US20030054037A1 - Pharmaceutical compositions of adsorbates of amorphous drug - Google Patents

Pharmaceutical compositions of adsorbates of amorphous drug Download PDF

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Publication number
US20030054037A1
US20030054037A1 US10/173,987 US17398702A US2003054037A1 US 20030054037 A1 US20030054037 A1 US 20030054037A1 US 17398702 A US17398702 A US 17398702A US 2003054037 A1 US2003054037 A1 US 2003054037A1
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Prior art keywords
phenyl
drug
amino
composition
methyl
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US10/173,987
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Walter Babcock
Dwayne Friesen
Ravi Shanker
Daniel Smithey
Ralph Tadday
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Bend Research Inc
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Individual
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Application filed by Individual filed Critical Individual
Priority to US10/173,987 priority Critical patent/US20030054037A1/en
Publication of US20030054037A1 publication Critical patent/US20030054037A1/en
Priority to US11/566,408 priority patent/US8703199B2/en
Priority to US12/180,769 priority patent/US8389006B2/en
Assigned to BEND RESEARCH, INC. reassignment BEND RESEARCH, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: PFIZER PRODUCTS INC., PFIZER INC.
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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Definitions

  • the present invention relates to pharmaceutical compositions of a low-solubility drug and a high surface area substrate, wherein the drug and substrate are combined to form an adsorbate.
  • Low-solubility drugs often show poor bioavailability or irregular absorption, the degree of irregularity being affected by factors such as dose level, fed state of the patient, and form of the drug.
  • Increasing the bioavailability of low-solubility drugs has been the subject of much research.
  • Increasing bioavailability hinges on improving the concentration of the drug in solution to improve absorption.
  • the amorphous form of a low-solubility drug that is capable of existing in either the crystalline or amorphous form may temporarily provide a greater aqueous concentration of drug relative to the equilibrium concentration obtained by dissolution of drug in a use environment.
  • Such amorphous forms may consist of the amorphous drug alone, a dispersion of the drug in a matrix material, or the drug adsorbed onto a substrate. It is believed that such amorphous forms of the drug may dissolve more rapidly than the crystalline form, often dissolving faster than the drug can precipitate from solution. As a result, the amorphous form may temporarily provide a greater-than equilibrium concentration-of drug.
  • amorphous form of a drug may not be stable physically in the amorphous form. Often the crystalline form of the drug has a lower free energy, and thus over time, the amorphous drug will tend to crystallize.
  • the rate of crystallization may be influenced by storage conditions, such as temperature and humidity, as well as the constituents of the composition.
  • Lovrecich U.S. Pat. No. 5,449,521, discloses amorphous drug absorbed onto a support material.
  • the support material may be crosslinked polymers, linear polymers, water soluble complexing agents, and porous inorganic materials.
  • the drug and support material are co-ground in a mill with its grinding chamber saturated with the vapour of one or more solvents able to solubilize the drug.
  • the resulting product is dried and sieved.
  • the resulting compositions are reported to have a reduced heat of fusion, a reduced melting point, an increased dissolution rate and increased solubilization kinetices.
  • composition comprising an amorphous drug form that is physically stable under typical storage conditions, and that may enhance the bioavailability of poorly soluble drugs.
  • the present invention overcomes the drawbacks of the prior art by providing in a first aspect of the invention, pharmaceutical compositions comprising a solid adsorbate with a low-solubility drug adsorbed onto a substrate, said substrate having a surface area of at least 20 m 2 /g, wherein at least a major portion of said drug in said adsorbate is amorphous, wherein the adsorbate provides improved concentration of said drug in a use environment relative to a slow-evaporation control composition comprising said drug and said substrate but formed by evaporation of solvent from a suspension of said drug in a solvent with said substrate suspended therein, said evaporation of said solvent for formation of said slow-evaporation control composition being conducted over a period of at least 30 minutes.
  • the present invention provides pharmaceutical compositions comprising a solid adsorbate with a low-solubility drug adsorbed onto a substrate, said substrate having a surface area of at least 20 m 2 /g, wherein at least a major portion of said drug in said adsorbate is amorphous; and a concentration-enhancing polymer.
  • the adsorbate provides improved concentration of said drug in a use environment relative to a slow-evaporation control composition comprising said drug and said substrate but formed by evaporation of solvent from a suspension of said drug in a solvent with said substrate suspended therein, said evaporation of said solvent for formation of said slow-evaporation control composition being conducted over a period of at least 30 minutes.
  • the adsorbate is more physically stable than said slow-evaporation control composition.
  • the drug in said adsorbate has a glass transition temperature substantially different from that of said drug in amorphous form alone that is not adsorbed to said substrate.
  • the drug is in the form of a layer of drug molecules adsorbed onto said substrate, said layer having a thickness that is no greater than about 3-fold the diameter of said drug.
  • the drug is adsorbed onto said substrate substantially in the form of a monolayer.
  • the drug has improved physical stability in said adsorbate relative to a control composition having an equivalent amount of said drug in amorphous form alone that is not adsorbed to said substrate.
  • the drug has a rate of crystallization in said adsorbate that is less than 90% of the crystallization rate of said drug in amorphous form.
  • Another preferred embodiment relates to the drug in said adsorbate having a relative degree of improvement in chemical stability of at least about 1.25 relative to said drug in amorphous form alone and not adsorbed to said substrate.
  • the drug in said adsorbate has a relative degree of improvement in chemical stability of at least 1.25 relative to at least one of a first control composition having an equivalent amount of said drug in amorphous form mixed with said concentration-enhancing polymer and a second control composition consisting of a solid amorphous dispersion of an equivalent amount of said drug and said concentration-enhancing polymer.
  • the drug is acid-sensitive and said concentration-enhancing polymer is acidic.
  • the surface area of said substrate is at least 50 m 2 /g, preferably at least 180 m 2 /g.
  • the adsorbate is in the form of agglomerates having a mean average diameter of from about 10 nm to about 100 ⁇ m, preferably from about 10 nm to about 1 ⁇ m.
  • the substrate is an inorganic oxide, preferably SiO 2 , TiO 2 , ZnO 2 , ZnO, Al 2 O 3 , or zeolite.
  • the substrate is a water insoluble polymer, preferably cross-linked polyvinyl pyrrolidinone, cross-linked cellulose acetate phthalate, cross-linked hydroxypropyl methyl cellulose acetate succinate, microcrystalline cellulose, polyethylene/polyvinyl alcohol copolymer, polyethylene/polyvinyl pyrrolidinone copolymer, cross-linked carboxymethyl cellulose, sodium starch glycolate, or cross-linked styrene divinyl benzene.
  • a water insoluble polymer preferably cross-linked polyvinyl pyrrolidinone, cross-linked cellulose acetate phthalate, cross-linked hydroxypropyl methyl cellulose acetate succinate, microcrystalline cellulose, polyethylene/polyvinyl alcohol copolymer, polyethylene/polyvinyl pyrrolidinone copolymer, cross-linked carboxymethyl cellulose, sodium starch glycolate, or cross-linked styrene divinyl benzene.
  • the substrate is an activated carbon, preferably a carbonized polymer such as polyimides, polyarylonitrile, phenolic resins, cellulose acetate, regenerated cellulose, and rayon.
  • activated carbon preferably a carbonized polymer such as polyimides, polyarylonitrile, phenolic resins, cellulose acetate, regenerated cellulose, and rayon.
  • Another preferred embodiment includes the drug in said adsorbate as substantially amorphous, preferably the drug is almost completely amorphous.
  • the drug and said concentration-enhancing polymer are co-adsorbed onto said substrate, preferably, the drug and said polymer are substantially in the form of an amorphous dispersion, more preferably, the dispersion is substantially homogeneous.
  • the composition is a mixture of said adsorbate and said concentration-enhancing polymer, preferably the composition is a mixture of particles of said adsorbate and particles of said concentration-enhancing polymer. More preferably, the adsorbate and said concentration-enhancing polymer are each in respective regions. Preferably, the mixture is formed by wet-granulation and/or dry-granulation.
  • the concentration-enhancing polymer has a hydrophobic portion and a hydrophilic portion.
  • the concentration-enhancing polymer is a cellulosic ionizable polymer, preferably hydroxypropyl methyl cellulose succinate, cellulose acetate succinate, methyl cellulose acetate succinate, ethyl cellulose acetate succinate, hydroxypropyl cellulose acetate succinate, hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl cellulose acetate phthalate succinate, cellulose propionate succinate, hydroxypropyl cellulose butyrate succinate, hydroxypropyl methyl cellulose phthalate, carboxymethyl cellulose, carboxyethyl cellulose, ethylcarboxymethyl cellulose, cellulose acetate phthalate, methyl cellulose acetate phthalate, ethyl cellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate, hydroxypropyl methyl cellulose acetate phthalate, cellulose propionate phthalate, hydroxypropyl methyl cellulose
  • the concentration-enhancing polymer is an ionizable, non-cellulosic polymer, preferably carboxylic acid functionalized polymethacrylates, carboxylic acid functionalized polyacrylates, amine-functionalized polyacrylates, amine-functionalized polymethacrylates, proteins, carboxylic acid functionalized starches or blends thereof.
  • the concentration-enhancing polymer is a non-ionizable cellulosic polymer, preferably hydroxypropyl methyl cellulose acetate, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, methyl cellulose, hydroxyethyl methyl cellulose, hydroxyethyl cellulose acetate, and hydroxyethyl ethyl cellulose or blends thereof.
  • the concentration-enhancing polymer is a non-ionizable, non-cellulosic polymer, preferably vinyl polymer or copolymer having at least one substituent selected from the group consisting of hydroxyl, alkylacyloxy, and cyclicamido, vinyl copolymers of at least one hydrophilic, hydroxyl-containing repeat unit and at least one hydrophobic, alkyl- or aryl-containing repeat unit, polyvinyl alcohols that have at least a portion of their repeat units in the unhydrolyzed form, polyvinyl alcohol polyvinyl acetate copolymers, polyethylene glycol polypropylene glycol copolymers, polyvinyl pyrrolidone, polyethylene polyvinyl alcohol copolymers, polyoxyethylene-polyoxypropylene block copolymers and blends thereof.
  • vinyl polymer or copolymer having at least one substituent selected from the group consisting of hydroxyl, alkylacyloxy, and cyclicamido, vinyl copo
  • the concentration-enhancing polymer is a neutralized acidic polymer.
  • the composition when administered to a use environment provides a dissolution area under the concentration versus time curve for a time period of at least 90 minutes between the time of introduction to said use environment and about 270 minutes following introduction to the use environment that is at least 1.25-fold the corresponding area under the curve provided by a control composition comprising an equivalent amount of crystalline drug alone.
  • the composition when administered to a use environment provides a maximum concentration of said drug in said use environment that is at least 1.25-fold a maximum concentration of said drug provided by a control composition comprising an equivalent amount of crystalline drug alone.
  • the composition when administered to a use environment provides a relative bioavailability of at least 1.25 relative to a control composition consisting of an equivalent amount of said drug in crystalline form alone.
  • the drug is selected from the group consisting of antihypertensives, antianxiety agents, anticlotting agents, anticonvulsants, blood glucose-lowering agents, decongestants, antihistamines, antitussives, antineoplastics, beta blockers, anti-inflammatories, antipsychotic agents, cognitive enhancers, cholesterol-reducing agents, antiobesity agents, autoimmune disorder agents, anti-impotence agents, antibacterial and antifungal agents, hypnotic agents, anti-Parkinsonism agents, anti-Alzheimer's disease agents, antibiotics, anti-depressants, antiviral agents, anti-atherosclerotic agents, glycogen phosphorylase inhibitors, and cholesterol ester transfer protein inhibitors.
  • the drug is [R-(R*S*)]-5-chloro-N-[2-hydroxy-3- ⁇ methoxymethylamino ⁇ -3-oxo-1-(phenylmethyl)propyl-1H-indole-2-carboxamide, 5-chloro-1H-indole-2-carboxylic acid [(1S)-benzyl-(2R)-hydroxy-3-((3R,4S)-dihydroxy-pyrrolidin-1-yl-)-3-oxypropyl]amide, [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester, [2R,4S]4-[acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino
  • a third aspect of the invention relates to methods of administering a drug comprising co-administering to a patient in need of said drug: (a) an adsorbate comprising a low-solubility drug adsorbed onto a substrate, said substrate having a surface area of at least 20 m 2 /g, wherein at least a major portion of said drug in said adsorbate is amorphous; and (b) a concentration-enhancing polymer.
  • the adsorbate is administered separately from said concentration-enhancing polymer or the concentration-enhancing polymer are administered at approximately the same time.
  • the adsorbate and said concentration-enhancing polymer are present in a single dosage form.
  • a fourth aspect of the present invention relates to methods for forming a pharmaceutical composition that include: (a) providing a substrate having a surface area of at least 20 m 2 /g; (b) adding said substrate to a solvent to form a suspension and agitating said suspension; (c) dissolving a low-solubility drug in said solvent; and (d) rapidly removing said solvent from said suspension to form an adsorbate comprising said low-solubility drug adsorbed onto said substrate, wherein at least a major portion of said drug in said adsorbate is in amorphous form.
  • the step of agitating comprises sonicating said suspension.
  • the step of removing said solvent from said suspension is accomplished by spray-drying said suspension.
  • the method further comprises the step of adding a concentration-enhancing polymer to said suspension.
  • the method further comprises the step of combining said adsorbate with a concentration-enhancing polymer.
  • the present invention relates to methods for forming a pharmaceutical composition, comprising: (a) providing a substrate having a surface area of at least 20 m 2 /g; (b) melting a low-solubility drug; (c)
  • the method further comprises the step of combining a concentration-enhancing polymer with said low-solubility drug and said substrate.
  • the method further comprises the step of combining said adsorbate with a concentration-enhancing polymer.
  • the present invention also relates to pharmaceutical compositions formed by the above-described methods.
  • the present invention relates to a solid adsorbate comprising a low solubility drug adsorbed onto a substrate, said substrate having a surface area of at least 20 m 2 /g, wherein at least a major portion of said drug in said adsorbate is amorphous, wherein said adsorbate provides improved concentration of said drug in a use environment relative to an equivalent amount of a slow-evaporation control composition.
  • the solid adsorbate further comprises a concentration-enhancing polymer.
  • the solid adsorbate is combined with a concentration-enhancing polymer.
  • composition in some embodiments provides improved stability of the amorphous drug in the adsorbate.
  • compositions are concentration-enhancing, providing improved concentration of drug in a use environment relative to a control composition comprising an equivalent amount of crystalline drug alone.
  • One key to the present invention was the recognition by the inventors that the formation of a drug/substrate adsorbate, wherein a major portion of the drug in the adsorbate is amorphous, leads to an initially enhanced concentration of drug in a use environment, and further, that this enhanced concentration can be sustained by interaction of the drug in solution with the adsorbate.
  • the interaction of the drug in solution with the adsorbate inhibits precipitation or crystallization of the drug, allowing the initially enhanced concentration of drug in solution to be sustained rather than decrease rapidly over time to that obtained when amorphous drug alone is dosed to the use environment.
  • the drug/substrate adsorbate and concentration-enhancing polymer are present together in the use environment.
  • the concentration-enhancing polymers of this invention may also act as crystallization or precipitation inhibitors.
  • the concentration-enhancing polymers may also interact with drug to form various types of polymer-drug assemblies such as aggregates or colloids.
  • polymer, drug and substrate may all interact in solution to form various drug/polymer/substrate assemblies such as aggregates or colloids.
  • the compositions of the present invention provide improved concentration of drug in the use environment.
  • the adsorbate when introduced to a use environment, provides an initial concentration of drug that exceeds the equilibrium concentration of drug.
  • the adsorbate and/or the concentration-enhancing polymer retards the rate at which the initially enhanced drug concentration falls to the equilibrium concentration.
  • the compositions of the present invention provide a dissolution area-under-the-concentration-versus-time-curve (“AUC”) that is greater than that provided by crystalline drug alone.
  • the compositions of the present invention provide an AUC that is greater than that provided by the drug in amorphous form alone.
  • compositions that include a concentration-enhancing polymer preferably provide an AUC or maximum drug concentration that exceeds that of a control composition that consists of amorphous drug alone (that is, free from both the substrate and the concentration-enhancing polymer).
  • the compositions provide an AUC or a maximum drug concentration that exceeds that provided by a control consisting of drug/substrate adsorbate but free from the concentration-enhancing polymer. Nevertheless, the advantages of the invention may be obtained by merely retarding the rate at which the enhanced drug concentration falls to the equilibrium concentration, even without increasing the maximum drug concentration relative to a control composition.
  • the compositions of the present invention may also provide enhanced bioavailability of the drug by increasing the concentration of drug which remains dissolved in the use environment, particularly in the GI tract. Improving the concentration of the drug in solution allows more rapid absorption of drug and, as a result, higher blood levels to be achieved. In some cases this enhanced absorption rate enables an effective level of drug to be reached that might not be reached by administration of conventional forms of the drug. In other cases, administration of the compositions of the invention allows effective blood levels to be reached at lower drug dosage levels, which in turn decreases the amount of drug that must be dosed, and reduces the blood level variability. Such compositions may also allow the size of the dosage form to be decreased, depending on the amount of substrate and/or polymer needed.
  • compositions of the present invention provide for a higher concentration of drug dissolved in the use environment, and because once a high drug concentration is achieved the concentration tends to remain high due to inhibition of precipitation or crystallization of the drug, the compositions may have a number of positive effects.
  • the compositions of the present invention may show less variability in drug absorption as a result of variation in the fed/fasted state of the GI tract of the human or animal.
  • absorption of drug may continue over a longer time period and an effective concentration of drug in the blood may be maintained over a longer time period.
  • stabilizing the drug as an adsorbate of the drug and substrate and then combining the adsorbate with the concentration-enhancing polymer provides another of the advantages of the present invention, which is to allow the use of concentration-enhancing polymers which, for whatever reason, are not suitable for forming a molecular dispersion with the particular drug.
  • the difficulty in forming a stable dispersion may be due to adverse interactions between the drug and polymer in the dispersion, resulting in chemical and/or physical instability of the drug in the dispersion.
  • an acidic cellulosic polymer may provide superior concentration-enhancement for some drugs, such polymers may chemically degrade acid-sensitive drugs when present in the dispersion.
  • the present invention solves this problem by forming an adsorbate of the drug and a substrate, and then combines the adsorbate with the concentration-enhancing polymer to form the composition. This provides the benefit of improved drug stability while at the same time providing the additional level of concentration-enhancement conferred by the presence of the concentration-enhancing polymer.
  • the present invention is directed toward adsorbates of a low-solubility drug and a high surface area substrate.
  • the compositions may optionally include concentration-enhancing polymers. Suitable drugs, substrates, and concentration-enhancing polymers, as well as methods for preparing the compositions, are discussed in detail below.
  • drug is conventional, denoting a compound having beneficial prophylactic and/or therapeutic properties when administered to an animal, especially humans.
  • the drug does not need to be a low-solubility drug in order to benefit from this invention, although low-solubility drugs represent a preferred class for use with the invention.
  • Even a drug that nonetheless exhibits appreciable solubility in the desired environment of use can benefit from the increased solubility/bioavailability made possible by this invention if it reduces the size of the dose needed for therapeutic efficacy or increases the rate of drug absorption in cases where a rapid onset of the drug's effectiveness is desired.
  • the drug is a “low-solubility drug,” meaning that the drug may be either “substantially water-insoluble,” which means that the drug has a minimum aqueous solubility at physiologically relevant pH (e.g., pH 1-8) of less than 0.01 mg/mL, “sparingly water-soluble,” that is, has an aqueous solubility up to about 1 to 2 mg/mL, or even low to moderate aqueous-solubility, having an aqueous-solubility from about 1 mg/mL to as high as about 20 to 40 mg/mL.
  • physiologically relevant pH e.g., pH 1-8
  • “sparingly water-soluble” that is, has an aqueous solubility up to about 1 to 2 mg/mL, or even low to moderate aqueous-solubility, having an aqueous-solubility from about 1 mg/mL to as high as about 20 to 40 mg/mL.
  • compositions of the present invention are preferred for low-solubility drugs having a solubility of less than 10 mg/mL, more preferred for low-solubility drugs having a solubility of less than 1 mg/mL, and even more preferred for low-solubility drugs having a solubility of less than 0.1 mg/mL.
  • the drug has a dose-to-aqueous solubility ratio greater than 10 mL, and more typically greater than 100 mL, where the drug solubility (mg/mL) is the minimum value observed in any physiologically relevant aqueous solution (e.g., those with pH values between 1 and 8) including USP simulated gastric and intestinal buffers, and dose is in mg.
  • a dose-to-aqueous solubility ratio may be calculated by dividing the dose (in mg) by the solubility (in mg/mL).
  • Preferred classes of drugs include, but are not limited to, antihypertensives, antianxiety agents, anticlotting agents, anticonvulsants, blood glucose-lowering agents, decongestants, antihistamines, antitussives, antineoplastics, beta blockers, anti-inflammatories, antipsychotic agents, cognitive enhancers, cholesterol-reducing agents, anti-atherosclerotic agents, antiobesity agents, autoimmune disorder agents, anti-impotence agents, antibacterial and antifungal agents, hypnotic agents, anti-Parkinsonism agents, anti-Alzheimer's disease agents, antibiotics, anti-depressants, antiviral agents, glycogen phosphorylase inhibitors, and cholesterol ester transfer protein inhibitors.
  • Each named drug should be understood to include the neutral form of the drug, pharmaceutically acceptable salts, as well as prodrugs.
  • antihypertensives include prazosin, nifedipine, amlodipine besylate, trimazosin and doxazosin; specific examples of a blood glucose-lowering agent are glipizide and chlorpropamide; a specific example of an anti-impotence agent is sildenafil and sildenafil citrate; specific examples of antineoplastics include chlorambucil, lomustine and echinomycin; a specific example of an imidazole-type antineoplastic is tubulazole; a specific example of an anti-hypercholesterolemic is atorvastatin calcium; specific examples of anxiolytics include hydroxyzine hydrochloride and doxepin hydrochloride; specific examples of anti-inflammatory agents include betamethasone, prednisolone, aspirin, piroxicam, valdecoxi
  • the invention is not limited by any particular structure or group of CETP inhibitors. Rather, the invention has general applicability to CETP inhibitors as a class, the class tending to be composed of compounds having low solubility.
  • Compounds which may be the subject of the invention may be found in a number of patents and published applications, including DE 19741400 A1; DE 19741399 A1; WO 9914215 A1; WO 9914174; DE 19709125 A1; DE 19704244 A1; DE 19704243 A1; EP 818448 A1; WO 9804528 A2; DE 19627431 A1; DE 19627430 A1; DE 19627419 A1; EP 796846 A1; DE 19832159; DE 818197; DE 19741051; WO 9941237 A1; WO 9914204 A1; WO 9835937 A1; JP 11049743; WO 200018721; WO 200018723; WO 200018724; WO 200017164; WO 200017165;
  • the invention is useful for CETP inhibitors that have sufficiently low aqueous solubility, low bioavailability or slow rate of absorption such that it is desirable to increase their concentration in an aqueous environment of use. Therefore, anytime one finds it desirable to raise the aqueous concentration of the CETP inhibitor in a use environment, the invention will find utility.
  • the CETP inhibitor is “substantially water-insoluble” which means that the CETP inhibitor has a minimum aqueous solubility of less than about 0.01 mg/mL (or 10 ⁇ g/ml) at any physiologically relevant pH (e.g., pH 1-8) and at about 22° C.
  • compositions of the present invention find greater utility as the solubility of the CETP inhibitors decreases, and thus are preferred for CETP inhibitors with solubilities less than about 2 ⁇ g/mL, and even more preferred for CETP inhibitors with solubilities less than about 0.5 ⁇ g/mL.
  • Many CETP inhibitors have even lower solubilities (some even less than 1.0 ⁇ g/mL), and require dramatic concentration enhancement to be sufficiently bioavailable upon oral dosing for effective plasma concentrations to be reached at practical doses.
  • the CETP inhibitor has a dose-to-aqueous solubility ratio greater than about 100 mL, where the solubility (mg/mL) is the minimum value observed in any physiologically relevant aqueous solution (e.g., those with pH values from 1 to 8) including USP simulated gastric and intestinal buffers, and dose is in mg.
  • compositions of the present invention find greater utility as the solubility of the CETP inhibitor decreases and the dose increases.
  • compositions are preferred as the dose-to-solubility ratio increases, and thus are preferred for dose-to-solubility ratios greater than 1000 mL, and more preferred for dose-to-solubility ratios greater than about 5000 ml.
  • the dose-to-solubility ratio may be determined by dividing the dose (in mg) by the aqueous solubility (in mg/ml).
  • CETP inhibitors are particularly difficult because their aqueous solubility is usually extremely low, typically being less than 2 ⁇ g/ml, often being less than 0.1 ⁇ g/ml. Such low solubilities are a direct consequence of the particular structural characteristics of species that bind to CETP and thus act as CETP inhibitors. This low solubility is primarily due to the hydrophobic nature of CETP inhibitors.
  • Clog P defined as the base 10 logarithm of the ratio of the drug solubility in octanol to the drug solubility in water, is a widely accepted measure of hydrophobicity. In general, Clog P values for CETP inhibitors are greater than 4 and are often greater than 5 to 7.
  • CETP inhibitors as a class pose a particular challenge for oral delivery.
  • Achieving therapeutic drug levels in the blood by oral dosing of practical quantities of drug generally requires a large enhancement in drug concentrations in the gastrointestinal fluid and a resulting large enhancement in bioavailability.
  • Such enhancements in drug concentration in gastrointestsinal fluid typically need to be at least about 10-fold and often at least about 50-fold or even at least about 200-fold to achieve desired blood levels.
  • the dispersions of the present invention have proven to have the required large enhancements in drug concentration and bioavailability.
  • the first property of this subclass of essentially insoluble, hydrophobic CETP inhibitors is extremely low aqueous solubility.
  • extremely low aqueous solubility is meant that the minimum aqueous solubility at physiologically relevant pH (pH of 1 to 8) is less than about 10 ⁇ g/ml and preferably less than about 1 ⁇ g/ml.
  • a second property is a very high does-to-solubility ratio. Extremely low solubility often leads to poor or slow absorption of the drug from the fluid of the gastrointestinal tract, when the drug is dosed orally in a conventional manner. For extremely low solubility drugs, poor absorption generally becomes progressively more difficult as the dose (mass of drug given orally) increases. Thus, a second property of this subclass of essentially insoluble, hydrophobic CETP inhibitors is a very high dose (in mg) to solubility (in mg/ml) ratio (ml). By “very high dose-to-solubility ratio” is meant that the dose-to-solubility ratio has a value of at least 1000 ml, and preferably at least 5,000 ml, and more preferably at least 10,000 ml.
  • a third property of this subclass of essentially insoluble, hydrophobic CETP inhibitors is that they are extremely hydrophobic.
  • extremely hydrophobic is meant that the Clog P value of the drug, has a value of at least 4.0, preferably a value of at least 5.0, and more preferably a value of at least 5.5.
  • a fourth property of this subclass of essentially insoluble CETP inhibitors is that they have a low melting point.
  • drugs of this subclass will have a melting point of about 150° C. or less, and preferably about 140° C. or less.
  • CETP inhibitors of this subclass typically have very low absolute bioavailabilities. Specifically, the absolute bioavailibility of drugs in this subclass when dosed orally in their undispersed state is less than about 10% and more often less than about 5%.
  • CETP inhibitors one class of CETP inhibitors that finds utility with the present invention consists of oxy substituted 4-carboxyamino-2-methyl-1,2,3,4-tetrahydroquinolines having the Formula I
  • R I-1 is hydrogen, Y I , W I -X I , W I —Y I ;
  • W I is a carbonyl, thiocarbonyl, sulfinyl or sulfonyl
  • X I is —O—Y I , —S—Y I , —N(H)—Y I or —N—(Y I ) 2 ;
  • Y I for each occurrence is independently Z I or a fully saturated, partially unsaturated or fully unsaturated one to ten membered straight or branched carbon chain wherein the carbons, other than the connecting carbon, may optionally be replaced with one or two heteroatoms selected independently from oxygen, sulfur and nitrogen and said carbon is optionally mono-, di- or tri-substituted independently with halo, said carbon is optionally mono-substituted with hydroxy, said carbon is optionally mono-substituted with oxo, said sulfur is optionally mono- or di-substituted with oxo, said nitrogen is optionally mono-, or di-substituted with oxo, and said carbon chain is optionally mono-substituted with Z I ;
  • Z I is a partially saturated, fully saturated or fully unsaturated three to eight membered ring optionally having one to four heteroatoms selected independently from oxygen, sulfur and nitrogen, or, a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated three to six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen;
  • said Z I substituent is optionally mono-, di- or tri-substituted independently with halo, (C 2 -C 6 )alkenyl, (C 1 -C 6 )alkyl, hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 4 )alkylthio, amino, nitro, cyano, oxo, carboxyl, (C 1 -C 6 )alkyloxycarbonyl, mono-N- or di-N,N-(C 1 -C 6 )alkylamino wherein said (C 1 -C 6 )alkyl substituent is optionally mono-, di- or tri-substituted independently with halo, hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 4 )alkylthio, amino, nitro, cyano, oxo, carboxyl, (C 1 -C 6 )alkyloxycarbonyl
  • R I-3 is hydrogen or Q I ;
  • Q I is a fully saturated, partially unsaturated or fully unsaturated one to six membered straight or branched carbon chain wherein the carbons, other than the connecting carbon, may optionally be replaced with one heteroatom selected from oxygen, sulfur and nitrogen and said carbon is optionally mono-, di- or tri-substituted independently with halo, said carbon is optionally mono-substituted with hydroxy, said carbon is optionally mono-substituted with oxo, said sulfur is optionally mono- or di-substituted with oxo, said nitrogen is optionally mono-, or di-substituted with oxo, and said carbon chain is optionally mono-substituted with V I ;
  • V I is a partially saturated, fully saturated or fully unsaturated three to eight membered ring optionally having one to four heteroatoms selected independently from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated three to six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen;
  • V I substituent is optionally mono-, di-, tri-, or tetra-substituted independently with halo, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 4 )alkylthio, amino, nitro, cyano, oxo, carbamoyl, mono-N- or di-N,N-(C 1 -C 6 )alkylcarbamoyl, carboxyl, (C 1 -C 6 )alkyloxycarbonyl, mono-N- or di-N,N-(C 1 -C 6 )alkylamino wherein said (C 1 -C 6 )alkyl or (C 2 -C 6 )alkenyl substituent is optionally mono-, di- or tri-substituted independently with hydroxy, (C 1 -C 6 )
  • R I-4 is Q I-1 or V I-1
  • Q I-1 is a fully saturated, partially unsaturated or fully unsaturated one to six membered straight or branched carbon chain wherein the carbons, other than the connecting carbon, may optionally be replaced with one heteroatom selected from oxygen, sulfur and nitrogen and said carbon is optionally mono-, di- or tri-substituted independently with halo, said carbon is optionally mono-substituted with hydroxy, said carbon is optionally mono-substituted with oxo, said sulfur is optionally mono- or di-substituted with oxo, said nitrogen is optionally mono-, or di-substituted with oxo, and said carbon chain is optionally mono-substituted with
  • V I-1 is a partially saturated, fully saturated or fully unsaturated three to six membered ring optionally having one to two heteroatoms selected independently from oxygen, sulfur and nitrogen;
  • V I-1 substituent is optionally mono-, di-, tri-, or tetra-substituted independently with halo, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, amino, nitro, cyano, (C 1 -C 6 )alkyloxycarbonyl, mono-N- or di-N,N-(C 1 -C 6 )alkylamino wherein said (C 1 -C 6 )alkyl substituent is optionally mono-substituted with oxo, said (C 1 -C 6 )alkyl substituent is also optionally substituted with from one to nine fluorines;
  • R I-3 must contain V I or R I-4 must contain V I-1 ; and R I-5 , R I-6 , R I-7 and R I-8 are each independently hydrogen, hydroxy or oxy wherein said oxy is substituted with T I or a partially saturated, fully saturated or fully unsaturated one to twelve membered straight or branched carbon chain wherein the carbons, other than the connecting carbon, may optionally be replaced with one or two heteroatoms selected independently from oxygen, sulfur and nitrogen and said carbon is optionally mono-, di- or tri-substituted independently with halo, said carbon is optionally mono-substituted with hydroxy, said carbon is optionally mono-substituted with oxo, said sulfur is optionally mono- or di-substituted with oxo, said nitrogen is optionally mono- or di-substituted with oxo, and said carbon chain is optionally mono-substituted with T I ;
  • T I is a partially saturated, fully saturated or fully unsaturated three to eight membered ring optionally having one to four heteroatoms selected independently from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated three to six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen;
  • T I substituent is optionally mono-, di- or tri-substituted independently with halo, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 4 )alkylthio, amino, nitro, cyano, oxo, carboxy, (C 1 -C 6 )alkyloxycarbonyl, mono-N- or di-N,N-(C 1 -C 6 )alkylamino wherein said (C 1 -C 6 )alkyl substituent is optionally mono-, di- or tri-substituted independently with hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 4 )alkylthio, amino, nitro, cyano, oxo, carboxy, (C 1 -C 6 )alkyloxycarbonyl, mono-N- or
  • the CETP inhibitor is selected from one of the following compounds of Formula I:
  • R II-1 is hydrogen, Y II , W II -X II , X II -Y II ;
  • W II is a carbonyl, thiocarbonyl, sulfinyl or sulfonyl
  • X II is —O—Y II , —S—Y II , —N(H)—Y II or —N—(Y II ) 2 ;
  • Y II for each occurrence is independently Z II or a fully saturated, partially unsaturated or fully unsaturated one to ten membered straight or branched carbon chain wherein the carbons, other than the connecting carbon, may optionally be replaced with one or two heteroatoms selected independently from oxygen, sulfur and nitrogen and said carbon is optionally mono-, di- or tri-substituted independently with halo, said carbon is optionally mono-substituted with hydroxy, said carbon is optionally mono-substituted with oxo, said sulfur is optionally mono- or di-substituted with oxo, said nitrogen is optionally mono-, or di-substituted with oxo, and said carbon chain is optionally mono-substituted with Z II ;
  • Z II is a partially saturated, fully saturated or fully unsaturated three to twelve membered ring optionally having one to four heteroatoms selected independently from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated three to six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen;
  • said Z II substituent is optionally mono-, di- or tri-substituted independently with halo, (C 2 -C 6 )alkenyl, (C 1 -C 6 )alkyl, hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 4 )alkylthio, amino, nitro, cyano, oxo, carboxy, (C 1 -C 6 )alkyloxycarbonyl, mono-N- or di-N,N-(C 1 -C 6 )alkylamino wherein said (C 1 -C 6 )alkyl substituent is optionally mono-, di- or tri-substituted independently with halo, hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 4 )alkylthio, amino, nitro, cyano, oxo, carboxy, (C 1 -C 6 )alkyloxycarbonyl, mono
  • R II-3 is hydrogen or Q II ;
  • Q II is a fully saturated, partially unsaturated or fully unsaturated one to six membered straight or branched carbon chain wherein the carbons, other than the connecting carbon, may optionally be replaced with one heteroatom selected from oxygen, sulfur and nitrogen and said carbon is optionally mono-, di- or tri-substituted independently with halo, said carbon is optionally mono-substituted with hydroxy, said carbon is optionally mono-substituted with oxo, said sulfur is optionally mono- or di-substituted with oxo, said nitrogen is optionally mono- or di-substituted with oxo, and said carbon chain is optionally mono-substituted with V II ;
  • V II is a partially saturated, fully saturated or fully unsaturated three to twelve membered ring optionally having one to four heteroatoms selected independently from oxygen, sulfur and nitrogen, or, a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated three to six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen;
  • V II substituent is optionally mono-, di-, tri-, or tetra-substituted independently with halo, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 4 )alkylthio, amino, nitro, cyano, oxo, carboxamoyl, mono-N- or di-N,N-(C 1 -C 6 )alkylcarboxamoyl, carboxy, (C 1 -C 6 )alkyloxycarbonyl, mono-N- or di-N,N-(C 1 -C 6 )alkylamino wherein said (C 1 -C 6 )alkyl or (C 2 -C 6 )alkenyl substituent is optionally mono-, di- or tri-substituted independently with hydroxy, (C 1 -C 6 )
  • R II-4 is Q II-1 or V II-1
  • Q II-1 a fully saturated, partially unsaturated or fully unsaturated one to six membered straight or branched carbon chain wherein the carbons, other than the connecting carbon, may optionally be replaced with one heteroatom selected from oxygen, sulfur and nitrogen and said carbon is optionally mono-, di- or tri-substituted independently with halo, said carbon is optionally mono-substituted with hydroxy, said carbon is optionally mono-substituted with oxo, said sulfur is optionally mono- or di-substituted with oxo, said nitrogen is optionally mono- or di-substituted with oxo, and said carbon chain is optionally mono-substituted with V II-1 ;
  • V II-1 is a partially saturated, fully saturated or fully unsaturated three to six membered ring optionally having one to two heteroatoms selected independently from oxygen, sulfur and nitrogen;
  • V II-1 substituent is optionally mono-, di-, tri-, or tetra-substituted independently with halo, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, amino, nitro, cyano, (C 1 -C 6 )alkyloxycarbonyl, mono-N- or di-N,N-(C 1 -C 6 )alkylamino wherein said (C 1 -C 6 )alkyl substituent is optionally mono-substituted with oxo, said (C 1 -C 6 )alkyl substituent is optionally substituted with from one to nine fluorines;
  • R II-5 , R II-6 , R II-7 and R II-8 are each independently hydrogen, a bond, nitro or halo wherein said bond is substituted with T II or a partially saturated, fully saturated or fully unsaturated (C 1 -C 12 ) straight or branched carbon chain wherein carbon may optionally be replaced with one or two heteroatoms selected independently from oxygen, sulfur and nitrogen wherein said carbon atoms are optionally mono-, di- or tri-substituted independently with halo, said carbon is optionally mono-substituted with hydroxy, said carbon is optionally mono-substituted with oxo, said sulfur is optionally mono- or di-substituted with oxo, said nitrogen is optionally mono- or di-substituted with oxo, and said carbon is optionally mono-substituted with T II ;
  • T II is a partially saturated, fully saturated or fully unsaturated three to twelve membered ring optionally having one to four heteroatoms selected independently from oxygen, sulfur and nitrogen, or, a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated three to six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen;
  • T II substituent is optionally mono-, di- or tri-substituted independently with halo, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 4 )alkylthio, amino, nitro, cyano, oxo, carboxy, (C 1 -C 6 )alkyloxycarbonyl, mono-N- or di-N,N-(C 1 -C 6 )alkylamino wherein said (C 1 -C 6 )alkyl substituent is optionally mono-, di- or tri-substituted independently with hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 4 )alkylthio, amino, nitro, cyano, oxo, carboxy, (C 1 -C 6 )alkyloxycarbonyl, mono-N- or
  • the CETP inhibitor is selected from one of the following compounds of Formula II:
  • R III-1 is hydrogen, Y III , W III -X III , W III —Y III ;
  • W III is a carbonyl, thiocarbonyl, sulfinyl or sulfonyl
  • X III is —O—Y III , —S—Y III , —N(H)—Y III or —N—(Y III ) 2 ;
  • Y III for each occurrence is independently Z III or a fully saturated, partially unsaturated or fully unsaturated one to ten membered straight or branched carbon chain wherein the carbons, other than the connecting carbon, may optionally be replaced with one or two heteroatoms selected independently from oxygen, sulfur and nitrogen and said carbon is optionally mono-, di- or tri-substituted independently with halo, said carbon is optionally mono-substituted with hydroxy, said carbon is optionally mono-substituted with oxo, said sulfur is optionally mono- or di-substituted with oxo, said nitrogen is optionally mono-, or di-substituted with oxo, and said carbon chain is optionally mono-substituted with Z III ;
  • Z III is a partially saturated, fully saturated or fully unsaturated three to twelve membered ring optionally having one to four heteroatoms selected independently from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated three to six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen;
  • said Z III substituent is optionally mono-, di- or tri-substituted independently with halo, (C 2 -C 6 )alkenyl, (C 1 -C 6 )alkyl, hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 4 )alkylthio, amino, nitro, cyano, oxo, carboxy, (C 1 -C 6 )alkyloxycarbonyl, mono-N- or di-N,N-(C 1 -C 6 )alkylamino wherein said (C 1 -C 6 )alkyl substituent is optionally mono-, di- or tri-substituted independently with halo, hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 4 )alkylthio, amino, nitro, cyano, oxo, carboxy, (C 1 -C 6 )alkyloxycarbonyl, mono
  • R III-3 is hydrogen or Q III ;
  • Q III is a fully saturated, partially unsaturated or fully unsaturated one to six membered straight or branched carbon chain wherein the carbons, other than the connecting carbon, may optionally be replaced with one heteroatom selected from oxygen, sulfur and nitrogen and said carbon is optionally mono-, di- or tri-substituted independently with halo, said carbon is optionally mono-substituted with hydroxy, said carbon is optionally mono-substituted with oxo, said sulfur is optionally mono- or di-substituted with oxo, said nitrogen is optionally mono- or di-substituted with oxo, and said carbon chain is optionally mono-substituted with V III ;
  • V III is a partially saturated, fully saturated or fully unsaturated three to twelve membered ring optionally having one to four heteroatoms selected independently from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated three to six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen;
  • V III substituent is optionally mono-, di-, tri-, or tetra-substituted independently with halo, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 4 )alkylthio, amino, nitro, cyano, oxo, carboxamoyl, mono-N- or di-N,N-(C 1 -C 6 )alkylcarboxamoyl, carboxy, (C 1 -C 6 )alkyloxycarbonyl, mono-N- or di-N,N-(C 1 -C 6 )alkylamino wherein said (C 1 -C 6 )alkyl or (C 2 -C 6 )alkenyl substituent is optionally mono-, di- or tri-substituted independently with hydroxy, (C 1 -C 6 )
  • R III-4 is Q III-1 or V III-1 ;
  • Q III-1 a fully saturated, partially unsaturated or fully unsaturated one to six membered straight or branched carbon chain wherein the carbons, other than the connecting carbon, may optionally be replaced with one heteroatom selected from oxygen, sulfur and nitrogen and said carbon is optionally mono-, di- or tri-substituted independently with halo, said carbon is optionally mono-substituted with hydroxy, said carbon is optionally mono-substituted with oxo, said sulfur is optionally mono- or di-substituted with oxo, said nitrogen is optionally mono- or di-substituted with oxo, and said carbon chain is optionally mono-substituted with
  • V III-1 is a partially saturated, fully saturated or fully unsaturated three to six membered ring optionally having one to two heteroatoms selected independently from oxygen, sulfur and nitrogen;
  • V III-1 substituent is optionally mono-, di-, tri-, or tetra-substituted independently with halo, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, amino, nitro, cyano, (C 1 -C 6 )alkyloxycarbonyl, mono-N- or di-N,N-(C 1 -C 6 )alkylamino wherein said (C 1 -C 6 )alkyl substituent is optionally mono-substituted with oxo, said (C 1 -C 6 )alkyl substituent optionally having from one to nine fluorines;
  • R III-3 must contain V III or R III-4 must contain V III-1 ; and R III-5 and R III-6 , or R III-6 and R III-7 , and/or R III-7 and R III-8 are taken together and form at least one four to eight membered ring that is partially saturated or fully unsaturated optionally having one to three heteroatoms independently selected from nitrogen, sulfur and oxygen;
  • said ring or rings formed by R III-5 and R III-6 , or R III-6 and R III-7 , and/or R III-7 and R III-8 are optionally mono-, di- or tri-substituted independently with halo, (C 1 -C 6 )alkyl, (C 1 -C 4 )alkylsulfonyl, (C 2 -C 6 )alkenyl, hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 4 )alkylthio, amino, nitro, cyano, oxo, carboxy, (C 1 -C 6 )alkyloxycarbonyl, mono-N- or di-N,N-(C 1 -C 6 )alkylamino wherein said (C 1 -C 6 )alkyl substituent is optionally mono-, di- or tri-substituted independently with hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 6 )
  • R III-5 , R III-6 , R III-7 and/or R III-8 are each independently hydrogen, halo, (C 1 -C 6 )alkoxy or (C 1 -C 6 )alkyl, said (C 1 -C 6 )alkyl optionally having from one to nine fluorines.
  • the CETP inhibitor is selected from one of the following compounds of Formula III:
  • R IV-1 is hydrogen, Y IV , W IV -X IV or W IV —Y IV ;
  • W IV is a carbonyl, thiocarbonyl, sulfinyl or sulfonyl
  • X IV is —O—Y IV , —S—Y IV , —N(H)—Y IV or —N—(Y IV ) 2 ;
  • Y IV for each occurrence is independently Z IV or a fully saturated, partially unsaturated or fully unsaturated one to ten membered straight or branched carbon chain wherein the carbons, other than the connecting carbon, may optionally be replaced with one or two heteroatoms selected independently from oxygen, sulfur and nitrogen and said carbon is optionally mono-, di- or tri-substituted independently with halo, said carbon is optionally mono-substituted with hydroxy, said carbon is optionally mono-substituted with oxo, said sulfur is optionally mono- or di-substituted with oxo, said nitrogen is optionally mono-, or di-substituted with oxo, and said carbon chain is optionally mono-substituted with Z IV ;
  • Z IV is a partially saturated, fully saturated or fully unsaturated three to eight membered ring optionally having one to four heteroatoms selected independently from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated three to six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen;
  • said Z IV substituent is optionally mono-, di- or tri-substituted independently with halo, (C 2 -C 6 )alkenyl, (C 1 -C 6 )alkyl, hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 4 )alkylthio, amino, nitro, cyano, oxo, carboxy, (C 1 -C 6 )alkyloxycarbonyl, mono-N- or di-N,N-(C 1 -C 6 )alkylamino wherein said (C 1 -C 6 )alkyl substituent is optionally mono-, di- or tri-substituted independently with halo, hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 4 )alkylthio, amino, nitro, cyano, oxo, carboxy, (C 1 -C 6 )alkyloxycarbonyl, mono
  • R IV-2 is a partially saturated, fully saturated or fully unsaturated one to six membered straight or branched carbon chain wherein the carbons, other than the connecting carbon, may optionally be replaced with one or two heteroatoms selected independently from oxygen, sulfur and nitrogen wherein said carbon atoms are optionally mono-, di- or tri-substituted independently with halo, said carbon is optionally mono-substituted with oxo, said carbon is optionally mono-substituted with hydroxy, said sulfur is optionally mono- or di-substituted with oxo, said nitrogen is optionally mono- or di-substituted with oxo; or said R IV-2 is a partially saturated, fully saturated or fully unsaturated three to seven membered ring optionally having one to two heteroatoms selected independently from oxygen, sulfur and nitrogen, wherein said R IV-2 ring is optionally attached through (C 1 -C 4 )alkyl;
  • R IV-2 ring is optionally mono-, di- or tri-substituted independently with halo, (C 2 -C 6 )alkenyl, (C 1 -C 6 )alkyl, hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 4 )alkylthio, amino, nitro, cyano, oxo, carboxy, (C 1 -C 6 )alkyloxycarbonyl, mono-N- or di-N,N-(C 1 -C 6 )alkylamino wherein said (C 1 -C 6 )alkyl substituent is optionally mono-, di- or tri-substituted independently with halo, hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 4 )alkylthio, oxo or (C 1 -C 6 )alkyloxycarbonyl;
  • R IV-3 is hydrogen or Q IV ;
  • Q IV is a fully saturated, partially unsaturated or fully unsaturated one to six membered straight or branched carbon chain wherein the carbons other than the connecting carbon, may optionally be replaced with one heteroatom selected from oxygen, sulfur and nitrogen and said carbon is optionally mono-, di- or tri-substituted independently with halo, said carbon is optionally mono-substituted with hydroxy, said carbon is optionally mono-substituted with oxo, said sulfur is optionally mono- or di-substituted with oxo, said nitrogen is optionally mono- or di-substituted with oxo, and said carbon chain is optionally mono-substituted with V IV ;
  • V IV is a partially saturated, fully saturated or fully unsaturated three to eight membered ring optionally having one to four heteroatoms selected independently from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated three to six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen;
  • V IV substituent is optionally mono-, di-, tri-, or tetra-substituted independently with halo, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 4 )alkylthio, amino, nitro, cyano, oxo, carboxamoyl, mono-N- or di-N,N-(C 1 -C 6 )alkylcarboxamoyl, carboxy, (C 1 -C 6 )alkyloxycarbonyl, mono-N- or di-N,N-(C 1 -C 6 )alkylamino wherein said (C 1 -C 6 )alkyl or (C 2 -C 6 )alkenyl substituent is optionally mono-, di- or tri-substituted independently with hydroxy, (C 1 -C 6 )
  • R IV-4 is Q IV-1 or V IV-1 ;
  • Q IV-1 a fully saturated, partially unsaturated or fully unsaturated one to six membered straight or branched carbon chain wherein the carbons, other than the connecting carbon, may optionally be replaced with one heteroatom selected from oxygen, sulfur and nitrogen and said carbon is optionally mono-, di- or tri-substituted independently with halo, said carbon is optionally mono-substituted with hydroxy, said carbon is optionally mono-substituted with oxo, said sulfur is optionally mono- or di-substituted with oxo, said nitrogen is optionally mono- or di-substituted with oxo, and said carbon chain is optionally mono-substituted with
  • V IV-1 is a partially saturated, fully saturated or fully unsaturated three to six membered ring optionally having one to two heteroatoms selected independently from oxygen, sulfur and nitrogen;
  • V IV-1 substituent is optionally mono-, di-, tri-, or tetra-substituted independently with halo, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, amino, nitro, cyano, (C 1 -C 6 )alkyloxycarbonyl, mono-N- or di-N,N-(C 1 -C 6 )alkylamino wherein said (C 1 -C 6 )alkyl substituent is optionally mono-substituted with oxo, said (C 1 -C 6 )alkyl substituent is also optionally substituted with from one to nine fluorines;
  • R IV-5 , R IV-6 , R IV-7 and R IV-8 are each independently hydrogen, a bond, nitro or halo wherein said bond is substituted with T IV or a partially saturated, fully saturated or fully unsaturated (C 1 -C 12 ) straight or branched carbon chain wherein carbon, may optionally be replaced with one or two heteroatoms selected independently from oxygen, sulfur and nitrogen wherein said carbon atoms are optionally mono-, di- or tri-substituted independently with halo, said carbon is optionally mono-substituted with hydroxy, said carbon is optionally mono-substituted with oxo, said sulfur is optionally mono- or di-substituted with oxo, said nitrogen is optionally mono- or di-substituted with oxo, and said carbon is optionally mono-substituted with T IV ;
  • T IV is a partially saturated, fully saturated or fully unsaturated three to eight membered ring optionally having one to four heteroatoms selected independently from oxygen, sulfur and nitrogen, or, a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated three to six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen;
  • T IV substituent is optionally mono-, di- or tri-substituted independently with halo, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 4 )alkylthio, amino, nitro, cyano, oxo, carboxy, (C 1 -C 6 )alkyloxycarbonyl, mono-N- or di-N,N-(C 1 -C 6 )alkylamino wherein said (C 1 -C 6 )alkyl substituent is optionally mono-, di- or tri-substituted independently with hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 4 )alkylthio, amino, nitro, cyano, oxo, carboxy, (C 1 -C 6 )alkyloxycarbonyl, mono-N- or
  • R IV-5 and R IV-6 , or R IV-6 and R IV-7 , and/or R IV-7 and R IV-8 may also be taken together and can form at least one four to eight membered ring that is partially saturated or fully unsaturated optionally having one to three heteroatoms independently selected from nitrogen, sulfur and oxygen;
  • said ring or rings formed by R IV-5 and R IV-6 , or R IV-6 and R IV-7 , and/or R IV-7 and R IV-8 are optionally mono-, di- or tri-substituted independently with halo, (C 1 -C 6 )alkyl, (C 1 -C 4 )alkylsulfonyl, (C 2 -C 6 )alkenyl, hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 4 )alkylthio, amino, nitro, cyano, oxo, carboxy, (C 1 -C 6 )alkyloxycarbonyl, mono-N- or di-N,N-(C 1 -C 6 )alkylamino wherein said (C 1 -C 6 )alkyl substituent is optionally mono-, di- or tri-substituted independently with hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 6 )
  • the CETP inhibitor is selected from one of the following compounds of Formula IV:
  • R V-1 is Y V , W V -X V or W V —Y V ;
  • W V is a carbonyl, thiocarbonyl, sulfinyl or sulfonyl
  • X V is —O—Y V , —S—Y V , —N(H)—Y V or —N—(Y V ) 2 ;
  • Y V for each occurrence is independently Z V or a fully saturated, partially unsaturated or fully unsaturated one to ten membered straight or, branched carbon chain wherein the carbons, other than the connecting carbon, may optionally be replaced with one or two heteroatoms selected independently from oxygen, sulfur and nitrogen and said carbon is optionally mono-, di- or tri-substituted independently with halo, said carbon is optionally mono-substituted with hydroxy, said carbon is optionally mono-substituted with oxo, said sulfur is optionally mono- or di-substituted with oxo, said nitrogen is optionally mono-, or di-substituted with oxo, and said carbon chain is optionally mono-substituted with Z V ;
  • Z V is a partially saturated, fully saturated or fully unsaturated three to eight membered ring optionally having one to four heteroatoms selected independently from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated three to six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen;
  • Z V substituent is optionally mono-, di- or tri-substituted independently with halo, (C 2 -C 6 )alkenyl, (C 1 -C 6 )alkyl, hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 4 )alkylthio, amino, nitro, cyano, oxo, carboxy, (C 1 -C 6 )alkyloxycarbonyl, mono-N- or di-N,N-(C 1 -C 6 )alkylamino wherein said (C 1 -C 6 )alkyl substituent is optionally mono-, di- or tri-substituted independently with halo, hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 4 )alkylthio, amino, nitro, cyano, oxo, carboxy, (C 1 -C 6 )alkyloxycarbonyl, mono
  • R V-2 is a partially saturated, fully saturated or fully unsaturated one to six membered straight or branched carbon chain wherein the carbons, other than the connecting carbon, may optionally be replaced with one or two heteroatoms selected independently from oxygen, sulfur and nitrogen wherein said carbon atoms are optionally mono-, di- or tri-substituted independently with halo, said carbon is optionally mono-substituted with oxo, said carbon is optionally mono-substituted with hydroxy, said sulfur is optionally mono- or di-substituted with oxo, said nitrogen is optionally mono- or di-substituted with oxo; or said R V-2 is a partially saturated, fully saturated or fully unsaturated three to seven membered ring optionally having one to two heteroatoms selected independently from oxygen, sulfur and nitrogen, wherein said R V-2 ring is optionally attached through (C 1 -C 4 )alkyl;
  • R V-2 ring is optionally mono-, di- or tri-substituted independently with halo, (C 2 -C 6 )alkenyl, (C 1 -C 6 )alkyl, hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 4 )alkylthio, amino, nitro, cyano, oxo, carboxy, (C 1 -C 6 )alkyloxycarbonyl, mono-N- or di-N,N-(C 1 -C 6 )alkylamino wherein said (C 1 -C 6 )alkyl substituent is optionally mono-, di- or tri-substituted independently with halo, hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 4 )alkylthio, oxo or (C 1 -C 6 )alkyloxycarbonyl;
  • R V-3 is hydrogen or Q V ;
  • Q V is a fully saturated, partially unsaturated or fully unsaturated one to six membered straight or branched carbon chain wherein the carbons, other than the connecting carbon, may optionally be replaced with one heteroatom selected from oxygen, sulfur and nitrogen and said carbon is optionally mono-, di- or tri-substituted independently with halo, said carbon is optionally mono-substituted with hydroxy, said carbon is optionally mono-substituted with oxo, said sulfur is optionally mono- or di-substituted with oxo, said nitrogen is optionally mono-, or di-substituted with oxo, and said carbon chain is optionally mono-substituted with V V ;
  • V V is a partially saturated, fully saturated or fully unsaturated three to eight membered ring optionally having one to four heteroatoms selected independently from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated three to six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen;
  • V V substituent is optionally mono-, di-, tri-, or tetra-substituted independently with halo, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 4 )alkylthio, amino, nitro, cyano, oxo, carboxamoyl, mono-N- or di-N,N-(C 1 -C 6 )alkylcarboxamoyl, carboxy, (C 1 -C 6 )alkyloxycarbonyl, mono-N- or di-N,N-(C 1 -C 6 )alkylamino wherein said (C 1 -C 6 )alkyl or (C 2 -C 6 )alkenyl substituent is optionally mono-, di- or tri-substituted independently with hydroxy, (C 1 -C 6 )
  • R V-4 is cyano, formyl, W V-1 Q V-1 , W V-1 V V-1 (C 1 -C 4 )alkyleneV V-1 or V V-2 ;
  • W V-1 is carbonyl, thiocarbonyl, SO or SO 2 ,
  • Q V-1 a fully saturated, partially unsaturated or fully unsaturated one to six membered straight or branched carbon chain wherein the carbons may optionally be replaced with one heteroatom selected from oxygen, sulfur and nitrogen and said carbon is optionally mono-, di- or tri-substituted independently with halo, said carbon is optionally mono-substituted with hydroxy, said carbon is optionally mono-substituted with oxo, said sulfur is optionally mono- or di-substituted with oxo, said nitrogen is optionally mono-, or di-substituted with oxo, and said carbon chain is optionally mono-substituted with V V-1 ;
  • V V-1 is a partially saturated, fully saturated or fully unsaturated three to six membered ring optionally having one to two heteroatoms selected independently from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated three to six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen;
  • V V-1 substituent is optionally mono-, di-, tri-, or tetra-substituted independently with halo, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, hydroxy, oxo, amino, nitro, cyano, (C 1 -C 6 )alkyloxycarbonyl, mono-N- or di-N,N-(C 1 -C 6 )alkylamino wherein said (C 1 -C 6 )alkyl substituent is optionally mono-substituted with oxo, said (C 1 -C 6 )alkyl substituent is also optionally substituted with from one to nine fluorines;
  • V V-2 is a partially saturated, fully saturated or fully unsaturated five to seven membered ring containing one to four heteroatoms selected independently from oxygen, sulfur and nitrogen;
  • V V-2 substituent is optionally mono-, di- or tri-substituted independently with halo, (C 1 -C 2 )alkyl, (C 1 -C 2 )alkoxy, hydroxy, or oxo wherein said (C 1 -C 2 )alkyl optionally has from one to five fluorines; and
  • R V-4 does not include oxycarbonyl linked directly to the C 4 nitrogen
  • R V-3 must contain V V or R V-4 must contain V V-1 ;
  • R V-5 , R V-6 , R V-7 and R V-8 are independently hydrogen, a bond, nitro or halo wherein said bond is substituted with T V or a partially saturated, fully saturated or fully unsaturated (C 1 -C 12 ) straight or branched carbon chain wherein carbon may optionally be replaced with one or two heteroatoms selected independently from oxygen, sulfur and nitrogen, wherein said carbon atoms are optionally mono-, di- or tri-substituted independently with halo, said carbon is optionally mono-substituted with hydroxy, said carbon is optionally mono-substituted with oxo, said sulfur is optionally mono- or di-substituted with oxo, said nitrogen is optionally mono- or di-substituted with oxo, and said carbon chain is optionally mono-substituted with T V ;
  • T V is a partially saturated, fully saturated or fully unsaturated three to twelve membered ring optionally having one to four heteroatoms selected independently from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated three to six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen;
  • T V substituent is optionally mono-, di- or tri-substituted independently with halo, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 4 )alkylthio, amino, nitro, cyano, oxo, carboxy, (C 1 -C 6 )alkyloxycarbonyl, mono-N- or di-N,N-(C 1 -C 6 )alkylamino wherein said (C 1 -C 6 )alkyl substituent is optionally mono-, di- or tri-substituted independently with hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 4 )alkylthio, amino, nitro, cyano, oxo, carboxy, (C 1 -C 6 )alkyloxycarbonyl, mono-N- or
  • R V-5 and R V-6 , or R V-6 and R V-7 , and/or R V-7 and R V-8 may also be taken together and can form at least one ring that is a partially saturated or fully unsaturated four to eight membered ring optionally having one to three heteroatoms independently selected from nitrogen, sulfur and oxygen;
  • rings formed by R V-5 and R V-6 , or R V-6 and R V-7 , and/or R V-7 and R V-8 are optionally mono-, di- or tri-substituted independently with halo, (C 1 -C 6 )alkyl, (C 1 -C 4 )alkylsulfonyl, (C 2 -C 6 )alkenyl, hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 4 )alkylthio, amino, nitro, cyano, oxo, carboxy, (C 1 -C 6 )alkyloxycarbonyl, mono-N- or di-N,N-(C 1 -C 6 )alkylamino wherein said (C 1 -C 6 )alkyl substituent is optionally mono-, di- or tri-substituted independently with hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 4
  • the CETP inhibitor is selected from one of the following compounds of Formula V:
  • Another class of CETP inhibitors that finds utility with the present invention consists of cycloalkano-pyridines having the Formula VI
  • a VI denotes an aryl containing 6 to 10 carbon atoms, which is optionally substituted with up to five identical or different substituents in the form of a halogen, nitro, hydroxyl, trifluoromethyl, trifluoromethoxy or a straight-chain or branched alkyl, acyl, hydroxyalkyl or alkoxy containing up to 7 carbon atoms each, or in the form of a group according to the formula —BNR VI-3 R VI-4 , wherein
  • R VI-3 and R VI-4 are identical or different and denote a hydrogen, phenyl or a straight-chain or branched alkyl containing up to 6 carbon atoms,
  • D VI denotes an aryl containing 6 to 10 carbon atoms, which is optionally substituted with a phenyl, nitro, halogen, trifluoromethyl or trifluoromethoxy, or a radical according to the formula R VI-5 -L VI —,
  • R IV-5 , R VI-6 and R VI-9 denote, independently from one another, a cycloalkyl containing 3 to 6 carbon atoms, or an aryl containing 6 to 10 carbon atom or a 5- to 7-membered, optionally benzo-condensed, saturated or unsaturated, mono-, bi- or tricyclic heterocycle containing up to 4 heteroatoms from the series of S, N and/or O, wherein the rings are optionally substituted, in the case of the nitrogen-containing rings also via the N function, with up to five identical or different substituents in the form of a halogen, trifluoromethyl, nitro, hydroxyl, cyano, carboxyl, trifluoromethoxy, a straight-chain or branched acyl, alkyl, alkylthio, alkylalkoxy, alkoxy or alkoxycarbonyl containing up to 6 carbon atoms each, an aryl or trifluoromethyl-substituted aryl
  • R VI-10 , R VI-11 and R VI-12 denote, independently from one another, an aryl containing 6 to 10 carbon atoms, which is in turn substituted with up to two identical or different substituents in the form of a phenyl, halogen or a straight-chain or branched alkyl containing up to 6 carbon atoms,
  • R VI-13 and R VI-14 are identical or different and have the meaning of R VI-3 and R VI-4 given above, or
  • R VI-5 and/or R VI-6 denote a radical according to the formula
  • R VI-7 denotes a hydrogen or halogen
  • R VI-8 denotes a hydrogen, halogen, azido, trifluoromethyl, hydroxyl, trifluoromethoxy, a straight-chain or branched alkoxy or alkyl containing up to 6 carbon atoms each, or a radical according to the formula
  • R VI-15 and R VI-16 are identical or different and have the meaning of RV VI-3 and R VI-4 given above, or
  • R VI-7 and R VI-8 together form a radical according to the formula ⁇ O or ⁇ NR VI-17 , wherein
  • R VI-17 denotes a hydrogen or a straight-chain or branched alkyl, alkoxy or acyl containing up to 6 carbon atoms each,
  • L VI denotes a straight-chain or branched alkylene or alkenylene chain containing up to 8 carbon atoms each, which are optionally substituted with up to two hydroxyl groups,
  • T VI and X VI are identical or different and denote a straight-chain or branched alkylene chain containing up to 8 carbon atoms, or
  • T VI or X VI denotes a bond
  • V VI denotes an oxygen or sulfur atom or an BNR VI-18 group, wherein
  • R VI-18 denotes a hydrogen or a straight-chain or branched alkyl containing up to 6 carbon atoms or a phenyl
  • E VI denotes a cycloalkyl containing 3 to 8 carbon atoms, or a straight-chain or branched alkyl containing up to 8 carbon atoms, which is optionally substituted with a cycloalkyl containing 3 to 8 carbon atoms or a hydroxyl, or a phenyl, which is optionally substituted with a halogen or trifluoromethyl,
  • R VI-1 and R VI-2 together form a straight-chain or branched alkylene chain containing up to 7 carbon atoms, which must be substituted with a carbonyl group and/or a radical according to the formula
  • a and b are identical or different and denote a number equaling 1, 2 or 3,
  • R VI-19 denotes a hydrogen atom, a cycloalkyl containing 3 to 7 carbon atoms, a straight-chain or branched silylalkyl containing up to 8 carbon atoms, or a straight-chain or branched alkyl containing up to 8 carbon atoms, which is optionally substituted with a hydroxyl, a straight-chain or a branched alkoxy containing up to 6 carbon atoms or a phenyl, which may in turn be substituted with a halogen, nitro, trifluoromethyl, trifluoromethoxy or phenyl or tetrazole-substituted phenyl, and an alkyl that is optionally substituted with a group according to the formula BOR VI-22 , wherein
  • R VI-22 denotes a straight-chain or branched acyl containing up to 4 carbon atoms or benzyl, or
  • R VI-19 denotes a straight-chain or branched acyl containing up to 20 carbon atoms or benzoyl, which is optionally substituted with a halogen, trifluoromethyl, nitro or trifluoromethoxy, or a straight-chain or branched fluoroacyl containing up to 8 carbon atoms,
  • R VI-20 and R VI-21 are identical or different and denote a hydrogen, phenyl or a straight-chain or branched alkyl containing up to 6 carbon atoms, or
  • R VI-20 and R VI-21 together form a 3- to 6-membered carbocyclic ring, and a the carbocyclic rings formed are optionally substituted, optionally also geminally, with up to six identical or different substituents in the form of trifluoromethyl, hydroxyl, nitrile, halogen, carboxyl, nitro, azido, cyano, cycloalkyl or cycloalkyloxy containing 3 to 7 carbon atoms each, a straight-chain or branched alkoxycarbonyl, alkoxy or alkylthio containing up to 6 carbon atoms each, or a straight-chain or branched alkyl containing up to 6 carbon atoms, which is in turn substituted with up to two identical or different substituents in the form of a hydroxyl, benzyloxy, trifluoromethyl, benzoyl, a straight-chain or branched alkoxy, oxyacyl or carboxyl containing up to 4 carbon atom
  • c is a number equaling 1, 2, 3 or 4,
  • d is a number equaling 0 or 1
  • R VI-23 and R VI-24 are identical or different and denote a hydrogen, cycloalkyl containing 3 to 6 carbon atoms, a straight-chain or branched alkyl containing up to 6 carbon atoms, benzyl or phenyl, which is optionally substituted with up to two identical or different substituents in the form of halogen, trifluoromethyl, cyano, phenyl or nitro, and/or the carbocyclic rings formed are optionally substituted with a spiro-linked radical according to the formula
  • W VI denotes either an oxygen atom or a sulfur atom
  • e is a number equaling 1, 2, 3, 4, 5, 6 or 7,
  • f is a number equaling 1 or 2
  • R VI-25 , R VI-26 , R VI-27 , R VI-28 , R VI-29 , R VI-30 and R VI-31 are identical or different and denote a hydrogen, trifluoromethyl, phenyl, halogen or a straight-chain or branched alkyl or alkoxy containing up to 6 carbon atoms each, or
  • R VI-25 and R VI-26 or R VI-27 and R VI-28 each together denote a straight-chain or branched alkyl chain containing up to 6 carbon atoms or
  • R VI-25 and R VI-26 or R VI-27 and R VI-28 each together form a radical according to the formula
  • W VI has the meaning given above
  • g is a number equaling 1, 2, 3, 4, 5, 6 or 7,
  • R VI-32 and R VI-33 together form a 3- to 7-membered heterocycle, which contains an oxygen or sulfur atom or a group according to the formula SO, SO 2 or BNR VI-34 , wherein
  • R VI-34 denotes a hydrogen atom, a phenyl, benzyl, or a straight-chain or branched alkyl containing up to 4 carbon atoms, and salts and N oxides thereof, with the exception of 5(6H)-quinolones, 3-benzoyl-7,8-dihydro-2,7,7-trimethyl-4-phenyl.
  • the CETP inhibitor is selected from one of the following compounds of Formula VI:
  • Another class of CETP inhibitors that finds utility with the present invention consists of substituted-pyridines having the Formula VII
  • R VII-2 and R VII-6 are independently selected from the group consisting of hydrogen, hydroxy, alkyl, fluorinated alkyl, fluorinated aralkyl, chlorofluorinated alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, alkoxyalkyl, and alkoxycarbonyl; provided that at least one of R VII-2 and R VII-6 is fluorinated alkyl, chlorofluorinated alkyl or alkoxyalkyl;
  • R VII-3 is selected from the group consisting of hydroxy, amido, arylcarbonyl, heteroarylcarbonyl, hydroxymethyl —CHO,
  • R VII-7 is selected from the group consisting of hydrogen, alkyl and cyanoalkyl
  • R VII-15a is selected from the group consisting of hydroxy, hydrogen, halogen, alkylthio, alkenylthio, alkynylthio, arylthio, heteroarylthio, heterocyclylthio, alkoxy, alkenoxy, alkynoxy, aryloxy, heteroaryloxy and heterocyclyloxy, and
  • R VII-16a is selected from the group consisting of alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, and heterocyclyl, arylalkoxy, trialkylsilyloxy;
  • R VII-4 is selected from the group consisting of hydrogen, hydroxy, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, aryl, heteroaryl, heterocyclyl, cycloalkylalkyl, cycloalkenylalkyl, aralkyl, heteroarylalkyl, heterocyclylalkyl, cycloalkylalkenyl, cycloalkenylalkenyl, aralkenyl, hetereoarylalkenyl, heterocyclylalkenyl, alkoxy, alkenoxy, alkynoxy, aryloxy, heteroaryloxy, heterocyclyloxy, alkanoyloxy, alkenoyloxy, alkynoyloxy, aryloyloxy, heteroaroyloxy, heterocyclyloy
  • R VII-5 is selected from the group consisting of hydrogen, hydroxy, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, aryl, heteroaryl, heterocyclyl, alkoxy, alkenoxy, alkynoxy, aryloxy, heteroaryloxy, heterocyclyloxy, alkylcarbonyloxyalkyl, alkenylcarbonyloxyalkyl, alkynylcarbonyloxyalkyl, arylcarbonyloxyalkyl, heteroarylcarbonyloxyalkyl, heterocyclylcarbonyloxyalkyl, cycloalkylalkyl, cycloalkenylalkyl, aralkyl, heteroarylalkyl, heterocyclylalkyl, cycloalkylalkenyl, cycloalkenylalkenyl, cyclo
  • R VII-15b is selected from the group consisting of hydroxy, hydrogen, halogen, alkylthio, alkenylthio, alkynylthio, arylthio, heteroarylthio, heterocyclylthio, alkoxy, alkenoxy, alkynoxy, aryloxy, heteroaryloxy, heterocyclyloxy, aroyloxy, and alkylsulfonyloxy, and
  • R VII-16b is selected form the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkoxy, and trialkylsilyloxy;
  • R VII-17 and R VII-18 are independently selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl;
  • R VII-19 is selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, —SR VII-20 , —OR VII-21 , and BR VII-22 CO 2 R VII-23 , wherein
  • R VII-20 is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aminoalkyl, aminoalkenyl, aminoalkynyl, aminoaryl, aminoheteroaryl, aminoheterocyclyl, alkylheteroarylamino, arylheteroarylamino,
  • R VII-21 is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl,
  • R VII-22 is selected from the group consisting of alkylene or arylene, and
  • R VII-23 is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl;
  • R VII-24 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, aralkenyl, and aralkynyl;
  • R VII-25 is heterocyclylidenyl
  • R VII-26 and R VII-27 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl;
  • R VII-28 and R VII-29 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl;
  • R VII-30 and R VII-31 are independently alkoxy, alkenoxy, alkynoxy, aryloxy, heteroaryloxy, and heterocyclyloxy;
  • R VII-32 and R VII-33 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl;
  • R VII-36 is selected from the group consisting of alkyl, alkenyl, aryl, heteroaryl and heterocyclyl;
  • R VII-37 and R VII-38 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl;
  • R VII-39 is selected from the group consisting of hydrogen, alkoxy, alkenoxy, alkynoxy, aryloxy, heteroaryloxy, heterocyclyloxy, alkylthio, alkenylthio, alkynylthio, arylthio, heteroarylthio and heterocyclylthio, and
  • R VII-40 is selected from the group consisting of haloalkyl, haloalkenyl, haloalkynyl, haloaryl, haloheteroaryl, haloheterocyclyl, cycloalkyl, cycloalkenyl, heterocyclylalkoxy, heterocyclylalkenoxy, heterocyclylalkynoxy, alkylthio, alkenylthio, alkynylthio, arylthio, heteroarylthio and heterocyclylthio;
  • R VII-41 is heterocyclyidenyl
  • R VII-42 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl, and
  • R VII-43 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, haloaryl, haloheteroaryl, and haloheterocyclyl;
  • R VII-44 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl;
  • R VII-45 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, haloalkyl, haloalkenyl, haloalkynyl, haloaryl, haloheteroaryl, haloheterocyclyl, heterocyclyl, cycloalkylalkyl, cycloalkenylalkyl, aralkyl, heteroarylalkyl, heterocyclylalkyl, cycloalkylalkenyl, cycloalkenylalkenyl, aralkenyl, heteroarylalkenyl, heterocyclylalkenyl, alkylthioalkyl, alkenylthioalkyl, alkynylthioalkyl, arylthioalkyl, heteroarylthioalkyl, heterocyclylthioalkyl, alkylthioalkyl, alky
  • R VII-46 is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl, and
  • R VII-47 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl;
  • R VII-48 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl, and
  • R VII-49 is selected from the group consisting of alkoxy, alkenoxy, alkynoxy, aryloxy, heteroaryloxy, heterocyclyloxy, haloalkyl, haloalkenyl, haloalkynyl, haloaryl, haloheteroaryl and haloheterocyclyl;
  • R VII-50 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, alkoxy, alkenoxy, alkynoxy, aryloxy, heteroaryloxy and heterocyclyloxy;
  • R VII-51 is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, haloalkyl, haloalkenyl, haloalkynyl, haloaryl, haloheteroaryl and haloheterocyclyl; and
  • R VII-53 is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl;
  • R VII-5 is selected from the group consisting of heterocyclylalkyl and heterocyclylalkenyl, the heterocyclyl radical of the corresponding heterocyclylalkyl or heterocyclylalkenyl is other than 6-lactone;
  • R VII-4 is aryl, heteroaryl or heterocyclyl, and one of R VII-2 and R VII-6 is trifluoromethyl, then the other of R VII-2 and R VII-6 is difluoromethyl.
  • the CETP inhibitor of Formula VIII is dimethyl 5,5-dithiobis[2-difluoromethyl-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridine-carboxylate].
  • a VIII stands for aryl with 6 to 10 carbon atoms, which is optionally substituted up to 3 times in an identical manner or differently by halogen, hydroxy, trifluoromethyl, trifluoromethoxy, or by straight-chain or branched alkyl, acyl, or alkoxy with up to 7 carbon atoms each, or by a group of the formula
  • R VIII-1 and R VIII-2 are identical or different and denote hydrogen, phenyl, or straight-chain or branched alkyl with up to 6 carbon atoms,
  • D VIII stands for straight-chain or branched alkyl with up to 8 carbon atoms, which is substituted by hydroxy
  • E VIII and L VIII are either identical or different and stand for straight-chain or branched alkyl with up to 8 carbon atoms, which is optionally substituted by cycloalkyl with 3 to 8 carbon atoms, or stands for cycloalkyl with 3 to 8 carbon atoms, or
  • E VIII has the above-mentioned meaning
  • L VIII in this case stands for aryl with 6 to 10 carbon atoms, which is optionally substituted up to 3 times in an identical manner or differently by halogen, hydroxy, trifluoromethyl, trifluoromethoxy, or by straight-chain or branched alkyl, acyl, or alkoxy with up to 7 carbon atoms each, or by a group of the formula
  • R VIII-3 and R VIII-4 are identical or different and have the meaning given above for R VIII-1 and R VIII-2 , or
  • E VIII stands for straight-chain or branched alkyl with up to 8 carbon atoms, or stands for aryl with 6 to 10 carbon atoms, which is optionally substituted up to 3 times in an identical manner or differently by halogen, hydroxy, trifluoromethyl, trifluoromethoxy, or by straight-chain or branched alkyl, acyl, or alkoxy with up to 7 carbon atoms each, or by a group of the formula
  • R VIII-5 and R VIII-6 are identical or different and have the meaning given above for R VIII-1 and R VIII-2 .
  • L III in this case stands for straight-chain or branched alkoxy with up to 8 carbon atoms or for cycloalkyloxy with 3 to 8 carbon atoms,
  • T VIII stands for a radical of the formula
  • R VIII-7 and R VIII-8 are identical or different and denote cycloalkyl with 3 to 8 carbon atoms, or aryl with 6 to 10 carbon atoms, or denote a 5- to 7-member aromatic, optionally benzo-condensed, heterocyclic compound with up to 3 heteroatoms from the series S, N and/or O, which are optionally substituted up to 3 times in an identical manner or differently by trifluoromethyl, trifluoromethoxy, halogen, hydroxy, carboxyl, by straight-chain or branched alkyl, acyl, alkoxy, or alkoxycarbonyl with up to 6 carbon atoms each, or by phenyl, phenoxy, or thiophenyl, which can in turn be substituted by halogen, trifluoromethyl, or trifluoromethoxy, and/or the rings are substituted by a group of the formula
  • R VIII-11 and R VIII-12 are identical or different and have the meaning given above for R VIII-1 and R VIII-2 ,
  • X VIII denotes a straight or branched alkyl chain or alkenyl chain with 2 to 10 carbon atoms each, which are optionally substituted up to 2 times by hydroxy,
  • R VIII-9 denotes hydrogen
  • R VIII-10 denotes hydrogen, halogen, azido, trifluoromethyl, hydroxy, mercapto, trifluoromethoxy, straight-chain or branched alkoxy with up to 5 carbon atoms, or a radical of the formula
  • R VIII-13 and R VIII-14 are identical or different and have the meaning given above for R VIII-1 and R VIII-2 , or
  • R VIII-9 and R VIII-10 form a carbonyl group together with the carbon atom.
  • R IX-1 is selected from higher alkyl, higher alkenyl, higher alkynyl, aryl, aralkyl, aryloxyalkyl, alkoxyalkyl, alkylthioalkyl, arylthioalkyl, and cycloalkylalkyl;
  • R IX-2 is selected from aryl, heteroaryl, cycloalkyl, and cycloalkenyl, wherein
  • R IX-2 is optionally substituted at a substitutable position with one or more radicals independently selected from alkyl, haloalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkoxy, halo, aryloxy, aralkyloxy, aryl, aralkyl, aminosulfonyl, amino, monoalkylamino and dialkylamino; and
  • R IX-3 is selected from hydrido, —SH and halo
  • R IX-2 cannot be phenyl or 4-methylphenyl when R IX-1 is higher alkyl and when R IX-3 is BSH.
  • the CETP inhibitor is selected from the following compounds of Formula IX:
  • Another class of CETP inhibitors that finds utility with the present invention consists of hetero-tetrahydroquinolines having the Formula X
  • a X represents cycloalkyl with 3 to 8 carbon atoms or a 5 to 7-membered, saturated, partially saturated or unsaturated, optionally benzo-condensed heterocyclic ring containing up to 3 heteroatoms from the series comprising S, N and/or O, that in case of a saturated heterocyclic ring is bonded to a nitrogen function, optionally bridged over it, and in which the aromatic systems mentioned above are optionally substituted up to 5-times in an identical or different substituents in the form of halogen, nitro, hydroxy, trifluoromethyl, trifluoromethoxy or by a straight-chain or branched alkyl, acyl, hydroxyalkyl or alkoxy each having up to 7 carbon atoms or by a group of the formula BNR X-3 R X-4 ,
  • R X-3 and R X-4 are identical or different and denote hydrogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms, or
  • a X represents a radical of the formula
  • D X represents an aryl having 6 to 10 carbon atoms, that is optionally substituted by phenyl, nitro, halogen, trifluormethyl or trifluormethoxy, or it represents a radical of the formula
  • R X-5 , R X-6 and R X-9 independently of one another denote cycloalkyl having 3 to 6 carbon atoms, or an aryl having 6 to 10 carbon atoms or a 5- to 7-membered aromatic, optionally benzo-condensed saturated or unsaturated,
  • R X-10 , R X-11 and R X-12 independently from each other denote aryl having 6 to 10 carbon atoms, which is in turn substituted with up to 2 identical or different substituents in the form of phenyl, halogen or a straight-chain or branched alkyl having up to 6 carbon atoms,
  • X X-13 and R X-14 are identical or different and have the meaning of R X-3 and R X-4 indicated above, or
  • R X-5 and/or R X-6 denote a radical of the formula
  • R X-7 denotes hydrogen or halogen
  • R X-8 denotes hydrogen, halogen, azido, trifluoromethyl, hydroxy, trifluoromethoxy, straight-chain or branched alkoxy or alkyl having up to 6 carbon atoms or a radical of the formula
  • R X-15 and R X-16 are identical or different and have the meaning of R X-3 and R X-4 indicated above, or
  • R X-7 and R X-8 together form a radical of the formula ⁇ O or ⁇ NR X-17 ,
  • R X-17 denotes hydrogen or straight chain or branched alkyl, alkoxy or acyl having up to 6 carbon atoms,
  • L X denotes a straight chain or branched alkylene or alkenylene chain having up to 8 carbon atoms, that are optionally substituted with up to 2 hydroxy groups,
  • T X and X X are identical or different and denote a straight chain or branched alkylene chain with up to 8 carbon atoms or
  • T X or X X denotes a bond
  • V X represents an oxygen or sulfur atom or an BNR X-18 -group, in which
  • R X-18 denotes hydrogen or straight chain or branched alkyl with up to 6 carbon atoms or phenyl
  • E X represents cycloalkyl with 3 to 8 carbon atoms, or straight chain or branched alkyl with up to 8 carbon atoms, that is optionally substituted by cycloalkyl with 3 to 8 carbon atoms or hydroxy, or represents a phenyl, that is optionally substituted by halogen or trifluoromethyl,
  • R X-1 and R X-2 together form a straight-chain or branched alkylene chain with up to 7 carbon atoms, that must be substituted by carbonyl group and/or by a radical with the formula
  • R X-19 denotes hydrogen, cycloalkyl with 3 up to 7 carbon atoms, straight chain or branched silylalkyl with up to 8 carbon atoms or straight chain or branched alkyl with up to 8 carbon atoms, that are optionally substituted by hydroxyl, straight chain or branched alkoxy with up to 6 carbon atoms or by phenyl, which in turn might be substituted by halogen, nitro, trifluormethyl, trifluoromethoxy or by phenyl or by tetrazole-substituted phenyl, and alkyl, optionally be substituted by a group with the formula BOR X-22 ,
  • R X-22 denotes a straight chain or branched acyl with up to 4 carbon atoms or benzyl, or
  • R X-19 denotes straight chain or branched acyl with up to carbon atoms or benzoyl, that is optionally substituted by halogen, trifluoromethyl, nitro or trifluoromethoxy, or it denotes straight chain or branched fluoroacyl with up to 8 carbon atoms and 9 fluorine atoms,
  • R X-20 and R X-21 are identical or different and denote hydrogen, phenyl or straight chain or branched alkyl with up to 6 carbon atoms, or
  • R X-20 and R X-21 together form a 3- to 6-membered carbocyclic ring, and the carbocyclic rings formed are optionally substituted, optionally also geminally, with up to six identical or different substituents in the form of triflouromethyl, hydroxy, nitrile, halogen, carboxyl, nitro, azido, cyano, cycloalkyl or cycloalkyloxy with 3 to 7 carbon atoms each, by straight chain or branched alkoxycarbonyl, alkoxy or alkylthio with up to 6 carbon atoms each or by straight chain or branched alkyl with up to 6 carbon atoms, which in turn is substituted with up to 2 identically or differently by hydroxyl, benzyloxy, trifluoromethyl, benzoyl, straight chain or branched alkoxy, oxyacyl or carbonyl with up to 4 carbon atoms each and/or phenyl, which may in turn be substituted with up to 6
  • c denotes a number equaling 1, 2, 3, or 4,
  • d denotes a number equaling 0 or 1
  • R X-23 and R X-24 are identical or different and denote hydrogen, cycloalkyl with 3 to 6 carbon atoms, straight chain or branched alkyl with up to 6 carbon atoms, benzyl or phenyl, that is optionally substituted with up to 2 identically or differently by halogen, trifluoromethyl, cyano, phenyl or nitro, and/or the formed carbocyclic rings are substituted optionally by a spiro-linked radical with the formula
  • W X denotes either an oxygen or a sulfur atom
  • Y X and Y′ X together form a 2 to 6 membered straight chain or branched alkylene chain
  • e denotes a number equaling 1, 2, 3, 4, 5, 6, or 7,
  • f denotes a number equaling 1 or 2
  • R X-25 , R X-26 , R X-27 , R X-28 , R X-29 , R X-30 and R X-31 are identical or different and denote hydrogen, trifluoromethyl, phenyl, halogen or straight chain or branched alkyl or alkoxy with up to 6 carbon atoms each, or
  • R X-25 and R X-26 or R X-27 and R X-28 respectively form together a straight chain or branched alkyl chain with up to 6 carbon atoms, or
  • R X-25 and R X-26 or R X-27 and R X-28 each together form a radical with the formula
  • g denotes a number equaling 1, 2, 3, 4, 5, 6, or 7,
  • R X-32 and R X-33 form together a 3- to 7-membered heterocycle, which contains an oxygen or sulfur atom or a group with the formula SO, SO 2 or —NR X-34 ,
  • R X-34 denotes hydrogen, phenyl, benzyl or straight or branched alkyl with up to 4 carbon atoms.
  • the CETP inhibitor is selected from the following compounds of Formula X:
  • a XI stands for cycloalkyl with 3 to 8 carbon atoms, or stands for aryl with 6 to 10 carbon atoms, or stands for a 5- to 7-membered, saturated, partially unsaturated or unsaturated, possibly benzocondensated, heterocycle with up to 4 heteroatoms from the series S, N and/or O, where aryl and the heterocyclic ring systems mentioned above are substituted up to 5-fold, identical or different, by cyano, halogen, nitro, carboxyl, hydroxy, trifluoromethyl, trifluoro-methoxy, or by straight-chain or branched alkyl, acyl, hydroxyalkyl, alkylthio, alkoxycarbonyl, oxyalkoxycarbonyl or alkoxy each with up to 7 carbon atoms, or by a group of the formula
  • R XI-3 and R XI-4 are identical or different and denote hydrogen, phenyl, or straight-chain or branched alkyl with up to 6 carbon atoms
  • D XI stands for a radical of the formula
  • R XI-5 , R XI-6 and R XI-9 independent of each other, denote cycloalkyl with 3 to 6 carbon atoms, or denote aryl with 6 to 10 carbon atoms, or denote a 5- to 7-membered, possibly benzocondensated, saturated or unsaturated, mono-, bi- or tricyclic heterocycle with up to 4 heteroatoms of the series S, N and/or O, where the cycles are possibly substitutedCin the case of the nitrogen-containing rings also via the N-functionCup to 5-fold, identical or different, by halogen, trifluoromethyl, nitro, hydroxy, cyano, carboxyl, trifluoromethoxy, straight-chain or branched acyl, alkyl, alkylthio, alkylalkoxy, alkoxy or alkoxycarbonyl with up to 6 carbon atoms each by aryl or trifluoromethyl substituted aryl with 6 to 10 carbon atoms each, or
  • R XI-10 , R XI-11 and R XI-12 independent of each other, denote aryl with 6 to 10 carbon atoms, which itself is substituted up to 2-fold, identical or different, by phenyl, halogen, or by straight-chain or branched alkyl with up to 6 carbon atoms,
  • R XI-13 and R XI-14 are identical or different and have the meaning given above for R XI-3 and R XI-4 , or
  • R XI-5 and/or R XI-6 denote a radical of the formula
  • R XI-7 denotes hydrogen, halogen or methyl
  • R XI-8 denotes hydrogen, halogen, azido, trifluoromethyl, hydroxy, trifluoromethoxy, straight-chain or branched alkoxy or alkyl with up to 6 carbon atoms each, or a radical of the formula —NR XI-15 R XI-16 ,
  • X XI-15 and R XI-16 are identical or different and having the meaning given above for R XI-3 and R XI-4 , or
  • R XI-7 and R XI-8 together form a radical of the formula ⁇ O or ⁇ NR XI-17 , in which
  • R XI-17 denotes hydrogen or straight-chain or branched alkyl, alkoxy or acyl with up to 6 carbon atoms each,
  • L XI denotes a straight-chain or branched alkylene- or alkenylene chain with up to 8 carbon atoms each, which is possibly substituted up to 2-fold by hydroxy
  • T XI and X XI are identical or different and denote a straight-chain or branched alkylene chain with up to 8 carbon atoms, or
  • T XI and X XI denotes a bond
  • V XI stands for an oxygen- or sulfur atom or for an —NR XI-18 group
  • R XI-18 denotes hydrogen or straight-chain or branched alkyl with up to 6 carbon atoms, or phenyl,
  • E XI stands for cycloalkyl with 3 to 8 carbon atoms, or stands for straight-chain or branched alkyl with up to 8 carbon atoms, which is possibly substituted by cycloalkyl with 3 to 8 carbon atoms or hydroxy, or stands for phenyl, which is possibly substituted by halogen or trifluoromethyl,
  • R XI-1 and R XI-2 together form a straight-chain or branched alkylene chain with up to 7 carbon atoms, which must be substituted by a carbonyl group and/or by a radical of the formula
  • a and b are identical or different and denote a number 1, 2 or 3
  • R XI-19 denotes hydrogen, cycloalkyl with 3 to 7 carbon atoms, straight-chain or branched silylalkyl with up to 8 carbon atoms, or straight-chain or branched alkyl with up to 8 carbon atoms, which is possibly substituted by hydroxy, straight-chain or branched alkoxy with up to 6 carbon atoms, or by phenyl, which itself can be substituted by halogen, nitro, trifluoromethyl, trifluoromethoxy or by phenyl substituted by phenyl or tetrazol, and alkyl is possibly substituted by a group of the formula —OR XI-22 ,
  • R XI-22 denotes straight-chain or branched acyl with up to 4 carbon atoms, or benzyl, or
  • R XI-19 denotes straight-chain or branched acyl with up to 20 carbon atoms or benzoyl, which is possibly substituted by halogen, trifluoromethyl, nitro or trifluoromethoxy, or denotes straight-chain or branched fluoroacyl with up to 8 carbon atoms and 9 fluorine atoms,
  • R XI-20 and R XI-21 are identical or different, denoting hydrogen, phenyl or straight-chain or branched alkyl with up to 6 carbon atoms, or
  • R XI-20 and R XI-21 together form a 3- to 6-membered carbocycle, and, possibly also geminally, the alkylene chain formed by R XI-1 and R XI-2 , is possibly substituted up to 6-fold, identical or different, by trifluoromethyl, hydroxy, nitrile, halogen, carboxyl, nitro, azido, cyano, cycloalkyl or cycloalkyloxy with 3 to 7 carbon atoms each, by straight-chain or branched alkoxycarbonyl, alkoxy or alkoxythio with up to 6 carbon atoms each, or by straight-chain or branched alkyl with up to 6 carbon atoms, which itself is substituted up to 2-fold, identical or different by hydroxyl, benzyloxy, trifluoromethyl, benzoyl, straight-chain or branched alkoxy, oxyacyl or carboxyl with up to 4 carbon atoms each, and/or phenyl—
  • c denotes a number 1, 2, 3 or 4,
  • d denotes a number 0 or 1
  • R XI-23 and R XI-24 are identical or different and denote hydrogen, cycloalkyl with 3 to 6 carbon atoms, straight-chain or branched alkyl with up to 6 carbon atoms, benzyl or phenyl, which is possibly substituted up to 2-fold, identical or different, by halogen, trifluoromethyl, cyano, phenyl or nitro, and/or the alkylene chain formed by R XI-1 and R XI-2 is possibly substituted by a spiro-jointed radical of the formula
  • W XI denotes either an oxygen or a sulfur atom
  • Y XI and Y′ XI together form a 2- to 6-membered straight-chain or branched alkylene chain
  • e is a number 1, 2, 3, 4, 5, 6 or 7,
  • f denotes a number 1 or 2
  • R XI-25 , R XI-26 , R XI-27 , R XI-28 , R XI-29 , R XI-30 and R XI-31 are identical or different and denote hydrogen, trifluoromethyl, phenyl, halogen, or straight-chain or branched alkyl or alkoxy with up to 6 carbon atoms each, or
  • R XI-25 and R XI-26 or R XI-27 and R XI-28 together form a straight-chain or branched alkyl chain with up to 6 carbon atoms, or
  • R XI-25 and R XI-26 or R XI-27 and R XI-28 together form a radical of the formula
  • g is a number 1, 2, 3, 4, 5, 6 or 7,
  • R XI-32 and R XI-33 together form a 3- to 7-membered heterocycle that contains an oxygen- or sulfur atom or a group of the formula SO, SO 2 or —NR XI-34 ,
  • R XI-34 denotes hydrogen, phenyl, benzyl, or straight-chain or branched alkyl with up to 4 carbon atoms.
  • Another class of CETP inhibitors that finds utility with the present invention consists of 2-aryl-substituted pyridines having the Formula (XII)
  • a XII and E XII are identical or different and stand for aryl with 6 to 10 carbon atoms which is possibly substituted, up to 5-fold identical or different, by halogen, hydroxy, trifluoromethyl, trifluoromethoxy, nitro or by straight-chain or branched alkyl, acyl, hydroxy alkyl or alkoxy with up to 7 carbon atoms each, or by a group of the formula —NR XII-1 R XII-2 ,
  • R XII-1 and R XII-2 are identical or different and are meant to be hydrogen, phenyl or straight-chain or branched alkyl with up to 6 carbon atoms,
  • D XII stands for straight-chain or branched alkyl with up to 8 carbon atoms, which is substituted by hydroxy
  • L XII stands for cycloalkyl with 3 to 8 carbon atoms or for straight-chain or branched alkyl with up to 8 carbon atoms, which is possibly substituted by cycloalkyl with 3 to 8 carbon atoms, or by hydroxy,
  • T XII stands for a radical of the formula R XII-3 -X XII — or
  • R XII-3 and R XII-4 are identical or different and are meant to be cycloalkyl with 3 to 8 carbon atoms, or aryl with 6 to 10 carbon atoms, or a 5- to 7-membered aromatic, possibly benzocondensated heterocycle with up to 3 heteroatoms from the series S, N and/or O, which are possibly substituted up to 3-fold identical or different, by trifluoromethyl, trifluoromethoxy, halogen, hydroxy, carboxyl, nitro, by straight-chain or branched alkyl, acyl, alkoxy or alkoxycarbonyl with up to 6 carbon atoms each or by phenyl, phenoxy or phenylthio which in turn can be substituted by halogen, trifluoromethyl or trifluoromethoxy, and/or where the cycles are possibly substituted by a group of the formula —NR XII-7 R XII-8 ,
  • R XII-7 and R XII-8 are identical or different and have the meaning of R XII-1 and R XII-2 given above,
  • X XII is a straight-chain or branched alkyl or alkenyl with 2 to 10 carbon atoms each, possibly substituted up to 2-fold by hydroxy or halogen,
  • R XII-5 stands for hydrogen
  • R XII-6 means to be hydrogen, halogen, mercapto, azido, trifluoromethyl, hydroxy, trifluoromethoxy, straight-chain or branched alkoxy with up to 5 carbon atoms, or a radical of the formula BNR XII-9 R XII-10 ,
  • R XII-9 and R XII-10 are identical or different and have the meaning of R XII-1 and R XII-2 given above, or
  • R XII-5 and R XII-6 together with the carbon atom, form a carbonyl group.
  • the CETP inhibitor is selected from the following compounds of Formula XII:
  • Another class of CETP inhibitors that finds utility with the present invention consists of compounds having the Formula (XIII)
  • R XIII is a straight chain or branched C 1-10 alkyl; straight chain or branched C 2-10 alkenyl; halogenated C 1-4 lower alkyl; C 3-10 cycloalkyl that may be substituted; C 5-8 cycloalkenyl that may be substituted; C 3-10 cycloalkyl C 1-10 alkyl that may be substituted; aryl that may be substituted; aralkyl that may be substituted; or a 5- or 6-membered heterocyclic group having 1 to 3 nitrogen atoms, oxygen atoms or sulfur atoms that may be substituted,
  • X XIII-1 , X XIII-2 , X XIII-3 , X XIII-4 may be the same or different and are a hydrogen atom; halogen atom; C 1-4 lower alkyl; halogenated C 1-4 lower alkyl; C 1-4 lower alkoxy; cyano group; nitro group; acyl; or aryl, respectively;
  • Y XIII is —CO—; or BSO 2 —;
  • Z XIII is a hydrogen atom; or mercapto protective group.
  • the CETP inhibitor is selected from the following compounds of Formula XIII:
  • n XIV is an integer selected from 0 through 5;
  • R XIV-1 is selected from the group consisting of haloalkyl, haloalkenyl, haloalkoxyalkyl, and haloalkenyloxyalkyl;
  • X XIV is selected from the group consisting of O, H, F, S, S(O), NH, N(OH), N(alkyl), and N(alkoxy);
  • R XIV-16 is selected from the group consisting of hydrido, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, alkoxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, aralkoxyalkyl, heteroaralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxyalkyl, haloalkenyloxyal
  • D XIV-1 , D XIV-2 , J XIV-1 , J XIV-2 and K XIV-1 are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more than one of D XIV-1 , D XIV-2 , J XIV-1 , J XIV-2 and K XIV-1 is a covalent bond, no more than one of D XIV-1 , D XIV-2 , J XIV-1 , J XIV-2 and K XIV-1 is O, no more than one of D XIV-1 , D XIV-2 , J XIV-1 , J XIV-2 and K XIV-1 is S, one of D XIV-1 , D XIV-2 , J XIV-1 , J XIV-2 and K XIV-1 must be a covalent bond when two of D XIV-1 , D XIV-2 , J XIV-1 , J
  • D XIV-3 , D XIV-4 , J XIV-3 , J XIV-4 and K XIV-2 are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more than one of D XIV-3 , D XIV-4 , J XIV-3 , J XIV-4 and K XIV-2 is a covalent bond, no more than one of D XIV-3 , D XIV-4 , J XIV-3 , J XIV-4 and K XIV-2 is O, no more than one of D XIV-3 , D XIV-4 , J XIV-3 , J XIV-4 and K XIV-2 is S, one of D XIV-3 , D XIV-4 , J XIV-3 , J XIV-4 and K XIV-2 must be a covalent bond when two of D XIV-3 , D XIV-4 , J XIV-3 , J
  • R XIV-2 is independently selected from the group consisting of hydrido, hydroxy, hydroxyalkyl, amino, aminoalkyl, alkylamino, dialkylamino, alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkoxyalkyl, aryloxyalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, aralkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxy, aloalkoxyalkyl, haloalkenyloxyalkyl
  • R XIV-2 and R XIV-3 are taken together to form a linear spacer moiety selected from the group consisting of a covalent single bond and a moiety having from 1 through 6 contiguous atoms to form a ring selected from the group consisting of a cycloalkyl having from 3 through 8 contiguous members, a cycloalkenyl having from 5 through 8 contiguous members, and a heterocyclyl having from 4 through 8 contiguous members;
  • R XIV-3 is selected from the group consisting of hydrido, hydroxy, halo, cyano, aryloxy, hydroxyalkyl, amino, alkylamino, dialkylamino, acyl, sulfhydryl, acylamido, alkoxy, alkylthio, arylthio, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, alkoxyalkyl, heteroarylthio, aralkylthio, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aroyl, heteroaroyl, aralkylthioalkyl, heteroaralkylthioalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, alken
  • Y XIV is selected from a group consisting of a covalent single bond, (C(R XIV-14 ) 2 ) qXIV wherein qXIV is an integer selected from 1 and 2 and (CH(R XIV-14 )) gXIV —W XIV —(CH(R XIV-14 )) pXIV wherein gXIV and pXIV are integers independently selected from 0 and 1;
  • R XIV-14 is independently selected from the group consisting of hydrido, hydroxy, halo, cyano, aryloxy, amino, alkylamino, dialkylamino, hydroxyalkyl, acyl, aroyl, heteroaroyl, heteroaryloxyalkyl, sulfhydryl, acylamido, alkoxy, alkylthio, arylthio, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, aralkoxyalkylalkoxy, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkoxythioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl,
  • R XIV-14 and R XIV-14 when bonded to the different atoms, are taken together to form a group selected from the group consisting of a covalent bond, alkylene, haloalkylene, and a spacer selected from a group consisting of a moiety having a chain length of 2 to 5 atoms connected to form a ring selected from the group of a saturated cycloalkyl having from 5 through 8 contiguous members, a cycloalkenyl having from 5 through 8 contiguous members, and a heterocyclyl having from 5 through 8 contiguous members;
  • R XIV-14 and R XIV-14 when bonded to the same atom are taken together to form a group selected from the group consisting of oxo, thiono, alkylene, haloalkylene, and a spacer selected from the group consisting of a moiety having a chain length of 3 to 7 atoms connected to form a ring selected from the group consisting of a cycloalkyl having from 4 through 8 contiguous members, a cycloalkenyl having from 4 through 8 contiguous members, and a heterocyclyl having from 4 through 8 contiguous members;
  • W XIV is selected from the group consisting of O, C(O), C(S), C(O)N(R XIV-14 ), C(S)N(R XIV-14 ), (R XIV-14 )NC(O), (R XIV-14 )NC(S), S, S(O), S(O) 2 , S(O) 2 N(R XIV-14 ), (R XIV-14 )NS(O) 2 , and N(R XIV-14 ) with the proviso that R XIV-14 is selected from other than halo and cyano;
  • Z XIV is independently selected from a group consisting of a covalent single bond, (C(R XIV-15 ) 2 ) qXIV-2 wherein qXIV-2 is an integer selected from 1 and 2, (CH(R XIV-15 )) jXIV —W—(CH(R XIV-15 ) kXIV wherein jXIV and kXIV are integers independently selected from 0 and 1 with the proviso that, when Z XIV is a covalent single bond, an R XIV-15 substituent is not attached to Z XIV ;
  • R XIV-15 is independently selected, when Z XIV is (C(R XIV-15 ) 2 ) qXIV wherein qXIV is an integer selected from 1 and 2, from the group consisting of hydrido, hydroxy, halo, cyano, aryloxy, amino, alkylamino, dialkylamino, hydroxyalkyl, acyl, aroyl, heteroaroyl, heteroaryloxyalkyl, sulfhydryl, acylamido, alkoxy, alkylthio, arylthio, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkylthioalkyl, alkoxyalkyl, heteroaryloxyalkyl,
  • R XIV-15 and R XIV-15 when bonded to the different atoms, are taken together to form a group selected from the group consisting of a covalent bond, alkylene, haloalkylene, and a spacer selected from a group consisting of a moiety having a chain length of 2 to 5 atoms connected to form a ring selected from the group of a saturated cycloalkyl having from 5 through 8 contiguous members, a cycloalkenyl having from 5 through 8 contiguous members, and a heterocyclyl having from 5 through 8 contiguous members;
  • R XIV-15 and R XIV-15 when bonded to the same atom are taken together to form a group selected from the group consisting of oxo, thiono, alkylene, haloalkylene, and a spacer selected from the group consisting of a moiety having a chain length of 3 to 7 atoms connected to form a ring selected from the group consisting of a cycloalkyl having from 4 through 8 contiguous members, a cycloalkenyl having from 4 through 8 contiguous members, and a heterocyclyl having from 4 through 8 contiguous members;
  • R XIV-15 is independently selected, when Z XIV is (CH(R XIV-15 )) jXIV —W—(CH(R XIV-15 )) kXIV wherein jXIV and kXIV are integers independently selected from 0 and 1, from the group consisting of hydrido, halo, cyano, aryloxy, carboxyl, acyl, aroyl, heteroaroyl, hydroxyalkyl, heteroaryloxyalkyl, acylamido, alkoxy, alkylthio, arylthio, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, alkoxyalkyl, heteroaryloxyalkyl, aralkoxyalkyl, heteroaralkoxyalkyl, alkylsulfonylalkyl, alkylsulfinylalkyl, alkenyloxyalkyl, alkyl,
  • R XIV-4 , R XIV-5 , R XIV-6 , R XIV-7 , R XIV-8 , R XIV-9 , R XIV-10 , R XIV-11 , R XIV-12 , and R XIV-13 are independently selected from the group consisting of perhaloaryloxy, alkanoylalkyl, alkanoylalkoxy, alkanoyloxy, N-aryl-N-alkylamino, heterocyclylalkoxy, heterocyclylthio, hydroxyalkoxy, carboxamidoalkoxy, alkoxycarbonylalkoxy, alkoxycarbonylalkenyloxy, aralkanoylalkoxy, aralkenoyl, N-alkylcarboxamido, N-haloalkylcarboxamido, N-cycloalkylcarboxamido, N-arylcarboxamidoalkoxy, cycloalkylcarbon
  • R XIV-4 and R XIV-5 , R XIV-5 and R XIV-6 , R XIV-6 and R XIV-7 , R XIV-7 and R XIV-8 , R XIV-8 and R XIV-9 , R XIV-9 and R XIV-10 , R XIV-10 and R XIV-11 , R XIV-11 and R XIV-12 , and R XIV-12 and R XIV-13 are independently selected to form spacer pairs wherein a spacer pair is taken together to form a linear moiety having from 3 through 6 contiguous atoms connecting the points of bonding of said spacer pair members to form a ring selected from the group consisting of a cycloalkenyl ring having 5 through 8 contiguous members, a partially saturated heterocyclyl ring having 5 through 8 contiguous members, a heteroaryl ring having 5 through 6 contiguous members, and an aryl with the provisos that no more than one of the group
  • R XIV-4 and R XIV-9 , R XIV-4 and R XIV-13 , R XIV-8 and R XIV-9 , and R XIV-8 and R XIV-13 are independently selected to form a spacer pair wherein said spacer pair is taken together to form a linear moiety wherein said linear moiety forms a ring selected from the group consisting of a partially saturated heterocyclyl ring having from 5 through 8 contiguous members and a heteroaryl ring having from 5 through 6 contiguous members with the proviso that no more than one of the group consisting of spacer pairs R XIV-4 and R XIV-9 , R XIV-4 and R XIV-13 , R XIV-8 and R XIV-9 , and R XIV-8 and R XIV-13 is used at the same time.
  • the CETP inhibitor is selected from the following compounds of Formula XIV:
  • n XV is an integer selected from 1 through 2;
  • a XV and Q XV are independently selected from the group consisting of —CH 2 (CR XV-37 R XV-38 ) vXV —(CR XV-33 R XV-34 ) uXV —T XV —(CR XV-35 R XV-36 ) wXV —H,
  • a XV and Q XV must be AQ-1 and that one of A XV and Q XV must be selected from the group consisting of AQ-2 and —CH 2 (CR XV-37 R XV-38 ) vXV —(CR XV-33 R XV-34 ) uXV —T XV —(CR XV-35 R XV-36 ) wXV —H;
  • T XV is selected from the group consisting of a single covalent bond, O, S, S(O), S(O) 2 , C(R XV-33 ) ⁇ C(R XV-35 ), and C ⁇ C;
  • vXV is an integer selected from 0 through 1 with the proviso that vXV is 1 when any one of R XV-33 , R XV-34 , R XV-35 , and R XV-36 is aryl or heteroaryl;
  • uXV and wXV are integers independently selected from 0 through 6;
  • a XV-1 is C(R XV-30 );
  • D XV-1 , D XV-2 , J XV-1 , J XV-2 , and K XV-1 are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more than one of D XV-1 , D XV-2 , J XV-1 , J XV-2 , and K XV-1 is a covalent bond, no more than one of D XV-1 , D XV-2 , J XV-1 , J XV-2 , and K XV-1 is O, no more than one of D XV-1 , D XV-2 , J XV-1 , J XV-2 , and K XV-1 is S, one of D XV-1 , D XV-2 , J XV-1 , J XV-2 , and K XV-1 must be a covalent bond when two of D XV-1 , D XV-2
  • B XV-1 , B XV-2 , D XV-3 , D XV-4 , J XV-3 , J XV-4 , and K XV-2 are independently selected from the group consisting of C, C(R XV-30 ), N, O, S and a covalent bond with the provisos that no more than 5 of B XV-1 , B XV-2 , D XV-3 , D XV-4 , J XV-3 , J XV-4 , and K XV-2 are a covalent bond, no more than two of B XV-1 , B XV-2 , D XV-3 , D XV-4 , J XV-3 , J XV-4 , and K XV-2 are O, no more than two of B XV-1 , B XV-2 , D XV-3 , D XV-4 , J XV-3 , J XV-5 , and K
  • B XV-1 and D XV-3 , D XV-3 and J XV-3 , J XV-3 and K XV-2 , K XV-2 and J XV-4 , J XV-4 and D XV-4 , and D XV-4 and B XV-2 are independently selected to form an in-ring spacer pair wherein said spacer pair is selected from the group consisting of C(R XV-33 ) ⁇ C(R XV-35 ) and N ⁇ N with the provisos that AQ-2 must be a ring of at least five contiguous members, that no more than two of the group of said spacer pairs are simultaneously C(R XV-33 ) ⁇ C(R XV-35 ) and that no more than one of the group of said spacer pairs can be N ⁇ N unless the other spacer pairs are other than C(R XV-33 ) ⁇ C(R XV-35 ), O, N, and S;
  • R XV-1 is selected from the group consisting of haloalkyl and haloalkoxymethyl
  • R XV-2 is selected from the group consisting of hydrido, aryl, alkyl, alkenyl, haloalkyl, haloalkoxy, haloalkoxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl and heteroaryl;
  • R XV-3 is selected from the group consisting of hydrido, aryl, alkyl, alkenyl, haloalkyl, and haloalkoxyalkyl;
  • Y XV is selected from the group consisting of a covalent single bond, (CH 2 ) q wherein q is an integer selected from 1 through 2 and (CH 2 ) j ——(CH 2 ) k wherein j and k are integers independently selected from 0 through 1;
  • Z XV is selected from the group consisting of covalent single bond, (CH 2 ) q wherein q is an integer selected from 1 through 2, and (CH 2 ) j —O—(CH 2 ) k wherein j and k are integers independently selected from 0 through 1;
  • R XV-4 , R XV-8 , R XV-9 and R XV-13 are independently selected from the group consisting of hydrido, halo, haloalkyl, and alkyl;
  • R XV-30 is selected from the group consisting of hydrido, alkoxy, alkoxyalkyl, halo, haloalkyl, alkylamino, alkylthio, alkylthioalkyl, alkyl, alkenyl, haloalkoxy, and haloalkoxyalkyl with the proviso that R XV-30 is selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen;
  • R XV-30 when bonded to A XV-1 , is taken together to form an intra-ring linear spacer connecting the A XV-1 -carbon at the point of attachment of R XV-30 to the point of bonding of a group selected from the group consisting of R XV-10 , R XV-11 , R XV-12 , R XV-31 , and R XV-32 wherein said intra-ring linear spacer is selected from the group consisting of a covalent single bond and a spacer moiety having from 1 through 6 contiguous atoms to form a ring selected from the group consisting of a cycloalkyl having from 3 through 10 contiguous members, a cycloalkenyl having from 5 through 10 contiguous members, and a heterocyclyl having from 5 through 10 contiguous members;
  • R XV-30 when bonded to A XV-1 , is taken together to form an intra-ring branched spacer connecting the A XV-1 -carbon at the point of attachment of R XV-30 to the points of bonding of each member of any one of substituent pairs selected from the group consisting of substituent pairs R XV-10 and R XV-11 , R XV-10 and R XV-31 , R XV-10 and R XV-32 , R XV-10 and R XV-12 , R XV-11 and R XV-31 , R XV-11 and R XV-32 , R XV-11 and R XV-12 , R XV-31 and R XV-32 , R XV-31 and R XV-12 , and R XV-32 and R XV-12 and wherein said intra-ring branched spacer is selected to form two rings selected from the group consisting of cycloalkyl having from 3 through
  • R XV-4 , R XV-5 , R XV-6 , R XV-7 , R XV-8 , R XV-9 , R XV-10 , R XV-11 , R XV-12 , R XV-13 , R XV-31 , R XV-32 , R XV-33 , R XV-34 , R XV-35 and R XV-36 are independently selected from the group consisting of hydrido, carboxy, heteroaralkylthio, heteroaralkoxy, cycloalkylamino, acylalkyl, acylalkoxy, aroylalkoxy, heterocyclyloxy, aralkylaryl, aralkyl, aralkenyl, aralkynyl, heterocyclyl, perhaloaralkyl, aralkylsulfonyl, aralkylsulfonylalkyl,
  • R XV-9 , R XV-10 , R XV-11 , R XV-12 , R XV-13 , R XV-31 , and R XV-32 are independently selected to be oxo with the provisos that B XV-1 , B XV-2 , D XV-3 , D XV-4 , J XV-3 , J XV-4 , and K XV-2 are independently selected from the group consisting of C and S, no more than two of R XV-9 , R XV-10 , R XV-11 , R XV-12 , R XV-13 , R XV-31 , and R XV-32 are simultaneously oxo, and that R XV-9 , R XV-10 , R XV-11 , R XV-12 , R XV-13 , R XV-31 , and R XV-32 are each independently selected to maintain the te
  • R XV-4 and R XV-5 , R XV-5 and R XV-6 , R XV-6 and R XV-7 , R XV-7 and R XV-8 , R XV-9 and R XV-10 , R XV-10 and R XV-11 , R XV-11 and R XV-31 , R XV-31 and R XV-32 , R XV-32 and R XV-12 , and R XV-12 and R XV-13 are independently selected to form spacer pairs wherein a spacer pair is taken together to form a linear moiety having from 3 through 6 contiguous atoms connecting the points of bonding of said spacer pair members to form a ring selected from the group consisting of a cycloalkenyl ring having 5 through 8 contiguous members, a partially saturated heterocyclyl ring having 5 through 8 contiguous members, a heteroaryl ring having 5 through 6 contiguous members, and an
  • R XV-37 and R XV-38 are independently selected from the group consisting of hydrido, alkoxy, alkoxyalkyl, hydroxy, amino, thio, halo, haloalkyl, alkylamino, alkylthio, alkylthioalkyl, cyano, alkyl, alkenyl, haloalkoxy, and haloalkoxyalkyl.
  • the CETP inhibitor is selected from the following compounds of Formula XV:
  • n XVI is an integer selected from 1 through 4.
  • R XVI-1 is selected from the group consisting of haloalkyl, haloalkenyl, haloalkoxymethyl, and haloalkenyloxymethyl with the proviso that R XVI-11 has a higher Cahn-Ingold-Prelog stereochemical system ranking than both R XVI-2 and (CHR XVI-3 ) n —N(A XVI )Q XVI wherein A XVI is Formula XVI-(II) and Q is Formula XVI-(III);
  • R XVI-16 is selected from the group consisting of hydrido, alkyl, acyl, aroyl, heteroaroyl, trialkylsilyl, and a spacer selected from the group consisting of a covalent single bond and a linear spacer moiety having a chain length of 1 to 4 atoms linked to the point of bonding of any aromatic substituent selected from the group consisting of R XVI-4 , R XVI-8 , R XVI-9 , and R XVI-13 to form a heterocyclyl ring having from 5 through 10 contiguous members;
  • D XVI-1 , D XVI-2 , J XVI-1 , J XVI-2 and K XVI-1 are independently selected from the group consisting of C, N, O, S and covalent bond with the provisos that no more than one of D XVI-1 , D XVI-2 , J XVI-1 , J XVI-2 and K XVI-1 is a covalent bond, no more than one D XVI-1 , D XVI-2 , J XVI-1 , J XVI-2 and K XVI-1 is be O, no more than one of D XVI-1 , D XVI-2 , J XVI-1 , J XVI-2 and K XVI-1 is S, one of D XVI-1 , D XVI-2 , J XVI-1 , J XVI-2 and K XVI-1 must be a covalent bond when two of D XVI-1 , D XVI-2 , J XVI-1 , J XVI-1
  • D XVI-3 , D XVI-4 , J XVI-3 , J XVI-4 and K XVI-2 are independently selected from the group consisting of C, N, O, S and covalent bond with the provisos that no more than one is a covalent bond, no more than one of D XVI-3 , D XVI-4 , J XIV-3 , J XVI-4 and K XVI-2 is O, no more than one of D XVI-3 , D XVI-4 , J XVI-3 , J XVI-4 and K XVI-2 is S, no more than two of D XVI-3 , D XVI-4 , J XVI-3 , J XVI-4 and K XVI-2 is O and S, one of D XVI-3 , D XVI-4 , J XVI-3 , J XVI-4 and K XVI-2 must be a covalent bond when two of D XVI-3 , D XVI-4 , J
  • R XVI-2 is selected from the group consisting of hydrido, aryl, aralklyl, alkyl, alkenyl, alkenyloxyalkyl, haloalkyl, haloalkenyl, halocycloalkyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy, halocycloalkoxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, dicyanoalkyl, and carboalkoxycyanoalkyl, with the proviso that R XVI-2 has a lower Cahn-Ingold-Prelog system ranking than both R XVI-1 and (CHR XVI-3 ) n —N(A XVI )Q XVI ;
  • R XVI-3 is selected from the group consisting of hydrido, hydroxy, cyano, aryl, aralkyl, acyl, alkoxy, alkyl, alkenyl, alkoxyalkyl, heteroaryl, alkenyloxyalkyl, haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, monocyanoalkyl, dicyanoalkyl, carboxamide, and carboxamidoalkyl, with the provisos that (CHR XVI-3 ) n —N(A XVI )Q XVI has a lower Cahn-Ingold-Prelog stereochemical system ranking than R XVI-1 and a higher Cahn-Ingold-Prelog stereochemical system ranking than R XVI-2 ;
  • Y XVI is selected from a group consisting of a covalent single bond, (C(R XVI-14 ) 2 ) q where q is an integer selected from 1 to 2 and (CH(R XVI-14 ) g —W XVI —(CH(R XVI-14 )) p wherein g and p are integers independently selected from 0 and 1;
  • R XVI-14 is selected from the group consisting of hydrido, hydroxy, cyano, hydroxyalkyl, acyl, alkoxy, alkyl, alkenyl, alkynyl, alkoxyalkyl, haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, monocarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl, carboalkoxy, carboxamide, and carboxamidoalkyl;
  • Z XVI is selected from a group consisting of a covalent single bond, (C(R XVI-15 ) 2 ) q , wherein q is an integer selected from 1 and 2, and (CH(R XVI-15 )) j —W XVI —(CH(R XVI-15 )) k wherein j and k are integers independently selected from 0 and 1;
  • W XVI is selected from the group consisting of O, C(O), C(S), C(O)N(R XVI-14 ), C(S)N(R XVI-14 ), (R XVI-14 )NC(O), (R XVI-14 )NC(S), S, S(O), S(O) 2 , S(O) 2 N(R XVI-14 ), (R XVI-14 )NS(O) 2 , and N(R XVI-14 ) with the proviso that R XVI-14 is other than cyano;
  • R XVI-15 is selected, from the group consisting of hydrido, cyano, hydroxyalkyl, acyl, alkoxy, alkyl, alkenyl, alkynyl, alkoxyalkyl, haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, monocarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl, carboalkoxy, carboxamide, and carboxamidoalkyl;
  • R XVI-4 , R XVI-5 , R XVI-6 , R XVI-7 , R XVI-8 , R XVI-9 , R XVI-10 , R XVI-11 , R XVI-12 , and R XVI-13 are independently selected from the group consisting of hydrido, carboxy, heteroaralkylthio, heteroaralkoxy, cycloalkylamino, acylalkyl, acylalkoxy, aroylalkoxy, heterocyclyloxy, aralkylaryl, aralkyl, aralkenyl, aralkynyl, heterocyclyl, perhaloaralkyl, aralkylsulfonyl, aralkylsulfonylalkyl, aralkylsulfinyl, aralkylsulfinylalkyl, halocycloalkyl, halocycloalkenyl,
  • R XVI-4 and R XVI-5 , R XVI-5 and R XVI-6 , R XVI-6 and R XVI-7 , R XVI-7 and R XVI-8 , R XVI-9 and R XVI-10 , R XVI-10 and R XVI-11 , R XVI-11 and R XVI-12 , and R XVI-12 and R XIV-13 are independently selected to form spacer pairs wherein a spacer pair is taken together to form a linear moiety having from 3 through 6 contiguous atoms connecting the points of bonding of said spacer pair members to form a ring selected from the group consisting of a cycloalkenyl ring having 5 through 8 contiguous members, a partially saturated heterocyclyl ring having 5 through 8 contiguous members, a heteroaryl ring having 5 through 6 contiguous members, and an aryl with the provisos that no more than one of the group consisting of spacer pairs R XVI-4 and R
  • R XVI-4 and R XVI-9 , R XVI-4 and R XVI-13 , R XVI-8 and R XVI-9 , and R XVI-8 and R XVI-13 is independently selected to form a spacer pair wherein said spacer pair is taken together to form a linear moiety wherein said linear moiety forms a ring selected from the group consisting of a partially saturated heterocyclyl ring having from 5 through 8 contiguous members and a heteroaryl ring having from 5 through 6 contiguous members with the proviso that no more than one of the group consisting of spacer pairs R XVI-4 and R XVI-9 , R XVI-4 and R XVI-13 , R XVI-8 and R XVI-9 , and R XVI-8 and R XVI-13 is used at the same time.
  • the CETP inhibitor is selected from the following compounds of Formula XVI:

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Cited By (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030198674A1 (en) * 2002-02-01 2003-10-23 Curatolo William J. Controlled release pharmaceutical dosage forms of a cholesteryl ester transfer protein inhibitor
WO2005011635A2 (en) 2003-08-04 2005-02-10 Pfizer Products Inc. Pharmaceutical compositions of adsorbates of amorphous drugs and lipophilic microphase-forming materials
US20050207990A1 (en) * 2004-03-10 2005-09-22 Adrian Funke Stabilised supersaturated solids of lipophilic drugs
US20060135551A1 (en) * 2004-12-20 2006-06-22 Anima Baruah Novel heterocyclic compounds and their pharmaceutical compositions
US20060178514A1 (en) * 2004-12-31 2006-08-10 Anima Baruah Novel benzylamine derivatives as CETP inhibitors
US20070015758A1 (en) * 2004-12-31 2007-01-18 Anima Baruah Novel benzylamine derivatives and their utility as cholesterol ester-transfer protein inhibitors
US20080008765A1 (en) * 2004-10-12 2008-01-10 Sandoz Ag Taste-Masking Pharmaceutical Compositions
US20080064763A1 (en) * 2005-02-03 2008-03-13 Babcock Walter C Pharmaceutical Compositions with Enhanced Performance
US20080063708A1 (en) * 2002-02-01 2008-03-13 Perlman Michael E Pharmaceutical Compositions of Amorphous Dispersions of Drugs and Lipophilic Microphase-Forming Materials
US7390503B1 (en) 2003-08-22 2008-06-24 Barr Laboratories, Inc. Ondansetron orally disintegrating tablets
US20080281248A1 (en) * 2007-04-02 2008-11-13 University Of Pittsburgh - Of The Commonwealth System Of Higher Education Removal of contrast agents from blood
EP2072042A1 (de) * 2007-12-21 2009-06-24 Lek Pharmaceuticals D.D. Aktive pharmazeutische Zutat auf einem festen Träger, amorph und mit verbesserter Löslichkeit
US20090169583A1 (en) * 2005-02-08 2009-07-02 Pfizer, Inc. Solid Adsorbates of Hydrophobic Drugs
WO2010040086A1 (en) * 2008-10-02 2010-04-08 University Of Pittsburgh - Of The Commonwealth System Of Higher Education Administration of an adsorbent polymer for treatment of systemic inflammation
US20100137447A1 (en) * 2007-04-30 2010-06-03 Ratiopharm Gmbh Method for the production of adsorbates of a rasagiline salt having a water-soluble adjuvant
WO2010115886A1 (en) * 2009-04-06 2010-10-14 Lek Pharmaceuticals D.D. Active pharmaceutical ingredient adsorbed on solid support
US7838029B1 (en) 2003-07-31 2010-11-23 Watson Laboratories, Inc. Mirtazapine solid dosage forms
WO2010147978A1 (en) 2009-06-16 2010-12-23 Pfizer Inc. Dosage forms of apixaban
US20110020455A1 (en) * 2008-03-11 2011-01-27 Aska Pharmaceutical Co., Ltd. Solid dispersion and pharmaceutical composition of the same, and production processes thereof
WO2011148253A2 (en) 2010-05-25 2011-12-01 Aurobindo Pharma Limited Solid dosage forms of antipsychotics
US20120003282A1 (en) * 2009-03-05 2012-01-05 Miller Warren K Pharmaceutical compositions of dextran polymer derivatives
US8815294B2 (en) 2010-09-03 2014-08-26 Bend Research, Inc. Pharmaceutical compositions of dextran polymer derivatives and a carrier material
US9000007B2 (en) 2011-09-27 2015-04-07 Dr. Reddy's Laboratories Ltd. 5-benzylaminomethyl-6-aminopyrazolo [3, 4 -B] pyridine derivatives as cholesteryl ester-transfer protein (CETP) inhibitors useful for the treatment of atherosclerosis
US9199967B2 (en) 2011-08-18 2015-12-01 Dr. Reddy's Laboratories Ltd. Substituted heterocyclic amine compounds as cholestryl ester-transfer protein (CETP) inhibitors
US9668998B2 (en) 2011-01-18 2017-06-06 Pfizer Limited Solid molecular dispersion of fesoterodine hydrogen fumarate and polymeric binder
US9757338B2 (en) 2010-03-01 2017-09-12 Dexcel Pharma Technologies Ltd. Sustained-release donepezil formulation

Families Citing this family (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040132771A1 (en) * 2002-12-20 2004-07-08 Pfizer Inc Compositions of choleseteryl ester transfer protein inhibitors and HMG-CoA reductase inhibitors
US8025899B2 (en) 2003-08-28 2011-09-27 Abbott Laboratories Solid pharmaceutical dosage form
US8377952B2 (en) 2003-08-28 2013-02-19 Abbott Laboratories Solid pharmaceutical dosage formulation
WO2005023225A1 (en) * 2003-09-05 2005-03-17 Ranbaxy Laboratories Limited Cilostazol adsorbate
ATE355052T1 (de) * 2003-11-18 2006-03-15 Helm Ag Verfahren zur herstellung von freifliessenden, pulverförmigen atorvastatin-adsorbaten
ATE344020T1 (de) * 2004-02-06 2006-11-15 Helm Ag Pharmazeutische zubereitungen mit amorphem tibolon
CA2577852A1 (en) 2004-08-31 2006-03-09 Pfizer Products Inc. Pharmaceutical dosage forms comprising a low-solubility drug and a polymer
DE102004055229A1 (de) * 2004-11-17 2006-05-18 Heidelberger Druckmaschinen Ag Zustandsabhängige Absicherung von Maschinen
US20090005384A1 (en) * 2005-01-25 2009-01-01 Kowa Co., Ltd Method for Producing Adsorptive Porous Body
CA2594694A1 (en) 2005-01-28 2006-08-03 Pfizer Products Inc. Drying of drug-containing particles
EP1767194A1 (de) * 2005-06-09 2007-03-28 Helm AG Verfahren zur Herstellung von Adsorbaten des Drospirenons
MX2009010568A (es) * 2007-04-03 2009-10-22 Reddys Lab Ltd Dr Formas solidas de pemetrexed.
CA3076115C (en) 2007-08-21 2022-06-28 Board Of Regents, The University Of Texas System Thermo-kinetic mixing for pharmaceutical applications
CN102046171B (zh) * 2008-05-30 2013-06-19 日东电工株式会社 经皮吸收制剂
JP2012506904A (ja) * 2008-10-28 2012-03-22 エージェンシー フォー サイエンス，テクノロジー アンド リサーチ 難水溶性成分のためのメソ多孔性材料賦形剤
KR101004205B1 (ko) * 2008-12-17 2010-12-24 동아제약주식회사 유데나필 함유 서방성 제제를 제조하기 위한 제어방출 조성물
WO2010092925A1 (ja) * 2009-02-12 2010-08-19 あすか製薬株式会社 固体分散体とその医薬組成物、並びにそれらの製造方法
EP3130396B1 (de) 2009-03-27 2021-03-17 Bend Research, Inc. Sprühtrocknungsverfahren
WO2011110662A1 (en) * 2010-03-11 2011-09-15 Danmarks Tekniske Universitet Supported biologically active compounds
WO2012031129A2 (en) 2010-09-03 2012-03-08 Bend Research, Inc. Spray-drying apparatus and methods of using the same
PT2611530T (pt) 2010-09-03 2019-05-09 Bend Res Inc Aparelho de secagem por pulverização e métodos de utilização do mesmo
EP2618924A1 (de) 2010-09-24 2013-07-31 Bend Research, Inc. Hochtemperatur-sprühtrocknungsverfahren und verfahren
US9060938B2 (en) 2011-05-10 2015-06-23 Bend Research, Inc. Pharmaceutical compositions of active agents and cationic dextran polymer derivatives
CN103732216A (zh) * 2011-08-16 2014-04-16 默沙东公司 无机基质和有机聚合物组合用于制备稳定的无定形分散体的用途
EA201891397A1 (ru) * 2014-02-05 2019-03-29 Лек Фармасьютикалз Д.Д. Твердые фармацевтические композиции антагонистов рецепторов андрогенов
EP3212169B1 (de) 2014-10-31 2021-01-13 Bend Research, Inc. Verfahren zur herstellung von in einer matrix dispergierten aktiven domänen
EP3226656B1 (de) * 2015-06-15 2020-11-25 Sumitomo Chemical Company Limited Verfahren zur herstellung eines organischen el-elements
CN113476408A (zh) * 2021-07-23 2021-10-08 兆科药业（广州）有限公司 一种苯丁酸甘油酯颗粒剂及其制备方法与应用

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5626878A (en) * 1995-01-10 1997-05-06 Warner Lambert Company Reduction of electrostatic forces between magnesium trisilicate adsorbates
US20020103225A1 (en) * 2000-08-03 2002-08-01 Curatolo William J. Pharmaceutical compositions of cholesteryl ester transfer protein inhibitors

Family Cites Families (60)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA1146866A (en) * 1979-07-05 1983-05-24 Yamanouchi Pharmaceutical Co. Ltd. Process for the production of sustained release pharmaceutical composition of solid medical material
FR2525108B1 (fr) * 1982-04-19 1989-05-12 Elan Corp Ltd Medicaments a haut degre de solubilite et procede pour leur obtention
JPS5942313A (ja) * 1982-09-01 1984-03-08 Teijin Ltd ポリビニルポリピロリドンを用いた製剤
DE3485000D1 (de) 1983-06-28 1991-10-10 Takeda Chemical Industries Ltd Gemahlene mischung.
US4581232A (en) 1983-07-20 1986-04-08 Warner-Lambert Company Magnesium trisilicate suitable for preparation of medicament adsorbates
IE63321B1 (en) * 1986-02-03 1995-04-05 Elan Corp Plc Drug delivery system
US4716033A (en) 1986-03-27 1987-12-29 Warner-Lambert Company Medicament adsorbates with surfactant and their preparation
US4717565A (en) 1986-03-27 1988-01-05 Warner-Lambert Company Process for the preparation of medicament adsorbates
US4711774A (en) * 1986-03-27 1987-12-08 Warner-Lambert Company Medicament adsorbates with complex magnesium aluminum silicate and their preparation
US5015479A (en) 1987-02-02 1991-05-14 Seamus Mulligan Sustained release capsule or tablet formulation comprising a pharmaceutically acceptable dihydropyridine
US4835186A (en) 1987-06-15 1989-05-30 American Home Products Corporation Spray dried ibuprofen
IT1216570B (it) 1988-04-08 1990-03-08 Vectorpharma Int Composizione farmaceutiche a rilascio controllato e procedimento per la loro preparazione.
IT1227626B (it) * 1988-11-28 1991-04-23 Vectorpharma Int Farmaci supportati aventi velocita' di dissoluzione aumentata e procedimento per la loro preparazione
IE60458B1 (en) 1989-10-26 1994-07-13 Elan Corp Plc Enhanced bioavailability adsorbates
US5300302A (en) 1990-10-04 1994-04-05 Nestec S.A. Pharmaceutical composition in gel form in a dispensing package
US5559158A (en) 1993-10-01 1996-09-24 Abbott Laboratories Pharmaceutical composition
SI9500059A (sl) 1995-02-23 1996-08-31 Lek Tovarna Farmacevtskih Postopek za pripravo trdnih površinskih disperzij amorfnih, v vodnih medijih slabo topnih učinkovin in njihova uporaba
WO1996032126A1 (en) 1995-04-14 1996-10-17 The Administrators Of The Tulane Educational Fund Analogs of growth hormone-releasing factor
WO1996039126A2 (en) * 1995-06-06 1996-12-12 Warner-Lambert Company Ranitidine salts on magnesium trisilicate as an adsorbate
DE19532061A1 (de) * 1995-08-31 1997-03-06 Bayer Ag N-Sulfonyliminodithioverbindungen
DE19610932A1 (de) 1996-03-20 1997-09-25 Bayer Ag 2-Aryl-substituierte Pyridine
DE19627419A1 (de) 1996-07-08 1998-01-15 Bayer Ag Cycloalkano-pyridine
DE19627431A1 (de) 1996-07-08 1998-01-15 Bayer Ag Heterocyclisch kondensierte Pyridine
HRP970330B1 (en) 1996-07-08 2004-06-30 Bayer Ag Cycloalkano pyridines
US6207671B1 (en) 1996-07-08 2001-03-27 Bayer Aktiengesellschaft Cycloalkano-pyridines
DE19627430A1 (de) 1996-07-08 1998-01-15 Bayer Ag Bicyclisch kondensierte Pyridine
AR008789A1 (es) 1996-07-31 2000-02-23 Bayer Corp Piridinas y bifenilos substituidos
DE19704243A1 (de) 1997-02-05 1998-08-06 Bayer Ag Neue 2-Amino-substituierte Pyridine
DE19704244A1 (de) 1997-02-05 1998-08-06 Bayer Ag 5-Hydroxy-alkyl substituierte Phenyle
JP2894445B2 (ja) 1997-02-12 1999-05-24 日本たばこ産業株式会社 Ｃｅｔｐ活性阻害剤として有効な化合物
US6403587B1 (en) 1997-02-26 2002-06-11 Pfizer Inc. Heteroaryl-hexanoic acid amide derivatives, their preparation and their use as selective inhibitors of MIP-1-α binding to its CCR 1 receptor
DE19709125A1 (de) 1997-03-06 1998-09-10 Bayer Ag Substituierte Chinoline
ATE364374T1 (de) * 1997-08-11 2007-07-15 Pfizer Prod Inc Feste pharmazeutische dispersionen mit erhöhter bioverfügbarkeit
WO1999014204A1 (en) 1997-09-16 1999-03-25 G.D. Searle & Co. Substituted 1,2,4-triazoles useful for inhibiting cholesteryl ester transfer protein activity
DE19741051A1 (de) 1997-09-18 1999-03-25 Bayer Ag Hetero-Tetrahydrochinoline
MA24643A1 (fr) 1997-09-18 1999-04-01 Bayer Ag Tetrahydro-naphtalenes substitues et composes analogues
DE19832159A1 (de) 1997-09-18 1999-03-25 Bayer Ag Substituierte Tetrahydro-naphthaline
DE19741400A1 (de) 1997-09-19 1999-03-25 Bayer Ag Benzyl-biphenyle
DE19741399A1 (de) 1997-09-19 1999-03-25 Bayer Ag Tetrahydrochinoline
EP1037534A4 (de) * 1997-09-29 2005-04-06 China Innovation Ct For Life S Eine fagopyrum cymosum (trev.) meisn zusammentstellung, verfahren zur herstellung und analyse davon sowie anwendungen
SK11262000A3 (sk) 1998-02-05 2001-01-18 Pfizer Products Inc. Deriváty dihydroxyhexánovej kyseliny a farmaceutický prostriedok,ktorý ich obsahuje
WO1999041237A1 (en) 1998-02-13 1999-08-19 G.D. Searle & Co. Substituted pyridines useful for inhibiting cholesteryl ester transfer protein activity
JPH11246404A (ja) 1998-03-04 1999-09-14 Taiho Yakuhin Kogyo Kk 吸収を改善した医薬組成物
US20010025046A1 (en) 1999-06-24 2001-09-27 Rong(Ron) Liu Self-emulsifying systems containing anticancer medicament
CA2339991C (en) * 1998-08-13 2007-01-02 Cima Labs Inc. Microemulsions as solid dosage forms for oral administration
US6376481B2 (en) 1998-09-02 2002-04-23 Mcneil-Ppc, Inc. Sterol esters in tableted solid dosage forms
US6197786B1 (en) 1998-09-17 2001-03-06 Pfizer Inc 4-Carboxyamino-2-substituted-1,2,3,4-tetrahydroquinolines
US6140342A (en) 1998-09-17 2000-10-31 Pfizer Inc. Oxy substituted 4-carboxyamino-2-methyl-1,2,3,4-tetrahydroquinolines
US6147090A (en) 1998-09-17 2000-11-14 Pfizer Inc. 4-carboxyamino-2-methyl-1,2,3,4,-tetrahydroquinolines
GT199900147A (es) 1998-09-17 1999-09-06 1, 2, 3, 4- tetrahidroquinolinas 2-sustituidas 4-amino sustituidas.
US6147089A (en) 1998-09-17 2000-11-14 Pfizer Inc. Annulated 4-carboxyamino-2-methyl-1,2,3,4,-tetrahydroquinolines
WO2000018723A1 (en) 1998-09-25 2000-04-06 Monsanto Company Substituted n-aliphatic-n-aromatic tertiary-heteroalkylamines useful for inhibiting cholesteryl ester transfer protein activity
ES2286909T3 (es) 1998-09-25 2007-12-01 Monsanto Company Aril y heteroaril-heteroalquilamidas terciarias policiclicas sustituidas como inhibidoras de la actividad de la proteina de transferencia de ester de colesterol.
ATE404178T1 (de) * 1999-02-10 2008-08-15 Pfizer Prod Inc Vorrichtung mit matrixgesteuerter wirkstofffreisetzung
PT1165051E (pt) * 1999-03-19 2003-11-28 Ranbaxy Lab Ltd Processo para a preparacao de uma forma de dosagem oral biodisponivel de cefuroxima axetil
KR100342943B1 (ko) 1999-08-04 2002-07-02 민경윤 비결정질 세푸록심 악세틸 고형분산체, 이의 제조 방법 및 이를 포함하는 경구투여용 조성물
AR027656A1 (es) * 2000-03-16 2003-04-09 Pfizer Prod Inc Composiciones farmaceuticas de inhibidores de la glucogeno-fosforilasa
US20010053791A1 (en) * 2000-03-16 2001-12-20 Babcock Walter C. Glycogen phosphorylase inhibitor
US6602523B1 (en) 2000-08-17 2003-08-05 Technology Holding, Llc. Composite material and process for increasing bioavailability and activity of a beneficial agent
US6596262B2 (en) * 2001-02-15 2003-07-22 Aeropharm Technology Incorporated Modulated release particles for aerosol delivery

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5626878A (en) * 1995-01-10 1997-05-06 Warner Lambert Company Reduction of electrostatic forces between magnesium trisilicate adsorbates
US20020103225A1 (en) * 2000-08-03 2002-08-01 Curatolo William J. Pharmaceutical compositions of cholesteryl ester transfer protein inhibitors

Cited By (68)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9486410B2 (en) * 2002-02-01 2016-11-08 Bend Research, Inc. Pharmaceutical compositions of amorphous dispersions of drugs and lipophilic microphase-forming materials
US10357455B2 (en) 2002-02-01 2019-07-23 Bend Research, Inc. Pharmaceutical compositions of amorphous dispersions of drugs and lipophilic microphase-forming materials
US20080063708A1 (en) * 2002-02-01 2008-03-13 Perlman Michael E Pharmaceutical Compositions of Amorphous Dispersions of Drugs and Lipophilic Microphase-Forming Materials
US20030198674A1 (en) * 2002-02-01 2003-10-23 Curatolo William J. Controlled release pharmaceutical dosage forms of a cholesteryl ester transfer protein inhibitor
US7838029B1 (en) 2003-07-31 2010-11-23 Watson Laboratories, Inc. Mirtazapine solid dosage forms
US20110046115A1 (en) * 2003-07-31 2011-02-24 Watson Laboratories, Inc. Mirtazapine Solid Dosage Forms
WO2005011635A2 (en) 2003-08-04 2005-02-10 Pfizer Products Inc. Pharmaceutical compositions of adsorbates of amorphous drugs and lipophilic microphase-forming materials
US9023393B2 (en) * 2003-08-04 2015-05-05 Bend Research, Inc. Pharmaceutical compositions of adsorbates of amorphous drugs and lipophilic microphase-forming materials
USRE47033E1 (en) * 2003-08-04 2018-09-11 Bend Research, Inc. Pharmaceutical compositions of adsorbates of amorphous drugs and lipophilic microphase-forming materials
US20050031693A1 (en) * 2003-08-04 2005-02-10 Pfizer Inc Pharmaceutical compositions of adsorbates of amorphous drugs and lipophilic microphase-forming materials
US7390503B1 (en) 2003-08-22 2008-06-24 Barr Laboratories, Inc. Ondansetron orally disintegrating tablets
WO2005087199A3 (en) * 2004-03-10 2009-01-15 Schering Ag Stabilised supersaturated solid solutions of steroidal drugs
US20050207990A1 (en) * 2004-03-10 2005-09-22 Adrian Funke Stabilised supersaturated solids of lipophilic drugs
US8715735B2 (en) 2004-03-10 2014-05-06 Bayer Intellectual Property Gmbh Stabilised supersaturated solids of lipophilic drugs
CN1984644B (zh) * 2004-03-10 2010-12-08 拜耳先灵医药股份有限公司 亲脂性药物的稳定的过饱和固体
KR101210695B1 (ko) * 2004-03-10 2012-12-11 바이엘 파마 악티엔게젤샤프트 친지성 약물의 안정화된 과포화 고체
WO2005087199A2 (en) * 2004-03-10 2005-09-22 Schering Aktiengesellschaft Stabilised supersaturated solid solutions of steroidal drugs
EP2087883A1 (de) * 2004-03-10 2009-08-12 Bayer Schering Pharma Aktiengesellschaft Stabilisierte übersättigte feste Lösungen von Steroid-Wirkstoffen
AU2005221403B2 (en) * 2004-03-10 2009-12-10 Bayer Schering Pharma Aktiengesellschaft Stabilised supersaturated solid solutions of steroidal drugs
EA012746B1 (ru) * 2004-03-10 2009-12-30 Байер Шеринг Фарма Акциенгезельшафт Порошкообразная композиция и способ ее получения, фармацевтическая лекарственная форма и способ ее получения, применение аморфного кремнезема
AU2005221403B8 (en) * 2004-03-10 2010-01-07 Bayer Schering Pharma Aktiengesellschaft Stabilised supersaturated solid solutions of steroidal drugs
US7767231B2 (en) * 2004-10-12 2010-08-03 Sandoz Ag Taste-masking pharmaceutical compositions
US20080008765A1 (en) * 2004-10-12 2008-01-10 Sandoz Ag Taste-Masking Pharmaceutical Compositions
US20060135551A1 (en) * 2004-12-20 2006-06-22 Anima Baruah Novel heterocyclic compounds and their pharmaceutical compositions
US7700774B2 (en) 2004-12-20 2010-04-20 Dr. Reddy's Laboratories Ltd. Heterocyclic compounds and their pharmaceutical compositions
US9040558B2 (en) 2004-12-31 2015-05-26 Dr. Reddy's Laboratories Ltd. Substituted benzylamino quinolines as cholesterol ester-transfer protein inhibitors
US20060178514A1 (en) * 2004-12-31 2006-08-10 Anima Baruah Novel benzylamine derivatives as CETP inhibitors
US8604055B2 (en) 2004-12-31 2013-12-10 Dr. Reddy's Laboratories Ltd. Substituted benzylamino quinolines as cholesterol ester-transfer protein inhibitors
US20070015758A1 (en) * 2004-12-31 2007-01-18 Anima Baruah Novel benzylamine derivatives and their utility as cholesterol ester-transfer protein inhibitors
US9782407B2 (en) 2004-12-31 2017-10-10 Dr. Reddy's Laboratories Ltd. Substituted benzylamino quinolines as cholesterol ester-transfer protein inhibitors
US9387252B2 (en) 2005-02-03 2016-07-12 Bend Research, Inc. Pharmaceutical compositions with enhanced performance
US8617604B2 (en) * 2005-02-03 2013-12-31 Bend Research, Inc. Pharmaceutical compositions with enhanced performance
US20080064763A1 (en) * 2005-02-03 2008-03-13 Babcock Walter C Pharmaceutical Compositions with Enhanced Performance
US20090169583A1 (en) * 2005-02-08 2009-07-02 Pfizer, Inc. Solid Adsorbates of Hydrophobic Drugs
US20080281248A1 (en) * 2007-04-02 2008-11-13 University Of Pittsburgh - Of The Commonwealth System Of Higher Education Removal of contrast agents from blood
US8827943B2 (en) 2007-04-02 2014-09-09 University of Pittsburg—Of the Commonwealth System of Higher Education Catheter
US8398576B2 (en) 2007-04-02 2013-03-19 University of Pittsburgh—of the Commonwealth System of Higher Education Removal of contrast agents from blood
US20100137447A1 (en) * 2007-04-30 2010-06-03 Ratiopharm Gmbh Method for the production of adsorbates of a rasagiline salt having a water-soluble adjuvant
US20100305087A1 (en) * 2007-12-21 2010-12-02 Lek Pharmaceuticals D.D. Active pharmaceutical ingredient on a solid support, amorphous and with an improved solubility
EP2072042A1 (de) * 2007-12-21 2009-06-24 Lek Pharmaceuticals D.D. Aktive pharmazeutische Zutat auf einem festen Träger, amorph und mit verbesserter Löslichkeit
WO2009080698A1 (en) * 2007-12-21 2009-07-02 Lek Pharmaceuticals D.D. Active pharmaceutical ingredient on a solid support, amorphous and with an improved solubility
US8722094B2 (en) 2008-03-11 2014-05-13 Aska Pharmaceutical Co., Ltd. Solid dispersion and pharmaceutical composition of the same, and production processes thereof
US20110020455A1 (en) * 2008-03-11 2011-01-27 Aska Pharmaceutical Co., Ltd. Solid dispersion and pharmaceutical composition of the same, and production processes thereof
US8647666B2 (en) * 2008-10-02 2014-02-11 University of Pittsburgh—of the Commonwealth System of Higher Education Administration of an adsorbent polymer for treatment of systemic inflammation
CN107320485A (zh) * 2008-10-02 2017-11-07 匹兹堡大学-属高等教育联邦体系 用于治疗全身性炎症的吸附剂聚合物的施用
US20140017309A1 (en) * 2008-10-02 2014-01-16 University Of Pittsburgh-Of The Commonwealth System Of Higher Education Enteral administration of sorbent polymer for treatment and prophylaxis of inflammation
US20110212172A1 (en) * 2008-10-02 2011-09-01 University Of Pittsburgh - Of The Commonwealth System Of Higher Education Administration of an adsorbent polymer for treatment of systemic inflammation
WO2010040086A1 (en) * 2008-10-02 2010-04-08 University Of Pittsburgh - Of The Commonwealth System Of Higher Education Administration of an adsorbent polymer for treatment of systemic inflammation
AU2009298112B2 (en) * 2008-10-02 2015-11-12 University Of Pittsburgh - Of The Commonwealth System Of Higher Education Administration of an adsorbent polymer for treatment of systemic inflammation
US9603807B2 (en) * 2008-10-02 2017-03-28 University of Pittsburgh—of the Commonwealth System of Higher Education Enteral administration of sorbent polymer for treatment and prophylaxis of inflammation
CN102227244A (zh) * 2008-10-02 2011-10-26 匹兹堡大学-属高等教育联邦体系 用于治疗全身性炎症的吸附剂聚合物的施用
US20120003282A1 (en) * 2009-03-05 2012-01-05 Miller Warren K Pharmaceutical compositions of dextran polymer derivatives
US9757464B2 (en) * 2009-03-05 2017-09-12 Bend Research, Inc. Pharmaceutical compositions of dextran polymer derivatives
US8685458B2 (en) * 2009-03-05 2014-04-01 Bend Research, Inc. Pharmaceutical compositions of dextran polymer derivatives
US20140161895A1 (en) * 2009-03-05 2014-06-12 Bend Research, Inc. Pharmaceutical compositions of dextran polymer derivatives
US20120088774A1 (en) * 2009-04-06 2012-04-12 Lek Pharmaceuticals D.D. Active pharmaceutical ingredient adsorbed on solid support
WO2010115886A1 (en) * 2009-04-06 2010-10-14 Lek Pharmaceuticals D.D. Active pharmaceutical ingredient adsorbed on solid support
AU2010233809B2 (en) * 2009-04-06 2015-03-12 Lek Pharmaceuticals D.D. Active pharmaceutical ingredient adsorbed on solid support
CN102448460A (zh) * 2009-04-06 2012-05-09 力奇制药公司 吸附在固体支持物上的活性药物成分
EA031818B1 (ru) * 2009-04-06 2019-02-28 Лек Фармасьютиклз Д.Д. Применение адсорбата, включающего тадалафил, для получения дозированной формы и ее применение для лечения эректильной дисфункции, а также способы получения указанного адсорбата и указанной дозированной формы
WO2010147978A1 (en) 2009-06-16 2010-12-23 Pfizer Inc. Dosage forms of apixaban
EP3520776A1 (de) 2009-06-16 2019-08-07 Pfizer Inc Darreichungsformen von apixaban
US9757338B2 (en) 2010-03-01 2017-09-12 Dexcel Pharma Technologies Ltd. Sustained-release donepezil formulation
WO2011148253A2 (en) 2010-05-25 2011-12-01 Aurobindo Pharma Limited Solid dosage forms of antipsychotics
US8815294B2 (en) 2010-09-03 2014-08-26 Bend Research, Inc. Pharmaceutical compositions of dextran polymer derivatives and a carrier material
US9668998B2 (en) 2011-01-18 2017-06-06 Pfizer Limited Solid molecular dispersion of fesoterodine hydrogen fumarate and polymeric binder
US9199967B2 (en) 2011-08-18 2015-12-01 Dr. Reddy's Laboratories Ltd. Substituted heterocyclic amine compounds as cholestryl ester-transfer protein (CETP) inhibitors
US9000007B2 (en) 2011-09-27 2015-04-07 Dr. Reddy's Laboratories Ltd. 5-benzylaminomethyl-6-aminopyrazolo [3, 4 -B] pyridine derivatives as cholesteryl ester-transfer protein (CETP) inhibitors useful for the treatment of atherosclerosis

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