alkyl- group in which the alkyl group is as defined above. Preferred hydroxyalkyl groups contain a lower alkyl group. Non-limiting examples of suitable hydroxyalkyl groups include hydroxyindenyl and 2-hydroxyethyl. "Alkyl" means an H-C(O)-, alkyl-C(O)- or cycloalkyl-C(0)- group in which each group is as previously described. The bond to the parent moiety is achieved via a carbonyl group. Preferred thiol groups contain a lower alkyl group. Non-limiting examples of suitable thiol groups include formazan, ethyl hydrazide and propyl fluorenyl. "Aryl group" means an aryl-C(O)- group in which the aryl group is as described above. The bond to the parent moiety is achieved via a carbonyl group. Non-limiting examples of suitable groups include benzamidine and 1-naphthylquinone. "Alkoxy" means an alkyl-oxy- group wherein the alkyl group is as described above. Non-limiting examples of suitable alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. The bond to the parent moiety is achieved via ether oxygen. "Aryloxy" means an aryl-fluorene- group in which the aryl group is as defined above. Non-limiting examples of suitable aryloxy groups include phenoxy and naphthyloxy. The bond to the parent moiety is achieved via ether oxygen. "Aralkyloxy" means an aralkyl-0- group in which the aralkyl group is as defined above. Non-limiting examples of suitable aralkyloxy groups include benzyloxy and 1- or 2-naphthylmethoxy. The bond to the parent moiety is achieved via ether oxygen. "Alkylthio" means an alkyl-S- group in which the alkyl group is as defined above. Non-limiting examples of suitable alkylthio groups include sulfonylthio and ethylthio. The bond to the parent moiety is achieved via sulfur. 141543.doc -33- 201016705 "Arylthio" means an aryl-s- group in which the aryl group is as previously described. Non-limiting examples of suitable arylthio groups include phenylthio and naphthylthio. The bond to the parent moiety is achieved via sulfur. "Aralkylthio" means an aralkyl-s- group in which the aralkyl group is as defined above. A non-limiting example of a suitable aralkylthio group is benzylthio. The bond to the parent moiety is achieved via sulfur. "Alkoxycarbonyl" means an alkyl-o-co- group. Non-limiting examples of suitable alkoxycarbonyl groups include methoxycarbonyl and ethoxycarbonyl. The bond to the parent moiety is achieved via a carbonyl group. "Aryloxycarbonyl" means an aryl-O-C(o)- group. Non-limiting examples of suitable aryloxycarbonyl groups include phenoxycarbonyl and naphthyloxycarbonyl. The bond to the parent moiety is achieved via a carbonyl group. "Aralkoxycarbonyl" means an aralkyl-o-c(o)- group. A non-limiting example of a suitable aralkyloxycarbonyl group is benzyloxycarbonyl. The bond to the parent moiety is achieved via a carbonyl group. "Alkylsulfonyl" means an alkyl-s(o2)- group. Preferred groups are those in which the alkyl group is a lower alkyl group. The bond to the parent moiety is achieved via a sulfonyl group. "Arylsulfonyl" means an aryl-s(o2)- group. The bond to the parent moiety is achieved via a sulfonyl group. The term "substituted" means that one or more hydrogen atoms on a given atom are substituted with a group selected from the specified group, with the proviso that the normal valence of the specified atom in the prior art is not exceeded and the substitution forms a stable compound. The combination of substituents and/or variables is only available if the combination produces a stable compound. 141543.doc -34- 201016705 "Stable compound" or "stable structure" means a compound that is robust enough to withstand separation from a reaction mixture to a useful level of purity and formulated into an effective therapeutic agent. The term "optionally substituted" means an optional substitution carried out using a specified group, functional group or moiety. The term "purified," "in purified form," or "in isolated and purified form" with respect to a compound refers to the physical state of the compound after separation from a synthetic process (e.g., from a reaction mixture), 0 or a natural source, or a combination thereof. Thus, the terms "purified," "in purified form," or "in isolated and purified form" refer to a process from a purification process or as described herein or well known to those skilled in the art (eg, chromatography, re The physical state of the compound after crystallization and the like is obtained in a purity sufficient to be characterized by standard analytical techniques as described herein or well known to those skilled in the art. The compound of formula I can be purified to a degree suitable for use as a pharmaceutically active substance. That is, the compound of formula I may have a purity of 95 wt% or more (excluding an adjuvant such as a pharmaceutically acceptable carrier, solvent, etc., which are used to formulate a compound of formula I to a suitable amount) For the usual form of administration to patients, such as pills, capsules, IV solutions, etc.). The purity may be 97 wt% or higher, or 99 wt% or higher. The purified hydrazine compound comprises a single isomer having a purity of (as described above) of 95 wt% or more, 97 wt% or more, or 99 wt% or more (as described above). Additionally, the purified compound of formula I may comprise a mixture of isomers, each isomeric having the structure of formula I, wherein the impurities (ie, compounds or other contaminants, do not comprise as described above) The amount of the agent is 5 wt% or 141543.doc -35. 201016705 is less, 3 wt% or less, or 1 wt ° / 〇 or less. For example, the purified compound of formula I can be an isomeric mixture of compounds of structure (I) wherein the ratio of the amounts of the two isomers is about 1:1 and the two are equally divided The combined amount of isomers is 95 wt% or higher, 97 wt% or higher, or 99 wt% or higher. It should also be noted that any carbon atom having an unsaturation valence and a hetero atom in the text, reaction schemes, examples, and tables herein are assumed to have a sufficient number of hydrogen atoms to saturate the valence. When a functional group in a compound is referred to as "protected," it is meant that the group is in a modified form to avoid undesired side reactions at the protected site when the compound is involved in the reaction. Suitable protecting groups can be those skilled in the art and can be referred to standard textbooks (e.g., T. W. Greene et al., Protective Groups in organic Synthesis (1991), Wiley, New York). When any variable (e.g., aryl, heterocycle, R2, etc.) occurs in either component or in Formula I more than once, the definition of each occurrence is independent of its definition at every other occurrence. The term "composition" as used herein is intended to cover a product comprising a specified quantity of the specified ingredients, and any product which may be produced directly or indirectly from a combination of specified quantities of the specified ingredients. Prodrugs and solvates of the compounds of the invention are also contemplated herein. A discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (1987) 14, ACS Symposium Series, and Bioreversible Carriers in Drug Design, (1987) Edward B. 141543.doc -36- 201016705

Edited by Roche, American Pharmaceutical Association and Pergamon Press. The term "prodrug" means a compound (e.g., a prodrug) which can be converted in vivo to produce a compound of formula I or a pharmaceutically acceptable salt, hydrate or solvate of the compound. Transformation can be achieved by various mechanisms (e.g., by metabolic or chemical processes), for example, by hydrolysis in blood. A discussion of the use of prodrugs is provided in T. Higuchi and W. Stella, "Pro-drugs as Novel Delivery System," (Vol. 14 of A.C.S Symposium Series) and Bioreversible

Carriers in Drug Design, edited by Edward B. Roche, American Pharmaceutical Association and Pergamon Press (l987). For example, if a compound of formula I or a pharmaceutically acceptable salt, hydrate or solvate of the compound contains a carboxylic acid functional group, the prodrug may comprise replacing the acid group with a group such as: An ester formed by a hydrogen atom: (CVC8) alkyl, (C2-C12) alkanoyl-oxymethyl, 1-(alkylhydrazineoxy)ethyl having 4 to 9 carbon atoms, having 5 to 1-carboyl-1-(alkylhydrargyloxy)-ethyl group having 10 carbon atoms, alkoxycarbonyloxymethyl group having 3 to 6 carbon atoms, 1 to 4 to 7 carbon atoms -(alkoxycarbonyloxy)ethyl, 1-methyl-1-(alkoxycarbonyloxy)ethyl having 5 to 8 carbon atoms, N- having 3 to 9 carbon atoms Alkoxycarbonyl)aminomethyl, 1-(N-(alkoxycarbonyl)amino)ethyl having 4 to 10 carbon atoms, 3-indenyl, 4-crotonyl lactone, γ- Butyrolactone-4-yl, di-NW-CCVCd alkylamino (C2-C3) alkyl (eg β-didecylaminoethyl), amine mercapto-(CVC2) alkyl, anthracene, Ν-bis(CrCd alkylamine-formylalkyl and hexahydropyrido(C2-C3)alkyl, pyrrolidino(C2-C3)alkyl Or morpholine (C2-C3) alkane 141543.doc -37- 201016705 base and the like. Likewise, if the compound of formula I contains an alcohol functional group, the prodrug can be substituted for the hydrogen of the alcohol group by using a group such as the one described below Atom formation: (G-C6) alkanoyloxyindenyl, 1-((Ci-C6) decyloxy)ethyl, 1-methyl-alkylhydrazineoxy)ethyl, (C) -C6) alkoxycarbonyloxymethyl, N_(Ci_C:6)alkoxycarbonylaminomethyl, amber fluorenyl, (Cl_c6)alkyl fluorenyl, α-amino (CrC4) alkyl, aromatic a base group and an α-amino group, or an α-amino group α-amino group, wherein each α-amino group is independently selected from a naturally occurring L-amino acid, hydrazine ( (〇) 2, -P(0) (〇(Cl_C6)alkyl) 2 or a glycosyl group (this group is obtained by removing a hydroxyl group from a hemiacetal form of a carbohydrate) and the like. If a compound of formula I is incorporated into an amine functional group, the prodrug can be formed by substituting a hydrogen atom in the amine group with a group such as R_carbonyl, R〇_, and NRR'-carbonyl (wherein R And R, each independently (Ci_Ci〇)alkyl, (CVC7)cyclodextrin, benzyl, or R-supplemental natural a-aminoindenyl or natural a-aminoindenyl), -C( 0H)C(0)0Y丨 (where γ 丨 is η, (Ci_C6) alkyl or benzyl), -C(OY2)Y3 (where γ2 is (c丨-c4) alkyl and γ3 is (Ci-CJ) Burning base, slow base (CVC6) alkyl group, amine group (C!-C4) yard base or single _; ^ _ or di- Ν, Ν · (CVC6) alkylaminoalkyl), -C (Y4) Y5 (wherein 丫4 is 1^ or methyl and ¥5 is mono-N- or mono-N,N-(C丨-C6) alkylamino, morphinyl, hexahydro-beta ratio or ratio And a compound of the present invention may exist as an unsolvate and a solvate with a pharmaceutically acceptable agent (for example, water, ethanol, and the like), and the present invention is intended Covers solvate and unsolvate forms II 141543.doc -38· 201016705. "Solvate" means this The physical association of a compound with one or more solvent molecules. The physical association involves varying degrees of ionic bonding and covalent bonding (including hydrogen bonding). In some cases, the solvate can be isolated, for example When one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid, the "solvate" encompasses both the solution phase and the solvable solvate. Non-limiting examples of suitable solvates include the ethanolate, methanol. And a solvate wherein the solvent molecule is a solvate of H2o. • One or more compounds of the invention may be converted to a solvate if desired.

The preparation of the compositions is generally known. So, for example, M

Caira et al, J. Pharmaceutical Sci., 93(3), 601-611 (2004) describe the preparation of a solvate of the antifungal fluconazole in ethyl acetate and from water. Similar preparations of solvates, hemisolvates, hydrates and the like are described in E. C. van T〇nder et al, AAPS Pharm SciTech, 5(1), article 12 (2004); and A. L.

Bingham et al., Chem. Commun., 603-604 (2001). A typical φ non-limiting process involves dissolving a compound of the invention in a desired amount of a desired solvent (organic solvent or water or a mixture of both) at ambient temperature and cooling the solution at a rate sufficient to form crystals, and then borrowing The crystals are separated by standard methods. Analytical techniques such as I.R. spectroscopy show the presence of a solvent (or water) in the crystal as a solvate (or hydrate). "Effective amount" or "therapeutically effective amount" is intended to describe the amount of a compound or composition of the invention that is effective to inhibit the above mentioned conditions and thereby produce a desired therapeutic, ameliorating, inhibiting or prophylactic effect. The compounds of formula I can form salts which are also within the scope of the invention. Responsibility 141543.doc -39- 201016705 Solution, unless otherwise stated, the compounds of the formula referred to herein include the salts thereof. The term "salt" as used herein means an acid salt formed using an inorganic acid and/or an organic acid, and a test 1± salt formed using an inorganic test and/or an organic test. In addition, when a compound of formula k contains an assay moiety (such as, but not limited to, a bite or sodium saliva) and an acidic moiety (such as, but not limited to, a slow acid), a zwitterion ("internal salt") is formed and is included in the term as used herein. Within the "salt". Preferred are pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts, although other salts may also be employed. For example, a compound of formula I can be formed by lyophilizing a compound of the formula with an amount (e.g., equivalent) of an acid or base in a medium such as a medium in which the salt can be precipitated or in an aqueous medium, followed by lyophilization. Salt. Exemplary acid addition salts include acetate, ascorbate, benzoate, besylate, hydrogen sulfate, borate, butyrate, citrate, camphorate, camphorsulfonate, fumaric acid Salt, hydrocyanate, hydrobromide, hydrocyanate, lactate, maleate, methanesulfonate, naphthalenesulfonate, nitrate, oxalate, citrate, propionate, water Salicylate, acaproate, sulfate, tartrate, thiocyanate, toluenesulfonate (also known as tosylate) and the like. In addition, acids which are generally considered to be suitable for the formation of pharmaceutically useful salts of self-initiating pharmaceutical compounds are discussed, for example, in P. Stahl et al., Camille G. (eds.) Handbook of Pharmaceutical Salts Properties, Selection and Use (2002). Zurich: Wiley-VCH; S. Berge et al., Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould,

International J. of Pharmaceutics (1986) 33 201-217 ; 141543.doc -40- 201016705

Anderson et al, The Practice of Medicinal Chemistry (1996), Academic Press, New York; and The Orange Book (Food & Drug Administration, Washington, D. C. on its website). The disclosures are hereby incorporated by reference. Exemplary basic salts include ammonium salts, alkali metal salts (eg, sodium, lithium, and potassium salts), soil metal salts (eg, I bow and magnesium salts), and organic tests (eg, organic amines such as dicyclohexylamine, A salt formed by a third-butylamine and a salt formed with an amino acid (for example, arginine, lysine, and the like). The basic nitrogen-containing group can be quaternized using reagents such as low-carbon alkyl halides (eg, 'methyl, ethyl, and butyl vapors, deserts, and hexides), sulphuric acid Esters (eg, dimethyl sulfate, diethyl sulfate, and dibutyl sulfate), long bond halides (eg, 'mercapto, lauryl, and stearyl vapors, bromides, and iodides), aralkyl Halides (for example, bromides of benzyl and phenethyl) and others. For the purposes of the present invention, all such acidic and basic salts are intended to be pharmaceutically acceptable salts within the scope of the invention and all acidic salts and salts are considered equivalent to the free form of the corresponding compound. The pharmaceutically acceptable ester of the compound of the present invention comprises the group: ()) a carboxylic acid ester obtained by esterifying a hydroxyl group, wherein the non-carbonyl moiety of the carboxy group moiety of the ester group is selected from a linear chain or Branched alkyl (eg, ethenyl, n-propyl, tert-butyl or n-butyl), alkoxyalkyl (eg, methoxyindenyl), aralkyl (eg, benzyl) An aryloxyalkyl group (eg, phenoxymethyl), an aryl group (eg, a phenyl group optionally substituted with, for example, a halogen, a Cm alkyl group, or a Cm alkoxy group or an amine group); a sulfonate, such as an alkyl group - or 141543.doc • 41- 201016705 an alkaryl group (eg, 'methyl sulphonate'); (3) an amino acid vinegar (eg, L % amine aryl); (4) sulphuric acid g and (5) single...two- or three-filled acid vinegar. The acid vinegar can be pushed, and further purified, for example, by a ruthenium 1.2 () alcohol or a reactive derivative thereof, or by 2,3-di((:6_24) mercaptoglycerol. The compound of the formula I, and The salts, solvates, vinegars and prodrugs thereof may exist in their tautomeric form (e.g., 'as a guanamine or an imino ether). All such tautomeric forms are contemplated herein as part of the present invention. The sigma can have an asymmetry or a palm center and thus exist as a different stereoisomer. All stereoisomers of the compound of formula j and mixtures thereof (including racemic mixtures) are intended to form In addition, the present invention encompasses all geometric and positional isomers. For example, a compound of the formula I is incorporated into a double bond or a fused ring, and the trans-form and the mixture of the two are included. Within the scope of the present invention, diastereoisomers can be diastereomeric according to methods known to those skilled in the art (e.g., by chromatography and/or fractional crystallization). The isomer mixture is separated into its individual diastereomers. Isomers can be separated by conversion of the enantiomeric mixture to a non-pair by reaction with a suitable optically active compound Φ (for example, a palmitic auxiliary such as palmitol or Mosher). The mixture of the diastereomers separates the diastereomers and converts (eg, hydrolyzes) the individual diastereomers to the corresponding pure enantiomers. Some of the compounds of the same formula can be destabilized. Isomers (e.g., substituted diaryls) are considered to be part of the knife of the present invention. Enantiomers can also be separated by using a pair of palmar Ηριχ columns. 141543.doc -42· 201016705 The compounds of i may also exist in different tautomeric forms, and such forms are encompassed within the scope of the invention. Likewise, for example, all keto-enol and imine-enamine forms of such compounds are included The present invention is a hydrazine (including the salts, solvates, etc. of the compounds)

All stereoisomers of Sl and prodrugs, as well as salts, solvates and esters of such prodrugs (eg, geometric isomers, optical isomers, and the like) (eg, • I, etc. a symmetrical carbon atom, including an enantiomeric form (which may exist even in the absence of an asymmetric carbon atom), a rotating rib form, a stagnation form, and a diastereomeric form All are encompassed within the scope of the invention, and positional isomers (e.g., 4-anthracene and 3-indolyl) are also encompassed within the scope of the invention. (For example, if a compound of the formula is incorporated into a double bond or a fused ring, the cis- and trans-forms, and mixtures thereof, are included within the scope of the invention. Also, by way of example, all ketones of such compounds Both enol and imine-enamine forms are encompassed by the present invention.) Individual stereoisomers of the present invention may, for example, be substantially free of other isomeric species, for example, as exogenous Mix the mixture, or mix with all other or its stereoisomers. The palm center of the present invention may be as defined by IUPAC 1974 Rec〇mmendations. The terms "salt r" "solvate", "vinegar", "prodrug" and the like are intended to be equivalent to the enantiomers, stereoisomers, rotamers, tautomers of the compounds of the invention. Salts, solvates, vinegars and prodrugs of the body, positional isomer, racemate or prodrug. The present invention also encompasses compounds of the present invention labeled with isotopes, except for one or more 141,543.doc • 43- 201016705 atoms, which are replaced by atoms having different atomic mass or mass numbers than those common in nature. The compounds described are identical. Examples of the isotope which may be incorporated in the compound of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and gas, for example, &, 3H, 丨3C, 丨4, respectively. Certain isotopically-labeled compounds of 15N, 丨8〇, 丨7〇, 3丨p, 32p, 35s, 丨咕 and 式 I, such as those using 3H and 丨4C, can be used for compounds and / or matrix tissue distribution analysis. The 氖 (ie 3h) and carbon 14 (ie c) isotopes are particularly preferred for their ease of preparation and detection. In addition, substitution with heavier isotopes such as deuterium (i.e., 2H) may provide certain therapeutic advantages in achieving greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and thus may be preferred in some circumstances. . Isotopically labeled compounds can generally be prepared by substituting an isotopically labeled reagent with a suitable isotopically labeled reagent, in accordance with procedures similar to those disclosed in the various schemes and/or examples below. The present invention is intended to include polymorphic forms of the formula compounds, and polymorphic forms of the salts, solvates, esters and prodrugs of the compounds of formula ι. The compounds of the invention have pharmacological properties; in particular, the compounds of formula Z may be agonists of nicotinic acid receptors. The compound of the formula I of the present invention, or a pharmaceutically acceptable salt, solvate or vinegar thereof, can be used for the treatment of a disease or condition comprising dyslipidemia and metabolic syndrome. Administration of a compound of phantom, or a pharmaceutically acceptable amount thereof, in any suitable form (for example, or in combination with a pharmaceutically acceptable carrier, excipient or diluent in a pharmaceutical composition) according to standard pharmaceutical practice Accepted salt, 141543.doc 201016705 Solvate or ester. A compound, or a pharmaceutically acceptable salt, solvate or ester thereof, may be administered orally or parenterally (including intravenous, intramuscular, intraperitoneal, subcutaneous, rectal or topical routes of administration), or (If so selected) is administered by a combination of one or more of the above methods. A pharmaceutical composition comprising at least one compound of the formula, or a pharmaceutically acceptable salt, solvate, ester, or tautomer thereof, may be in a form suitable for oral administration, such as a tablet, a lozenge , capsules, diamonds, aqueous or oily suspensions, dispersible powders or granules, emulsions, syrups or ugly agents. The oral compositions can be prepared by any conventional pharmaceutical method, and may also contain a sweetener, a bridging agent, a coloring agent, and a preservative. The amount of a compound of Formula 1 administered to a patient, or a pharmaceutically acceptable salt, solvate, vinegar, or tautomer thereof, can be administered by a physician based on the age of the patient and the severity of the response and the condition being treated. Come sure ^. For example. The amount of the compound administered to the patient, or a pharmaceutically acceptable salt, solvate, vinegar, or tautomer thereof, may range from about 〇i mg/kg body weight/day to about 60 __ between. In one embodiment, the amount is from about 〇5 mg/kg/d to about 4 〇 mg/kg/d. In another embodiment, this amount (K5 mg/kg/d to about 1 mg/kg/d. In another embodiment this amount is from about 丄mg/kg/d to about 5 mg/kg/d. In yet another embodiment, the amount is from about _ to about 3 cans g/d. In a particular embodiment, the amount is about i ^ g/d. In another embodiment, the amount is About 3 mg/kg/d. In another particular embodiment 'this amount is about 5 mg/kg/d. In another particular embodiment, this amount is about 7 mg/kgm - in a particular embodiment, this amount is about 10 mg/kg/d. 141543.doc -45- 201016705 The compound of formula i, or a pharmaceutically acceptable salt, solvate or pharmaceutically acceptable salt thereof, may also be administered in combination with other therapeutic agents. One or more compounds of formula I or a pharmaceutically acceptable salt, solvate or ester thereof may be administered together with one or more other active ingredients selected from the group consisting of hydroxy substituted azetidinone Compound, substituted β-indoleamine compound, HMG CoA reductase inhibitor compound, HMG CoA synthetase inhibitor, squalene synthesis inhibitor, squalene epoxidase inhibitor, sterol biosynthesis inhibitor Final acid derivative, bile acid sequestrant, inorganic cholesterol chelating agent, sulfhydryl-based CoA: cholesterol Ο-hydrazinotransferase inhibitor, cholesteryl ester transfer protein inhibitor, fish oil containing ω3 fatty acid, natural water-soluble fiber, plant stay Fatty acid esters of alkanols and/or plant alkanols, antioxidants, PPAR alpha agonists, PPAR gamma-agonists, FXR receptor modulators, LXR receptor agonists, lipoprotein synthesis inhibitors, renin vascular stress Inhibitors, microsomal triglyceride transporter inhibitors, bile acid reuptake inhibitors, PPAR δ agonists, triglyceride synthesis inhibitors, squalene epoxidase inhibitors, low density lipoprotein receptors Inducer or activator, platelet aggregation inhibitor, 5-LO or FLAP inhibitor, PPAR δ partial agonist, acid or acid receptor agonist, 5 ΗΤ transporter inhibitor, ΝΕ transporter inhibitor, CB! Antagonist/Inverse agonist, ghrelin antagonist, Η3 antagonist/inverse agonist, MCH1R antagonist, MCH2R agonist/antagonist, ΝΡΥ1 antagonist, ΝΡΥ5 antagonist, ΝΡΥ2 agonist, ΝΡΥ4 Agonists, mGluR5 antagonists, lipoproteins, lipoprotein agonists/modulators, lipoprotein derivatives, tyrosin antagonists, chytridin receptor antagonists, BRS3 agonists, CCK-A agonists, CNTF, CNTF derivative 141543.doc • 46- 201016705 Biological, CNTF agonist/continued ctTm P agent, 5HT2c agonist, Mc4r agonist, monoamine reuptake inhibitor, serotonin reuptake inhibitor, glim, GLP- 1 agonist, GUm mimetic, phentermine, tropine, plant drug compound 57, ghrelin antibody, Μ agonist, ACC inhibitor, p3 agonist, DGAT1 inhibitor, DGAT2 inhibitor, FAS inhibitor , Inhibitors, thyroid hormone beta agonists, UCIM activators, UCP-2 activators UCP-3 activators, conjugated estrogens, glucocorticoid agonists / φ antagonists, 11β HSIM inhibitors, SCD] Inhibitors, lipase inhibitors, fatty acid transporter inhibitors, bis-acid transporter inhibitors, glucose transporter inhibitors, vinegar transporter inhibitors, antidiabetic agents, antihypertensive agents, anti-lipidemia agents Dp receptor antagonist Agent, apolipoprotein-B secretion/microsomal triglyceride transfer protein B/MTP) inhibitor, sympathomimetic agonist, dopamine agonist, melanocyte stimulating hormone receptor analog, melanin aggregation hormone antagonist , galanin receptor antagonist, purine peptide agonist, neuropeptide γ agonist sputum, thyroxine agent, dehydroepiandrosterone, dehydroepiandrosterone analog, urocortin-binding protein antagonism Agent, glucagon-like peptide 丨 丨 receptor agonist, human guinea pig-associated protein (AGRP), neuromedin 〇 receptor agonist, norepinephrine-induced anorectic agent, appetite suppressant, Hormone sensitive lipase antagonists, MSH_receptor analogs, alpha-glucosidase inhibitors, apo A1 milano reverse cholesterol transport inhibitors, fatty acid binding protein inhibitors (FABP) and fatty acid transporter inhibitors (FATP). Non-limiting examples of hydroxy-substituted azetidinone compounds and substituted β-indoleamine compounds used in combination with the nicotinic acid receptor agonists of the invention are disclosed in 141543.doc-47-201016705 U.S. Patent Nos. 5,767,115, 5,624,920, 5,668,990, 5,656,624 and 5,688,787, 5,756,470, U.S. Patent Application Nos. 2002/0137690 and 2002/0137689, and PCT patents. The application WO 2002/066464 (the entire contents of each of which is incorporated herein by reference). A preferred azetidinone compound is ezetimibe (e.g., ZETIA® available from Schering-Plough Corporation). A non-limiting example of a HMG CoA reductase inhibitor compound for use in combination with a nicotinic acid receptor agonist of the invention is lovastatin (e.g., MEVACOR® from Merck & Co.), simvastatin (e.g. , purchased from Merck & Co. (ZOCOR®), pravastatin (for example, PRAVACHOL® from Bristol Meyers Squibb), atorvastatin (for example, LIPITOR® from Pfizer), fluvastatin, Xi Li Rutastatin, CI-981, rivastatin (7-(4-fluorophenyl)-2,6-diisopropyl-5-decyloxydecylpyridin-3-yl)-3,5-dihydroxy -6-heptanoate calcium, rosuvastatin calcium (CRESTOR® from AstraZeneca Pharmaceuticals), pita statin (eg, NK-104, Negma Kowa, Japan). A non-limiting example of an HMG CoA synthetase inhibitor for use in combination with a nicotinic acid receptor agonist of the invention is, for example, (hydroxy-methyl)-4.-sideoxy-2'R-oxacyclobutane Base]-3,5,7R-trimethyl-2,4-undecylene diacid). A non-limiting example of a squalor thin synthetic inhibitor for use in combination with an acid-receptor agonist of the present invention is, for example, squalene 1. A non-limiting example of an inhibitor of keratin epoxide 141543.doc -48- 201016705 in combination with a nicotinic acid receptor agonist of the invention is, for example, NB-598 hydrochloride ((E)-N-B Base-N-(6,6-dimethyl-2-hept-4-ynyl)-3-[(3,3'-and thiophen-5-yl)methoxy]benzene-methylamine). A non-limiting example of a sterol biosynthesis inhibitor for use in combination with a nicotinic acid receptor agonist of the invention is, for example, DMP-565. A nicotinic acid derivative for use in combination with a nicotinic acid receptor agonist of the invention (for example, a compound comprising a pyridine-3-phthalate structure or a pyrazine-2-furoate structure, comprising an acid form, a salt, Non-limiting examples of esters, zwitterions and tautomers are niceritrol, nicofuranose and acipimox (5-methyl D than 嗓-2) - formic acid 4-oxide). A non-limiting example of a bile acid sequestrant for use in combination with a nicotinic acid receptor agonist of the invention is cholestyramine (a styrene-diethylene containing a quaternary ammonium cationic group capable of binding bile acids) a benzene copolymer, such as QUESTRAN® or QUESTRAN LIGHT® from Bristol-Myers Squibb, colestipol (diethyltriamine and 1-chloro-2,3-epoxy) Copolymers of propane, such as COLESTID® tablets from Pharmacia), colesevelam hydrochioride (for example, WelChol® tablets from Sankyo (poly(allylamine hydroformate)), used in rings Oxygenpropane cross-links and is alkylated with 1-bromodecane and (6-bromohexyl)-trimethyl bromide), water-soluble derivatives (eg 3,3-ionene, N-(naphthenes) Alkylamines and polyglucamides, insoluble quaternized polystyrenes, saponins, and mixtures thereof. A non-limiting example of an inorganic cholesterol chelating agent for use in combination with a nicotinic acid receptor agonist of the invention is salicylic acid plus montmorillonite clay, aluminum hydroxide 141543.doc -49- 201016705 and calcium carbonate antacid . A non-limiting example of a thiol-CoA:cholesterol-hydrazinotransferase ("ACAT") inhibitor used in combination with a nicotinic acid receptor agonist of the invention is avasimibe ([[2, 4,6-indole (1-mercaptoethyl)phenyl]ethinyl]aminosulfonic acid, 2,6-bis(1-methylethyl)phenyl ester, previously referred to as CI-1011), HL-004, lecimibide (DuP-128) and CL-277082 (N-(2,4-difluorophenyl)-N-[[4-(2,2-dimethylpropyl)) Phenyl] indenyl]-N-heptyl-urea), and P. Chang et al., "Current, New and Future Treatments in Dyslipidaemia and Atherosclerosis", Drugs, July 2000; 60(1); 55-93 Compounds (which are incorporated herein by reference). Non-limiting examples of cholesterol ester transfer protein ("CETP") inhibitors for use in combination with a nicotinic acid receptor agonist of the invention are disclosed in the following: PCT Patent Application No. WO 00/38721, U.S. Patent Nos. 6,147,090, 6,958,346, 6,924,313, 6,609,082, 6,861,561, 6,803,388, 6,794,396, 6,787,570, 6,753,346, 6,723,752, 6,723,753, 6,710,089, No. 6,699,898, 6,696,472, 6,696,435, 6,683,113, 5,519,001, 5,512,548, 6,410,022, 6,426,365, 6,448,295, 6,387,929, 6,683,099, 6,677,382, Nos. 6,677,380, 6,677,379, 6,677,375, 6,677,353, 6,677,341, 6,605,624, 6,586,433, 6,451,830, 6,451,823, 6,462,092, 6,458,849, 141543.doc -50- 201016705

6,458,803, 6,455,519, 6,583,183, 6,562,976, 6,555,113, 6,544,974, 6,521,607, 6,489,366, 6,482,862, 6,479,552, 6,476,075, 6,476,057 and No. 6,897,317 (hereby incorporated by reference herein in its entirety herein in its entirety in its entirety in the the the the the the the the the the the the the the the the the the the Letters, Vol. 6, No. 7, 1996, pp. 919-922 (incorporated herein by reference); the natural products set forth below: S. Co val et al., "Wiedendiol-A and -B , Cholesteryl Ester Transfer Protein Inhibitors From The Marine Sponge Xestosponga Wiedenmayeri", Bioorganic & Medicinal Chemistry Letter, Vol. 5, No. 6, pp. 605-610, 1995 (which is incorporated herein by reference); Compounds in Barrett et al. J. Am. Chem. Soc_, 18 8, 7863-63 (1996) (hermby incorporated by reference); Compounds of the following: Kuo et al. J. Am. Chem. Soc., 117, 10629-34 (1995) (hereby incorporated by reference); Chem. Lett. 6, 1 95 1-54 (1996) (which is incorporated herein by reference); the disclosure of which is hereby incorporated by reference to: Incorporated herein by reference;; the compounds set forth below: Busch et al. Lipids, 25, 216-220, (1990) (which is incorporated herein by reference); the compounds set forth in the following: Morton and Zilversmit J. Lipid Res., 35, 836-47 (1982) (hereby incorporated by reference, 141, 543. , 42-47 (1996) (which is incorporated herein by reference); the compound set forth in the following: Bisgaier et al. Lipids, 29, 81 1-8 (1994) (which is incorporated herein by reference); a compound described in European Patent No. 818, 448, which is incorporated herein by reference; Compounds of the type disclosed in the following: PCT Application Nos. WO 98/35937, WO 9914174, WO 9839299, and WO 9914215, each incorporated herein by reference. a compound in the European application EP 796846, EP 801060, 818448, and 81 8197 (each incorporated herein by reference); probucol or a derivative thereof (eg AGI-1067) And other derivatives disclosed in U.S. Pat. , which is an imidazolidinyl-pyrimidine derivative that directly stimulates LDL receptor activity, as described in M. Huettinger et al., "Hypolipidemic activity of HOE-402 is Mediated by Stimulation of the LDL Receptor Pathway", Arterioscler. Thromb. 1993; 13:1005-12, which is incorporated herein by reference); 4-carboxyamino-2-substituted-1,2,3,4-tetrahydroquinoline (eg, Toperp, described in WO 00 /017164, WO 00/017166, WO 00/140190, WO 0 0/213797, and WO 2005/033082 (each incorporated herein by reference). Tochap can be combined with an HMG-CoA reductase inhibitor (eg, atorvastatin) (WO 00/213 797, WO 2004/056358, WO 2004/056359, and WO 2005/01 1634) ° 141543.doc -52- 201016705 A non-limiting example of a fish oil containing an omega 3 fatty acid for use in combination with a nicotinic acid receptor agonist of the invention is 3-PUFA. Non-limiting examples of GLP-1 mimetics for use in combination with a nicotinic acid receptor agonist of the invention comprise insulin secretagogue-3, insulin secretagogue-4, Byetta-exenatide, benefit Liraglutinide, CJC-1131 (ConjuChem), 依泽那太-1^11(八11^1111), 81]^-51077 (Ipsen/LaRoche) 'ZP-10 (Zealand Pharmaceuticals)' and revealed in International Publication No. WO 00/0761 No. 7 compound. Non-limiting examples of natural water soluble fibers for use in combination with the nicotinic acid receptor agonists of the present invention are valerian, coca, oat and pectin. A non-limiting example of a fatty acid ester of a plant-sparanol and/or a plant-salkanol used in combination with a nicotinic acid receptor agonist of the invention is a dihydrocolumyl alcohol ester in BENECOL® margarine. A non-limiting example of an antioxidant for use in combination with a nicotinic acid receptor agonist of the invention comprises probucol. Non-limiting examples of PPAR alpha agonists for use in combination with a nicotinic acid receptor agonist of the invention include becloHbrate, benzafbrate, ciprofibrate, Clofibrate, etoHbrate, fenoHbrate and gemfibrozil. A non-limiting example of a lipoprotein synthesis inhibitor for use in combination with a nicotinic acid receptor agonist of the invention is included in an acid test (niacin or nicotinic acid). Non-limiting examples of 5HT (serotonin) transport inhibitors for use in combination with a nicotinic acid receptor agonist of the invention include paroxetine, flu 141543.doc-53-201016705 fluoxetine, fenflurine Fenfluramine, fluvoxamine, sertraline, and imipramine ° NE (norepinephrine) used in combination with the nicotinic acid receptor agonist of the present invention Non-limiting examples of transport inhibitors include GW 320659, desipramine, talsupram, and nomifensine ° in combination with a nicotinic acid receptor agonist of the invention Non-limiting examples of CBi antagonists/inverse agonists include rimonabant, SR-147778 (Sanofi Aventis), and compounds set forth below: U.S. Patent No. 5,532,237 No. 4,973,587, U.S. Patent No. 5,013,837, U.S. Patent No. 5,081,122, U.S. Patent No. 5,112,820, U.S. Patent No. 5,292,736, U.S. Patent No. 5,624,941, U.S. Patent No. 6,028,084 WO 96/33159, WO 98/33765, WO 98/43636, WO 98/43635, WO 01/09120, WO 98/31227, WO 98/41519, WO 98/37061, WO 00/10967, WO 001 10968, WO WO 01/58869, WO 02/076949, and EP-658546 (each of which is incorporated herein by reference). Non-limiting examples of ghrelin antagonists for use in combination with a nicotinic acid receptor agonist of the invention include those described in WO 01/87335 and WO 02/08250 (each of which is incorporated by reference) In this article). The ghrelin antagonist is also known as the GHS (growth hormone secretagogue receptor) antagonist. The pharmaceutical combinations and methods of the invention thus comprise the use of a GHS antagonist in place of a ghrelin antagonist (in combination with the nicotinic acid receptor agonist of the invention 141543.doc • 54· 201016705).

Non-limiting examples of h3 antagonists/inverse agonists for use in combination with a nicotinic acid receptor agonist of the invention include thioperamide, N-(4-pentenyl)amino decanoic acid 3- (1Η-imidazol-4-yl)propyl ester, clobenpropit, iodophenpropit, imoproxifan, and GT2394 (Gliatech), which are described in WO 02/15905 (in The reference is incorporated herein by reference to Ki-Kononowicz, K. et al., Pharmazie, 55: 349-55 (2000) (incorporated herein by reference). Imidazolyl-4-yl)propanol]carbamate, hexahydropyridine-containing as described in Lazewska, D. et al, Pharmazie, 56: 927-32 (2001) (incorporated herein by reference) Histamine H3-receptor antagonists, described as benzophenone derivatives in Sasse, A. et al., Arch. Pharm. (Weinheim) 334:45-52 (2001) (incorporated herein by reference) And related compounds, substituted N-phenylaminocarboxylic acid S, as described in Reidemeister, S. et al, Pharmazie, 55: 83-6 (2000) (incorporated herein by reference) Sasse, A., etc. J. Med Chem 43:.. 3335-43 (2000) where in the Phouesay (proxifan) derivative (by key for each of the above references are incorporated herein by reference). Non-limiting examples of MCH1R (melanin-concentrating hormone 1 receptor) antagonists and MCH2R (melanin-aggregating hormone 2 receptor) agonists/antagonists used in combination with a nicotinic acid receptor agonist of the invention include those described therein WO 01/82925, WO 01/87834, WO 02/06245, WO 02/04433, WO 02/51809, and Japanese Patent No. 13226269 (each of which is incorporated herein by reference) T-226296 (Takeda). 141543.doc • 55· 201016705 Non-limiting examples of NPY1 antagonists for use in combination with a nicotinic acid receptor agonist of the invention include those described in U.S. Patent No. 6,001,836, WO 96/14307, WO 01/ 23387, WO 99/51600, WO 01/85690, WO 01/85098, WO 01/85173, and WO 01/89528 (each of which is incorporated herein by reference) and BIBP3226 'J- 115814 'BIBO 3304 > LY-357897 ' CP-671906 and GI-264879A. Non-limiting examples of NPY5 antagonists for use in combination with a nicotinic acid receptor agonist of the invention include those described in U.S. Patent No. 6,140,354, U.S. Patent No. 6,191,160, U.S. Japanese Patent No. 6, 258, 837, U.S. Patent No. 6,313, 298, U.S. Patent No. 6,337, 332, U.S. Patent No. 6,329,395, U.S. Patent No. 6,340,683, U.S. Patent No. 6,326,375, U.S. Patent No. 6,335,345, EP-01010691, EP-01044970 WO 97/19682, WO 97/20820, WO 97/20821, WO 97/20822, WO 97/20823 'WO 98/27063, WO 00/64880, WO 00/68197 > WO 00/69849, WO 01/ 09120, WO 01/85714, WO 01/85730 'WO 01/07409, WO 01/02379, WO 01/02379, WO 01/23388, WO 01/23389, WO 01/44201, WO 01/62737, WO 01/ 62738, WO 01/09120, WO 02/22592, WO 02/48152, WO 02/49648, WO 01/14376, WO 04/1 10375, WO 05/000217 and Norman et al., J. Med. Chem. 43: 4288-4312 (2000) (each of which is incorporated herein by reference); and 152, 804, GW-569180A, GW-594884A, 141543.doc - 56- 201016705

GW-587081X > GW-5481 18X; FR226928, FR240662, FR 252384; 1229U91 > GI-264879A 'CGP71683A > LY-377897, PD-160170, SR-120562A, SR-120819A and JCF-104.

Non-limiting examples of NPY2 agonists for use in combination with a nicotinic acid receptor agonist of the invention include PYY3-36, NPY3-36, as described in Batterham et al, Nature. 418:650-654 (2003), And other Y2 agonists (eg, N-ethyl [Leu(28,31)] NPY 24-36 (White-Smith and Potter, Neuropeptides 33: 526-33 (1999)), TASP-V (Malis et al, Br J. Pharmacol. 126:989-96 (1999)), Ring-(28/32)-Bagua-[1^328-Glu3 2]-(25_3 6)-pNPY (Cabrele and Beck-Sickinger J-Pept -Sci. 6:97-122 (2000))) (Each of the above references is hereby incorporated by reference). Non-limiting examples of NPY4 agonists for use in combination with a nicotinic acid receptor agonist of the invention include pancreatic peptides as described in Batterham et al, J. Clin Endocrinol. Metab 88: 3989-3992 (2003) (PP), and other Y4 agonists (e.g., 1229U91 (Raposinho et al, Neuroendocrinology 71: 2-7 (2000))) (both references are hereby incorporated by reference). A non-limiting example of an mGluR5 (metabolic glutamate 5 subtype receptor) antagonist for use in combination with a nicotinic acid receptor agonist of the invention comprises 2-mercapto-6-(phenylethynyl)-° Bis-pyridine (MPEP) and (3-[(2-mercapto-1,3-thiazol-4-yl)ethynyl]pyridine) (MTEP) and their compounds described below: Anderson J. et al. J, Eur J Pharmacol. Jul. 18, 2003; 473(1): 35-40; 141543.doc -57- 201016705

Cosford Ν· et al, Bioorg Med Chem Lett. Feb. 10, 2003; 13(3): 351-4; and Anderson J. et al., J Pharmacol Exp Ther. December 2002: 303(3): 1044-5 1 (Each of the above references is incorporated herein by reference). Non-limiting examples of lipoproteins, lipoprotein derivatives, and lipoprotein agonists/modulators used in combination with a nicotinic acid receptor agonist of the invention comprise recombinant human lipoprotein (PEG-OB, Hoffman) La Roche) and recombinant metformin human lipoprotein (Amgen). Lipid leptin derivatives (e.g., truncated forms of lipoprotein) for use in the present invention include those described in U.S. Patent No. 5,552,524, U.S. Patent No. 5,552,523, U.S. Patent No. 5,552,522, U.S. Patent No. 5,521,283, WO 96/23513, WO 96/23514, WO 96/23515, WO 96/23516 'WO 96/23517 'WO 96/23518 'WO 96/23519 ' and WO 96/23520 (above reference Each of the documents is incorporated herein by reference. Non-limiting examples of opioid antagonists for use in combination with a nicotinic acid receptor agonist of the invention include nalmefene (Revex.TM), 3-methoxynaltrexone, Naloxone, and naltrexone, and an opioid antagonist as described in WO 00/21509, which is incorporated herein by reference. Non-limiting examples of orexin receptor antagonists for use in combination with a nicotinic acid receptor agonist of the invention comprise SB-334867-A, and are described in WO 01/96302, WO 01/68609, WO 02/ 51232, and WO 02/5 1838 (each of which is hereby incorporated by reference in its entirety by reference in its entirety in its entirety in its entirety in its entirety in Non-limiting examples of CNTF (specific ciliary neurotrophic factor) for use in combination with a nicotinic acid receptor agonist of the invention include GI-181771 (GlaxoSmithKline), SR146131 (Sanofi-Aventis), Cloth Butabindide, PD 170, 292, PD 149164 (Pfizer). Non-limiting examples of CNTF derivatives and CNTF agonists/modulators for use in combination with a nicotinic acid receptor agonist of the invention comprise axokine (Regeneron) and are described in WO 94/09134, WO 98/22128, and WO 99/43 813 (each incorporated herein by reference). Non-limiting examples of 5HT2c agonists for use in combination with a nicotinic acid receptor agonist of the invention include BVT933, DPCA37215,

WAY 161 503, and R-1065, and theirs are described in U.S. Patent Nos. 3,914,250, WO 02/6596, WO 02/48124, WO 02/10169, WO 01/66548, WO 02/44152, WO 02/51844, WO 02/ 40456, and WO 02/40457 (each incorporated herein by reference). Non-limiting examples of Mc4r agonists for use in combination with a final acid receptor agonist of the invention include CHIR86036 (Chiron), ME-10142 and ME-10145 (Melacure) and those described in WO 01/991752, WO 01 /74844, WO 02/12166, WO 02/11715, and WO 02/12178, each of which is incorporated herein by reference. Non-limiting examples of monoamine reuptake inhibitors for use in combination with a nicotinic acid receptor agonist of the invention include sibutramine 141543.doc-59-201016705 (MeridiaTM/ReductilTM), and Illustrated in WO 01/27068, WO 01/62341, U.S. Patent No. 4,746,680, U.S. Patent No. 4,806,570, U.S. Patent No. 5,436,272, and U.S. Patent No. 2002/0006,964, each incorporated herein by reference. Medium). Non-limiting examples of serotonin reuptake inhibitors for use in combination with a nicotinic acid receptor agonist of the invention include dexfenfluramine, fluoxetine, and those described in U.S. Patent No. 6,365,633. WO 01/27060, and WO 01/1 62341, each of which is incorporated herein by reference. A non-limiting example of a thiol estrogen for use in combination with a nicotinic acid receptor agonist of the invention comprises oleoyl estrone. Non-limiting examples of 11β HSD-1 inhibitors for use in combination with a nicotinic acid receptor agonist of the invention are described in WO 03/065983 and WO 03/104207, both of which are incorporated herein by reference. Medium). A non-limiting example of a lipase inhibitor for use in combination with a nicotinic acid receptor agonist of the invention comprises orlistat. The antidiabetic agent used in combination with the nicotinic acid receptor agonist of the present invention comprises a replenishing gland, a meglitinide, an aj powder enzyme inhibitor, an alpha-glucoside hydrolase inhibitor, and a ppAR-gamma agonist. Agent, ppARa/γ agonist, biguanide, ΡΤΡ-1Β inhibitor, DP-IV inhibitor, DPP-IV inhibitor, insulin secretagogue, fatty acid oxidation inhibitor, Α2 antagonist, c-jun amine-terminal kinase inhibition Agent, insulin, insulin mimetic, glycogen phosphorylase inhibitor, VPAC2 receptor agonist, glucokinase activator, and non-thiazide bismuth PPAR ligand. Combination with a nicotinic acid receptor agonist of the invention 141543.doc -60- 201016705 A non-limiting example of a sulfonylurea used comprises hexyl urea acetate, chlorpropamide, diabinese, glibenclamide ( Glibenclamide), glipizide, glyburide, glimepiride, gliclazide, glipentide, gliclazide Gliquidone), glisolamide, tolazamide, and tolbutamide.

Non-limiting examples of meltelatin used in combination with a nicotinic acid receptor agonist of the invention include repaglinide, mitiglinide and nateglinide. Non-limiting examples of alpha-amylase inhibitors for use in combination with a nicotinic acid receptor agonist of the invention comprise amylase aprotin, trestatin and AI-3688 ° with a nicotinic acid receptor of the invention Non-limiting examples of alpha-glucoside hydrolase inhibitors used in combination with agonists include saccharide, lipothelin, camiglibose, emiglitate, miglitol , voglibose (voglibose), pradimicin-Q, salbostatin, CKD-711, MDL-25, 637, MDL-73, 945 and MOR 14. Non-limiting examples of PPAR-gamma agonists for use in combination with a nicotinic acid receptor agonist of the invention include balaglitazone, ciglitazone, daglitazone, en Glynet (611 Lv 320116), Ixaglitazone (13 & § 1 ^ 320116) (~^(1; -555), 11 piglitazone, rosiglitazone, Troglitazone, tesaglitazar, neglitazone 141543.doc -61 - 201016705 (netoglitazone), GW-409544, GW-501516, CLX-0921, 5-BTZD, GW-0207 LG-100641, LY-300512, LY-519818, R483 (Roche) and T131 (Tularik). A non-limiting example of a PPARa/gamma agonist for use in combination with a nicotinic acid receptor agonist of the invention comprises CLX- 0940, GW-1536, GW-1929, GW-2433, KRP-297, L-796449, LR-90, MK-0767, and SB 219994. The use of the biguanide in combination with the nicotinic acid receptor agonist of the present invention. A limiting example comprises butadiene, metformin and phenformin. PTP-1B inhibitor (protein tyramine) used in combination with a nicotinic acid receptor agonist of the invention Non-limiting examples of phosphatase-1B inhibitors include in-401, 674, KR61639, OC-060062, OC-83839, OC-297962, MC52445, and MC52453 ° in combination with a nicotinic acid receptor agonist of the invention Non-limiting examples of DPP-IV inhibitors (dipeptidyl peptidase I Vi inhibitors) include sitagliptin, saxagliptin, denag丨iptin, vitamins He is vildagliptin, alogliptin, alogliptin benzoate, Galvus (Novartis), ABT-279 and ABT-341 (Abbott) 'ALS-2-0426 (Alantos), ARI -2243 (Arisaph), BI-A and BI-B (Boehringer Ingelheim), SYR-322 (Takeda), MP-513 (Mitsubishi), DP-893 (PHzer) and RO-0730699 (Roche), isoleucine Thiazosin, NVP-DPP728, P32/98, LAF 237, TSL 225, pyrrolidine guanine, TMC-2A/2B/2C, CD-26 inhibitor and SDZ 274-444. 141543.doc -62- 201016705 Non-limiting examples of insulin secretagogues for use in combination with a nicotinic acid receptor agonist of the invention include linogliride and A-41 66. Non-limiting examples of fatty acid oxidation inhibitors for use in combination with a nicotinic acid receptor agonist of the invention comprise clomoxir and etomoxir and the nicotinic acid receptor agonist of the invention Non-limiting examples of A2 antagonists used in combination with a combination include midaglizole, isaglidole, deriglidole, idazoxan, φ Earoxan and fluparoxan. Non-limiting examples of membrane island mimetics for use in combination with an acid-receptor agonist of the present invention include biota, LP-1 00, novarapid, insulin detemir, Lai Insulin lispro, insulin glargine, zinc sulphate suspension (slow and ultra-slow), Lys-Pro insulin, GLP-1 (73-7) (insulintropin )), and GLP-1 (7-36)-NH2. Non-limiting examples of glycogen phosphorylase inhibitors used in combination with niacinic acid receptor agonists of the invention include CP-368, 296, CP-316, 819 and . BAYR3401. Non-limiting examples of non-thiazolidinedione PPAR ligands for use in combination with a nicotinic acid receptor agonist of the invention include JT-501 and farglitazar (GW-2570/GI-262579). The antihypertensive agent used in combination with the nicotinic acid receptor agonist of the present invention comprises a diuretic, a β-adrenergic blocker, an α-adrenergic blocker, an aldosterone inhibitor, an α blocker, calcium Channel blocker, vascular tone 141543.doc -63 · 201016705 Invertase inhibitor, neutral endopeptidase inhibitor, angiotensin II receptor antagonist, endothelin inhibitor, vasodilator, a2 a An agonist, and an alpha/beta adrenergic blocker. Non-limiting examples of diuretics for use in combination with a nicotinic acid receptor agonist of the invention include oxyketene, thiazine, dichlorphenamide, hydrofluoroazine, indapamide (indapamide) ), hydrogen gas, bumetanide, ethacrynic acid, furosemide, torsemide, amiloride, amphetamine Non-limiting examples of beta-adrenergic blockers for use in combination with pirated vinegar and epirenone 0 in combination with a nicotinic acid receptor agonist of the invention include acebutolol, arbutinol Atenolol, betaxolol, bevantolol, bisoprolol, bopindolol, carteolol, carvedil Carvedilol, celiprolol, esmolol, indenolol, metaprolol, nadolol, nebivolol ( Nebivolol), penbutolol, 0 pin 0 pindolol, propano Lol), sotalol, tertatolol, tilisolol and timolol. Non-limiting examples of alpha 1 blockers for use in combination with a nicotinic acid receptor agonist of the invention include terazosin, urapidil, prazosin, cloth The 0 call (bunazosin), trimazosin, doxazosin, naftopidil, indoramin, WHIP 164 and ΧΕΝ010. 64- 141543.doc 201016705

Non-limiting examples of calcium channel blockers for use in combination with a nicotinic acid receptor agonist of the invention include amlodipine, aranidipine, azelnidipine, and benidipine ( Barnidipine), benidipine, bepridil, cinaldipine, clevidipine, diltiazem, efenidipine, felodipine , gallopamil, isradipine, lacidipine, lemildipine, lercanidipine, nicardipine, nifedipine Nilvadipine, nimodipine, nisoldipine, nitrendipine, manidipine, pranidipine, and verapamil A non-limiting example of an angiotensin converting enzyme inhibitor for use in combination with a nicotinic acid receptor agonist of the invention comprises alapril, benazepril (bena) Zepril), ceronapril, captopril, cilazapril, delagril, enalapril, fosinopril , imidapril, lisinopril, moteltopril, moexipril, quinapril, quinaprilat, remy Ramipril, perindopril, peridropril, quanipril, spirapril, temocapril, trandolapril And zofenopril ° 141543.doc -65- 201016705 A non-limiting example of the use of a neutral endopeptidase inhibitor in combination with a nicotinic acid receptor agonist of the invention comprises omapatrilat (omapatrilat) ), candoxatril, ecadotril, fosidotril, sampatrilat, AVE7688 and ER4030. Non-limiting examples of angiotensin 受体 receptor antagonists for use in combination with a nicotinic acid receptor agonist of the invention include candesartan, eprosartan, irbesartan ), losartan, pratosartan, tasosartan, telmisartan, valsartan, EXP-3137, F16828K, RNH6270, aerated sand Tandan potassium and valsartan potassium hydrochlorothiazide. Non-limiting examples of endothelin antagonists for use in combination with a nicotinic acid receptor agonist of the invention comprise tezosentan, A3081 65 and YM62899 ° in combination with a nicotinic acid receptor agonist of the invention Non-limiting examples of vasodilators for use include hydralazine or apresoline, clonidine or catapres, minoxidil or loniten, and nicotinyl alcohol or roniacol. Non-limiting examples of a2a agonists for use in combination with a nicotinic acid receptor agonist of the invention include lofexidine, tiamenidine, moxonidine, limonidine (rilmenidine) and guanabenz. Non-limiting examples of alpha/beta adrenergic blockers for use in combination with a nicotinic acid receptor agonist of the invention include nipradilol, arotinolol, and alkalolol ( Amosulalol). -66- 141543.doc 201016705 In a particularly preferred embodiment, the invention relates to a composition comprising a first component and a second component, the first component being at least one compound of formula I, or a salt or solvate thereof , vinegar or month ί] The second component is at least one compound selected from the group consisting of LIPITOR®, ZETIA®, VYTORIN®, ZOCOR® and CRESTOR®. In another preferred embodiment, the invention relates to a composition comprising a first component and a second component, the first component being at least one compound of the formula, or a salt, solvate, ester or prodrug thereof, This second component is a platelet aggregation inhibitor. In a particularly preferred embodiment, the invention relates to a composition comprising a first component and a second component, the first component being at least one compound of formula j, or a salt, solvate ester or prodrug thereof, The second component is a platelet aggregation inhibitor, wherein the platelet aggregation inhibitor is a thrombin receptor antagonist, in particular, for example, in U.S. Patent Nos. 6,063,847, 6,326, 38, 7,037,920, 6,645,987. Thrombin receptor antagonists as set forth in U.S. Patent Nos. 7,235,567, 6, 894, 065, and U.S. Patent No. 7,304,078, the disclosures of which are incorporated herein by reference. Those skilled in the art will appreciate that the compounds of the invention described herein exhibit excellent nicotinic acid receptor agonist activity. The term "pharmaceutical composition" is also intended to encompass both the overall composition and the individual dosage form 70, which include more than one (eg, two) pharmaceutically active agents (eg, a compound of the invention and a list of other agents selected from the list herein). Other pharmaceutical agents) as well as any pharmaceutically inactive excipients. The total composition and each individual agent may contain a fixed amount of the above-mentioned "medicine active drug 141543.doc-67-201016705". The overall composition is a material that has not yet formed a separate dosage unit. An exemplary dry dosage unit is an oral dosage unit' such as a key, a pill, and the like. Similarly, the methods described herein for administering a pharmaceutical composition of the present invention to treat a patient are also intended to encompass administration of the above-described overall compositions and separate agents. Pharmaceutically acceptable inert carriers for the preparation of pharmaceutical compositions from the compounds described herein can be either solid or liquid. The solid form preparations contain powders, troches, dispersed granules, capsules, pills and suppositories. Powders and binders may comprise from about 5% to about 95% of the active ingredient. Suitable solid carriers are well known in the art' for example, carbonic acid, magnesium stearate, talc, sugar or lactose. Tablets, powders, pills and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers and methods of preparing various compositions can be found in A. Gennaro (ed.), Remingt〇n, s pharmaceuticai % (10)s, 18th ed., (1990), Mack PubIishing c〇, (6) (10),

In Pennsylvania. Liquid form #| contains solution, liquid and (4). Examples may be aqueous or propylene glycol solutions (parenteral injection) or sweeteners and opacifiers may be added to oral solutions, suspensions and emulsions. Liquid form preparations can also be administered intranasally. The gas-soluble solution suitable for inhalation may comprise a solution and a powdered solid which may be combined with a pharmaceutically acceptable carrier (for example, an inert compressed gas (e.g., nitrogen)). Also included are solid form preparations intended to be converted into liquid form preparations for oral or parenteral administration just prior to use. These liquid forms contain 141543.doc • 68 - 201016705 solutions, suspensions and emulsions. The compounds of the invention may also be delivered transdermally. Compositions for transdermal delivery may be in the form of creams, lotions, aerosols and/or emulsions and may be included in a matrix or storage transdermal patch which is conventionally used in the art for this purpose. The compounds of the invention may also be delivered subcutaneously. The compound is preferably administered orally. Preferably, the pharmaceutical preparation is in unit dosage form. In this form, the preparation can be subdivided into unit dosages containing appropriate quantities of the active ingredient in an appropriate amount (e.g., effective amount to achieve the desired purpose). The amount of active compound in a unit dosage formulation may vary or be adjusted from about 1 mg to about 100 mg, preferably from about 1 mg to about 5 mg, more preferably from about 1 mg to about 25 mg, depending on the particular application. The actual dosage used will vary depending on the needs of the patient and the severity of the condition being treated. Those skilled in the art will be able to determine the appropriate dosage regimen for use in a particular situation. For convenience, the total daily dose can be divided into several parts and submitted on a daily basis as needed. The clinical attending physician can adjust the amount and frequency of administration of the compound of the present invention and/or its pharmaceutically acceptable salt, taking into account factors such as the age, condition, and size of the patient and the severity of the symptoms to be treated. A typical recommended dosage regimen for oral administration can range from about 1 mg/day to about 5 mg/day, preferably from 1 mg/day to 200 mg/day, in two to four divided doses. If the compound of formula I releases acetaminosalicylic acid when hydrolyzed or metabolized in vivo, then the amount of acetaminosalicylic acid released should be bioequivalent to no more than 80 mg/day of ingestion 0 141543.doc -69 - 201016705 Another aspect of the invention comprises a therapeutically effective amount of at least one compound of formula i, or a pharmaceutically acceptable salt, solvate, vinegar or prodrug of the compound, and a pharmaceutically acceptable carrier, vehicle Or a set of thinners. A further aspect of the invention comprises a kit of at least one compound of formula I, or a pharmaceutically acceptable salt, solvate, ester or prodrug of the compound, and a quantity of at least one of the above therapeutic agents, two of which An amount of more or more ingredients can produce the desired therapeutic effect. The invention disclosed herein is exemplified by the following preparations and examples, but should not be construed as limiting the scope of the invention. Those skilled in the art will be aware of alternative mechanism paths and similar structures. When displaying NMR data, the 1 Η spectrum is based on Variant VXR-200 (200 MHz, ]H) 'Varian Gemini-300 (300 MHZ) 'Varian Mercury VX-400 (400 MHz), or Bruker-Biospin AV-500 (500 Obtained on MHz) and reported in ppm, proton number and multiplicity are described in parentheses. This analysis was performed using an Applied Biosystems API-100 mass spectrometer and a C18 column (10-95% CH3CN-H20 (containing 0.05% TFA) gradient) when the LC/MS data was presented. The observed parent ion is given. The following solvents and reagents may refer to the abbreviations in parentheses:

Me=methyl Et=ethyl Pr=propyl Bu=butyl Ph=phenyl Ac=ethenyl 141543.doc -70- 201016705 μΙ=microliter

AcOEt or EtOAc=acetic acid ethyl acetate AcOH or HOAc=acetic acid ACN=acetonitrile atm=atmospheric pressure

Boc or BOC = tri-butoxycarbonyl. DCE = dichloroethane DCM or CH2C12 = dichloromethane DIPEA = diisopropylethylamine DMAP = 4-dimethylaminopyridine DMF = dimethylformamidine Amine DN1S = dimethyl sulfide 0 ^ DMSO = dimethyl subhard EDCI = ( 1-(3-didecylaminopropyl)-3-ethylcarbodiimide Fmoc or FMOC = 9-fluorenylmethoxy Carbonyl group Q g = hour. hal = halogen HOBt = l-hydroxybenzotriazole LAH = lithium aluminum hydride LCMS = liquid chromatography mass spectrometry min = minutes mg = milligrams mL = ml 141543.doc -71 - 201016705 mmol = milli Mole MCPBA = 3-chloroperoxybenzoic acid MeOH = decyl alcohol MS = mass spectrometry NMR = nuclear magnetic resonance spectrum RT or rt = room temperature (ambient temperature, about 25 ° C) TEA or Et3N = triethylamine TFA = trifluoroacetic acid THF = tetrahydro π-propan TLC = thin layer chromatography TMS = trimethylmethanyl Tr = triphenyl fluorenyl example The compounds of the invention can generally be prepared as described in the preparation of the reaction schemes and the following examples. The commercially available solvents, reagents, and intermediates were used in the receiving state. Non-marketed reagents and intermediates were prepared in the following manner. 4 NMR spectra were obtained on a Gemini AS-400 (400 MHz) with a low magnetic field distance of Me4Si. The pm report, proton number, multiplicity, and coupling constant (Hertz) are described in parentheses. When presenting LC/MS data, the analysis was performed using the following conditions: Applied Biosystems API-100 mass spectrometer and Shimadzu SCL-10A LC column (Altech starting C18, 3 microns, 33 mm >< 7 mm ID; gradient flow: 0 min - 10% CH3CN, 5 min - 95% CH3CN, 7 min - 95% 14I543.doc -72- 201016705 CH3CN, 7.5 min - 10% CH3CN, 9 min - stop). Give retention time and observed parent ion. Synthetic reaction diagram · Reaction diagram 1.

A ......- Α-α + B ......♦ A-B

Reaction Figure 2.

A ......* A-CI + l-B ......* A-L-B

Reaction Figure 3.

B + L-------B-L ........> B-L + A .......- A-L-B 141543.doc -73- 201016705

Reaction Figure 4. B + L· -B-L·

♦ B-L + A

* A-L-B

Wang, Zhengqiang; Bennett, Eric M.; Wilson, Daniel J.; Srtomon, Christine; Vince, Robert. Journal of Medicinal Chemisty (2007), 50(13⁄4. 341&3419. PedroK H: Van Maarsween· JanH; 〇ttenhe |m, Harry CJ; Kruse, Chris G.; Scheeren, Hans W. Journal of agaiic Cherristry (1990), 55(13), reaction diagram s.

A-S〇2Me + B ......* A-B 74- 141543.doc 201016705

Reaction Figure 6· A-S〇2Me

A~OPMB

OTf -A-OPMB

1) B; 2) H^Pd/C

A-L-B

:1) B-L :2) H^Pd/C

A-L-B

Preparation of intermediates: 75- 141543.doc 201016705

Fu, Xiaozhong; Jang. Saihons Li, Chuan; Xin. Jiv); Yang, Yushe; Ji, Ruyun. BcKirjanic & Metfdnal Chemisty Letters (2007). 17(2). 465-470.

Wang, Zhengqiane; Bermett Eric M.; VMson, Daniel J.; Salomon, Chrisfne; Vince, Robert Joirnd of Medcinal Chemistry (2007), 50(15), 3416-3419. Hermkens. Pedro Η. H; Van Maarseveen, Jan H; Ottenhei (m. Harry C J.; Kruse, Chris G.; Scheeren. Hans w. Journal of Organic Chemisfry (1990), 55(13). Preparation Example 1

step 1 :

Compound la (1 mmol) in POCl3 (5.0 mL) was heated at 7 〇cCT for 1 hour. The reaction mixture was cooled and excess p〇cl3 was removed under reduced pressure. The residue was purified by flash chromatography using EtOAc / hexanes eluting to afford compound 1b. Step 2:

-76· 141543.doc 201016705 NEt3 (2 mmol) was added dropwise to a mixture of compound lb (1 mmol) and lc (l.i mmo1) in DMF (5 mL). The reaction mixture was stirred for 8 hours and then diluted with Et EtOAc/NaHC.sub.3 (satu.). The aqueous phase was extracted with EtOAc (EtOAc) (EtOAc)EtOAc. i. Preparation Example 2

To a mixture of compound 2a (1 mmol) and 2b (1.0 mmol) was added dropwise EtOAc (EtOAc). The reaction mixture was stirred for 8 hours and then diluted with EtOAC / NaHC.sub.3 (satu.). The water-phase was extracted using Et〇Ac (3χ), and the organic phase was combined and dried (MgSCU) using water (1X), brine washing. The solvent was removed under reduced pressure and the residue was purified using EtOAc EtOAc EtOAc EtOAc Step 2:

141543.doc • 77- 201016705 Add NaH (1.05 mmol) to a mixture of compound 2d (1 mmol) and 2c (1.05 mmol) in THF/DMF (1/1 5 mL). The reaction mixture was stirred for 3 h then diluted with EtOAc /EtOAc (EtOAc). The aqueous phase was extracted with EtOAc (3×), and then combined with water and brine, and dried (MgS04). The solvent was removed under reduced pressure and the residue was purified using flash chromatography using EtOAc/hexane eluting to afford compound.

step 1

Compound 3a (1 mmol) in CH2C12 (2.0 mL) was added dropwise to a solution of compound 3b (1 mmol) and NEt3 (1.1 mmol) in CH2C12 (5 mL). The reaction mixture was stirred for 3 h then diluted with EtOAc / NaHC.sub.3 (lN). The aqueous phase was extracted with EtOAc (3×), and the combined organic phase was washed with water (1×) and brine (MgS04). The solvent was removed under reduced pressure and the residue was purified using EtOAc EtOAc EtOAc EtOAc Step 2: 14I543.doc -78- 201016705

Dmap (0.2 mmoL) and DCC (1.1 mmol) were added to a solution of compound 3d (1.0 mmol) and 3c (1.0 mmol) in CH2C12 (6 mL). The reaction mixture was stirred for 8 hours and then filtered through Celite. The solvent was removed under reduced pressure and the residue was purified using EtOAc (EtOAc) Other compounds of Formula 1 (including those of Table 1), and salts, solvates, vinegars and prodrugs thereof can be prepared by preparation analogous to those described above for the preparation of the solid. Although the invention has been elucidated in connection with the above specific embodiments, many of them have been

It is intended to be within the spirit and scope of the invention. 141543.doc 79-

Claims (1)

201016705 VII. Scope of application: 1. A compound of formula I: R'-G-RI where R' represents a recoverable residue of a non-steroidal anti-inflammatory drug (NSAID); G represents a hydrolyzable or metabolizable linking group And R represents a recoverable residue of an acid receptor agonist; or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof. ❹ 2. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, wherein G represents a linking group selected from the group consisting of Ο, S, NR1, -0 -alkylalkyl-S-, -S-alkylene-S-,-0-exylaryl-0-,-0-exylaryl-S-, -S-exylaryl-S-, -Ο-arylalkyl-anthracene-,-fluorene-arylalkylene-S-,-S-arylalkylene group _S-, -〇-extended heteroaryl-heteroaryl-S-, -S- Heteroaryl-S-, polyalkylene glycol, -c(o)o-alkylene-indole-, -c(o)o-alkylene-S-, -oc(o)-extension Alkyl-oxime-, -OC(O)-alkylene-S-, -c(o)o-exoaryl-〇-, -c(o)o-exoaryl-S-, -oc( o)-Exoaryl-〇-,-0-c(o)-exylaryl-S-, -c(o)o-extended aryl-〇-, -c(o)o-extension -S-, -oc(o)-heteroaryl-0-, -OC(O)-heteroaryl-S- and -C(0)-polyalkylene glycol; and R1 represents hydrogen , alkyl or aryl. 3. The compound of claim 2, or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, wherein G represents a linking group selected from the group consisting of: 0, S, NR1, -0 ( CH2)n0-,-0(C(R2)2)0-,-0(CH2)nS-,-0(C(R2)2)S-, -S(CH2)nS-, -S(C(C( R2) 2) S-, -Ο-aryl-Ο- 141543.doc 201016705 , -〇-aryl-s-, -S-aryl-s-, -ο-heteroaryl-ο-, -ο -heteroaryl-s-, -S-heteroaryl-S-, PEG (polyethylene glycol) and PPG (polypropylene glycol); and R1 represents hydrogen, alkyl or aryl; R2 represents alkyl; Represents 0-10. 4. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, wherein R' represents an NSAID having a recoverable residue selected from the group consisting of: 141543.doc -2- 201016705 The asterisk indicates the connection point with G. 5. The compound of claim 1, or a pharmaceutically acceptable salt, solvent, ester or prodrug thereof, wherein R' represents an NSAID having the structure: 141543.doc 201016705 Or a recoverable residue having the following structure: The asterisk indicates the connection point with G. 6. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, wherein R represents a recoverable residue of a nicotinic acid receptor agonist having the following structure: Wherein R3 represents an alkyl group, a cycloalkyl group or a heteroalkyl group; and R4 represents a fluorene, an alkyl group or a cycloalkyl group; and 141543.doc 201016705 an asterisk indicates a point of attachment to G. 7. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, wherein R represents a recoverable residue of the acid accepting receptor agonist having the following structure: Wherein φ R5 and R6 each independently represent a haloalkyl group; and the asterisk indicates a point of attachment to G. 8. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, S- or prodrug thereof, wherein R represents an acid-receptor agonist having the following structure: Or a recoverable residue having the following structure: 0 where the asterisk indicates the point of attachment to G. 9. A compound selected from the group consisting of compounds having the formula: 141543.doc 201016705 141543.doc -6· 201016705 And pharmaceutically acceptable salts, solvates, brews and prodrugs thereof. The substance comprises at least one of the compounds of claim 1 and a pharmaceutically acceptable carrier. 11. A composition comprising at least one of the compounds of claim 9 and a pharmaceutically acceptable carrier. 12. The composition of claim 10, further comprising at least one selected from the group consisting of: and a group of other therapeutic agents: a cyclyl substituted (tetra) cyclobutane compound, a substituted beta ketone amine compound , HMG COA reductase inhibitor compound, HMG COA synthetase inhibitor, keratin synthesis inhibition 141543.doc 201016705 agent, squalene epoxidase inhibitor, sterol biosynthesis inhibitor, nicotinic acid derivative, bile Acid chelating agent, aspirin (asPirin), NSAID agent, Vytorin®, ezetimibe, inorganic cholesterol chelating agent, sulfhydryl-based CoA: cholesterol 〇-thiotransferase inhibitor, cholesteryl ester transfer protein inhibitor Fish oil of ω3 fatty acid, natural water-soluble fiber, fatty acid ester of plant residual alkanol and/or phytosterol, antioxidant, PPAR α agonist, PPAR γ-agonist, FXR receptor modulator, LXR receptor agonist Agent, lipoprotein synthesis inhibitor, renin angiotensin inhibitor, microsomal triglyceride transport inhibitor, bile acid re-sorption inhibitor, PPAR δ agonist, triglyceride synthesis inhibitor Squalene epoxidase inhibitor, low-density lipoprotein receptor inducer or activator, platelet aggregation inhibitor, 5-L0 or FLAP inhibitor, PPAR δ partial agonist, nicotinic acid or nicotinic acid receptor agonist Agent, 5ΗΤ transporter inhibitor, ΝΕtransporter inhibitor, CB! antagonist/inverse agonist, ghrelin antagonist, Η3 antagonist/inverse agonist, MCH1R antagonist, MCH2R agonist/anti-drug , ΝΡΥ1 antagonist, ΝΡΥ5 antagonist, ΝΡΥ2 agonist, ΝΡΥ4 agonist, mGluR5 antagonist, leptin, lipoprotein agonist/modulator, lipoprotein derivative, opioid antagonist, orexin (orexin) receptor antagonist, BRS3 agonist, CCK-A agonist, CNTF, CNTF derivative, CNTF agonist/modulator, 5HT2c agonist, Mc4r agonist, monoamine reuptake inhibitor, serotonin reuptake Inhibitor, GLP-1 mimetic, phentermine, topiramate, phytoharm compound 57, ghrelin antibody, Mc3r agonist, ACC inhibitor, β3 141543.doc • 8 - 201016705 Agents, DGAT1 inhibitors, DGAT2 inhibitors, FAS inhibitors, PDE inhibitors, thyroid hormone beta agonists, UCP-1 activators, UCP-2 activators, UCP-3 activators, thiol estrogens, glucocorticoids Hormone agonist/antagonist, 11β HSD-1 inhibitor, SCD-1 inhibitor, lipase inhibitor, fatty acid transporter inhibitor, dicarboxylic acid transporter inhibitor, glucose transporter inhibitor, valate transporter Inhibitors, antidiabetic agents, antihypertensive agents, anti-lipidemia agents, _DPP-IV inhibitors, apolipoprotein-Β secretion/microsomal triglyceride trans-transferase (apo-B/MTP) inhibition Agent, sympathomimetic agonist, dopamine agonist, melanocyte stimulating hormone receptor analogue, melanin aggregation hormone antagonist, lepton, galanin receptor antagonist, sequel Bombesin agonist, neuropeptide-Y antagonist, pseudo-salvoid agent, dehydroepiandrosterone, dehydroepiandrosterone analog, urocortin-binding protein antagonist, glucagon-like Peptide-1 receptor agonist, human guinea pig Related protein (AGRP), neurotransmitter U receptor φ agonist, norepinephrine-induced anorectic agent, appetite suppressant, hormone-sensitive lipase antagonist, MSH-receptor analog, α-Port Sugar, enzyme inhibitor, apo A1 milano reverse cholesterol transport inhibitor, fatty acid binding protein inhibitor (FABP) and fatty acid transporter inhibitor (FATP). 13. The composition of claim 12, wherein the at least one additional therapeutic agent is selected from the group consisting of lovastatin, simvastatin, pravastatin, atorvastatin (atorvastatin), vavastatin, cerivastatin 141543.doc 201016705 (cerivastatin), rivastatin, rosuvastatin, rosuvastatin calcium, pitavastatin , torcetrapib, Vytorin®, ezetimibe, aspirin, ibuprofen, acetaminophen, DPP-IV inhibitor, GLP-1 mimetic, and combinations thereof. 14. The composition of claim 11, further comprising at least one other therapeutic agent selected from the group consisting of a hydroxy substituted azetidinone compound, a substituted beta-endoamine compound, HMG Co A Reductase inhibitor compounds, HMG CoA synthetase inhibitors, squalene synthesis inhibitors, squalene epoxidase inhibitors, sterol biosynthesis inhibitors, acid test derivatives, bile acid sequestrants, aspirin, NS AID, Vytorin®, ezetimibe, inorganic cholesterol chelating agent, sulfhydryl-based CoA: cholesterol Ο-hydrazinotransferase inhibitor, cholesteryl ester transfer protein inhibitor, fish oil containing ω3 fatty acid, natural water-soluble fiber, plant 甾Fatty acid esters of alkanols and/or plant stanols, antioxidants, PPAR alpha agonists, PPAR gamma-agonists, FXR receptor modulators, LXR receptor agonists, lipoprotein synthesis inhibitors, renin vascular stress Inhibitors, microsomal triglyceride transport inhibitors, bile acid reuptake inhibitors, PPAR δ agonists, triglyceride synthesis inhibitors, squalene epoxidase inhibitors, low density lipids Protein receptor inducer or activator, platelet aggregation inhibitor, 5-LO or FLAP inhibitor, PPAR δ partial agonist, nicotinic acid or nicotinic acid receptor agonist, 5 ΗΤ transporter inhibitor, ΝΕ transporter inhibition Agent, CB! Antagonist/Inverse agonist, ghrelin antagonist, Η3 antagonist/inverse agonist, MCH1R antagonist, MCH2R agonist/antagonism 141543.doc • 10-201016705 agent, NPY1 antagonist, NPY5 antagonist, NPY2 agonist, NPY4 agonist, mGluR5 antagonist, lipoprotein, lipoprotein agonist/modulator, lipoprotein derivative, opioid antagonist, orexin receptor antagonist, BRS3 agonist, CCK-A Agonists, CNTF, CNTF derivatives, organisms, CNTF agonists/modulators, 5HT2c agonists, Mc4r agonists, monoamine reuptake inhibitors, serotonin reuptake inhibitors, GLP-1 mimics, phentermine, care η ratio ester, botanical drug compound 57, hunger φ antibody, Mc31 mobilizer, ACC inhibitor, β3 agonist, DGAT1 inhibitor, DGAT2 inhibitor, fas inhibitor, PDE inhibitor, thyroid hormone β agonist , UCP-1 activator, UCP-2 activator, UCP-3 activator, thiol estrogen, glucocorticoid agonist/antagonist, uβ HSD-1 inhibitor, SCD-1 inhibitor, lipase inhibitor, fatty acid transporter inhibitor , dicarboxylic acid transporter inhibitor, glucose transporter inhibitor, phosphate transporter inhibitor, antidiabetic agent, antihypertensive agent, anti-lipidemia agent, Dpp_IV inhibitor, φ apolipoprotein_B secretion/particle Triglyceride transfer protein (apo_ b/μτρ) inhibitor, sympathomimetic agonist, dopamine agonist, melanocyte hormone receptor analogue, melanin aggregation hormone antagonist, alizarin, galanin Body antagonists, bombesin agonists, neuropeptide antagonists, pseudo-salvoid agents, dehydroepiandrosterone, analogs of dehydroepiandrosterone, urocortin-binding protein antagonists, glucagon-like Peptide q receptor agonist, human guinea pig-associated protein (AGRp), neurotransmitter U receptor agonist, norepinephrine-induced food reduction, your appetite suppressant, hormone-sensitive lipase antagonist, MSH_ Receptor Analogs, alpha] glucosidase 141543.doc 11 201016705 P sugar inhibitors, apo A1 milano reverse cholesterol transport inhibitors, fatty acid binding protein inhibitors (FABP), and fatty acid transporter protein inhibitors (FATP). 15. The composition of claim 14, wherein the at least one additional therapeutic agent is selected from the group consisting of lovastatin, simvastatin, pravastatin, atorvastatin, fluvastatin, cisivava Statins, rivastatin, Rosuvvastat/Ding Ma Pivata > Ding, Tochamp, Vytorin®, Erythromycin, Aspirin, Ibuprofen, Acetaminophen, Dpp_IV Inhibitor, GLP- 1 simulant and its combination. 16. Use of at least one compound of claim 1 or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof for the manufacture of a medicament for the treatment of a disease in a patient: metabolic syndrome, Dyslipidemia, ~ blood disease, peripheral nervous system and central nervous system disorders, blood diseases, cancer, inflammation, respiratory diseases, gastrointestinal diseases, diabetes or non-alcoholic fatty liver disease. 17. The use of claim 16, wherein the medicament is used in combination with at least one other therapeutic agent selected from the group consisting of: a hydroxy substituted azetidinone compound, a substituted albile amine compound, hmg c 〇a reductase inhibitor compound, HMG C〇A synthetase inhibitor, horn synthesis inhibitor, keratin epoxidase inhibitor, sterol biosynthesis inhibitor, nicotinic acid derivative, bile acid sequestrant, inorganic Cholesterol chelating agent, aspirin, NSAHD agent, ezetimibe, 8-branched CoA: cholesterol 〇 醒 基 base transferase inhibitor, cholesterol vinegar transfer protein inhibitor, fish oil containing C03 fatty acid, natural water-soluble fiber, plant 141543. Doc •12- 201016705 Fatty acid vinegar, Omacor®, antioxidants, PP AR α agonists, PP AR γ-agonists, FXR receptor modulators, LXR receptor agonists, lipoprotein synthesis inhibitors , renin angiotensin inhibitor, microsomal triglyceride transporter inhibitor, bile acid reuptake inhibitor, PPAR δ agonist, triacetin synthesis inhibitor, squalene epoxidase inhibitor, low Density lipoprotein receptor inducer or activator, platelet aggregation inhibitor, 5-LO or FLAP inhibitor, PPAR δ partial agonist, nicotinic acid or nicotinic acid receptor agonist, 5HT transporter inhibitor, ΝΕ transport Protein inhibitors, CB, antagonists/inverse agonists, ghrelin antagonists, Η3 antagonists/inverse agonists, MCH1R antagonists, MCH2R agonists/antagonists, ΝΡΥ1 antagonists, ΝΡΥ5 antagonists, ΝΡΥ2 agonists, ΝΡΥ4 Agonists, mGluR5 antagonists, lipoproteins, lipoprotein agonists/modulators, lipoprotein derivatives, dentate antagonists, orexin receptor antagonists, BRS3 agonists, CCK-A agonists , CNTF, CNTF derivative , CNTF agonists / modulators, 5HT2c agonists, Mc4r agonists, monoamine reuptake inhibitors, serotonin reuptake inhibitors, GLP-1 mimetics, phentermine, Torr. Ratio, plant drug compound 57, ghrelin antibody, Mc3r agonist, ACC inhibitor, β3 agonist, DGAT1 inhibitor, DGAT2 inhibitor, FAS inhibitor, PDE inhibitor, scorpion gonadotropin beta agonist, UCP -1 activator, UCP-2 activator, UCP-3 activator, thiol estrogen, glucocorticoid agonist/antagonist, 11β HSD-1 inhibitor, SCD-1 inhibitor, lipase inhibitor, fatty acid Transporter inhibitor, dicarboxylate transporter inhibitor, glucose transporter inhibitor, phosphate transporter 141543.doc -13- 201016705 white inhibitor, antidiabetic agent, antihypertensive agent, anti-lipidemia agent, DPP -IV inhibitor, apolipoprotein-B secreting/microsomal triglyceride transfer protein (apo-B/MTP) inhibitor, sympathomimetic agonist, dopamine agonist, melanocyte stimulating hormone receptor analog, Melanin-aggregating hormone antagonist, alizarin, galanin receptor antagonist, purine peptide agonist, neuropeptide antispasmodic antagonist, pseudo-salrogant drug, dehydroepiandrosterone, dehydroepiandrosterone Analog, urocortin Protein antagonism, agent, glucagon-like peptide-1 receptor agonist, human guinea pig-associated protein (AGRP), neurotransmitter receptor agonist, norepinephrine-induced lurassive appetite, appetite suppression Agents, hormone-sensitive lipase antagonists, MSH-receptor analogs, alpha-glucosidase inhibitors, ap〇Α1 milano reverse cholesterol transport inhibitors, fatty acid binding protein inhibitors (FABP), and fatty acid transporter inhibitors ( FΑτρ). 18. Use of at least one compound of claim 9, or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, for the manufacture of a medicament for the treatment of a disease in a patient Metabolic syndrome, dyslipidemia, cardiovascular disease, peripheral nervous system and central nervous system disorders, blood stasis, cancer, inflammation, respiratory disease, gastrointestinal disease, diabetes or nonalcoholic fatty liver disease. For example, the use of the item 18 wherein the drug is used in combination with at least one other therapeutic agent selected from the group consisting of: a hydroxy substituted azetidinone compound, a substituted β-lactam compound, 〇c〇A reduction, inhibitor compound, HMG CoA synthetase inhibitor, kerene synthesis P preparation, squalene epoxidase inhibitor, sterol biosynthesis inhibitor, 141543.doc •14- 201016705 nicotinic acid Derivatives, bile acid sequestrants, inorganic cholesterol chelating agents, aspirin, NSAID agents, ezetimibe, Vytorin®, thiol Co A : cholesterol 0-thiotransferase inhibitors, cholesteryl ester transfer protein inhibitors, containing ω3 Fatty fish oil, natural water soluble fiber, vegetable stanol and/or fatty acid ester of plant alkanol, 〇macor®, antioxidant, PPAR alpha agonist, PPAR gamma agonist, FXR receptor modulator, LXR Receptor agonists, lipoprotein synthesis inhibitors, renin angiotensin inhibitors, microsomal triglyceride transporter inhibitors, bile acid reuptake inhibitors, PPAR δ agonists, triglycerides Inhibitors, squalene epoxidase inhibitors, low-density lipoprotein receptor inducers or activators, platelet aggregation inhibitors, 5-LO or FLAP inhibitors, PPAR δ partial agonists, nicotinic acid or nicotine Acid receptor agonists, 5HT transporter inhibitors, sputum transporter inhibitors, CBi antagonists/inverse agonists, ghrelin antagonists, H3 antagonists/inverse agonists, MCH1R antagonists, MCH2R agonists/antagonists, NPY1 antagonist, NPY5 antagonist, NPY2 agonist, NPY4 agonist, mGluR5 antagonist, lipoprotein, lipoprotein agonist/modulator, lipoprotein derivative, opioid antagonist, orexin receptor antagonist , BRS3 agonist, CCK-A agonist, CNTF, CNTF derivative, CNTF agonist/modulator, 5HT2c agonist, Mc4r agonist, monoamine reuptake inhibitor, serotonin reuptake inhibitor, GLP-1 simulation , phentermine, topiramate, botanical compound 57, ghrelin antibody, Mc3r agonist, ACC inhibitor, β3 agonist, DGAT1 inhibitor, DGAT2 inhibitor, FAS inhibitor, PDE inhibitor, thyroid hormone beta agonist UCP -1 activation 141543.doc -15· 201016705 agent, UCP.2 activator, ucp_3 activator, brewing base hormone, hormone hormone agonist/antagonist, 11β HSEM inhibitor m private, agent, lipase inhibitor, fatty acid Transporter inhibitors, dicarboxylate inhibitors, glucose transporter inhibitors, vinegar vinegar transport inhibitors, antidiabetic agents, antihypertensive agents, anti-lipidemia agents, DPP-IV inhibitors, Apolipoprotein_B secretion/microsomal triglyceride transfer protein (apo_B/MTP) inhibitor, sympathomimetic agonist, dopamine agonist, melanocyte stimulating hormone receptor analog, melanin aggregation hormone antagonist, 痩, galanin receptor antagonist, bomb field peptide agonist, neuropeptide-Y antagonist, thyroxine agent, dehydroepiandrosterone, dehydroepiandrosterone analog, urocortin-binding protein antagonist , glucagon-like peptide-1 receptor agonist, human guinea pig-associated protein (AGRP), neurotransmitter U receptor agonist, norepinephrine-induced anorectic agent, appetite suppressant, hormone sensitivity Lipase Agents, MSH-receptor analogs, alpha] -glucosidase inhibitors, apo A1 milano reverse cholesterol transport inhibitors, fatty acid binding protein inhibitors (FABP), and fatty acid transporter protein inhibitors (FATP). 14I543.doc •16· 201016705 IV. Designation of representative drawings: (1) The representative representative of the case is: (none) (2) The symbol of the symbol of the representative figure is simple: 5. If there is a chemical formula in this case, please reveal the best display. Chemical formula of the invention: R'-G-RI 141543.doc