MXPA06005203A - Combinations of lipid modulating agents and substituted azetidinones and treatments for vascular conditions - Google Patents

Abstract

The present invention provides compositions, therapeutic combinations and methods including:(a) at least one lipid modulating agent;and (b) at least one substituted azetidinone or substituted -lactam sterol absorption inhibitor which can be useful for treating vascular conditions, diabetes, obesity and lowering plasma levels of sterols or 5alpha-stanols.

Description

COMBINATIONS OF MODIFIED AGENTS OF LIPID AND SUBSTITUTE AZETIDINONES AND TREATMENTS FOR CONDITIONS VASCULARS BACKGROUND OF THE INVENTION FIELD OF THE INVENTION The present invention relates to compositions and therapeutic combinations comprising certain agents for the modulation of substituted lipids and azetidinones or substituted β-lactams to treat vascular and lipid-like conditions such as those associated with atherosclerosis, hypercholesterolemia and other vascular conditions in subjects. Heart disease of atherosclerotic coronary artery disease (CHD) represents the leading cause of death and vascular morbidity in the western world. Risk factors for heart disease of atherosclerotic heart disease include hypertension, diabetes mellitus, family history, male gender, cigarette smoking, and high serum cholesterol. A total cholesterol level and an excess of 225-250 mg / dl is associated with a significant increase in the risk of CHD. The objective of a recently revised low-density lipoprotein NCEP ATP III (LDL-C) for patients with CHD or with an equivalent CHD risk is << 100 mg / dl (2.59 mmol / l), for individuals with two or more risk factors is < 130 mg / dl (2.59 mmol / l) and for individuals with less than two risk factors is < 160 mg / dl (4.14 mmol / l). The regulation of cholesterol homeostasis in the body in mammals and animals involves the regulation of dietary cholesterol and the modulation of cholesterol biosynthesis, bile acid biosynthesis, and the catabolism of plasma lipoproteins containing cholesterol. The liver is the main organ responsible for the biosynthesis of cholesterol and cafabolism and, for this reason, it is a major determinant of cholesterol levels in plasma. The liver is the site of the synthesis and secretion of very low density lipoproteins (VLDL) that is subsequently metabolized to low density lipoproteins (LDL) in the circulation. LDL are the lipoproteins that carry a predominant cholesterol in the plasma and an increase in their concentration is correlated with an increase in the aerosol. When the absorption of end-meal colesferol is reduced, by any means, less cholesterol is discharged to the liver. The consequence of this action is the decrease in the production of hepatic lipoprolein (VLDL) and an increase in the hepatic elimination of cholesterol in the plasma, mainly as LDL. In this way, the neural effect of the inhibition of the intestinal cholesterol absorption is a decrease in the levels of cholesterol in the plasma and an advance of the formation of the lesion aminosclerico. U.S. Patent Nos. 5,767,115, 5,624,920, 5,668,990, 5,656,624 and 5,688,787, respectively, disclose azolidinone compounds subsumed with hydroxy and substituted β-lactam compounds useful for decreasing cholesterol and / or inhibiting the formation of lesions containing cholesterol in the arterial walls of mammals. U.S. Patent No. 5,756,470, U.S. Patent Application No. 2002/0137690, U.S. Patent Application No. 2002/137689, and U.S. Patent Application No. PCT WO 2002/066464 describe sugar-substituted azetidinones. and amino acids with amino acids useful for the prevention or sparing of atherosclerosis and the reduction of plasma cholesterol levels. U.S. Patent Nos. 5,846,966 and 5,661,145, respectively, disclose treatments for inhibiting atherosclerosis and reducing plasma cholesterol levels by using hydroxy-substituted azeidinone compounds or substituted β-lactam compounds in combination with reductase inhibitor compounds. (HMG-CoA) that act to block the reductase (HMG-CoA) of the coenzyme of hydroxymethylglylaryl (enzyme limited in its speed in the synthesis of cholesterol hepatic). Despite recent improvements in the treatment of vascular disease, there is still a need to improve the compounds, compositions and procedures for hyperlipidemia, atherosclerosis and other vascular conditions that provide a more efficient treatment distribution.

BRIEF DESCRIPTION OF THE INVENTION In one embodiment, the present invention provides a composition comprising: (a) at least one agent for the modulation of lipid; and (b) at least one substituted azetidinone compound or a substituted β-lactam compound or a pharmaceutically acceptable salt or solvate thereof. In another embodiment, a composition is provided comprising: (a) at least one agent for modulating lipid; and (b) a compound represented by the following formula (II): or a pharmaceutically acceptable salt or solvate thereof. The therapeutic combinations also provided comprise: (a) a first amount of at least one agent for lipid modulation; and (b) a second quantity of at least one substituted azetidinone compound or a substituted β-lactam compound or a pharmaceutically acceptable salt or solvate thereof, wherein the first amount and the second amount together comprise a therapeutically effective amount for the irradiation or prevention of a vascular condition, diabetes, obesity, or decrease in the concentration of sterol in the plasma of a subject. Pharmaceutical compositions for the treatment or prevention of a vascular condition, diabetes, obesity or decrease of a concentration of a concentration of a eseryol in the plasma of a mammal, comprise a positive ephedrine quantity of the above compositions or therapeutic combinations and also provided a pharmaceutically acceptable carrier. Methods for tracing or preventing the vascular condition, diabetes, obesity or decreased concentration of a sterol in the plasma of a subject comprises the step of administering to a mammal in need of such an irradiation an effective amount of the above compositions or therapeutic combinations. also provided. All numbers express quantities of ingredients, reaction conditions, etc., used in this specification and in the claims shall be understood as being modified in all insenses by term "approximately" except for those that appear in the operative examples or when otherwise indicated.

DETAILED DESCRIPTION OF THE INVENTION The compositions and therapeutic combinations of the present invention comprise at least one "agent for modulating lipid", as used herein means a compound that functions as HDL, including synthetic HDL containing lipid such as phosphatidyl choline, phosphatidyl serine, phosphatidyl ethanolamine, and other phospholipids in combination with HDL associated with proteins such as apoA-l or variants thereof including an apoAI-Milano and biologically active peptides derived therefrom, reverse lipid inert peptides (RLT), enzymes associated with HDL such as paraoxonase, and apo E, alone or formulated in combination with liposomes or emulsions. See the patent application of E. U. A. No. 2003/0109442 on pages 3-9, which is incorporated herein by reference. As used herein, proteins associated with HDL include sequences present in proteins associated with HDL that are associated with HDL and synthetic peptides having an equivalent bond or functional characteristics. Compounds that enhance HDL function include liposomes, where HDL acts as a transporter of the cells to a liposome. Suitable liposomal formulations are described WO 95/23592 by the University of British Columbia. The formulations described herein typically consist of a helical protein such as an ApoA-1, a lipid, and a carrier. Plasma ApoA-1 is a single polypeptide chain of 243 amino acids, the primary sequence of which is known (Brewer and Oros, Biochem, Biophys, Res.Com. 80: 623-630 (1978)). An ApoA-1 is synthesized as a precursor of amino acid 267 in the cell. The preproapolipoprotein A-I is first processed intracellularly through the N-terminal separation of 18 amino acids to produce proapolipoprotein A-I, and then it is further separated from the 6 amino acids in the plasma or lymph through the activity of specific proteases to produce apolipoprotein A-I. The main structural requirement of the ApoA-1 molecule is believed to be the presence of repeating units of amino acids, presumably existing in an unsympathetic Helical conformation and other, FEBS Lett: -5. This structure allows the main biological activities of ApoA-1, that is, the lipid and lecithin binding: actinyltransferase activity of colesferol LCAT. Human Al-Milano apolipoprotein (ApoA-IM) is a naphural variant of ApoA-1 / Weisgraber and others, J. Clin. Invesl 66: 901-907 (1980)). In ApoA-IM the amino acid Arg173 is replaced by the amino acid Cys 173. Since ApoA-IM contains a Cys residue per polypeptide chain it can exist in a monomeric, homodimeric, or heterodimeric form. These forms are chemically interchangeable and the term ApoA-IM is not discriminated, in the present context between the forms. At the DNA level the variant of the result of a suspension of C to T in the sequence of the gene, ie, the CGC codon changed to TGC allows the colliding of a cys instead of an arg at the position of amino acid 173. Without However, this variant of ApoA-l is one of the most interesting variants, and that the ApoA-IM objects are characterized by a marked reduction in the level of HDL cholesterol, but without a separate increase in the risk of arterial disease ( Franceschini et al., J. Clin. Invest 66: 892-900 (1980)). Another useful variant of ApoA-l is the Paris variant where arginine 151 is replaced with a cysteine. The systemic infusion of ApoA-1 alone (Miyazaki and Oros, Arterioscler Thromb Vasc Biol. 15: 1882-1888 (1995) or HDL (Badimon et al., Lab Invest. 60: 455-461 (1989) and J. Clin Invest. 85: 1234-1241 (1990)) in clinical studies in experimental animals and in early humans (Nanjee et al., Arterioscler Thromb Vasc Biol. 19: 979 (1999) and Ericsson et al., Circulation. 100: 594-598 (1999). )) have been shown to exert significant biochemical changes, as well as reducing the extent and severity of airway lesions, it has now been found that it can be admiered locally at the site of damage, and significantly reduces stenosis or restenosis, as will be discussed more detailed below and will be demonstrated by the following examples: Other apolipoproteins associated with HDL with alpha helical characteristics can also be used Examples include Apo E, proApoA-1, ApoA-1Paris, ApoA-11, proApoA-ll, ApoA-IV, ApoC-1, ApoC-11, and ApoC-ll, the alpha helical sequences, within these proteins, and apolipoproteins modified to include one or more sulfhydryl groups, as described by Bielicki and Oda, Biochemistry 41: 2089-2096 (2002).

Additional proteins associated with HDL can also be used. Examples include paraoxonase, cholesteryl ester transfer protein, LCAT, and phospholipid transfer protein. The above proteins can also be used alone, in combination, or in complex form as a lipid alone or as a complex combination with lipid. In addition, mixtures of the complexes may also be useful. An example is the complexes comprised of ApoA-1 with lipid and complexes comprising paraoxonase with lipid administered as a mixture. Another example includes complexes that comprise more than one protein component. For example, complexes comprising ApoA-1, paraoxonase and a lipid are also useful. The lipids form a complex with ApoA-l that improves its effectiveness. Typically, the lipid is mixed with ApoA-1 before administration. The apolipoprotein and the lipids are mixed in an aqueous solution in appropriate proportions and can be complexed through methods known in the art and include freeze drying, solubilization of the detergent followed by dialysis, microfluidization, sonication, and homogenization. The efficiency of the complex can be used, for example, through variable pressure, ultrasonic frequency, or deigene concentration. An example of a commonly used degenerate used to prepare apolipoprofein-lipid complexes is sodium colloid. In some cases it is desirable to mix the lipid and the apolipoprotein before administration. The lipids may be in solution or in the form of liposomes or emulsions formed using standard techniques such as sonication or extrusion. Sonication is usually carried out with a tip sonicator, such as a Branson tip sonifier, in an ice bath. Typically the suspension is subjected to several cycles of sonication. The extrusion can be carried out through biomembrane extruders, such as the Lipex Biomembrane Extruder. The defined pore size in the extrusion filters can generate unilamellar liposomal vesicles of specific sizes. Liposomes can also be formed through extrusion by an asymmetric ceramic filter, such as a Ceraflow Microfilier, commercially available from Norton Company, Worcester Mass., Or through polycarbonate filter or other types of polymerized materials (i.e. plastics) commonly known. In some cases it is preferable to administer apolipoprotein alone, essentially free of lipid, to treat the damaged artery. The sterile aqueous solution is added to the apolipoprotein. The apolipoprotein in solution can be administered to bring a damaged artery. An alternative freeze-drying preparation of the complexes can be hydrated with an aqueous solution before administration. In other cases, the frozen preparations of the complexes in aqueous solution are thawed until a homogeneous solution is achieved before administration to a damaged blood vessel. Preferred lipids are phospholipids, more preferably including at least one phospholipid, typically soy phosphatidylcholine, egg phosphatidylcholine, soy phosphatidylglycerol, egg phosphatidylglycerol, palmitoyl-oleoyl-phosphatidyl choline diastearoylphosphatidylcholine, or distearoylphosphatidylglycerol. Other useful phospholipids include, for example, phosphatidylcholine, phosphatidylglycerol, sphingomyelin, phosphatidylserine, phosphatidic acid, N- (2,3-di (9-Z) -octadecenyloxy)) - prop-1-yl-N, N, N chloride - trimethylammonium fosfaíidileíanolamina, lysolecithin, lysophosphatidylethanolamine, fosfatidilinosiíol, cephalin, cardiolipin, cerebrosides, diceíilfosfato, dioleoylphosphatidyl choline, dipalmitoylphosphatidylcholine, dipalmitoylphosphatidylglycerol, dioleoylphosphatidylglycerol, esíearoil-palmiíoil-fosfaíidilcolina, di-palmitoyl-fosfatidileíanolamina, phosphatidylethanolamine disíearoil, dimyrisyl-phosphaidylserine, and dioleyl-phosphaididylcholine. Lipids that do not contain phosphorus can also be used, including stearylamine, dodecylamine, pyrilane palmitate, and fatty acid amides. Additional lipids suitable for use are well known to those skilled in the art and are cited in a variety of well known sources, for example, McCutcheon's Detergents and Emulsifiers and McCutcheon's Functional Materials, Allured Publishing Co., Ridgewood, NJ, both of the which are incorporated herein by reference. Generally, it is desirable that the lipids be liquid-crystalline at 38 ° C, 35 ° C, or 32 ° C. Lipids in a liquid-crystalline state typically accepted cholesferol more efficiently than lipids in a gel state. Since patients typically have a core temperature of around 37 ° C, lipids that are liquid-crystalline at 37 ° C are generally in the liquid-crystalline state during treatment. The concentration of lipid in the formulation may vary. Those skilled in the art can vary these concentrations to optimize treatment with different lipid components or individual patients. ApoA-l is combined with the lipid in a ratio through weight between 1: 05 to 1: 3, with more lipid being preferred for cholesterol elimination. A ratio of about 1: 1 is preferred to produce the most homogeneous population and for purposes of a stable and reproducible production of lots. In one embodiment, the agent for lipid modulation is ETC-216 which is a synthetic HDL complex composed of 14 mg / ml of recombinant Milano apolipoprotein A1 and 13 mg / ml of 1-palmitor-2-oleyl phosphaidylcholine complex (POPC) in sucrose-mannitol-phosphate pH buffer solution (6.4% sterile sucrose, 0.8% mannitol in 6 mmoles / i phosphate pH regulator, pH 7.4) (Esperion Therapeutics, Inc.), as ready to inject solution or saline. In an alternative embodiment, the genes encoding a protein to be distributed should be administered, rather than the protein. The transfer of the gene can be obtained by using a direct transfer of the genetic material, in a plasmid or viral vector, or through the transfer of the genetic material in the cells or carriers such as cationic liposomes. Such methods are well known in the art and are readily adaptable for use in the gene-mediated toxin therapies described herein. As reviewed by Francis, et al., Am. J. Pharmacogenomics 1 (1): 55-66 (2001), gene therapy offers a novel method for the prevention and treatment of cardiovascular diseases. Technical advances in viral vector systems and the development of fusigenic liposome vectors have been crucial in the development of effective gene therapy strategies targeting the vasculature and myocardium in animal models. Gene transfer techniques have been evaluated as potential treatment alternatives for both vascular occlusive genetic diseases (familial hypercholesterolemia) and acquired (atherosclerosis, resenosis, arterial thrombosis) as well as cardiac disorders including heart failure, myocardial ischemia, coronary atherosclerosis of graft, and hypertension. See also, Teiger, et al., J. Cardiovasc. Pharmacol. 33 (5): 726-732 (1999). The studies of Wolf et al., Biotechniques 11: 474-85 (1991), demonstrate the injection of naked DNA into muscle which allows the long-term and low expression levels of the proteins encoded within the DNA sequence. The administration of naked DNA to the smooth muscle layers can be achieved through the use of an intramural device, such as an INFILTRATOR®, and allows the expression of proteins or alpha helical domains to irritate damaged blood vessels. The transfer vectors can be any construction of the nucleotide used to distribute genes within the cells (e.g., a plasmid), or as part of a general strategy to destroy genes, for example, as part of a recombinant retrovirus or adenovirus (Ram et al., Cancer Res. 53: 83-88, (1993)). Suitable means for transfection, including viral vectors, chemical transferences, or physico-mechanical methods, such as electroporation and direct DNA diffusion, are described by, for example, Wolf, JA, and others, Science, 247, 1465-1468. , (1990); and Wolf, J. A. Naíure, 352, 815-818, (1991). As used herein, plasmid or viral vectors are agents that transport the gene into a cell without degradation and include a promoter that produces the expression of the gene in the cell to which it is distributed. In a preferred embodiment the vectors are derived from either a virus or a retrovirus. Preferred viral vectors are adenovirus, adeno-associated virus, herpes virus, vaccinia virus, chicken virus, AIDS virus, neural virus, Sindbis and other RNA viruses, including these viruses with HIV virus. Also preferred are viral families that share the properties of these viruses that make them suitable for use as vectors. Preferred refroviruses include the murine Maloney leukemia virus, MMLV, and reirovirus expressing the desirable properties of MMLV as a vecfor. Reirolary vectors are capable of carrying a large genetic payload, i.e., a transgene or marker gene, than other viral vectors, and for this reason they are a commonly used vector. However, they are not useful in the non-proliferation of cells. A retrovirus is an animal virus that belongs to the Retroviridae virus family, including any types, subfamilies, genes or tropisms. Reírovirales vectors, in general, are described through Verma, I. M., the reírovirales vectors for the transference of the gene. In MICROBIOLOGY-1985, American Society for Microbiology, p. 229-232 Washington, (1985), which is incorporated herein by reference. Examples of methods for using retroviral vectors for gene therapy are described in the patents of US Pat. Nos. 4,868,116 and 4,980,286; PCT applications WO 90/02806 and WO 89/07136; and Mulligan, (Science 260: 926-932 (1993)). The adenovirus vectors are relatively stable and easy to work with, they have alias concentrations, and they can be distributed in an aerosol formulation, and they can be transfected without dividing the cells. The construction of defective replication adenoviruses has been described by (Berner et al., J. Virology 61: 1213-1220 (1987); Massie et al., Mol. Cell. Biol. 6: 2872-2883 (1986); Haj-Ahmad; et al, J. Virology 57: 267-274 (1986), Davidson et al., J. Virology 61: 1226-1249 (1987); Zhang "Generation and identification of recombinant adenovirus by iiposome-mediated transfection and PCR analysis" BioTechniques 15 : 868-872 (1993)). The benefit of using these viruses as vectors is that they limit the extent to which they can spread to other cell types, since they can replicate from an initial infected cell, but are unable to form new infectious viral particles. Recombinant adenoviruses have demonstrated that they achieve an alpha efficiency in gene transfer after direct, in vivo distribution to the epithelium of the airways, hepaocytes, vascular endothelium, the CNS parenchyma and a number of other tissue sites (Morsy, J. Clin Invest. 92: 1580-1586 (1993); Kirshenbaum, J. Clin. Invest. 92: 381-387 (1993); Roessler, J. Clin. Invest. 92: 1085-1092 (1993); Moullier, Narute Genetics 4: 154-159 (1993), La Salle, Science 259: 988-990 (1993), Gomez-Foix, J. Biol. Chem. 267: 25129-25134 (1992), Rich, Human Gene Therapy 4: 461-476 (1993), Zabner, Nature Genetics 6: 75-83 (1994), Guzman, Circulation Research 73: 1201-1207 (1993), Boui, Human Gene Therapy 5: 3-10 (1994), Zabner, Cell 75: 207-216 (1993), Caillaud, Eur. J. Neuroscience 5: 1287-1291 (1993), and Ragoi, J. Gen. Virology 74: 501-507 (1993)). Recombinant adenoviruses achieve transduction of the gene through binding to specific cell surface receptors, after which the virus is internalized via receptor-mediated endocytosis, in the same manner as a wild-type or non-native adenovirus. defective replication (Chardonnet and Dales, Virology 40: 462-477 (1970); Brown and Buriingham, J. Virology 12: 386-396 (1973); Svensson and Persson, J. Virology 55: 442-449 (1985); Seh, and others, J. Virol. 51: 650-655 (1984); Seth et al., Mol. Cell. Biol. 4: 1528-1533 (1984); Varga et al., J. Virology 65: 6061-6070 (1991); Wickham et al., Cell 73: 309-319 (1993)). Viral vectors of smallpox are large and have several sites for inserting genes, they are erodible and can be stored at ambient temperature. A preferred embodiment is a viral vector that has been engineered to suppress the immune response of the host organism obtained by the viral antigens. Preferred vectors of this type can carry purification regions for inhibition 8 or 10. Viral vectors have the ability to sequence more aliases (ability to produce genes) in most chemical and physical methods to introduce genes into cells. Typically, viral vectors contain both anterior and non-structural genes, subsequent structural genes, the polymerase l-RNA transcription, inverted terminal repeats necessary for replication and encapsidation, and promoters to control transcription and replication of the viral genome. When engineered as vectors, viruses typically have one or more of the above genes removed and a gene or gene cassette / promoter is inserted into the viral genome instead of the viral DNA removed. The constructions of this type can carry up to 8 kb of foreign genetic material. The necessary functions of the removed prior genes are typically delivered through cell lines that have been engineered to express the gene products of the above genes in rans. Genes inserted in viral and retroviral usually contain promoters, and / or enhancers to control the expression of the desired gene product. A promoter is generally a DNA sequence or sequences that function in a relatively fixed location with respect to the site of transcription initiation. A promoter contains core elements required for basic interaction of RNA polymerase and transcription factors, and may contain upstream elements and response elements. Preferred promoters that control transcription from the vectors in mammalian host cells can be obtained from several sources, for example, the genomes of viruses such as: polyoma, Simian Virus 40 (SV40), adenovirus, retrovirus, hepatitis B, and more preferably cytomegalovirus, or of heterologous mammalian promoters, for example, the promoter of beta-actin. The anterior and posterior promoters of SV40 viruses are conveniently obtained as an SV40 restriction fragment that also contains the SV40 viral origin of replication (Fiers et al., Nalure, 273: 113 (1978)). The immediate prior promoter of the convenient human cytomegalovirus is obiected as a Hindi E restriction fragment (Greenway, P. J. et al., Gene 18: 355-360 (1982)). Of course, promoters of the host cell or related species are also useful here. The enhancer usually refers to a DNA sequence which operates at a non-fixed distance from the start site of the transmission and can be any 5 '(Laimins, L. et al., Proc. Nati. Acad. Sci. 78: 993 (1981)) or 3 '(Lusky, M. L, et al., Mol Cell Bio 3: 1108 (1983)) for the transcription unit. In addition, enhancers can run within an intron (Banerji, JL et al., Cell 33: 729 (1983)) as well as within the coding sequence itself (Osborne, TF et al., Mol.Cell Bio 4: 1293 ( 1984)). These are usually between 10 and 300 bp in length and work in cis. The breeders work to increase the transcription from their nearby promoters. The breeders also generally contain response elements that mediate the regulation of transcription. Promoters may also contain response elements that mediate the regulation of transcription. Breeders usually determine the regulation of the expression of a gene. Many mammalian gene enhancer sequences are now known (globin, elastase, albumin, α-fetoprotein and insulin), a eukaryotic cell virus enhancer will typically be used. Preferred examples are the SV40 enhancer on the anterior side of the replication origin (bp 100-270), the cytomegalovirus anterior promoter enhancer, the polyoma enhancer on the anterior side of the replication origin and the adenovirus enhancers. The promoter and / or enhancer can be specifically activated either through light or specific chemical events that activate its function. The systems can be regulated through reactive fales such as acetylcholine and dexameiasone. You will also hear ways to improve the expression of the viral vector gene through exposure to irradiation, such as gamma irradiation, or alkylation chemotherapy drugs. It is preferred that the promoter and / or enhancer region act as a positive promoter and / or enhancer to maximize the expression of the region of the phrascription unit to be transcribed. In addition, it is preferred that the promoter and / or enhancer region be active in all types of eukaryotic cells. A preferred promoter of this type is the CMV promoter (650 bases). Other preferred promoters are the SV40 promoters, cytomegalovirus (promoter of full length), and the relroviral vector LTF. It has been shown that all specific regulatory elements can be cloned and used to determine the expression vectors that are selectively expressed in the specific cell types. Expression vectors used in eukaryotic host cells also contain the sequences necessary for the termination of transcription that can affect mRNA expression. These regions are transcribed as polyadenylated segments in the untranslated portion of the tissue factor protein encoding mRNA. The 3 'untranslated regions also include the description termination sites. It is preferred that the labeling unit also contain a polyadenylation region. A benefit of this region is that it implemented the probability that the idiosyncratic unit will be processed and transported as mRNA. The identification and use of polyadenylation signals in expression constructs are well established. It is preferred that the homologous polyadenylation signals are used in the transgene constructs. In a preferred embodiment of the transcription unit, the polyadenylation region is derived from the above polyadenylation signal SV40 and consists of about 400 bases. It is also preferred that the transverse units contain only standard sequences in combination with the above sequences that improve the expression of or stability of the construct. Viral vectors can include nucleic acid sequences that encode a label product. This marker product is used to determine if the gene has been distributed to the cell and once it has been distributed has been expressed. Examples of selectable markers suitable for mammalian cells are dihydrofolate reductase (DHFR), thymidite kinase, neomycin, the neomycin analog G418, hydromycin, and puromycin. When said selectable markers are successfully transferred into the host cells of the mammal, the host cell of the transformed mammal can survive if placed under a selective pressure. In a preferred embodiment, the iniramural DNA distribution encoding ApoA-1, ApoA-IV, ApoE, paraoxonase, or alpha helical regions, dense of these proteins are distributed to an artery with or without lipid to fuse damaged blood vessels. DNA that encodes a number of different proteins can also be distributed. For example, as described by Chen, and others, Jpn. J. Pharmacol. 89 (4): 327-336 (2002), cardiovascular gene transfer is not only a powerful technique to study the function of specific genes in cardiovascular biology and pathobiology, but it is also a promising strategy to bring cardiovascular diseases. Since since the mid-90s, the synrase of nitric oxide (NOS), the enzyme that traces the formation of nitric oxide (NO) of L-arginine, has received considerable attention as a potential candidate for cardiovascular gene therapy, due to that it does NOT exercise critical and diverse functions in the cardiovascular system, and abnormalities in biology are NOT apparent in a number of cardiovascular disease processes including cerebral vasospasm, atherosclerosis, restenosis after angioplasty, transplant vasculopathy, hypertension, diabetes melütus , impotence, and delayed wound healing. There are three NOS isoforms, ie, endothelial (eNOS), neuronal (nNOS) and inducible (¡NOS). The three NOS isoforms have been used in the cardiovascular gene transfer modes with promising results. Kipshidse, et al., J. Am, Coll. Cardio. 39 (10): 1686-1691 (2002) describes the decrease in neointimal formation through the intramural distribution of the antisense oligonucleotides, Turunen, et al., Mol Ther 6 (3): 306 (2002), describes the therapy of nuclear lacZ-activated gene, and TIMP-1 encodes adenoviruses that were coupled to a peptide motif (HWGF) that can bind to matrix metalloproleinase (MMP) -2 and MMP-9. local in vivo intravascular catheter of an adenovirus encoding TIMP-1 activated by HWGF (AdTIMP-1 (HWGF)) significantly reduced intimate thinning in a model of aortic stripping in rabbits compared to the control adenovirus. and the release for a much longer period of time at the site of the need for treatment.The agent for lipid modulation can be administered in a therapeutically effective amount and in a form to treat the specified condition. In general, the formulation is administered at the treatment site. The current total dosage when it is distributed locally is significantly lower than the dosage that could be systematically administered to achieve the same local dosage, however, the local concentration is much higher than in previous studies where ApoA-1 was administered systically. As noted above, the preferred specifications for ApoA-IM is between 4 and 6 mg ApoA-IM / blood vessel (typically up to three segments are delivered with an ionic dosage of about 4 to 18 mg ApoA-IM), or Enlarge about 0.5 and 0.3 mg of ApoA-IM / kg of body weight in a 70 kilogram mammal. The preferred ratio of protein to lipid is between 1: 0.5 to 1: 3, with more lipid being preferred for cholesterol removal, but at a more equal amount of protein to lipid being preferred for stability and consistency purposes of the preparations for regulatory approval. Protein-to-lipid proportions for preparations different from those containing ApoA-IM were tested at various protein-to-lipid ratios and stability and consistency, and characteristics (such as the size of the complex and the flow capacity of cholesterol) were determined for a regulatory approval. Although it has been shown that a single administration is effective, multiple doses can also be administered. For example, intravenous administration on day -1, 0, 1, 2, and 3, of 20 mg ApoA-IM / kg body weight resulted in all damaged blood vessels expanding the balloon, increasing an increase in the lumen area in relation to the controls, 4 weeks after the procedure. The exact dose, however, was determined by the attending physician and is dependent on such factors as the potency of the compound administered, the age, weight, condition and response of the patient. The term "effective ephedrine quantity" means that amount of the therapeutic agents of the invention., such as the lipid modulating agent (s), substituted azetidinone (s) or substituted β-lactam (s) and other pharmacological or therapeutic agents described above, which will obtain a biological response or medical of a subject, tissue, system, animal or mammal that is being sought by the administrator (such as a researcher, doctor or veterinarian) that includes relief of the symptoms of the condition or disease being treated and prevention, deceleration or arrest of the base of one or more conditions, for example vascular conditions, such as hyperlipidemia (for example atherosclerosis, hypercholesterolemia or siiosterolemia), vascular inflammation, effusion, diabetes, obesity and / or reducing the level of the sterol ( is) (such as cholesterol) in the plasma. As used herein, "combination therapy" or "therapeutic combination" means the administration of two or more therapeutic agents such as lipid modulating agents, substituted acefidinone (s), or substituted β-lactam (s) ( s), to prevent or traverse a condition, for example a vascular condition, such as hyperlipidemia (eg, atherosclerosis, hypercholesterolemia or sitosterolemia), vascular inflammation, effusion, diabetes, obesity and / or reduce the level of esoteric (en) (ial as cholesterol), in the plasma or tissue. As used herein, "vascular" comprises cardiovascular, cerebrovascular, and combinations thereof. The compositions, combinations and trappings of the present invention can be administered through any suitable means which produces contact with these compounds with the site of action in the body, for example in the plasma, liver or small intestine of a subject (mammalian). or be human or another animal). Said administration includes co-administration of these therapeutic agents in a substantially simultaneous form, such as a single tablet or capsule having a fixed ratio of the active ingredients or in multiple capsules, separated for each therapeutic agent. Also, such administration includes the use of each type of therapeutic agent in a sequential manner. In any case, the treatment that uses the combination therapy will provide beneficial effects in the traisation of the condition. A potential advantage of the combination therapy described herein may be a reduction in the required amount of an individual therapeutic compound or in the overall amount of the therapeutic compounds that are effective in the treatment of the condition. By using a combination of therapeutic agents, the side effects of an individual compound can be reduced as compared to a monotherapy, which can improve patient acceptance. Also, the therapeutic agents can be selected to provide a broader scale of complementary effects or complementary modes of action. As explained above, the compositions, pharmaceutical compositions and therapeutic combinations of the present invention comprise one or more sterol absorption inhibitors that substituted succinate azetidinone or substituted β-lactam discussed in more detail below. As used herein, "sterol absorption inhibitor" means a compound capable of inhibiting the absorption of one or more esterases, including but not limited to cholesyrol, phytosterols (such as sitosterol, campesterol, stigmaserol and avenosterol), tin steels 5a (such as cholestanol, campesfanol 5a, sitostanol 5a) and / or mixtures thereof, when a therapeutically effective amount (inhibition of the absorption of spheric and / or esfanol 5a) is administered to a mammal or human. In one embodiment, the substituted azetidinones useful in the compositions, therapeutic combinations and method of the present invention are represented by the following formula (I): or pharmaceutically acceptable salts or solvates of the compounds of the formula (I), wherein, in the above formula (I): Ar 1 and Ar 2 are independently selected from the group consisting of aryl and R 4 -substituted aryl; Ar3 is aryl or substituted R5-aryl; X, Y and Z are independently selected from the group consisting of -CH2-, -CH (lower alkyl) - and -C (lower dialkyl) -; R and R2 are independently selected from the group consisting of -OR, -O (CO) R6, -0 (CO) OR9 and -0 (CO) NR6R7; R1 and R3 are independently selected from the group consisting of hydrogen, lower alkyl and aryl; q is 0 or 1; r is 0 or 1; m, n and p are independently selected 0, 1, 2, 3 or 4; provided that at least one of q and r is 1, and the sum of m, n, p, q and r is 1, 2, 3, 4, 5 or 6; and provided that when p is 0 and r is 1, the sum of m, q and n is 1, 2, 3, 4 or 5; R 4 is 1-5 subsides independently selected from the group consisting of lower alkyl, -OR 6, -0 (CO) R 6, -0 (CO) OR 9, -O (CH 2) ?. 5OR6, -O (CO) NR6R7, -NR6R7, -NR6 (CO) R7, -NR6 (CO) OR9, -NR6 (CO) NR7R8, -NR6SO2R9, -COOR6, -CONRR, -COR, -S02NR6R7, S ( O) 0-2R9, -O (CH2) 1-10-COOR6, -O (CH2) 1-10CONR6R7- (lower alkylene) COOR6, -CH = CH-COOR6-CF3, -CN, -N02 and halogen; R5 is 1-5 substituents independently selected from the group consisting of -OR6, -0 (CO) R6, -0 (CO) OR9, -0 (CH2) 1-5OR6, -0 (CO) NR6R7, -NR6R7, - NR6 (CO) R7, -NR6 (CO) OR9, -NR6 (CO) NR7R8, -NR6S02R9, -COOR6, -CONR6R7, -COR6, -S02NR6R7, S (O) 0-2R9, -O (CH2) 1- 10-COOR6, -O (CH2) 1-10CONR6R7, - (lower alkylene) COOR6 and -CH = CH-COOR6; R6, R7 and R8 are independently selected from the group consisting of hydrogen, lower alkyl, aryl and aryl-lower alkyl sub-acid; and R9 is lower alkyl, aryl or aryl-substituted lower alkyl. Preferably, R4 is 1-3 independently selected substituents, and R5 is preferably 1-3 substituents independently selected. As used herein, the term "alkyl" or "lower alkyl" means straight or branched alkyl chains having from 1 to 6 carbon atoms and "alkoxy" means alkoxy groups having from 1 to 6 carbon atoms. Non-limiting examples of lower alkyl groups include, for example, methyl, ethyl, propyl and butyl. "Alkenyl" means straight or branched carbon chains having one or more double bonds in the chain, conjugated or unconjugated. Similarly, "alkynyl" means straight or branched carbon chains having one or more triple bonds in the chain. When an alkyl, alkenyl or alkynyl chain links two other variables and is therefore bivalent, the terms alkylene, alkenylene and alkynylene are used. "Cycloalkyl" means a saturated carbon ring of 3 to 6 carbon atoms, while "cycloalkylene" refers to a corresponding bivalent ring, wherein the binding points to other groups include all positional isomers. "Halogen" refers to fluoro, chloro, bromo, or iodo radicals. "Aryl" means phenyl, naphthyl, indenyl, tetrahydronaphthyl or indanyl. "Phenylene" means a bivalent phenyl group, including the ortho, meta and para substitution.

The statements where, for example, R, R1, R2 and R3, are said to be independently selected from a group of substituents, means that R, R1, R2 and R3 independently selected, but also where a variable R, R1, R12 and R3 occur more than once in a molecule, each occurrence is independently selected (for example, if R is -OR6, wherein R6 is hydrogen, R2 can be -OR6 where R6 is lower alkyl). Those skilled in the art will recognize that the size and nature of the substituent (s) will affect the number of substituents that may be present. The compounds of the invention have at least one asymmetric carbon atom and consequently all isomers, including the enantiomers, stereoisomers, rotamers, tautomers, and racemates of the compounds of the formula (I-XI) (when they exist) are contemplated as being part of this invention. The invention includes the isomers d and I both in pure form and in mixture, including racemic mixtures. The isomers can be prepared using conventional techniques, either through the reaction of optically pure or optically enriched enriched starting materials or through the separation of the isomers of a compound of the formula I-XI. The isomers may also include geometric isomers, for example, when a double bond is present. Those skilled in the art will appreciate that for some of the compounds of the formula I-XI, an isomer will show a greater pharmacological activity than other isomers.

The compounds of the invention with an amino group can form pharmaceutically acceptable salts with organic and inorganic acids. Examples of suitable acids for the formation of salts are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic and other mineral and carboxylic acid acids well known to those skilled in the art. in the technique. The salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt. The free base form can be regenerated by bringing the salt with a dilute aqueous base solution suitable as dilute aqueous sodium bicarbonate. The free base form differs from its respective salt form in some way in certain physical properties, such as solubility in polar solvents, but the salt is equivalent to its respective free base forms for the purposes of the invention. Certain compounds of the invention are acids (for example those compounds which possess a carboxyl group). These compounds form pharmaceutically acceptable salts with inorganic and organic bases. Examples of said salts are the sodium, potassium, calcium, aluminum, gold and silver salts. They also include salts formed with pharmaceutically acceptable amines such as ammonia, alkylamines, hydroxylalkyl amines, N-methylglucamine and the like. As used herein, "solvate" means a molecular or ionic complex of molecules or solvent ions with those of the solute (e.g., one or more compounds of the formula I-XI, isomers of the compounds of the formula I-XI, or prodrugs of the compounds of the formula I-XI). Non-limiting examples of useful solvents include polar solvents, protic solids such as water and / or alcohols (for example meianol). As used herein, "prodrug" means compounds that are precursors of drugs that, after administration to a patient, release the drug in vivo through some physiological chemical process (e.g., a prodrug that is being fused at a pH). physiological through the action of the enzyme becomes the desired drug form). Preferred compounds of Formula (I) are those wherein Ar 1 is phenyl or R 4 -substituted phenyl, more preferably (4-R 4) -substituted phenyl. Ar2 is preferably phenyl or substituted R4-phenyl, more preferably (4-R4) -substituted phenyl). Ar 3 is preferably R 5 -substituted phenyl, more preferably (4-R 5) -substituted phenyl. When Ar1 is (4-R4) -substiluted phenyl, R4 is preferably a halogen. When Ar 2 and Ar 3 are R 4 - and R 5 -substituted phenyl, respectively, R 4 is preferably halogen or -OR 6 and R 5 is preferably -OR 6, wherein R 6 is lower alkyl or hydrogen. Especially preferred are the compounds wherein each of Ar1 and Ar2 are 4-fluorophenyl and Ar3 is 4-hydroxyphenyl or 4-mephoxyphenyl. X, Y and Z are each preferably -CH2. R1 and R3 are each independently hydrogen. R and R2 are preferably -OR6 wherein R6 is hydrogen, or a group readily metabolizable to a hydroxyl (such as -C (CO) R6, - (CO) OR9 and -0 (CO) NR6R7, defined above). The sum of m, n, p, qyr is preferably 2, 3 or 4, more preferably 3. Preferred are the compounds where m, n, and r are each zero, q is 1 and p is 2. Also preferred are the compounds of the Formula (I) where p, q, and n are each zero, r is 1 and m is 2 or 3. More preferred are the compounds where m, nyr with each zero, q is 1, p is 2 Z is -CH2"and R is -OR6, especially when R6 is hydrogen Also more preferred with the compounds of Formula (I) wherein, p, q and n are each zero, r is 1, m is 2, X is -CH 2 - and R 2 is -OR 6, especially when R 6 is hydrogen Another group of preferred compounds of Formula (I) are those wherein Ar 1 is phenyl or R 4 -substituted phenyl, Ar 2 is phenyl or R 4 -substituted phenyl and Ar 3 is R5-substituted phenyl Also preferred are compounds wherein Ar1 is phenyl or R4-substiuuted phenyl, Ar 2 is phenyl or R 4 -subfined phenyl, Ar 3 is R 5 -substituted phenyl, and the sum of m, n, p, qyr is 2, 3 or 4, more preferably 3. Most preferred are compounds wherein Ar 1 is phenyl or R 4 -substituted phenyl, Ar 2 is phenyl or R 4 -substituted phenyl, Ar 3 is R 5 -substituted phenyl, and wherein m, n and r are each zero, q is 1 and p is 2, or where p, q and n are each zero, r is 1 and m is 2 or 3. In a preferred embodiment, a substituted azetidinone of the formula (I) useful in the compositions, therapeutic combinations and methods of the present invention is represented by the following formula (II) (ezetimibe): or pharmaceutically acceptable salts or solvates of the compounds of the formula (II). The compound of the formula (II) can be an anhydrous or hydrated form. A product that contains the ezeimibe compound is commercially available as a ZETIA® ezetimibe formulation from MSP Pharmaceuíicals. The compounds of formula I can be prepared through a variety of methods well known to those skilled in the art, for example such as those described in U.S. Patent Nos. 5,631, 365, 5,767,115, 5,846,966, 6,207,822, PCT Application Application No. 02/079174, and PCT Patent Application WO 93/02048, each of which is incorporated herein by reference and in the following example. The alternated substituted azetidinones useful in the compositions, therapeutic combinations and methods of the present invention are represented by the following formula (III): or a pharmaceutically acceptable salt thereof or a solvate thereof, wherein, in formula (III) above: Ar1 is R3-substituted aryl; Ar 2 is R 4 -substituted aryl; Ar3 is R5-substituted aryl; Y and Z independently are selected from the group consisting of -CH2-, -CH (lower alkyl) - and -C (lower dialkyl) -; A is selected from -O-, -S-, -S (O) - or -S (0) 2-; R1 is selected from the group consisting of -OR6, -0 (CO) R, -0 (CO) OR9 and -0 (CO) NR6R7; R2 is selected from the group consisting of hydrogen, lower alkyl, and alkyl; or R1 and R2 together are = 0; q is 1, 2 or 3; p is 0, 1, 2, 3 or 4; R5 is 1-3 substituents independently selected from the group consisting of -OR, -0 (CO) R6, -0 (CO) OR9, -0 (CH2)? ^ OR9, -0 (CO) NR6R7, -NR6R7, - NR6 (CO) R7, -NR6 (CO) OR9, -NR6 (CO) NR7R8, -NR6 S02.-lower alkyl, -NR6S02-aryl, -CONR6R7, -COR6, -S02NR6R7, S (O) 0.2-alkyl, S (O) 0-2-aryl, -O (CH2) 1-10-COOR6, -O (CH2)? -10CONR6R7, o-halogen, m-halogen, o-lower alkyl, m-lower alkyl, - ( lower alkylene) -COOR, and -CH = CH-COOR6; R3 and R4 are independently 1-3 susfiuuyeníes independently selected from the group consisting of R5, hydrogen, p-lower alkyl, aryl, -N02, -CF and p-halogen; R6, R7 and R8 are independently selected from the group consisting of hydrogen, lower alkyl, aryl and lower alkyl substituted with aryl; and R9 is lower alkyl, aryl or lower alkyl substituted with aryl. The methods for making compounds of formula III are well known to those skilled in the art. Non-limiting examples of suitable methods are described in the pamphlet of E. U. A. No. 5,688,990, which is incorporated herein by reference. In another embodiment, substituted azeidinones useful in the compositions, therapeutic combinations and methods of the present invention are represented by formula (IV): or a pharmaceutically acceptable salt thereof or a solvate thereof, wherein, in the above formula (IV): A is selected from the group consisting of a 2-substituted heteroarylcycloalkyl, substituted R2-heteroaryl, substituted benzofused substituted R2-heterocycloalkyl, and R2 -substituted benzofused heteroaryl; Ar 1 is aryl or R 3 -substituted aryl; Ar2 is aryl or R4-aryl susiiuuido; Q is a bond or, with the carbon ring in position 3 of azetidinone, forms the spiro group and R1 is selected from the group consisting of: - (CH2) q-, where q is 2-6, provided that Q form a spiro ring, which can also be zero or 1; - (CH2) eG- (CH2) r-, where G is -O-, -C (O) -, phenylene, -NR- or -S (O) 0-2, e is 0-5 and r is 0 -5, provided that the sum of eyr is 1-6; - (alkylene of 2 to 6 carbon atoms) -; and - (CH2) f-V- (CH2) g-, wherein V is cycloalkylene of 3 to 6 carbon atoms, f is 1 -5 and g is 0-5, provided that the sum of f and g is 1-6; R5 is selected from: -CH-, -C (alkyl of 1 to 6 carbon atoms) -, -CF-, -C (OH) -, - C (C6H4R9) -, -N-, or + NO-; R6 and R7 are independently selected from the group consisting of -CH2-, -CH (alkyl of 1 to 6 carbon atoms) -, -C (di- (alkyl of 1 to 6 carbon atoms, -CH = CH- and -C (Alkyl of 1 to 6 carbon atoms) = CH-; or R5 together with an adjacent R6, or R5 june with an adjacent R7, forms a group -CH = CH- or a -CH = C (alkyl of 1 to 6 carbon atoms) -; a and b are independently 0, 1, 2 or 3, provided that both are not zero; provided that when R7 is -CH = CH- or-C (alkyl of 1 to 6 carbon atoms) = CH-, a is 1; provided that when R7 is -CH = CH- or -C (alkyl of 1 to 6 carbon atoms) = CH-, b is 1; provided that when a is 2 or 3, R6 's may be the same or different; and provided that when b is 2 or 3, the R7's may be the same or different; and when Q is a link, R1 can also be selected from: -M -Y.r k-S (0) c > _? ~; wherein M is -O-, -S-, -S (O) - or -S (0) 2-; X, Y and Z are independently selected from the group consisting of -CH2-, -CH (alkyl of 1 to 6 carbon atoms) - and -C (di-alkyl of 1 to 6 carbon atoms); R10 and R12 are independently selected from the group consisting of -OR14, -0 (CO) R14, -0 (CO) OR16 and -0 (CO) NR14R15; R11 and R13 are independently selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms and aryl; or R10 and R11 juni are = 0, or R12 and R13 juni are = 0; d is 1, 2 or 3; h is O, 1, 2, 3 or 4; s is O or 1; t is O or 1; m, n and p are independently 0-4; provided that at least one of s and t are 1, and the sum of m, n, p, s, and t is 1 -6; provided that when p is 0 and t is 1, the sum of m, s and n is 1-5; and provided that when p is 0 and s is 1, the sum of m, i and n is 1-5; v is O or 1; j and k are independently 1-5, provided that the sum of j, k and v is 1-5; R2 is 1-3 substituents on the ring carbon atoms selected from the group consisting of hydrogen, alkyl of 1 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, cycloalkenyl of 3 to 6 carbon atoms, R 17 -substituted aryl, R 17 -substituted benzyl, R 17 -substituted benzyloxy, R 17 -substituted aryloxy, halogen, -NR 14 R 15, NR 14 R 15 (alkylene of 1 to 6 carbon atoms) -, NR 14 R 15 C (0) ( alkyl of 1 to 6 carbon atoms) -, -NHC (0) R16, OH, alkoxy of 1 to 6 carbon atoms, -OC (0) R16, -COR14, hydroxy-alkyl of 1 to 6 carbon atoms carbon, alkoxy of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms, N02, -S (O) 0-2R16, -S02NR1 R15 and -OC-C6-alkylene COOR; when R2 is a substitution in a helerocycloalkyl ring, R2 is as defined, or is = 0 or and, wherein R is a substitute in a substitutable ring nitrogen, is hydrogen, alkyl of 1 to 6 carbon atoms, aryl, alkoxy of 1 to 6 carbon atoms, aryloxy, alkylcarbonyl of 1 to 6 carbon atoms, arylcarbonyl , hydroxy, - (CH2) r6CONR 8R18, wherein J is -O-, -NH-, -NR? 8- or -CH2-; R3 and R4 are independently selected from the group consisting of 1-3 substituents independently selected from the group consisting of alkyl of 1 to 6 carbon atoms, -OR14, -0 (CO) R14, - 0 (CO) OR16, -0 (CH2) 1-5OR14, -0 (CO) NR14R15, -NR14R15, -NR14 (CO) R15, -NR14 (CO) OR16, -NR14 (CO) NR15R19, -NR14S02R16, -COOR14, -CONR14R15, -COR14, -S02NR14R15, S (O) 0-2R16, -O (CH2) 1-10-COOR14, -O (CH2) MOCONR ^ R15, - (alkylene of 1 to 6 carbon atoms) -COOR14, -CH = CH- COOR14, -CF3, -CN, -N02 and halogen; R8 is hydrogen, alkyl of 1 to 6 carbon atoms, aryl-alkyl of 1 to 6 carbon atoms, -C (0) R14 or -COOR; R9 and R17 are independently 1-3 groups independently selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, -COOH, N02, -NR14R15, OH and halogen; R14 and R15 are independently selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, aryl and alkyl of 1 to 6 carbon atoms suspended with aryl; R16 is alkyl of 1 to 6 carbon atoms, aryl or R17-aryl susíiuuido; R18 is hydrogen or alkyl of 1 to 6 carbon atoms; and R19 is hydrogen, hydroxy or alkoxy of 1 to 6 carbon atoms. The methods for making the compounds of Formula IV are well known to those in the art. Non-limiting examples of suitable methods are described in the U.S. Patent. No. 5,656,624, which is incorporated herein by reference. In another embodiment, the substituted azetidinones useful in the compositions, therapeutic combinations and methods of the present invention are represented by Formula (V): (V) or a pharmaceutically acceptable salt thereof or a solvate thereof, wherein, in the above Formula (V): Ar 1 is aryl, R 10 -subusified or heyaryaryl aryl; Ar2 is aryl or substituted R4-aryl; Ar3 is aryl or substituted R5-aryl; X and Y are independently selected from the group consisting of -CH2-, -CH (lower alkyl) - and -C (di-alkik) lower) -; R is -OR6, -0 (CO) R6, -0 (CO) OR9 or -0 (CO) NR6R7; R1 is hydrogen, lower alkyl or aryl; or R and R1 together are = 0; q is 0 or 1; r is 0.1 or 2; m and n are independently 0, 1, 2, 3, 4 or 5; provided that the sum of m, n and q is 1, 2, 3, 4, or 5; R4 is 1-5 substituents independently selected from the group consisting of lower alkyl, -OR6, -0 (CO) R6, -0 (CO) OR9, -0 (CH2) 1- 5OR6, -0 (CO) NR6R7, - NR6R7, -NR6 (CO) R7, -NR6 (CO) OR9, -NR6 (C0) NR7R8, - NR6S02R9, -COOR6, -CONR6R7, -COR6, -S02NR6R7, S (O) 0-2R9, -0 (CH2 )? -? o- COOR6, -O (CH2) 1.10CONR6R7, - (alkylene of 1 to 6 carbon atoms) COOR6, and -CH = CH-COOR6; R5 is 1-5 substituents independently selected from the group consisting of -OR6, -O (CO) R6, -0 (CO) OR9, -OÍCH ^ -sOR6, -0 (CO) NR6R7, -NR6R7, -NR6 (CO) R7, -NR6 (CO) OR9, -NR6 (CO) NR7R8, -NR6S02R9, -COOR6, -CONR6R7, -COR6, -S02NR6R7, S (0) or-2R9, -0 (CH2)? -? Or -COOR6 , -O (CH2)? - 10CONR6R7, -CF3, -CN, -N02, halogen, - (lower alkylene) COOR6 and -CH = CH-COOR6; R6, R7 and R8 are independently selected from the group consisting of hydrogen, lower alkyl, aryl and lower alkyl substituted with aryl; R9 is lower alkyl, aryl or lower alkyl substituted with aryl; and R10 is 1-5 substituents independently selected from the group consisting of lower alkyl, -OR6, -0 (CO) R6, -0 (CO) OR9, -0 (CH2)? -5OR6, -0 (CO) NR6R7, -NR6R7, -NR6 (CO) R7, -NR6 (CO) OR9, -NR6 (CO) NR7R8, -NR6S02R9, -COOR6, -CONR6R7, -COR6, -S02NR6R7, S (0) or -R9, -O ( CH2) 1-10- COOR6, -0 (CH2)? -? OCONR6R7, -CF3, -CN, -N02, and halogen.

The methods for making the compounds of Formula V are well known to those skilled in the art. Non-limiting examples of suitable methods are described in the U.S. Patent. No. 5,624,920, which is incorporated herein by reference. In another embodiment, the soluble urididinones useful in the compositions, feperaluic combinations and methods of the present invention are represented by Formula (VI): or pharmaceutically acceptable salts thereof, or a solvate thereof: R1 is -CH-, -C (lower alkyl) -, -CF-, -C (OH) -, -C (C6H5) -, -C (C6H4-R15) - I I -N-, or + NO-; R2 and R3 are independently selected from the group consisting of: -CH2-, -CH (lower alkyl) -, -C (di-lower alkyl) -, -CH = CH- and -C (lower alkyl) = CH-; or R-i together with an adjacent R2, or R1 together with an adjacent R3, form a group -CH = CH- or -CH = C (lower alkyl) -; u and v are independently 0, 1, 2 or 3, provided that both are not zero; provided that when R2 is -CH = CH- or -C (lower alkyl) = CH-, v is 1; provided that when R3 is -CH = CH- or -C (lower alkyl) = CH-, u is 1; provided that when v is 2 or 3, the R2's may be the same or different; and provided that when u is 2 or 3, the R3, s may be the same or different; R4 is selected from B- (CH2) mC (0) -, where m is 0, 1, 2, 3, 4 or 5; B- (CH2) q-, where q is 0, 1, 2, 3, 4, 5 or 6; B- (CH2) eZ- (CH2) r, wherein Z is -O-, -C (O) -, phenylene, -N (R8) - or -S (0) o-2-, e is 0, 1, 2, 3, 4 or 5 and r is 0, 1, 2, 3, 4 or 5, provided that the sum of e and r is 0,1, 2, 3, 4, 5 or 6; B- alkylene of 2 to 6 carbon atoms; B-alkadienylene of 4 to 6 carbon atoms; B- (CH2) tZ-alkenylene of 2 to 6 carbon atoms-, where Z is as defined above, and where t is 0, 1, 2 or 3, provided that the sum of I and the number of atoms of carbon in the alkenylene chain is 2, 3, 4, 5 or 6; B- (CH2) fV- (CH2) g-, where V is cycloalkylene of 3 to 6 carbon atoms, f is 1, 2, 3, 4, or 5 and g is 0, 1, 2, 3, 4, or 5, provided that the sum of f and g is 1, 2, 3, 4, 5, or 6; B- (CH2) tV-alkenylene of 2 to 6 carbon atoms- or B-alkenylene of 2 to 6 carbon atoms-V- (CH2) 7-, where V and t are as defined above, provided that the sum t and the number of carbon atoms in the alkenylene chain is 2, 3, 4, 5 or 6; B- (CH2) aZ- (CH2) bV- (CH2) d-, wherein Z and V are as defined above already, b, and d are independently 0, 1, 2, 3, 4, 5, or 6, provided that the sum of a, b, and d is 0, 1, 2, 3, 4, 5, or 6; or T- (CH2) S-, wherein T is cycloalkyl of 3 to 6 carbon atoms and s is 0, 1, 2, 3, 4, 5, or 6; or I R-i and R4 together form the group B-CH = C-; B is selected from indanyl, indenyl, naphthyl, teirahydropyranyl, heteroaryl or heteroaryl substituted with W, wherein the heteroaryl is selected from the group consisting of pyrrolyl, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, imidazolyl, thiazolyl, pyrazolyl, thienyl, oxazolyl, and furanyl, and for the heteroaryls containing nitrogen, the N-oxides thereof, or W is 1 to 3 subsfitures independently selected from a group consisting of lower alkyl, hydroxy-lower alkyl, lower alkoxy, alkoxyalkyl, alkoxycarbonylalkoxy, lower alkoxyimino-lower alkyl, lower alkanedioyl, lower alkyl-lower alkanedioyl, allyloxy, -CF3, -OCF3, benzyl, R -benzyl, benzyloxy, R7-benzyloxy, phenoxy, R7-phenoxy, dioxolanyl, N02-, N (R8) (Rg), N (R8) (R9) -lower-alkylene, N (R8) (R9) -loweralkyloxy-, OH, halogen, -CH, -N3, -NHC (O) OR10, -NHC (O) R10, Rn02SNH-, (Rn02S) 2N-, - S (0) 2NH2, -S (0) or-2R8, tert-butyldimethyl -syloxymethyl, -C (0) R12, -COORT 9, - CON (R8) (R9), -CH = CHC (0) Ri2, -lower-alkylene-C (0) R? 2, R? OC (0) (lower alkyleneoxy) -, N (R8) (R9) C (0) (lower alkylenyloxy) - and /% - CH2- N Ria? For susiiution in the ring carbon atoms, and Substitutes in the nitrogen atoms of the substituted heteroaryl ring, when present, are selected from the group consisting of lower alkyl, lower alkoxy, -C (0) OR? or, -C (0) R-? o, OH , N (R8) (Rg) - lower alkylene-, N (R8) (R9) - lower alkenyloxy-, -S (0) 2NH2 and 2- (methylsulfyl) -deoxymethyl; R is 1-3 groups independently selected from the group consisting of lower alkyl, lower alkoxy, -COOH, N02, -N (R8) (R9), OH, and halogen; R8 and Rg are independently selected from H or lower alkyl; R-io is selected from lower alkyl, phenyl, R7-phenyl, benzyl or R -benzyl; Rn is selected from OH, lower alkyl, phenyl, benzyl, R7-phenyl or R7-benzyl; R12 is selected from H, OH, alkoxy, phenoxy, benzyloxy, ~ _ / l * -N (R8) (R9), lower alkyl, phenyl, or R -phenyl; R 3 is selected from -O-, -CH 2 -, -NH-, -N (lower alkyl) - or -NC (0) R 19; Ri5. Rie and R17 are independently selected from the group consisting of H and the groups defined for W; or R15 is hydrogen and R16 and R17, together with the adjacent carbon atoms to which they are bonded, form a dioxolanyl ring; Ri is H, lower alkyl, phenyl or phenyl lower alkyl; and R_o and R21 are independently selected from the group consisting of phenyl, phenyl unsubstituted with W, naphthyl, naphthyl substituted with W, indanyl, indenyl, tetrahydronaphthyl, benzodioxolyl, heteroaryl, heteroaryl substituted with W, benzofused heteroaryl, benzofused heteroaryl substituted with W and cyclopropyl, wherein the heteroaryl is as defined above. Methods for making compounds of formula VI are well known to those skilled in the art. Non-limiting examples of suitable methods are described in U.S. Patent No. 5,698,548, which is incorporated herein by reference. In another embodiment, the substituted azetidinones useful in the compositions, therapeutic combinations and methods of the present invention are represented by the formulas (VIIA) and (VIIB): or a pharmaceutically acceptable salt or solvate thereof, wherein: A is -CH = CH, -CsC- or - (CH2) P- wherein p is 0, 1, or 2; B is B 'is D is - (CH2) mC (0) - or - (CH2) q- where m is 1, 2, 3 or 4 and q is 2, 3 or 4; E is alkyl of 10 to 20 carbon atoms or -C (0) -alkyl of 9 to 19 carbon atoms, wherein the alkyl is straight or branched, saturated or contains one or more double bonds; R is hydrogen, alkyl of 1 to 15 carbon atoms, straight or branched, saturated or contains one or more double bonds, or B- (CH2) r-, wherein r is 0, 1, 2, or 3; Ri, R2, R3, Rr, R2 ', and R3 are independently selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, N02, NH2, OH, halogen, lower alkylamino, lower dialkylamino, -NHC (0) OR5, R602SNH- and -S (0) 2NH2; R4 is wherein n is 0, 1, 2 or 3; R5 is lower alkyl; and R6 is OH, lower alkyl, phenyl, benzyl or substituted phenyl wherein the substituents are 1-3 independently selected groups consisting of lower alkyl, lower alkoxy, carboxy, N02, NH2, OH, halogen, lower alkylamino and lower dialkylamino; or a pharmaceutically acceptable salt thereof or a solvate thereof. In another embodiment, the eseryol absorption inhibitors useful in the compositions and methods of the present invention are represented by Formula (VIII): or a pharmaceutically acceptable salt thereof or a solvate thereof, wherein, in Formula (VIII) above, R26 is H or OG1; G and G1 are independently selected from the group consisting of H, and R4 OH, G is not H; R, Ra and Rb are independently selected from the group consisting of H, -OH, halogen, -NH2, azido, alkoxy of 1 to 6 carbon atoms-alkoxy of 1 to 6 carbon atoms or -W-R30; W is independently selected from the group consisting of -NH-C (O) -, -OC (O) -, -0-C (0) -N (R31) -, -NH-C (0) -N (R31 ) - and -0-C (S) -N (R31) -; R2 and R6 are independently selected from the group consisting of H, alkyl of 1 to 6 carbon atoms, aryl and arylalkyl of 1 to 6 carbon atoms; R3, R4, R5, R7, R3a and R4a are independently selected from the group consisting of H, alkyl of 1 to 6 carbon atoms, aryl-alkyl of 1 to 6 carbon atoms, -C (O) alkyl of 1 to 6 carbon atoms and -C (O) aryl; R30 is selected from the group consisting of R32-substituted T, R32-substituted-T-alkyl of 1 to 6 carbon atoms, R32-substituted-alkenyl of 2 to 4 carbon atoms, R32-substituted-alkyl of 1 to 6 carbon atoms, R32-substituted-cycloalkyl of 3 to 7 carbon atoms and R32-substituted-cycloalkyl of 3 to 7 carbon atoms-alkyl of 1 to 6 carbon atoms; R31 is selected from the group consisting of H and alkyl of 1 to 4 carbon atoms; T is selected from the group consisting of phenyl, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, iathiazolyl, benzothiazolyl, thiadiazolyl, pyrazolyl, imidazolyl and pyridyl; R32 is independently selected from 1-3 substituents independently selected from the group consisting of halogen, alkyl of 1 to 4 carbon atoms, -OH, phenoxy, -CF3, -N02, alkoxy of 1 to 4 carbon atoms, methylenedioxy, oxo, alkylsulfanyl of 1 to 4 carbon atoms, alkylsulfinyl of 1 to 4 carbon atoms, alkylsulfonyl of 1 to 4 carbon atoms, -N (CH 3) 2, -C (0) -NH-alkyl of 1 to 4 atoms of carbon, -C (0) -N (alkyl of 1 to 4 carbon atoms) 2, -C (0) -alkyl of 1 to 4 carbon atoms, -C (O) -alkoxy of 1 to 4 carbon atoms and pyrrolidinylcarbonyl; or R32 is a covalent linkage and R31, the nitrogen to which it is bound and R32 form a pyrrolidinyl, piperidinyl, N-meityl-piperazinyl, indolinyl or morpholinyl group, or a substituted alkoxycarbonyl of 1 to 4 carbon atoms-pyrrolidinyl, piperidinyl, N-methylpiperazinyl, indolinyl or morpholinyl group; Ar 1 is aryl or R 1 -substituted aryl; Ar2 is aryl or R11-substituted aryl; Q is a bond or, with the ring carbon at position 3 of azetidinone, forms the spiro group R1 is selected from the group consisting of - (CH2) q-, where q is 2-6, provided that when Q forms a spiro group, q may also be zero or 1; - (CH2) eE- (CH2) r-, where E is -O-, -C (O) -, phenylene, -NR22- or - S (0) o-2-, e is 0-5 and r is 0-5, provided that the sum of eyr is 1-6; -alkenylene of 2 to 6 carbon atoms-; and - (CH2) f-V- (CH2) g-, wherein V is cycloalkylene of 3 to 6 carbon atoms, f is 1 -5 and g is 0-5, provided that the sum of f and g is 1-6; R12 is -C 1 H-, -C '-alkyl of 1 to 6 carbon atoms, -C' F-, -C '(OH) -, -C' (C6H4-R 2233) -, -N! - I, or - + NO "; R13 and R14 are independently selected from the group consisting of -CH2-, -CH-alkyl of 1 to 6 carbon atoms-, -C-di-alkyl of 1 to 6 carbon atoms, -CH = CH- and -C- alkyl of 1 to 6 carbon atoms = CH-, or R12 June with an adjacent R13, or R12 together with an adjacent R14, form a group -CH = CH- or a group -CH = C -alkyl of 1 to 6 carbon atoms, a and b are independently 0,1, 2 or 3, provided that both are not zero, provided that when R 13 is -CH = CH- or -C-alkyl of 1 to 6 carbon atoms = CH-, a is 1, provided that when R14 is -CH = CH- or -C-alkyl of 1 to 6 carbon atoms = CH-, b is 1, provided that when a is 2 or 3, the R13's can be equal or different, and provided that when b is 2 or 3, the R14, s can be the same or different, and when Q is a link, R1 can also be: 'rí M is -O-, -S-, -S (O) - or -S (0) 2-; X, Y and Z are independently selected from the group consisting of -CH2-, -CH-alkyl of 1 to 6 carbon atoms- and -C-d1-alkyl of 1 to 6 carbon atoms; R10 and R11 are independently selected from the group consisting of 1-3 independently selected substituents from the group consisting of alkyl of 1 to 6 carbon atoms, -OR19, -0 (CO) R19, -O (CO) OR21, - 0 (CH2)? - 5OR19, -0 (CO) NR19R2 °, -NR19R20, -NR19 (CO) R20, -NR19 (CO) OR21, -NR19 (CO) NR20R25, -NR19S02R21, -COOR19, -CONR19R20, - COR19, -S02NR19R20, S (O) 0-2R21, -0 (CH2) 1-? O -COOR19, -O (CH2) 1-10CONR19R20, -alkylene of 1 to 6 carbon atoms-COOR19, -CH = CH-COOR19 , - CF3, - CN, -N02 and halogen; R15 and R17 are independently selected from the group consisting of -OR19, -0 (CO) R19, -0 (CO) OR21 and -0 (CO) NR19R2 °; R16 and R18 are independently selected from the group consisting of H, alkyl of 1 to 6 carbon atoms and aryl; or R15 and R16 juni are = 0, or R17 and R18 juni are = 0; d is 1, 2 or 3; h is O, 1, 2, 3 or 4; s is O or 1; t is O or 1; m, n and p are independently 0-4; provided that at least one of s and t is 1, and the sum of m, n, p, s and t is 1-6; provided that when p is 0 and t is 1, the sum m, s and n is 1-5; and provided that when p is 0 and s is 1, the sum of m, t and n is 1-5; v is 0 or 1; j and k are independently 1-5, provided that the sum of j, k and v is 1-5; and when Q is a bond and Ri is s (°.) or-_ ~ Ar1 can also be pyridyl, isoxazolyl, furanyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, pyrazinyl, pyrimidinyl or pyridazinyl; R19 and R20 are selected independently of the group consisting of H, alkyl of 1 to 6 carbon atoms, aryl and aryl-substituted alkyl of 1 to 6 carbon atoms, R21 is alkyl of 1 to 6 carbon atoms, aryl or R24-ary or susíifuido R22 is H, alkyl of 1 to 6 carbon atoms, aryl-alkyl of 1 to 6 carbon atoms, -C (0) R19 or -COOR19; R23 and R24 are independently 1-3 groups independently selected from the group consisting of of H, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, -COOH, N02, -NR19R20, -OH and halogen, and R25 is H, -OH or alkoxy of 1 to 6 carbon atoms The methods for making the compounds of Formula VIII are well known to those skilled in the art.The non-limiting examples of the methods equates are described in the U.S. Patent. No. 5,756,470, which is incorporated herein by reference. In another embodiment, the substituted azetidinones useful in the compositions and methods of the present invention are represented by the following Formula (IX): or a pharmaceutically acceptable salt or solvate thereof, wherein in Formula (IX): R1 is selected from the group consisting of H, G, G1, G2, -S03H and -PO3H; G is selected from the group consisting of: H, 3-1 OR (sugar derivatives) wherein R, Ra and Rb each is independently selected from the group consisting of H, -OH, halogen, -NH2, azido, alkoxy of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms or -W-R30; W is independently selected from the group consisting of -NH-C (O) -, -OC (O) -, -0-C (0) -N (R31) -, -NH-C (0) -N (R31) ) -and -0-C (S) -N (R31); R2 and R6 are each independently selected from the group consisting of H, alkyl of 1 to 6 carbon atoms, acetyl, aryl and arylalkyl of 1 to 6 carbon atoms; R3, R4, R5, R7, R3a and R4a are each independently selected from the group consisting of H, alkyl of 1 to 6 carbon atoms, acetyl, aryl-alkyl of 1 to 6 carbon atoms, -C (0) -alkyl of 1 to 6 carbon atoms and -C (0) aryl; R30 is independently selected from the group consisting of substituted R32-T, R32-substituted-T-alkyl of 1 to 6 carbon atoms, R32-substituted-alkenyl of 2 to 4 carbon atoms, R32-substituted-alkyl of 1 to 6 carbon atoms, R32-substituted-cycloalkyl of 3 to 7 carbon atoms and R32-susphiuido-cycloalkyl of 3 to 7 carbon atoms-alkyl of 1 to 6 carbon atoms; R31 is independently selected from the group consisting of H and alkyl of 1 to 4 carbon atoms; T is independently selected from the group consisting of phenyl, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, benzothiazolyl, diazodiazol, pyrazolyl, imidazolyl and pyridyl; R32 is independently selected from 1-3 substituents wherein each is independently selected from the group consisting of H, halogen, alkyl of 1 to 4 carbon atoms, -OH, phenoxy, -CF3, -N02, alkoxy of 1 to 4 carbon atoms, methylenedioxy, oxo, alkylsulfanyl of 1 to 4 carbon atoms, alkylsulfinyl of 1 to 4 carbon atoms, alkylsulfonyl of 1 to 4 carbon atoms, -N (CH 3) 2, -C (0) -NH- alkyl of 1 to 4 carbon atoms, -C (0) -N (alkyl of 1 to 4 carbon atoms) 2, -C (O) -alkyl of 1 to 4 carbon atoms, -C (O) -alkoxy from 1 to 4 carbon atoms and pyrrolidinylcarbonyl; or R32 is a covalent bond and R31, the nitrogen to which it is bound and R32 forms a pyrrolidinyl, piperidinyl, N-methyl-piperazinyl, indolinyl or morpholinyl group, or an alkoxycarbonyl group of 1 to 4 carbon atoms-substituted pyrrolidinyl, piperidinyl , N-methylpiperazinyl, indolinyl or morpholinyl; G1 is represented by the structure: wherein R33 is independently selected from the group consisting of a substituted alkyl, R34-substituted alkyl, (R35) (R36) alkyl-, R34 is one of the three substituents, each R34 being independently selected from the group consisting of HOOC-, HO-, HS-, (CH3) S-, H2N-, (NH2) (NH) C (NH) -, (NH2) ) C (0) - and HOOCCH (NH3 +) CH2SS-; R35 is independently selected from the group consisting of H and NH2-; R36 is independently selected from the group consisting of H, unsubstituted alkyl, R34-substituted alkyl, unsubstituted cycloalkyl and substituted R34-cycloalkyl; G2 is represented by the structure: wherein R and R each is independently selected from the group consisting of alkyl of 1 to 6 carbon atoms and aryl; R26 is one of five substituents, each R26 being independently selected from the group consisting of: a) H; b) -OH; c) -OCH3; d) fluorine; e) chlorine; f) -0-G; g) -0-G1; h) -O-G2; i) -S03H; and j) -P03H; provided that when R1 is H, R26 is not H, -OH, -OCH3 or -O-G; Ar 1 is aryl, R 10 -substituted aryl, heteroaryl or R 10 -shelfarinated heteroaryl; Ar 2 is aryl, R 11 -substituted aryl, heteroaryl or substituted R 11 -heteroaryl; L is selected from the group consisting of: a) a covalent link; b) - (CH2) q-, where q is 1-6; c) - (CH2) eE- (CH2) r-, where E is -O-, -C (O) -, phenylene, -NR22- or -S (0) o-2-, e is 0-5 yr is 0-5, as long as the sum of eyr is 1-6; d) -alkenylene of 2 to 6 carbon atoms; e) - (CH2) f-V- (CH2) g-, wherein V is cycloalkylene of 3 to 6 carbon atoms, f is 1-5 and g is 0-5, provided that the sum of f and g is 1-6; f) .15 R, 17? 15 -M- Y, -C- -h "" m - (% - "tCJb-?> R, '16 R1 .16 where M is -O-, -S-, -S (O) - or -S (0) 2-, X, Y and Z each is independently selected from the group consisting of -CH2-, -CH-alkyl of 1 to 6 carbon atoms- and -C-di-alkyl of 1 to 6 carbon atoms - R8 is selected from the group consisting of H and alkyl, R10 and R11 each independently selected from the group consisting of 1-3 substituents each of which is independently selected from the group consisting of alkyl of 1 to 6 carbon atoms, -OR19, -0 (CO) R19, -0 (CO) OR21, -0 (CH2) 1-5OR19, -0 (CO) NR19R2 °, -NR19R20, -NR19 (CO) R20, -NR19 (CO) OR21, -NR19 (CO) NR20R25, -NR19S02R21, -COOR19, -CONR19R20, -COR19, -S02NR19R20, S (O) 0-2R21, -O (CH2) 1-10-COOR19, -alkylene from 1 to 6 carbon atoms-COOR19, -CH = CH-COOR19, -CF3, -CN, -N02 and halogen, R15 and R17 each independently selected from the group consisting of -OR19, -OC (0) R19 , -OC (0) OR21, -OC (0) NR19R2 °, R16 and R 8 each one independently selects from the group consisting of H, alkyl of 1 to 6 carbon atoms and aryl; R15 and R16 together are = 0, or R17 and R18 together are = 0; d is 1, 2 or 3; h is 0,1, 2, 3 or 4; s is O or 1; t is 0 or 1; m, n and p each is independently selected from 0-4; provided that at least one of s and t is 1, and the sum of m, n, p, s and t is 1-6; provided that when p is 0 and t is 1, the sum of m, n and p is 1-5; and provided that when p is 0 and s is 1, the sum of m, í and n is 1-5; v is 0 or 1; j and k are each independently 1-5, provided that the sum from j, k and v be 1-5; Q is a bond, - (CH2) q-, where q is 1-6, or, with the ring carbon in position 3 of azetidinone, forms the spiro group. where R12 is i i? i i f. -CH-, -C who? * C ce) -. -CF-, -C (OH) -. -C (CeH rR ^) -. -N-, or - ^ NO "; R13 and R14 are each independently selected from the group consisting of -CH2-, -CH-alkyl of 1 to 6 carbon atoms-, -C-di-alkyl of 1 to 6 carbon atoms), -CH = CH- and -C-alkyl of 1 to 6 atoms of carbon = CH-; or R12 june with an adjacent R13, or R12 together with an adjacent R14, forms a group -CH = CH- or a group -CH = C-alkyl from 1 to 6 carbon atoms-; a and b are each independently 0, 1, 2 or 3, provided that both are not zero; provided that when R13 is -CH = CH- or -C-alkyl of 1 to 6 carbon atoms = CH-, a is 1; provided that when R14 is -CH = CH- or -C-alkyl of 1 to 6 carbon atoms = CH-, b is 1; provided that when a is 2 or 3, the R13, s may be the same or different; and provided that when b is 2 or 3, the R1, s may be the same or different; and when Q is a link and L is then Ar1 may also be pyridyl, isoxazolyl, furanyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, pyrazinyl, pyrimidinyl or pyridazinyl; R19 and R20 are each independently selected from the group consisting of H, alkyl of 1 to 6 carbon atoms, aryl and aryl-substituted alkyl of 1 to 6 carbon atoms; R21 is alkyl of 1 to 6 carbon atoms, aryl or R 24 -substituted aryl; R22 is H, alkyl of 1 to 6 carbon atoms, arylalkyl of 1 to 6 carbon atoms, -C (0) R19 or -COOR19; R23 and R24 are each independently selected from the group consisting of 1-3 substituents which are each independently selected from the group consisting of H, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, - COOH, N02, -NR19R20, -OH and halogen; and R25 is H, -OH or alkoxy of 1 to 6 carbon atoms. Examples of the compounds of Formula (IX) which are useful in the methods and combinations of the present invention and methods for making said compounds are described in the E.U.A. Serial No. 10 / 166,942, filed June 11, 2002, incorporated herein by reference. An example of a useful compound of this invention is one represented by formula X: X where R1 is defined as above. A more preferred compound is one represented by the formula Other useful compound is represented by formula XII: Other useful and substituted azetidinone compounds include N-sulfinyl-2-azetidinones such as those described in US Pat. No. 4,983,597, ethyl 4- (2-oxoazetidin-4-yl) phenoxy-alkanoates such as those described in Ram et al., Lndian J. Chem. Sect. B. 29B, 12 (1990), p. 1134-7, and diphenyl azetidinones and derivatives described in U.S. Patent Publication Nos. 2002/0039774, 2002/0128252, 2002/0128253 and 2002/0137689, and WO 2002/066464, each of which is incorporated herein by reference. by reference. The compounds of the formula I-XII can be prepared by known methods including the methods explained above and, for example, WO 93/02048 describes the preparation of compounds wherein -R1-Q- is alkylene, alkenylene, or interrupted alkylene by a heterogeneous atom, phenylene or cycloalkylene; WO 94/17038 describes the preparation of compounds wherein Q is a spirocyclic group: WO 95/08532 describes the preparation of compounds wherein -R1-Q- is an alkylene group substituted by hydroxy; PCT / US95 / 03196 discloses compounds wherein -R1-Q- is an alkylene substituted by hydroxy linked to a portion Ar1 through a group -O- or S (O) 0-2-; and US Series No. 08 / 463,619 filed on June 5, 1995, describes the preparation of compounds wherein -R1-Q- is an alkylene group substituted with hydroxy linked to the azetidinone ring through the group -S (O) 0-2-. The daily dose of the sterol absorption inhibitors administered to the subject may range from 0.1 to about 1000 mg per day, preferably around 0.25 to about 50 mg / day, and more preferably about 10 mg per day, given in an individual dose or from 2 to 4 divided doses. The exact dose however is determined by the attending physician and is dependent on the potency of the compound administered, the age, weight, condition and response of the patient. For the administration of pharmaceutically acceptable salts of the above compounds, the weights indicated above refer to the weight of the acid equivalent or the base equivalent of the therapeutic compound derived from the salt. In one embodiment of the present invention, the therapeutic compositions or combinations may further comprise one or more pharmacological or therapeutic agents or drugs such as inhibitors of cholesterol biosynthesis and / or lipid lowering agents as explained below. In another embodiment, the composition or treatment may further comprise one or more cholesterol biosynthesis inhibitors co-administered with and in combination with the agent for the modulation of substituted lipid and azetidinone or substituted β -laclam explained above. The most limiting examples of inhibitors of cholesterol biosynthesis inhibitors for use in the compositions, therapeutic combinations and methods of the present invention include competitive inhibitors of CoA HMG reductase, the rate limiting step in cholesterol biosynthesis, kinase inhibitors. of squalene, squalene epoxidase inhibitors and mixtures thereof. Non-limiting examples of suitable CoA HMG inhibitors include alpha-amino acids such as lovastatin (eg, MEVACOR® is available from Merck & amp; amp;; Co.), pravastain (for example, PRAVACHOL® which is available from Bristol Meyers Squibb), fluvastain, simvastatin (for example ZOCOR® which is available from Merck &Co.), atorvastatin, cerivastaine, CI-981, rivasiaphine (7). - (4-fluo-phenyl) -2,6-diisopropyl-5-methoxymethyl-pyridin-3-yl) -3,5-dihydroxy-6-hepaenoate) of rivastatin, rosuvastatin, piiavastatin (such as NK-104) from Negma Kowa of Japan); CoA synthetase inhibitors of HMG, for example L-659,699 ((E, E) -11 [3'R- (hydroxylmethyl) -4'-oxo-2'R-oxyenyl] -3.5, 7R-irimethyl-2,4-undecadienoic acid); inhibitors of squalene synthesis, for example escualesíafina 1; and squalene epoxidase inhibitors, for example, from NB-598 (hydrochloride (E) -N-ethyl-N- (6,6-dimethyl-2-hepien-4-ynyl) -3 - [(3, 3'-bioiofen-5-yl) methoxy] benzene-meamyamine) and other inhibitors of sterol biosynthesis DMP-565. Preferred HMG CoA reductase inhibitors include lovastatin, travasilatin, rosuvasiaine, and simvastatin. The preferred HMG CoA reductase inhibitors are simvastatin. A preferred combination product containing ezelimibe and simvastatin that can be coadministered with the agent for lipid modulation is VYTORIN ™ ezeimibe / simvastatin which is commercially available from MSP Pharmaceuicals, Inc. Generally, a daily oral dosage of the inhibitor (s) of Cholesterol biosynthesis can range from about 0.1 to about 160 mg per day, and preferably about 0.2 to about 80 mg per day in single or 2-3 divided doses. In another preferred embodiment, the composition or treatment comprises the compound of the formula (II) in combination with one or more agents for the modulation of lipid and one or more inhibitors of cholesterol biosynthesis. In such a mode, preferably the agent for lipid modulation is ETC-216. Preferably the cholesterol biosynthesis inhibitor comprises one or more CoA reductase inhibitors of HMG, such as, for example, lovastatin, ravasiaina and / or simvastatin. More preferably, the composition or process comprises the compound of the formula (II) in combination simvastain and ETC-216. In alternative modality, the compositions, therapeutic combinations or methods of the present invention may further comprise one or more bile acid sequestrants (inorganic insoluble anion resins), coadministered with or in combination with the modulating agent (s). of lipid and substituted azetidinone or substituted β-lactam as explained above.

Bile acid sequestrants bind to bile acids in the intestine, disrupt the enterohepatic circulation of bile acids and cause an increase in fecal excretion of spheres. The use of bile acid sequestrants is desirable due to its non-sysiemic mode of action. Bile acid sequestrants can decrease intrahepatic cholesterol and promote the synthesis of apo B / E (LDL) receptors that bind LDL in plasma to also produce cholesterol levels in the blood. Nonlimiting examples of suitable bile acid sequestrants include colesfiramina (styrene divinylbenzene copolymer containing quaternary ammonium cationic groups capable of binding bile acids as QUESTRAN® SLEDAI or QUESTRAN LIGHT® which are available colesfiramina Bristol-Myers Squibb), colesíipol ( a copolymer of diethylene phriamine and 1-chloro-2,3-epoxypropane, as tablets of COLESTID® which are available from Pharmacia), colesevalam hydrochloride (such as WelChol® tablets of poly (allylamine hydrochloride) entangled with epichlorohydrin and alkylated 1 -bromodecano and (6-bromohexyl bromide) -trimeíilamonio) that eslán available from Sankyo), water soluble derivatives such as 3,3-SLEDAI ioene, N- (cycloalkyl) alkylamines and poliglusam, insoluble cualerinizados polystyrenes, saponins and mixtures thereof. Suitable inorganic cholespherol sequestrants include bismuth salicylate plus montmorillonie clay, aluminum hydroxide and calcium carbonate antacids.

Generally, a total daily dosage of bile acid sequestrants is in the range of about 1 to about 50 grams per day, preferably from about 2 to about 16 grams per day in single or 2-4 divided doses. In an alternative embodiment, the irradiation compositions of the present invention may further comprise one or more inhibitors of loyal bile acid transferase ("IBAT") (or inhibitors of apical sodium co-dependent bile acid transport ("ASBT"). )). IBAT inhibitors can inhibit the transfer of bile acid to reduce LDL cholesterol levels. Non-limiting examples of IBAT inhibitors include the real benzoyelins as the therapeutic compounds comprising a 2,3,4,5-tetrahydro-1-benzothiepine 1,1-dioxide structure such as are described in PCT patent application WO 00/38727 which is incorporated herein by reference. Generally, total daily dosage of the IBAT inhibitor can be in the range of about 0.01 to about 1000 mg / day, or preferably about 0.1 to about 50 mg / day in single or 2-4 divided doses. In another preferred embodiment, the compositions or methods of the present invention may further comprise nicoinic acid (niacin) and / or derivatives thereof. As used herein, "nicotinic acid derivative" means a compound comprising a pyridine-3-carboxylate structure or a pyrazin-2-carboxylate structure including the acid forms, salts, zwitterionic esters and ioiuomers when available. Examples of the nicotinic acid derivatives include niceritrol, nicofuranose and acipimox (5-methyl 4-pyrazine-2-carboxylic acid oxide). Nicotinic acid and its derivatives inhibit hepatic VLDL production and its metabolite LDL and increased HDL and apo A-1 levels. An example of a suitable nicoíínico acid production is NIASPAN® (prolonged release tablets of niacin) that are available from Kos. Generally, a total daily dosage of nicotinic acid or a derivative thereof may be in the range of from about 500 to about 10,000 mg / day preferably from about 1000 to about 8000 mg / day, and more preferably from about 3000 to about 6000 mg / day in single or divided doses. In another alternative embodiment, the compositions or treatments of the present invention may further comprise one or more of AcylCoA inhibitors: Cholesterol O-acyltransferase ("ACAT"), which can reduce the levels of LDL and VLDL. ACAT is an enzyme responsible for the esterification of excess cellular cholesterol and can reduce the synthesis of VLDL, which is a product of the esterification of cholesterol, and the overproduction of lipoproteins containing apo B-100. Non-limiting examples of useful ACAT inhibitors include avasimibe ([[2,4,6-tris (1-methylethyl) phenyl] acetyl] sulfamic acid, 2,6-bis (1-methyleryl) phenyl ester, formally known as CI-1011), HL-004, lecimibide (DuP-128) and CL-277082 (N- (2,4-difluorophenyl) -N - [[4- (2,2-dimethylpropyl) phenyl] meilyl-N- heptylurea). See, P. Chang and others, "Current, New and Future Treatmenís in Dyslipidaemia and Aherosclerosis", Drugs 2000 Jul; 60 (1); 55-93, which is incorporated herein by reference. Generally, a total daily dosage of inhibitors) ACAT can be on the scale of about 0.1 to about 1000 mg / day in single or 2-4 divided doses. In another alternative embodiment, the compositions or treatments of the present invention may further comprise one or more inhibitors of Cholesteryl Ester Transfer Protein ("CETP"). CETP is responsible for the in-transfer or transfer of cholesteryl ester carrying HDL and triglycerides in VLDL. Non-limiting examples of suitable CETP inhibitors are described in PCT patent application No. WO 00/38721 and U. U.

No. 6,147,090, which are incorporated herein by reference. The hydrolase inhibitors of the pancreatic cholesteryl ester (pCEH), such as WAY-121898, can also be co-administered with or in combination. Generally, a total daily dosage of the CETP inhibitor (s) may be in the range of about 0.01 to about 1000 mg / day, and preferably about 0.5 to about 20 mg / kg of body weight / day in single or divided doses . In another embodiment of the present invention the compositions or treatments of the present invention may further comprise probucol or derivatives thereof (such as AGI-1067 and other derivatives described in US Pat. Nos. 6,121, 319 and 6,147,250), which may reduce LDL levels. Generally, a total daily dosage of probucol or derivatives thereof may be on the scale of about 10 about 2000 mg / day, and preferably about 500 to about 15,000 mg / day in single or 2-4 divided doses. In another alternative embodiment, the treatment compositions of the present invention may further comprise activators of the low density lipoprotein (LDL) receptor. Non-limiting examples of suitable LDL receptor activators include HOE.403, an imidazolidinyl-pyrimidine derivative which directly stimulate LD receptor activity. See, M.

Huetíinger and oíros, "Hypolipidemic acfivity of HOE-402 is Mediated by Simulation of the LDL Receptor Pathway ", Arterioscler, Thromb, 1993; 13: 1005-12. Generally, a total daily dosage of the activator (s) of the LDL receptor can range from about 1 to about 1000 mg / day in single or 2-4 divided doses. In another alternative embodiment, the compositions or treatments of the present invention can further comprise fish oil, which contains omega-3 fatty acids (3-PUFA), which can reduce VLDL and triglyceride levels. Generally a total daily dosage of fish oil or Omega 3 fatty acids can range from about 1 to about 30 grams per day in single or 2-4 divided doses. In another alternative embodiment, the treatment compositions of the present invention may further comprise natural water-soluble fibers, such as pláníago, guar, oat and pectin, which can reduce cholesterol levels. Generally, a total daily dosage of natural water soluble fibers can be in the range of 0.1 to about 10 grams per day in single or 2-4 divided doses. In another alternative embodiment, the treatment compositions of the present invention may further comprise plant sterols, plant stanols and / or fatty acid esters of plant stanols, such as siloesyanol ester used in BENECOL® margarine, which can reduce the cholesterol levels. Generally, a total daily dosage of plant spheres, plant stanols and / or fatty acid esters of plant stanols can range from about 0.5 to about 20 grams per day in single or 2-4 divided doses. In another alternative embodiment, the irradiation compositions of the present invention may further comprise antioxidants such as probucol, tocopherol, ascorbic acid, β-carotene and setenium, or vitamins such as vitamin B6 or vitamin B12. Generally, a total daily dosage of antioxidants or vitamins can be on the scale of about 0.5 to about 10 grams per day in single or 2-4 divided doses. In alternative form, the compositions or treatments of the present invention may further comprise monolith and macrophage inhibitors such as polyunsaturated fatty acids (PUFA)., formed of thyroid including firoxin analogs such as CGS-26214 (a compound of firoxin with a fluorinated ring), gene therapy and the use of recombinant proteins such as apo E. recombinante. Generally, a total daily dosage of these agents may be in the range of about 0.01 to about 1000 mg / day in single or 2-4 divided doses. Also useful with the present invention are compositions or therapeutic combinations which also comprise hormone replacement agents and compositions. Hormone titile agents and compositions for hormone replacement therapy of the present invention include androgens, estrogens, progesins, and pharmaceutically acceptable salts thereof and derivatives thereof. The combinations of these agents and compositions are also useful. Dosage of androgen and esophageal combinations vary, desirably from about 1 mg to about 4 mg of androgen and from about 1 mg to about 3 mg of estrogen. Examples include, but are not limited to, combinations of androgen and esophagen such as the combination of esterified esogens (sodium estrone sulfate and sodium aquilin sulfate), and methylsiosterone (17-hydroxy-17-methyl-, (17B ) -andost-4-in-3-one) available from Solvay Pharmaceuticals, Inc., Marieta, GA, under the trade name of Eslraiesí.

Estrogens and estrogen combinations may vary in dosage from about 0.01 mg to 8 mg, desirably from about 0.3 mg to about 3.0 mg. Examples of estrogens and useful estrogen combinations include: (a) a mixture of nine (9) synthetic estrogen substances including sodium estrone sulfate, sodium mequilin sulfate, sodium 17a- dihydroequilin sulfate, sodium 17a-estradiol sulfate, 17-sodium dihydroequilin sulfate, 17P-sodium dihydroequilen sulfate, sodium equilenin sulfate and sodium 17p-estradiol sulfate; available from Duramed Pharmaceuticals, Inc., Cincinnati, OH, under the trade name Cenestin; (b) Efinyl estradiol (19-nor-17 a-pregna-1, 3, 5 (10) rtrien-20-ine-3,17-diol, available from Schering Plow Corporation, Kenifworth, NJ, under the trade name of Estinyl; (c) esterified spherical combinations such as sodium sulphonate sulfate and sodium equilin sulfate, available from Solvay under the tradename of Estratab and from Monarca Pharmaceuticals, Bristol, TN, under the trade name Menest; (d) estropipafo (piperazine-1, 3,5 (10) -yrien-17-one, 3- (sulfoxyl) -strone sulfate) available from Pharmacia &Upjohn, Peapack, NJ, under the trade name of Ogen and Women First Health Care, Inc., San Diego, CA, under the tradename of Ortho-Est; and (e) conjugated estrogens (17a-dihydroequilin, 17a-estradiol, and 17P-dihydroequilin) available from Wyeth-Ayerst Pharmaceuticals, Philadelphia, PA, under the trade name of Premarin Progestins and estrogens can also be administered with a variety of dosages, usually from a about 0.05 to about 2.0 mg of progestin and from about 0.001 mg to about 2 mg of estrogen, desirably from about 0.1 mg to about 1 mg of progestin and from about 0.01 mg to about 0.5 mg of esophagen. Examples of combinations of progesin and esophagen that can vary in dosage and regimen include: (a) the combination of esraradiol (estra-1, 3, 5 (1-O-rinien-3, 17p-diol) hemihydrate) and norethindrone (17- acetoxy-19-nor-17 a-pregn-4-en-20-ind 3-one); which is available from Pharmacia & Upjohn, Peapack, NJ, under the commercial name of Activella; (b) the combination of levonorgestrel (d (-) - 13 (3-ethyl-17 a-efinyl-17 3-hydroxygon-4-en-3-one) and ethynyl radical, available from Wyefh-Ayersí under the trade name of Alesse, of Watson Laboratories, Inc., Corona, CA, under the trade names of Levora and Trivora, Monarca Pharmaceuticals, under the trade name of Nordetie, and of Wyeth-Ayerst under the trade name of Trifasil; (c) the combination of ethynediol diacetate (diacetate 19-nor-17 a-pregn-4-en-20-ine-3,17-diol) and ethinyl estradiol, available from GD Searle & Co., Chicago, IL, under the trade name of Demulen and Watson under the trade name of Zovia; (d) the combination of desogestrel (13-ethyl-11-methylene-18,19-dinor-17a-pregn-4-en-20-in-17-ol) and ethinyl estradiol; available from Organon under the tradenames of Desogen and Mircetie, and from Ortho-McNeil Pharmaceutical, Raritan, NJ, under the tradename of Orto-Cept; (e) the combination of norethindrone and ethinyl estradiol; available from Parke-Davis, Morris Plains, NJ, under the trade name Estrosipe and femhrt, from Waíson under the trade name Microgesin, Necon, and Tri- Norinyl, from Ortho-McNeil under the trade name of Modicon and Orto-Novum , and Warner Chilcoíf Laboratories, Rockaway, NJ, under the trade name Ovcon; (f) the combination of norgestrel ((±) -13-ethyl-17-hydroxy-18,19-dinor-17 a-preg-4-en-20-in-3-one) and ethinyl esiradiol; available from Wyeth-Ayerst under the trade names of Ovral and Lo / Ovral, and from Watson under the trade name of Ogestrel and Low Ogestrel; (g) the combination of norethindrone, ethinyl esiradiol, and mestranol (3-methoxy-19-nor-17 a-pregna-1, 3,5 (10) -trien-20-in-17-ol); available from Watson under the trade name of Brevicon and Norinil; (h) the combination of 17-estradiol (este-1,3, 5 (10) -írieno-3,17-diol) and micrometric norgestimate (3-oxime of 17a-17- (Acefiloxil) -13-etil-18 , 19-dinorpregn-4-en-20-in-3-one); available from Ortho-McNeil under the trade name of Ortho-Prefest; (i) the combination of norgestimate (18,19-dinor-17-pregn-4-en-20-in-3-one, 17 - (acetyloxy) -13-ethyl-, oxime, (17 (a) - (+) -) and ethinyl estradiol, available from Ortho-McNeil under the tradename of Ortho Cyclen and Ortho Tri-Cyclen, and (j) the combination of conjugated spherogens (sodium estrone sulfate and sodium aquiline sulfate) and medroxyprogesterone acetate (20-dione, 17- / acetyloxy) -6-methyl-, (6 (a)) - pregn-4-ene-3); available from Wyeth-Ayersí under the commercial name of Premfase and Prempro. In general, a progestin dosage can vary from about .05 mg to about 10 mg or up to about 200 mg if micron progesterone is administered. Examples of progestins include norethindrone; available from ESI Lederle, Inc., Philadelphia, PA, under the tradename of Aygestin, Ortho McNeil under the trade name of Micronor, and Watson under the trade name of Nor-QD; norgestrel; available from Wyefh-Ayersí under the trade name of Ovreííe; microméiric progesterone (pregn-4-ene-3, 20-dione); available from Solvay under the trade name of Promeírium; and medroxyprogesterone acetate; available from Pharmacia & Upjohn under the commercial name of Provera. The compositions, therapeutic combinations or methods of the present invention may further comprise one or more drugs for the control of obesity. Useful obesity control medications include, but are not limited to, drugs that reduce energy intake or suppress appetite, drugs that increase energy expenditure, and the agents that divide nutrients. Suitable obesity control drugs include, but are not limited to, drugs that reduce energy intake or suppress appetite, drugs that increase energy expenditure, and agents that divide nutrients. Appropriate obesity control medications include, but are not limited to, noradrenergic agents (such as acetylpropion, mazindol, phenylpropanolamine, phenerimine, phendimeizrazine, fendamine, tartrate, mephamfetamine, phendimeizrazine, and acrimony); serophonergic agents (such as sibuyramine, fenfluramine, dexfenfluramine, fluoxetine, fluvoxamine and paroxlin); erymogenic agents (such as ephedrine, caffeine, theophylline, and selective β3-adrenergic agonists); beta-blocking agents; cainite or AMPA receptor antagonists; receptors that stimulate leptin lipolysis; Phosphodiesterase enzyme inhibitors; compounds having nucleotide sequences of the gene of mahogany gene; polypeptides of fibroblast growth factor 10; inhibitors of monoamine oxidase (fales such as befloxaine, moclobemide, brofaromine, phenoxaine, esoprone, befol, oloxatone, pirlindol, amiflamin, serchloremin, bazinaprine, lazabemide, milacemide and caroxazone); compounds for increasing lipid metabolism (such as evodiamine compounds); and lipase inhibitors (such as orlistat). Generally, a total dosage of the above-described obesity control medicaments may be on a scale of 1 to 3,000 mg / day, desirably about 1 to 1,000 mg / day and more desirably about 1 to 200 mg. / day in individual doses or 2-4 divided. The compositions, therapeutic combinations or methods of the present invention may further comprise one or more blood modifiers that are chemically different from the azetidinone and substituted β-lactam compounds (such as the above l-XII compounds) and the agents for the lipid modulation explained above, for example, may contain one or more different atoms, have a different configuration of the atoms or a different number of one or more atoms than the sterol absorption inhibitors or agents for modulating the lipid explained above. Useful blood modifiers include, but are not limited to anticoagulants (argatroban, bivalirudin, sodium dalteparin, desirudin, dicumarol, sodium liapolate, nafamostatmesylate, fenprocoumon, tinzaparin sodium, warfarin sodium); antithrombotic (anagrelide hydrochloride, bivalirudin, cilostazol, sodium dalteparin, danaparoid sodium, dazoxiben hydrochloride, efegatran sulfate, enoxaparin sodium, fluretofen, ifeiroban, sodium ifetroban, lamifiban, lotrafiban hydrochloride, napsagatran, orbofiban acetate, roxifiban acetate, sibrafiban, tinzaparin sodium, trifenagrel, abciximab, zolimomab aritox); fibrinogen receptor antagonists (roxifiban acetate, fradafiban, orbofiban, lotrafiban hydrochloride, tirofiban, xemilofiban, monoclonal antibody 7E3, sibrafiban); platelet inhibitors (cilostazol, clopidogrel bisulfate, epoprostenol, sodium epoprostenol, ticlopidine hydrochloride, aspirin, ibuprofen, naproxen, sulindae, idometacin, mefenamate, droxicam, diclofenac, sulfinpyrazone, piroxicam, dipyridamole); inhibitors of platelet aggregation (acadesine, beraprost, sodium beraprost, calcium cyprotensin, iiazigrel, lifarizine, lotrafiban hydrochloride, orbofiban acetate, oxagranate, fradafiban, orbofiban, tirofiban, xemilofiban); hemorrhagic agent agents (pentoxifylline); Coagulation inhibitors associated with lipoprotein; Factor Vlla inhibitors (4H-31-benzoxazin-4-ones, 4H-3, 3-benzoxazin-4-ions, quinazolin-4-ones, quinazolin-4-ions, benzoyzin-4-ones, peptides derived from TFPl of analogs of peptide derived from imidazoloyl boronic acid, trifluoroacety of naphthalene-2-sulfonic acid, {. 1- [3- (aminoiminomethyl) -benzyl] -2-oxo-pyrrolidin-3- (S) -yl.}. amide, dibenzofuran acid 2-Sulfonic acid {. 1 - [3- (aminomethyl) -bencll] -5-oxo-pyrrolidin-3-yl} -amide,-trifluoroacetate. ) -benzyl] -2-oxo-pyrrolidin-3- (S) -yl.} - folic acid-4-sulfonic acid amide, trifluoroacetic acid. {1- [3- (aminoiminomethyl) -benzyl] -2 -oxo-pyrolin-3- (S) -yl.}. -amide) 3,4-dihydro-1 H-isoquinoline-2-sulfonic acid; Factor Xa inhibitors (disubstituted pyrazolines, disulfide-containing Iriazolines, disubstituted n - [(aminoiminomethyl) phenyl] propylamides, sustained n - [(aminomethyl) phenyl] propylamides, tissue factor pathway inhibitor (TFPI), low molecular weight heparins, heparinoids, benzimidazolines, benzoxazolinones, benzopiperazinones, indanones, dibasic acid (amidinoaryl) propane, amidinophenyl-pyrrolidines, amidinophenyl-pyrrolines, amidinophenyl-isoxazolidines, amidinoindoles, amidinoazoles, bis-arylsulfonylaminobenzamide derivatives, inhibitors of peptide factor Xa) . The compositions, therapeutic combinations or methods of the present invention may further comprise one or more cardiovascular agents that are chemically different from the compounds of substituted azelidinone and substituted β-lactam (such as the above compounds I-XI) and agents for modulating the lipids explained above, for example, may contain one or more different atoms, have a different configuration of atoms or a different number of one or more atoms than the inhibitor (s) for the absorption of the sterol or activators of the PPAR receptor explained previously. Cardiovascular agents include but are not limited to calcium channel blockers (clentiazem maleate, amlodipine besylate, isradipine, nimodipine, felodipine, nilvadipine, nifedipine, teludipine hydrochloride, diltiazem hydrochloride, belfosdil, verapamil hydrochloride, fostedil); adrenergic blockers (fenspiride hydrochloride, labetalol hydrochloride, proroxan, alfuzosin hydrochloride, acebutolol, acebufolol hydrochloride, alprenolol hydrochloride, atenolol, bunolol hydrochloride, carteolol hydrochloride, celiprolol hydrochloride, cefamolol hydrochloride, cycloprolol hydrochloride, hydrochloride of dexpropranolol, diacetolol hydrochloride, dilevalol hydrochloride, esmolol hydrochloride, exaprolol hydrochloride, flestolol sulfate, labetalol hydrochloride, levobetaxolol hydrochloride, levobunolol hydrochloride, metalol hydrochloride, metoprolol, metoprolol tartrate, nadolol, pamatoiol sulfate , penbutolol sulfate, pracololol, propranolol hydrochloride, soiolol hydrochloride, imolol, fimolol maleate, iprenolol hydrochloride, folamolol, bisoprolol, bisoprolol fumarate, nebivolol); adrenergic stimulants; angiofensin-converting enzyme (ACE) inhibitors (benazepril hydrochloride, benazeprilai, capfopril, delapril hydrochloride, fosinopril sodium, libenzapril, moexipril hydrochloride, pentopril, perindopril, quinapril hydrochloride, quinaprilai, ramipril, spirapril hydrochloride, espiraprilaf, leprotide, enalapril maleate, lisinopril, calcium zofenopril, perindopril erbumine); antihypertensive agents (altiazide, benzylzide, capipril, carvedilol, sodium chlorothiazide, clonidine hydrochloride, cyclothiazide, delapril hydrochloride, dilevalol hydrochloride, doxazosin mesylate, fosinopril sodium, guanfacine hydrochloride, melidopa, meicooprolol succinate, moexipril hydrochloride , monatepil maleate, pelanserin hydrochloride, phenoxybenzamine hydrochloride, prazosin hydrochloride, primidolol, quinapril hydrochloride, quinaprilat, ramipril, terazosin hydrochloride, candesartan, candesartan cilexetil, telmisartan, amlodipine besilate, amlodipine maleate, bevantolol hydrochloride); angiotensin 11 receptor antagonists (candesartan, irbesartan, potassium losartan, candesartan cilexetil, telmisartan); agenis anfi-angina (besilario of amlodipine, maleate of amlodipine, hydrochloride betaxolol, hydrochloride bevantolol, hydrochloride butoprazine, carvedilol, maleate of cinepazet, succinate of metoprolol, molsidomina, maleate of monatepil, primidolol, clorhidato of ranolazina, osifen, hydrochloride of verapamil); coronary vasodilators (fossetil, azaclorzine hydrochloride, cromarone hydrochloride, clonitrate, dilifiazem hydrochloride, dipyridamole, droprenylamine, erythrityl tertranyrate, isosorbide dinitrate, isosorbide mononitrate, lidoflazine, myoflazine hydrochloride, mixidine, molsidomine, nicorandil, nifedipine, nisoldipine , nitroglycerin, oxprenolol hydrochloride, pentrinitrol, perhexiline maleate, prenylamine, propane nitrate, terodiline hydrochloride, iolamolol, verapamil); diuretics (the combination of the production of hydrochlorothiazide and spironolactone and the combination of the product of hydrochlorothiazide and triamrene). The compositions, therapeutic combinations or methods of the present invention may further comprise one or more antidiabetic drugs for reducing blood glucose levels in a human being. Useful antidiabetic medications include, but are not limited to, drugs that reduce energy intake or suppress appetite, drugs that increase energy expenditure and agents that divide nutrients. Suitable antidiabetic medicaments include, but are not limited to, sulfonylurea (such as acetohexamide, chlorpropamide, gliamylide, gliclazide, glimepiride, glipizide, glyburide, glibenclamide, iolazamide, and lolbufamide), meglifinide (such as repaglinide and nateglinide), biguanide (such as such as metformin and buformin), alpha-glucosidase inhibitor (such as acarbose, miglyol, camiglibose, and voglibose), certain peptides (such as amlintide, pramlintide, exendin, and GLP-1 agonistic peptides), and orally administrable insulin or composition of insulin for the intestinal distribution of the same. Generally, the total dosage of the antidiabetic drugs described above is on a scale of 0.1 to 1,000 mg / day in single or divided doses. Mixtures of any of the pharmacological and therapeutic agents described above can be used in the compositions and therapeutic combinations of the present invention. The compositions and therapeutic combinations of the present invention can be administered to a subject or a mammal in need of such treatment in an effective therapeutic amount to irritate one or more conditions, for example, vascular conditions such as atherosclerosis, hyperlipidemia, (including, but not limited to cholesterolemia, hypertriglyceridemia, sitosterolemia), vascular inflammation, shock, diabetes, obesity and / or reduce the level of eserol in the plasma. The compositions and methods can be administered by means of any suitable means which produces contact with these compounds with the site of action in the body, for example in the plasma, liver or small intestine of a mammal or human being. The pharmaceutical treatment compositions and therapeutic combinations of the present invention may further comprise one more pharmaceutically acceptable carriers one or more excipients and / or one or more additives. Non-limiting examples of pharmaceutically acceptable carriers include solids and / or liquids such as ethanol, glycerol, water and the like. The amount of the carrier in the composition of the fragrance may be in the range of 5 to 99% by weight of the total weight of the composition of the composition or therapeutic combination. Non-limiting examples of suitable pharmaceutically acceptable excipients and additives include compatible non-toxic fillers, binders such as starch, disintegrants and pH regulators, preservatives, antioxidants, lubricants, flavorings, thinners, emulsifying agents and the like. The amount of excipient or additive may be in the range from 0.1 to about 90% by weight of the total weight of the composition of the treatment or the therapeutic combination. One skilled in the art will understand that the amount of carrier (s) excipients and additives (if present) may vary. The irradiation compositions of the present invention can be administered in any conventional dosage form, preferably an oral dosage form such as a capsule, tablet, powder, dragee, suspension or solution. The formulations and pharmaceutical compositions can be prepared using conventional and pharmaceutically acceptable techniques. Several examples of the preparation of the dosage formulations are provided below. The following formulations exemplify some of the dosage forms of this invention. In each formulation, the term "Active Compound I" designates a substituted azetidinone compound, a β-lactam compound or any of the compounds of the formulas I-XI described hereinbefore or pharmaceutically acceptable salts or solvates thereof and, The term "Active Compound II" refers to an agent for lipid modulation described hereinbefore.

EXAMPLE No. Ingredient mg / tablet 1 Active compound 1 10 2 Lactose monohydrate MF 55 3 Microcrystalline cellulose NF 20 4 Povidone (K29-32) USP 4 5 Croscarmellose sodium NF 8 6 Sodium lauryl sulfate 2 7 Magnesium stearate MF 1 Total 100 In the present invention, the above-described tablet can be co-administered with a treatment comprising a dosage of active compound II, for example an infusion of ETC-216.

Manufacturing Method Mix item No. 4 with purified water in a suitable mixer to form the binder solution. Spray the solution of the agluíinanfe and then water on the articles 1, 2, 6 and a portion of the article 5 in a fluid bed processor to granulate the ingredients. Continue the fluidization to dry the soaked granules. Sort the dried granules and mix them with article No. 3 and the rest of article 5. Add to article No. 7 and mix. Compress the mixture to the appropriate size and weight in a suitable tablet machine. It is contemplated that there are two active ingredients administered as an individual composition, the dosage forms described above for sustained azephydinone or β-lacfama compounds can be easily modified using the knowledge of one skilled in the art.

Since the present invention relates to the processing conditions as explained above, such as the concentrations of sterol in the plasma (especially cholesterol) or the levels through the treatment with a combination of the ingredients, wherein the active ingredients are can be administered separately, the invention also relates to separate pharmaceutical combinations in the form of a combination. That is, a set is contemplated wherein two separate units are combined: a pharmaceutical composition comprising at least one peroxisome proliferator-activated receptor and a separate pharmaceutical composition comprising at least one sterol absorption inhibitor as described earlier. The set will preferably include addresses for the administration of the separate components. The shape of the whole is particularly advantageous when the separate components should be administered in the form of different doses (eg, oral and parenteral) or administered at different dosage intervals. The irradiation compositions and therapeutic combinations of the present invention can inhibit the intestinal absorption of cholesterol in mammals, as shown in the example below and can be useful in the irradiation and / or prevention of conditions, eg, vascular conditions, Fales such as atherosclerosis, hypercholesterolemia and sitosterolemia, shock, obesity and the decrease of plasma cholesterol levels in mammals, in particular mammals. In another embodiment of the present invention, the compositions and therapeutic combinations of the present invention can inhibit the absorption of sterol or 5a-splanol or reduce the plasma concentration of at least one sterol selected from the group consisting of cycloesiols (such as sitoesterol, campesterol, stigmaesterol and avenosferol) and / or sienol 5a (eg as cholestanol, campestanol 5a, sifoesianol 5a), choleslerol and mixtures thereof. The plasma concentration can be reduced through administration or a mammal in need of such treatment of an effective amount of at least one irradiation composition or a therapeutic combination comprising at least one agent for the modulation of lipids and at least one sterol absorption inhibitor described above. The reduction in plasma concentration of sterols or steels 5a may be on the scale of about 1 and about 70%, and preferably at about 10 to about 50%. Methods for measuring total blood cholesterol in serum and total LDL cholesterol are well known to those skilled in the art and for example include those described in PCT WO 99/38498 on page 11, incorporated here by reference. Methods for determining serum lipid levels in serum are described in H. Gyllin and others, "Serum Sterols During Stanol Ester Feeding in a Mildly Hypercholesi-erolemic Populafion," J. Lipid Res. 40: 593-600 (1999), incorporated here for reference. The treatments of the present invention can also reduce the size of the presence of plaque deposits in vascular blood vessels. The volume of the plaque can be measured using (IVUS), where a very small ultrasound probe is inserted into an artery to direct the image and measure the size of atherosclerotic plaques, in a manner well known to those with experience in the technique. To illustrate the invention are the following examples, however, will not be considered as limiting the invention to its details. Unless otherwise indicated, all parts and percentages in the following examples as well as throughout this specification are by weight.

EXAMPLES Preparation of the compound of the formula (II) Step 1): To a solution of (S) -4-phenyl-2-oxazolidinone (41 g, 0.25 moles) in 200 ml of CH2Cl2, 4-dimethylaminopyridine (2.5 g, 0.02 moles) and triethylamine (84.7 ml, 0.61 moles) and the reaction mixture was cooled to 0 ° C. Methyl-4- (chloroformyl) butyrate (50 g, 0.3 mol) was added as a solution in 375 ml of CH 2 Cl 2 dropwise over 1 hour, and the reaction was allowed to warm to 220 ° C. After 17 hours, water and H2SO4 (2N, 100 ml) were added, and the layers were separated, and the organic layer was washed sequentially with NaOH (10%), NaCl (saturated) and water. The organic layer was dried over MgSO4 and concentrated to obtain a semicrisial production.

Step 2): To a solution of TiCl 4 (18.2 ml, 0.165 moles) in 600 ml of CH 2 Cl 2 at 0 ° C, titanium isopropoxide (16.5 ml, 0.055 moles) was added. After 15 minutes, the product of Step 1 (49.0 g, 0.17 moles) was added as a solution in 100 ml of CH2Cl2. After 5 minutes, diisopropylethylamine (DIPEA) (65.2 ml, 0.37 moles) was added and the reaction mixture was stirred at 0 ° C for 1 hour, the reaction mixture was cooled to -20 ° C, and 4-benzyloxybenzylidine was added. (4-fluoro) aniline (114.3 g, 0.37 mol) as a solid. The reaction mixture was stirred vigorously for 4 hours at -20 ° C, then acetic acid was added as a solution in CH2Cl2 dropwise over 15 minutes, the reaction mixture was allowed to warm to 0 ° C, and H 2 SO ( 2N). The reaction mixture was stirred for an additional 1 hour, the layers were separated, washed with water, separated and the organic layer was dried. The crude product was crystallized from ethanol / water to obtain the pure intermediate. Step 3): To a solution of the product from Step 2 (8.9 g, 14. 9 mmol) in 100 ml of toluene at 50 ° C, N, 0-bis (imymethylsilyl) acetamide (BSA) (7.50 ml, 30.3 mmol) was added. After 0.5 hours, solid TBAF (0.39 g, 1.5 mmol) was added and the reaction mixture was stirred at 50 ° C for 3 more hours. The reaction mixture was cooled to 22 ° C, 10 ml of CH3OH was added. The reaction mixture was washed with HCl (1 N), NaHCO 3 (1 N) and NaCl (brine), and the organic layer was dried over MgSO 4. Step 4): To a solution of the Step 3 product (0.94 g, 2.2 mmol) in 3 mL of CH3OH, 1 mL of water and LiOH.H20 (102 mg, 2.4 mmol) was added. The reaction mixture was stirred at 22 ° C for 1 hour and then additional LiOH-H20 (54 mg, 1.3 mmol) was added. After a total of 2 hours, HCl (1 N) and EtOAc were added, the layers were separated, the organic layer was dried and concentrated in vacuo. To a solution of the resulting product (0.91 g, 2.2 mmol) in CH2Cl2 at 220 ° C, CICOCOCI (0.29 mL, 3.3 mmol) was added and the mixture was stirred for 16 hours. The solvent was removed in vacuo. Step 5): To a stirred suspension of 4-fluorophenyl-zinc chloride (4.4 mmol) prepared from 4-fluorophenylmagnesium bromide (1 M in THF, 4.4 mL, 4.4 mmol) and ZnCl 2 (0.6 g, 4.4 mmol) at 4 ° C, tetrakis (triphenyl-phosphine) palladium (0.25 g, 0.21 mmol) was added followed by the product of Step 4 (0.94 g, 2.2 mmol) as a solution in 2 ml of THF. The reaction was stirred for 1 hour at 0 ° C and then 0.5 hour at 220 ° C. HCl (1 N, 5 mL) was added and the mixture was extracted with EOAc. The organic layer was concentrated to an oil and purified by silica gel chromatography to obtain 1- (4-fluorophenyl) -4 (S) - (4-hydroxyphenyl) -3 (R) - (3- oxo-3-phenylpropyl) -2-azeidinone: HRMS calculated for C 24 H-? 9 F 2 N 0 3 = 408.1429, 408.1411 was found. Step 6): To the production of Step 5 (0.95 g, 1.91 mmol) in 3 mL of THF, (R) -tetrahydro-l-methyl-3, 3-diphenyl-1 H, 3H-pyrrolo- [1, 2-c] [1, 3, 2] oxazaborolo (120 mg, 0.43 mmol) and the mixture was cooled to -200 ° C.

After 5 minutes, the borohydride-dimethylsulfide complex (2M in THF, 0.85 ml, 1.7 mmol) was added dropwise over 0.5 hours.

After a total of 1.5 hours, CH3OH was added followed by HCl (1 N) and the reaction mixture was extracted with ElOAc to obtain 1- (4-fluorophenyl) -3 (R) - [3 (S) - (4 -fluorophenyl) -3-hydroxypropyl)] - 4 (S) - [4- (phenylmethoxy) phenyl] -2-azetidinone (compound 6A-1) as an oil. 1H in CDCl3 d H3 = 4.68. J = 2.3 Hz. Cl (M + H) 500. The use of (S) -α-hydro-1-methyl-3, 3-diphenyl-1H, 3H-pyrrolo- [1, 2-c] [1, 3,2] oxazaborolo gives the corresponding 3 (R) -hydroxypropyl azetidinone (compound 6B-1). 1H in CDCl3 d H3 = 4. 69. J = 2. 3 Hz. Cl (M + H) 500. To a solution of compound 6A-1 (0.4 g, O.dmmoles) in 2 ml of ethanol, 10 was added. % Pd / C (0.03 g) and the reaction mixture was agitated under pressure (4.22 kg / cm2) of H2 gas for 16 hours. The reaction mixture was filtered and the solvent was concentrated to obtain compound 6A. Mp 164-166 ° C; Cl (M + H) 410. [a [25D. -28.1 ° (c 3, CH 3 OH). Elemental analysis calculated for C24H21F2N03: C 70.41; H 5.17; N 3.42; C 70.25 was found; H 5.19; N 3.54. Compound 6 B-1 was similarly irradiated to obtain compound 6B. Mp 29.5-132.5 ° C; Cl (M + H) 410. Elemental analysis calculated for C 24 H 21 F 2 N 0 3: C 70.41; H 5.17; N 3.42; C 70.30 was found; H 5.14; N 3.52. Step 6 '(Alternative): To a solution of the product from Step 5 (0.14 g, 0.3 mmol) in 2 ml of ethanol, 10% Pd / C (0.03 g) was added and the reaction was stirred under pressure (4.22 kg / cm2) of H2 gas for 16 hours. The reaction mixture was filtered and the solvent was concentrated to give a 1: 1 mixture of compounds 6A and 6B. It will be appreciated by those skilled in the art that changes can be made to the embodiments described above without departing from the broad concept of the invention. It is understood, therefore, that this invention is not limited to the particular embodiments described, but it is intended to cover the modifications that are denoted by the spirit and spirit of the invention, as defined in the appended claims.

Claims (8)

NOVELTY OF THE INVENTION CLAIMS

1. A composition comprising: (a) at least one agent for the modulation of the lipid selected from the group consisting of synthetic HDL, phospholipids, phospholipids in combination with HDL associated with biologically active peptides derived therefrom, reverse lipid transport peptides (RLT), enzymes associated with HDL, and apo E, alone or formulated in combination with liposomes or emulsions; and (b) at least one substituted azetidinone compound or a substituted β-lactam compound or salt or solvate thereof.

2. The composition according to claim 1, further characterized in that the substituted azetidinone compound is represented by Formula (I): or pharmaceutically acceptable salts or solvates thereof, wherein in Formula (I) above: Ar 1 and Ar 2 are independently selected from the group consisting of aryl and R 4 -substituted aryl; Ar3 is aryl or substituted R5-aryl; X, Y and Z are independently selected from the group consisting of -CH2-, -CH (lower alkyl) - and -C (lower dialkyl) -; R and R2 are independently selected from the group consisting of -OR, -0 (CO) R6, -0 (CO) OR9 and -0 (CO) NR6R7; R1 and R3 are independently selected from the group consisting of hydrogen, lower alkyl and aryl; q is 0 or 1; r is 0 or 1; m, n and p are independently selected 0, 1, 2, 3 or 4; provided that at least one of q and r is 1, and the sum of m, n, p, q and r is 1, 2, 3, 4, 5 or 6; and provided that when p is 0 and r is 1, the sum of m, q and n is 1, 2, 3, 4 or 5; R4 is 1-5 substituents independently selected from the group consisting of lower alkyl, -OR6, -0 (CO) R6, -0 (CO) OR9, -0 (CH2) 1-5OR6, -0 (CO) NR6R7, - NR6R7, -NR6 (CO) R7, -NR6 (CO) OR9, -NR6 (CO) NR7R8, -NR6S02R9, -COOR6, -CONRR, -COR, -S02NR6R7, S (O) 0-2R9, -O (CH2 )?.? 0-COOR6, -0 (CH2) ?. 10CONR6R7- (lower alkylene) COOR6, -CH = CH-COOR6-CF3, -CN, -N02 and halogen; R5 is 1-5 substituents independently selected from the group consisting of -OR6, -0 (CO) R6, -0 (CO) OR9, -0 (CH2) 1-5OR6, -0 (CO) NR6R7, -NR6R7, - NR6 (CO) R7, -NR6 (CO) OR9, -NR6 (CO) NR7R8, -NR6S02R9, -COOR6, -CONR6R7, -COR6, -S02NR6R7, S (O) 0-2R9, -O (CH2) 1- 10-COOR6, -O (CH2) 1-10CONR6R7, - (lower alkylene) COOR6 and -CH = CH-COOR6; R6, R7 and R8 are independently selected from the group consisting of hydrogen, lower alkyl, aryl and aryl-substituted lower alkyl; and R9 is lower alkyl, aryl or aryl substiuuted lower alkyl.

3. The composition according to claim 1, further characterized in that the azeidinone compound is represented by the following Formula (II): or a pharmaceutically acceptable salt or solvate thereof.

4. The composition according to claim 1, further characterized in that the agent for the modulation of the lipid is a synthetic HDL complex comprising the complex of apolipoprotein A-1 of Milano and phosphatidyl choline of 1-palmitoii-2-oleyl.

5. A composition comprising: (a) at least one agent for the modulation of the lipid selected from the group consisting of synthetic HDL, phospholipids, phospholipids in combination with HDL associated with biologically derived peptides derived therefrom, transferase peptides of the Inverse lipid (RLT), enzymes associated with HDL, and apo E, alone or formulated in combination with liposomes or emulsions; and (b) a compound represented by the following Formula (II): or a pharmaceutically acceptable salt or solvate thereof.

6. A therapeutic combination comprising: (a) a first quantity of at least one agent for the modulation of the lipid selected from the group consisting of synthetic HDL, phospholipids, phospholipids in combination with HDL associated with biologically derived peptides derived therefrom , inverse lipid transferase peptides (RLT), enzymes associated with HDL, and apo E, alone or formulated in combination with liposomes or emulsions; and (b) a second quantity of at least one substituted azetidinone compound or a substituted β-lactam compound or a pharmaceutically acceptable salt or solvate thereof, wherein the first quantity and the second quantity together comprise an effective ferapulous amount for the shaping or prevention of a vascular condition, diabetes, obesity, or decrease in the concentration of sterol in the plasma of a subject.

7. A pharmaceutical composition for the treatment or prevention of a vascular condition, diabetes, obesity or the reduction of a concentration of a spherical plasma in a subject, comprising a therapeutically effective amount of a composition, or therapeutic combination of any of claims 1, 5, or 6 and a pharmaceutically acceptable carrier.

8. The use of a therapeutic composition or combination of any of claims 1, 5, 6, or 7, for preparing a medicament for treating or preventing a vascular condition, diabetes, obesity or the reduction of a concentration of a esoterol in the plasma of a subject.