US20030054038A1 - Pharmaceutical compositions of drugs and neutralized acidic polymers - Google Patents

Pharmaceutical compositions of drugs and neutralized acidic polymers Download PDF

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Publication number
US20030054038A1
US20030054038A1 US10/175,566 US17556602A US2003054038A1 US 20030054038 A1 US20030054038 A1 US 20030054038A1 US 17556602 A US17556602 A US 17556602A US 2003054038 A1 US2003054038 A1 US 2003054038A1
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Prior art keywords
phenyl
composition
amino
cellulose acetate
polymer
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US10/175,566
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Inventor
Marshall Crew
Dwayne Friesen
Rodney Ketner
Ravi Shanker
James West
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Bend Research Inc
Original Assignee
Crew Marshall D.
Friesen Dwayne T.
Ketner Rodney J.
Shanker Ravi M.
West James B.
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Application filed by Crew Marshall D., Friesen Dwayne T., Ketner Rodney J., Shanker Ravi M., West James B. filed Critical Crew Marshall D.
Priority to US10/175,566 priority Critical patent/US20030054038A1/en
Publication of US20030054038A1 publication Critical patent/US20030054038A1/en
Priority to US11/213,118 priority patent/US8147872B2/en
Priority to US11/422,133 priority patent/US8173142B2/en
Assigned to BEND RESEARCH, INC. reassignment BEND RESEARCH, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: PFIZER PRODUCTS INC., PFIZER INC.
Abandoned legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1611—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4706—4-Aminoquinolines; 8-Aminoquinolines, e.g. chloroquine, primaquine
    • A—HUMAN NECESSITIES
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • 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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • 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
    • A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7024—Esters of saccharides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/716—Glucans
    • A61K31/717—Celluloses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/143—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds

Definitions

  • This invention relates to pharmaceutical compositions of drugs and neutralized acidic polymers that provide improved chemical and physical properties.
  • Forming a dispersion of a drug and polymer may enhance drug concentration in a use environment.
  • Curatolo, et al., EP 0 901 786 A2 disclose forming pharmaceutical spray dried amorphous dispersions of sparingly soluble drugs and the polymer hydroxypropyl methyl cellulose acetate succinate.
  • the spray dried dispersions disclosed in Curatolo et al. provide superior aqueous concentration relative to dispersions formed from other methods and relative to the crystalline drug alone.
  • amorphous drug may separate from the dispersion polymer, either as a drug-enriched amorphous phase or as a crystalline phase, thereby decreasing the concentration enhancement provided by the dispersion.
  • the inventors have also found that for some drugs, the drugs are not chemically stable within some dispersion polymers.
  • the inventors have observed that for dispersions containing certain drugs and acidic polymers, the drug chemically degrades in the dispersion over time, resulting in a loss of potency and an increase in unwanted impurities.
  • Hodges et al. U.S. Pat. No. 5,225,202 disclose an enteric coated composition which includes a medicament which is sensitive to a low pH environment of less than 3.
  • the composition has an enteric coating formed of neutralized hydroxypropylmethyl cellulose acetate phthalate, plasticizer and anti-adherent.
  • compositions of low-solubility drugs and polymers that have improved physical stability, chemical stability, and/or improved concentration enhancement and bioavailability.
  • the present invention provides, in one aspect, pharmaceutical compositions comprising a mixture of a low-solubility drug in a solubility-improved form and a neutralized acidic enteric polymer, wherein said composition provides enhanced concentration of said low-solubility drug in a use environment relative to a control composition, wherein said control composition comprises an equivalent quantity of said low-solubility drug and is free from a concentration-enhancing polymer.
  • the mixture is a solid amorphous dispersion of said low-solubility drug and said neutralized acidic enteric polymer.
  • the degree of neutralization of said neutralized acidic enteric polymer is at least 0.1, preferably at least 0.5, more preferably at least 0.9, more preferably about 1.
  • the neutralized acidic enteric polymer comprises a counterion selected from the group consisting of sodium, potassium, calcium, magnesium, aluminum, ammonium, iron, and amine.
  • the neutralized acidic enteric polymer comprises a blend of polymers.
  • the neutralized acidic enteric polymer is cellulosic, preferably selected from the group consisting of hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose succinate, hydroxypropyl cellulose acetate succinate, hydroxyethyl methyl cellulose succinate, hydroxyethyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, hydroxyethyl methyl cellulose acetate succinate, hydroxyethyl methyl cellulose acetate succinate, hydroxyethyl methyl cellulose acetate phthalate, cellulose acetate phthalate, methyl cellulose acetate phthalate, ethyl cellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate, hydroxypropyl methyl cellulose acetate phthalate, hydroxypropyl cellulose acetate succinate succinate, hydroxypropyl methyl cellulose acetate succinate phthalate, hydroxyprop
  • the neutralized acidic enteric polymer is selected from the group consisting of hydroxypropyl methyl cellulose acetate succinate, cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methyl cellulose phthalate, and carboxymethyl ethyl cellulose.
  • the neutralized acidic enteric polymer is a neutralized form of a polymer selected from the group consisting of carboxylic acid functionalized vinyl polymers, carboxylic acid functionalized polymethacrylates, and carboxylic acid functionalized polyacrylates.
  • the neutralized acidic enteric polymer has a glass transition temperature of at least 40° C.
  • the neutralized acidic enteric polymer is ionically crosslinked, preferably the neutralized acidic enteric polymer is ionically crosslinked with a multivalent cationic species.
  • the multivalent cationic species is selected from the group consisting of calcium, magnesium, aluminum, iron (II), iron (III), and a diamine.
  • the composition further comprises a base.
  • the base is selected from the group consisting of sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, aluminum hydroxide, ammonia, ammonium hydroxide, ammonium acetate, sodium acetate, potassium acetate, calcium acetate, magnesium acetate, sodium citrate, trisodium phosphate, disodium phosphate, ethylene diamine, monoethanol amine, diethanol amine, triethanolamine, potassium citrate, sodium carbonate, sodium bicarbonate, sodium acetate, amine-functional polyacrylates, and sodium polyacrylic acid.
  • the base comprises at least 5 wt % of said composition.
  • the drug has a solubility in aqueous solution in the absence of said polymer of less than 1 mg/ml, preferably less than 0.1 mg/ml, at any pH of from about 1 to about 8.
  • the drug has a dose-to-aqueous-solubility ratio of at least 10 ml.
  • the low-solubility drug is acid-sensitive.
  • the acid-sensitive drug has at least one functional group selected from the group consisting of sulfonyl ureas, hydroxamic acids, hydroxy amides, carbamates, acetals, hydroxy ureas, esters, and amides
  • the acid-sensitive drug is selected from the group consisting of quinoxaline-2-carboxylic acid [4(R)-carbamoyl-1(S)-3-fluorobenzyl-2(S),7-dihydroxy-7-methyl-octyl]amide; quinoxaline-2-carboxylic acid [1-benzyl-4-(4,4-difluoro-1-hydroxy-cyclohexyl)-2-hydroxy-4-hydroxycarbamoyl-butyl]-amide; (+)-N- ⁇ 3-[3-(4-fluorophenoxy)phenyl]-2-cyclopenten-1-y
  • the composition provides improved chemical stability of said drug relative to a second control composition, wherein said second control composition comprises a dispersion of an equivalent quantity of said low-solubility drug and an unneutralized form of said neutralized acidic enteric polymer.
  • the composition provides a relative degree of improvement in stability for said drug of at least 1.25, preferably at least 3, more preferably at least 10, when stored at 40° C. and 75% relative humidity.
  • the maximum concentration of said drug in said use environment is at least 1.25-fold that of said control composition.
  • the neutralized acidic enteric polymer is present in a sufficient amount so that said composition provides in said use environment an area under the concentration versus time curve for any period of at least 90 minutes between the time of introduction into the use environment and about 270 minutes following introduction to said use environment that is at least 1.25-fold, preferably at least 2-fold, that of said control composition.
  • the neutralized acidic enteric polymer is present in a sufficient amount so that said composition provides a relative bioavailability that is at least 1.25 relative to said control composition.
  • the composition further comprises a second concentration-enhancing polymer.
  • the present invention relates to pharmaceutical compositions comprising a solid amorphous dispersion of an acid-sensitive drug and a neutralized acidic dispersion polymer, wherein said composition provides improved chemical stability of said drug relative to a control composition comprised of a dispersion of an equivalent quantity of said drug and an unneutralized form of said acidic polymer.
  • the degree of neutralization of said neutralized acidic polymer is at least 0.1, more preferably at least 0.5, more preferably at least 0.9, more preferably at least 1.
  • the neutralized acidic dispersion polymer has a counterion selected from the group consisting of sodium, potassium, calcium, magnesium, aluminum, ammonium, iron, and amine.
  • the neutralized acidic dispersion polymer comprises a blend of polymers.
  • the neutralized acidic dispersion polymer is cellulosic.
  • neutralized acidic dispersion polymer is a neutralized form of a polymer selected from the group consisting of hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose succinate, hydroxypropyl cellulose acetate succinate, hydroxyethyl methyl cellulose succinate, hydroxyethyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, hydroxyethyl methyl cellulose acetate succinate, hydroxyethyl methyl cellulose acetate phthalate, cellulose acetate phthalate, methyl cellulose acetate phthalate, ethyl cellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate, hydroxypropyl methyl cellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate, hydroxyprop
  • the neutralized acidic polymer is a neutralized form of a polymer selected from the group consisting of hydroxy propyl methyl cellulose acetate succinate, cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methyl cellulose phthalate, carboxymethyl cellulose, carboxymethyl ethyl cellulose.
  • the neutralized acidic dispersion polymer is a neutralized form of a polymer selected from the group consisting of carboxylic acid functionalized vinyl polymers, carboxylic acid functionalized polymethacrylates, and carboxylic acid functionalized polyacrylates.
  • the neutralized acidic dispersion polymer has a glass transition temperature of at least 40° C.
  • the composition further comprises a base.
  • the composition comprises a physical mixture of said dispersion and said base.
  • the base is selected from the group consisting of sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, aluminum hydroxide, ammonia, ammonium hydroxide, ammonium acetate, sodium acetate, potassium acetate, calcium acetate, magnesium acetate, sodium citrate, trisodium phosphate, disodium phosphate, ethylene diamine, monoethanol amine, diethanol amine, triethanolamine, potassium citrate, sodium carbonate, sodium bicarbonate, sodium acetate, amine-functional polyacrylates, and sodium polyacrylic acid.
  • the dispersion has a pH greater than 5.
  • the acid-sensitive drug has a solubility in aqueous solution in the absence of said neutralized acidic polymer of less than 1 mg/ml, preferably less than 0.1 mg/ml, at any pH of from about 1 to about 8.
  • the acid-sensitive drug has a dose-to-aqueous-solubility ratio of at least 10 ml.
  • the acid-sensitive drug has at least one functional group selected from the group consisting of sulfonyl ureas, hydroxamic acids, hydroxy amides, carbamates, acetals, hydroxy ureas, esters, and amides.
  • the acid-sensitive drug is selected from the group consisting of quinoxaline-2-carboxylic acid [4(R)-carbamoyl-1(S)-3-fluorobenzyl-2(S),7-dihydroxy-7-methyl-octyl]amide; quinoxaline-2-carboxylic acid [1-benzyl-4-(4,4-difluoro-1-hydroxy-cyclohexyl)-2-hydroxy-4-hydroxycarbamoyl-butyl]-amide; (+)-N- ⁇ 3-[3-(4-fluorophenoxy)phenyl]-2-cyclopenten-1-yl ⁇ -N-hydroxyurea; omeprazole; etoposide; famotidine; erythromycin; quinapril; lansoprazole; and progabide.
  • quinoxaline-2-carboxylic acid [4(R)-carbamoyl-1(S)-3-fluorobenzyl-2(S),7-
  • the composition provides a relative degree of improvement for said drug of at least 1.25, preferably at least 3, more preferably at least 10, when stored at 40° C. and 75% relative humidity.
  • the neutralized acidic polymer is concentration-enhancing and present in a sufficient amount to provide a maximum concentration of said acid-sensitive drug in a use environment that is at least 1.25-fold that of a second control composition, said second control composition comprising an equivalent quantity of said acid-sensitive drug but free from a concentration-enhancing polymer.
  • the neutralized acidic polymer is concentration-enhancing and is present in a sufficient amount so that said composition provides in a use environment an area under the concentration versus time curve for any period of at least 90 minutes between the time of introduction into the use environment and about 270 minutes following introduction to the use environment that is at least 1.25-fold, preferably at least 2-fold, that of a control composition, said second control composition comprising an equivalent quantity of said acid-sensitive drug and free from a concentration-enhancing polymer.
  • the neutralized acidic polymer is concentration-enhancing and is present in an amount so that said dispersion provides a relative bioavailability that is at least 1.25 relative to a second control composition, said second control composition comprising an equivalent quantity of said acid-sensitive drug and free from a concentration-enhancing polymer.
  • the composition further comprises a second polymer, said second polymer being concentration-enhancing.
  • the present invention relates to methods for treating a condition in an animal comprising administering to an animal in need of such treatment a therapeutic amount of the above-described compositions.
  • the present invention relates to methods for forming a solid pharmaceutical composition, comprising the steps of: (a) neutralizing an acidic enteric polymer to form a neutralized acidic enteric polymer; and (b) combining a low-solubility drug with said neutralized acidic enteric polymer, said neutralized acidic enteric polymer being present in a sufficient amount in said composition so as to be concentration-enhancing.
  • step (a) further comprises the steps of
  • the low-solubility drug and said acidic enteric polymer are both dissolved in a common solvent to form a solution.
  • the method further comprises the step of adding a base to said solution.
  • the solvent is removed from said solution forming a solid amorphous dispersion.
  • the acidic enteric polymer is neutralized prior to being combined with said drug.
  • the acidic enteric polymer is combined with said drug prior to neutralizing said acidic enteric polymer.
  • the drug and said neutralized acidic enteric polymer are combined to form a solid amorphous dispersion.
  • the drug at least partially neutralizes said polymer.
  • the fifth aspect of the present invention relates to methods for forming a pharmaceutical composition, comprising the steps of: (a) neutralizing an acidic polymer to form a neutralized acidic polymer; and (b) forming a solid amorphous dispersion of an acid-sensitive drug and said neutralized acidic polymer, said dispersion providing improved chemical stability relative to a control composition comprised of an equivalent quantity of said acid-sensitive drug and the unneutralized form of said neutralized acidic polymer.
  • the acidic polymer is neutralized prior to being combined with said acid-sensitive drug.
  • the acidic polymer and said drug are combined prior to neutralizing said acidic polymer.
  • the present invention relates to methods for forming a pharmaceutical composition, comprising the steps of: (a) forming a solid amorphous dispersion of an acid-sensitive drug and an acidic polymer; and (b) neutralizing said acidic polymer after forming said dispersion.
  • the acidic polymer is neutralized by combining said dispersion with a base.
  • neutralized acidic enteric polymers provide several advantages over conventional unneutralized acidic enteric polymers.
  • Compositions of neutralized acidic enteric polymers and drugs tend to be more physically and chemically stable than unneutralized polymers.
  • the compositions may provide improved uniformity of drug potency and concentration enhancement when administered to a use environment after being stored under typical ambient storage conditions.
  • neutralized acidic enteric polymers also may provide greater concentration enhancement and faster dissolution. This may lead to improved bioavailability of the low-solubility drug.
  • acidic dispersion polymers are preferred for use with low-solubility drugs because such polymers often provide greater concentration enhancement than that provided by non-acidic polymers.
  • the inventors have recognized that a problem with forming dispersions of acid-sensitive drugs is that for some dispersions, the drug does not remain chemically stable in the dispersion over time.
  • acid-sensitive drugs dispersed in an acidic polymer such as hydroxypropyl methyl cellulose acetate succinate or cellulose acetate phthalate, both of which have carboxylic acid functional groups, have a tendency to chemically degrade over time.
  • acidic ionic groups on the acidic polymer either catalyze degradation of the drug or react directly with the drug. Such reactions may occur due to the acidic environment induced by the presence of the carboxylic acid groups (for example, a high hydrogen ion activity) or by direct interaction of the drug and the carboxylic acid groups.
  • the present invention is able to realize the advantages of forming dispersions of low-solubility, acid-sensitive drugs by improving the chemical stability of the acid-sensitive drug in the dispersion, while retaining the superior concentration enhancement provided by the use of acidic dispersion polymers.
  • the term “use environment” may refer to either the in vivo environment of the gastrointestinal (GI) tract of an animal, particularly a human, or the in vitro environment of a test solution, such as phosphate buffered saline (PBS) or model fasted duodenal (MFD) solution.
  • GI gastrointestinal
  • PBS phosphate buffered saline
  • MFD model fasted duodenal
  • compositions of the present invention may be dosed in a variety of dosage forms, including both immediate release and controlled release dosage forms, the latter including both delayed and sustained release forms.
  • the composition may include blends of polymers.
  • compositions of the present invention comprise mixtures of a drug and a neutralized acidic polymer.
  • the present invention finds utility anytime it is desired to improve the aqueous concentration of a low-solubility drug, and finds particular utility when the drug is acid-sensitive.
  • the composition comprises a mixture of a low-solubility drug and a neutralized acidic enteric polymer.
  • Compositions formed from neutralized acidic enteric polymers provide improved physical and/or chemical drug stability, concentration-enhancement and dissolution properties relative to the unneutralized form of the acidic enteric polymer.
  • the invention will find utility for any low-solubility drug and/or composition which may benefit from improved physical or chemical stability, improved concentration enhancement, and/or improved dissolution.
  • the drug and neutralized acidic enteric polymer may be mixed in any conventional fashion so as to achieve a relatively uniform mixture.
  • the drug and polymer may exist in drug-rich and polymer-rich domains, may exist together as a homogeneous solid solution or in some state in between.
  • the mixture may be formed by any conventional method, such as by blending, milling, or granulating.
  • a preferred mixture is a molecular dispersion.
  • a composition comprises a dispersion of an acid-sensitive drug and a neutralized acidic polymer.
  • Dispersions of the present invention formed from neutralized acidic polymers improve the chemical stability of acid-sensitive drugs relative to dispersions of the same drug in the unneutralized acidic form of the polymer.
  • the dispersions of the second embodiment simultaneously provide enhanced chemical stability and enhanced drug concentration in a use environment and, in turn, enhanced bioavailability.
  • the dispersions may be used to prevent degradation of the drug due to interactions with dispersion polymers, other acidic dispersion species, or other acidic excipients present in the composition.
  • Suitable drugs particularly acid-sensitive drugs, acidic polymers and methods for making the various compositions of low-solubility drug and acidic polymer are discussed in more detail below.
  • the term “drug” is conventional, denoting a compound having beneficial prophylactic and/or therapeutic properties when administered to an animal, especially humans.
  • 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.
  • 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 the dose is in mg.
  • the dose-to-aqueous-solubility-ratio may be determined by simply dividing the dose (in mg) by the aqueous solubility (in mg/mL).
  • the drug must be formulated in a manner so as to be capable of providing an initially enhanced drug concentration that is greater than the equilibrium concentration of the drug in the use environment (i.e., a super-saturated drug concentration). It is believed that the polymers of the present invention do not have the ability to enhance the solubility of the drug in the use environment. Instead, the polymers inhibit or retard the rate at which the initially enhanced concentration of drug decreases to the equilibrium concentration of drug.
  • the drug may be formulated as a solid amorphous dispersion of drug and polymer such that the dispersion provides an initial concentration of drug in the use environment that is greater than the equilibrium concentration of drug in the use environment.
  • the drug may be formulated in a solubility-improved form.
  • Solubility-improved forms include crystal and highly soluble salt forms of the drug, high-energy crystalline forms of the drug (such as polymorphs), amorphous drug, a mixture of the drug and a solubilizing agent, and drug predissolved in a solution. Examples of such solubility-improved forms are more fully described in commonly assigned pending patent application titled Pharmaceutical Compositions Providing Enhanced Drug Concentrations, Ser. No. 09/742,785, filed Dec. 20, 2000, which claims priority to provisional patent application Serial No. 60/171,841, filed Dec. 23, 1999, the disclosure of which is incorporated by reference.
  • the drug may be a basic drug which dissolves readily in gastric solution. Upon entering intestinal solution, a drug concentration that exceeds the equilibrium concentration of drug in the intestinal solution may be temporarily achieved.
  • basic drugs are disclosed in commonly assigned pending patent application Ser. No. 09/495,438, filed Jan. 31, 2000, which claims priority to provisional patent application Serial No. 60/119,283, filed Feb. 9, 1999, the relevant disclosure of which is herein incorporated by reference.
  • 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, 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-artheriosclerotic 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-
  • 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 9914215A1;WO 9914174; DE 19709125A1; DE 19704244A1; 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; WO 2000
  • 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 0.1 ⁇ 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 , W 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
  • substituents R II-5 , R II-6 , R II-7 and R II-8 is not hydrogen and is not linked to the quinoline moiety through oxy.
  • 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; wherein 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
  • 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-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 neteroatoms 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-3 must contain V IV or R IV-4 must contain V IV-1 ;
  • 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 )
  • R IV-2 is carboxyl or (C 1 -C 4 )alkylcarboxyl, then R IV-1 is not hydrogen.
  • 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 VI-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 R 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 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 atoms each and/or a phenyl, which may in turn be substituted with up
  • 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
  • Y VI and Y VI together form a 2- to 6-membered straight-chain or
  • 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:
  • 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
  • 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 heterocyclylidenyl
  • 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 VII 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 VIII 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; provided 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, mono-, bi-, or tricyclic heterocyclic ring from the series consisting of S, N and/or O, in which the rings are substituted, optionally, in case of the nitrogen containing aromatic rings via the N function, with up to 5 identical or different substituents in the form of halogen, trifluoromethyl, nitro, hydroxy, cyano, carbonyl, trifluoromethoxy, straight straight-chain or branched acyl, alkyl, alkylthio, alkylalkoxy, alkoxy, or alkoxycarbonyl each having up to 6 carbon atoms, by aryl or trifluoromethyl-substituted aryl each having 6 to 10 carbon atom
  • 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,
  • R 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 20 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
  • 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.
  • 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 ,
  • R XI-15 and R XI-16 are identical or different and have 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 cycloalkyoxy 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.
  • R XI-1 and R XI-2 are substituted, also geminally, possibly up to 5-fold, identical or different, by phenyl, benzoyl, thiophenyl or sulfobenzyl—which themselves are possibly substituted by halogen, trifluoromethyl, trifluoromethoxy or nitro, and/or the alkylene chain formed by R XI-1 and R XI-2 is possibly substituted by a radical of the formula
  • 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.
  • 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.
  • 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, oraryl 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.
  • 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 ,
  • 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 I, 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:
  • Another class of CETP inhibitors that finds utility with the present invention consists of substitued N-Aliphatic-N-Aromatic tertiary-Heteroalkylamines having the Formula XV
  • 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- XV38 ) 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
  • 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
  • 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-4 , and K XV
  • 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 —O—(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 subsitituent pairs R XV-10 and R XV-11 , R XV-10 and R XV-31 , R XV-1 and R XV-32 , R XV-1 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
  • 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-1 , R XV-12 , R XV-1 , R XV-3 , 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 tetravalent nature of carbon
  • 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 ary
  • 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-1 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 XVI-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 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 XVI-3 , J XVI-4 and K XVI-2 are O and S, and no more than four of D XVI-3 , D XVI-4 , J XVI-3 , J XVI- 4 and
  • R XVI is selected from the group consisting of hydrido, aryl, aralkyl, 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 wherein q is an integer selected from 1 and 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 )) 1 —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;
  • [0902] 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, cycloalkylsulfinyl, cycloalkylsulfinylalkyl, cycloalkylsulfonyl, cycloalkylsulfonylalkyl, heteroarylamino, N-heter
  • R XVI-10 , R XVI-10 and R XVI-11 , R XVI-11 and R XVI-12 , and R XVI-12 and R XVI-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 XVI-5 , R XVI-5 and R XVI-6 , R XVI-6 and R XVI-7 , and R XVI-7 and R XVI-8 is used at the same time and that no more than one of
  • [0904] 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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