Classifications

• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
  • A61P11/14—Antitussive agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/08—Antiepileptics; Anticonvulsants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/22—Anxiolytics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • 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
  • A61P3/04—Anorexiants; Antiobesity agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
  • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/12—Antihypertensives

Definitions

• the invention relates to compositions of a dispersion comprising amorphous drug and a matrix combined with a concentration-enhancing polymer that improves the stability of the drug and/or enhances the concentration of the drug in a use environment.
• Low-solubility drugs often show poor bioavailability or irregular absorption, the degree of irregularity being affected by factors such as dose level, fed state of the patient, and form of the drug.
• Increasing the bioavailability of low-solubility drugs has been the subject of much research.
• Increasing bioavailability hinges on improving the concentration of the drug in solution to improve absorption.
• the amorphous form of a low-solubility drug that is capable of existing in either the crystalline or amorphous form may temporarily provide a greater aqueous concentration of drug relative to the equilibrium concentration obtained by dissolution of drug in a use environment.
• Such amorphous forms may consist of the amorphous drug alone, a dispersion of the drug in a matrix material, or the drug adsorbed onto a substrate. It is believed that such amorphous forms of the drug may dissolve more rapidly than the crystalline form, often dissolving faster than the drug can precipitate from solution. As a result, the amorphous form may temporarily provide a greater-than equilibrium concentration of drug.
• HPMCAS hydroxypropylmethyl cellulose acetate succinate
• HPMCAS is a dispersion polymer.
• a dispersion may be formed of a drug and conventional matrix material such as PVP, HPC or HPMC and then the dispersion is triturated with HPMCAS.
• amorphous form of a drug may not be stable physically in the amorphous form. Often the crystalline form of the drug has a lower free energy, and thus over time, the amorphous drug will tend to crystallize.
• the rate of crystallization may be influenced by storage conditions, such as temperature and humidity, as well as the constituents of the composition.
• the drug in the resulting amorphous dispersion of polymer and drug may in some cases be unstable.
• the dispersion may be physically unstable, causing the amorphous drug to separate from the dispersion and/or crystallize.
• the drug in the amorphous dispersion may be chemically unstable. The drug may degrade over time at moderate temperature and humidity levels or the drug may convert to a lower energy and lower solubility amorphous or crystalline form.
• the drug and preferred polymer may not both be amenable to a processing method that results in a dispersion of the drug and preferred polymer.
• the drug and preferred polymer may not both be soluble to a sufficient extent in an appropriate processing solvent to allow formation of the dispersion.
• the drug or polymer or both may suffer unacceptable decomposition upon heating to allow the formation of the preferred composition to be practical.
• composition comprising an amorphous drug that is physically and/or chemically stable under typical storage conditions, may be formed via practical processing conditions, and that may enhance the bioavailability of poorly soluble drugs.
• the present invention in one aspect, relates to pharmaceutical compositions comprising: (a) a solid dispersion comprising a low-solubility drug and a matrix, wherein at least a major portion of said drug in said dispersion is amorphous; and (b) a concentration-enhancing polymer, said dispersion being free from at least a portion of said concentration-enhancing polymer; wherein said composition provides improved stability of said drug relative to at least one of a first control composition consisting of a mixture of said low-solubility drug in undispersed amorphous form and said concentration-enhancing polymer, and a second control composition consisting of a dispersion of said low-solubility drug and said concentration-enhancing polymer.
• the present invention relates to pharmaceutical compositions comprising: (a) a solid dispersion comprising a low-solubility drug and a matrix, wherein at least a major portion of said drug in said dispersion is amorphous; and (b) a concentration-enhancing polymer, said dispersion being free from at least a portion of said concentration-enhancing polymer; wherein at least 10 wt % of said matrix is non-polymeric.
• the present invention relates to pharmaceutical compositions comprising: (a) a solid dispersion comprising a low-solubility drug and a matrix, wherein at least a major portion of said drug in said dispersion is amorphous; and (b) a concentration-enhancing polymer, said dispersion being free from at least a portion of said concentration-enhancing polymer; wherein said concentration-enhancing polymer is non-cellulosic.
• the present invention relates to pharmaceutical compositions, comprising: (a) a solid dispersion comprising a low-solubility drug and a matrix, wherein at least a major portion of said drug in said dispersion is amorphous; and (b) a concentration-enhancing polymer, said dispersion being free from at least a portion of said concentration-enhancing polymer, wherein said concentration-enhancing polymer is selected from the group consisting of non-ionizable cellulosic polymers and neutralized acidic polymers.
• the present invention relates to pharmaceutical compositions, comprising: (a) a solid dispersion comprising a low-solubility drug and a matrix, wherein at least a major portion of said drug in said dispersion is amorphous; and (b) a concentration-enhancing polymer, said dispersion being free from at least a portion of said concentration-enhancing polymer, wherein said concentration-enhancing polymer is an ionizable cellulosic polymer having at least one of an ester-linked carboxylic acid-functional aromatic substituent and an ether-linked carboxylic acid-functional aromatic substituent.
• the present invention relates to pharmaceutical compositions, comprising: (a) a solid dispersion comprising a low-solubility drug and a matrix, wherein at least a major portion of said drug in said dispersion is amorphous; (b) an amphiphilic, cellulosic concentration-enhancing polymer, said dispersion being free from at least a portion of said amphiphilic, cellulosic concentration-enhancing polymer; (c) said amphiphilic cellulosic concentration-enhancing polymer having at least one hydrophobic substituent selected from the group consisting of ether-linked alkyl substituents, ester-linked alkyl substituents, ether-linked aryl substituents and ester-linked aryl substituents; (d) said amphiphilic cellulosic concentration-enhancing polymer having at least one hydrophilic substituent selected from the group consisting of ether-linked hydroxy alkyl substituents, ester-linked hydroxy alkyl substituents,
• the drug has improved physical stability in said composition relative to said first control composition.
• At least a major portion of said drug is dissolved in said matrix.
• the drug has a solubility in said matrix that is at least 30% of a concentration of said drug in said matrix.
• the drug has a weight ratio to said matrix of said dispersion of less than 20.
• the dispersion has a glass transition temperature that is greater than a glass transition temperature of at least one of said low-solubility drug in undispersed amorphous form and said second control composition.
• the dispersion has a glass transition temperature that is greater than about 50° C. at 50% relative humidity.
• the drug in said dispersion has a crystallization rate that is less than 90% of a crystallization rate of said drug in undispersed amorphous form.
• the drug in said composition has a relative degree of improvement in chemical stability of at least 1.25 relative to at least one of said first control composition and said second control composition.
• the drug is acid-sensitive and said concentration-enhancing polymer is acidic.
• the drug in said composition has improved stability, preferably improved physical stability, relative to at least one of a first control composition consisting of a mixture of said low-solubility drug in undispersed amorphous form and said concentration-enhancing polymer, and a second control composition comprising a dispersion of said drug and said concentration-enhancing polymer.
• At least 10 wt % of said matrix is non-polymeric.
• Preferred components of said matrix are selected from the group consisting of alcohols, organic acids, organic bases, amino acids, sugars, fatty acid esters, alkyl sulfates, phospholipids, waxes and salts.
• the matrix has at least one polymeric component.
• Preferred components of said matrix are selected from the group consisting of polyethylene glycols, polyoxyethylene glycols, polyethylene-polypropylene glycol copolymers, polyethylene oxides, polyvinylpyrrolidone, polyvinyl alcohols, polyethylene-vinyl alcohol copolymers, polyvinyl alcohol polyvinyl acetate copolymers, carboxylic acid-functionalized polymethacrylates, amine-functionalized polymethacrylates, proteins, xanthan gum, carrageenan, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxy methyl cellulose, chitosan, chitin, polydextrose, dextrin and starch.
• the drug is substantially amorphous in said dispersion.
• the dispersion is substantially homogeneous.
• the dispersion is completely homogeneous.
• the composition is a solid mixture in which said concentration-enhancing polymer is suspended as a separate phase within said dispersion.
• the composition is a mixture of particles of dispersion and particles of concentration-enhancing polymer.
• the mixture is formed by at least one of dry-granulation and wet-granulation.
• the dispersion and said concentration-enhancing polymer are each in separate regions.
• compositions further comprise a blend of concentration-enhancing polymers selected from the group consisting of ionizable cellulosic polymers, non-ionizable cellulosic polymers, ioniziable non-cellulosic polymers, non-ionizable non-cellulosic polymers, and neutralized acidic polymers.
• the concentration-enhancing polymer has a hydrophobic portion and a hydrophilic portion.
• the concentration-enhancing polymer is an ionizable cellulosic polymer such as polymers selected from the group consisting of hydroxypropyl methyl cellulose succinate, cellulose acetate succinate, methyl cellulose acetate succinate, ethyl cellulose acetate succinate, hydroxypropyl cellulose acetate succinate, hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl cellulose acetate phthalate succinate, cellulose propionate succinate, hydroxypropyl cellulose butyrate succinate, hydroxypropyl methyl cellulose phthalate, cellulose acetate phthalate, methyl cellulose acetate phthalate, ethyl cellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate, hydroxypropyl methyl cellulose acetate phthalate, cellulose propionate phthalate, hydroxypropyl cellulose butyrate phthalate, cellulose acetate trimell
• the concentration-enhancing polymer is selected from the group consisting of hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, cellulose acetate phthalate, and cellulose acetate trimellitate, and blends thereof.
• the concentration-enhancing polymer is a non-ionizable cellulosic polymer, such as polymers selected from the group consisting of hydroxypropyl methyl cellulose acetate, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, methyl cellulose, hydroxyethyl methyl cellulose, hydroxyethyl cellulose acetate, and hydroxyethyl ethyl cellulose, and blends thereof.
• the concentration-enhancing polymer is an ionizable, non-cellulosic polymer, such as polymers selected from the group consisting of carboxylic acid functionalized polymethacrylates, carboxylic acid functionalized polyacrylates, amine-functionalized polyacrylates, amine-fuctionalized polymethacrylates, proteins, and carboxylic acid functionalized starches, and blends thereof.
• the concentration-enhancing polymer is a non-ionizable, non-cellulosic polymer such as polymers selected from the group consisting of vinyl polymers and copolymers having at least one substituent selected from the group consisting of hydroxyl, alkylacyloxy, and cyclicamido; vinyl copolymers of at least one hydrophilic, hydroxyl-containing repeat unit and at least one hydrophobic, alkyl- or aryl-containing repeat unit; polyvinyl alcohols that have at least a portion of their repeat units in the unhydrolyzed form, polyvinyl alcohol polyvinyl acetate copolymers, polyethylene glycol polypropylene glycol copolymers, polyvinyl pyrrolidone, and polyethylene polyvinyl alcohol copolymers, and blends thereof.
• non-ionizable, non-cellulosic polymer such as polymers selected from the group consisting of vinyl polymers and copolymers having at least one substituent selected from the group consisting of
• the concentration-enhancing polymer is selected from the group consisting of hydroxypropyl cellulose acetate phthalate succinate, hydroxypropyl methyl cellulose phthalate, cellulose acetate phthalate, methyl cellulose acetate phthalate, ethyl cellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate, hydroxypropyl methyl cellulose acetate phthalate, cellulose propionate phthalate, hydroxypropyl cellulose butyrate phthalate, cellulose acetate trimellitate, methyl cellulose acetate trimellitate, ethyl cellulose acetate trimellitate, hydroxypropyl cellulose acetate trimellitate, hydroxypropyl methyl cellulose acetate trimellitate, hydroxypropyl cellulose acetate trimellitate succinate, cellulose propionate trimellitate, cellulose butyrate trimellitate, cellulose acetate terephthalate, cellulose acetate is
• the amphiphilic, cellulosic concentration-enhancing polymer is selected from the group consisting of hydroxypropyl cellulose acetate succinate, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose acetate, hydroxypropyl methyl cellulose succinate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate phthalate, hydroxyethyl methyl cellulose, hydroxyethyl methyl cellulose succinate, hydroxyethyl cellulose acetate succinate, hydroxyethyl methyl cellulose acetate succinate, hydroxyethyl methyl cellulose acetate succinate, hydroxyethyl methyl cellulose acetate phthalate, hydroxyethyl cellulose acetate, hydroxyethyl ethyl cellulose, carboxymethyl ethyl cellulose, cellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate, methyl cellulose a
• concentration-enhancing polymer is neutralized.
• concentration-enhancing polymer is a neutralized acidic polymer.
• the composition when administered to a use environment provides a dissolution area under the concentration versus time curve for a time period of at least 90 minutes during the 270 minutes immediately following introduction to said use environment that is at least 1.25-fold the corresponding area under the curve provided by a control composition comprising an equivalent amount of undispersed amorphous drug alone.
• the composition when administered to a use environment provides a maximum concentration of said drug in said use environment that is at least 1.25-fold a maximum concentration of said drug provided by a control composition comprising an equivalent amount of undispersed amorphous drug alone.
• the composition when administered to an animal provides a relative bioavailability of at least 1.25 relative to a control composition comprising an equivalent amount of undispersed amorphous drug alone.
• the composition when administered to a use environment provides a dissolution area under the concentration versus time curve for a time period of at least 90 minutes during the 270 minutes immediately following introduction to said use environment that is at least 1.25-fold the corresponding area under the curve provided by a control composition comprising an equivalent amount of said dispersion but with no concentration-enhancing polymer.
• the composition when administered to a use environment provides a maximum concentration of said drug in said use environment that is at least 1.25-fold a maximum concentration of said drug provided by a control composition comprising an equivalent amount of said dispersion but with no concentration-enhancing polymer.
• the composition when administered to an animal provides a relative bioavailability of at least 1.25 relative to a control composition comprising an equivalent amount of said dispersion but with no concentration-enhancing polymer.
• the drug is selected from the group consisting of antihypertensives, antianxiety agents, anticlotting agents, anticonvulsants, blood glucose-lowering agents, decongestants, antihistamines, antitussives, antineoplastics, beta blockers, anti-inflammatories, antipsychotic agents, cognitive enhancers, cholesterol-reducing agents, antiobesity agents, autoimmune disorder agents, anti-impotence agents, antibacterial and antifungal agents, hypnotic agents, anti-Parkinsonism agents, anti-Alzheimer's disease agents, antibiotics, anti-depressants, antiviral agents, anti-atherosclerotic agents, glycogen phosphorylase inhibitors, and cholesterol ester transfer protein inhibitors.
• the drug is a glycogen phosphorylase inhibitor selected from the group consisting of [R-(R′S′)]-5-chloro-N-[2-hydroxy-3- ⁇ methoxymethylamino ⁇ -3-oxo-1-(phenylmethyl)propyl-1H-indole-2-carboxamide and 5-chloro-1H-indole-2-carboxylic acid [(1S)-benzyl-(2R)-hydroxy-3-((3R,4S)-dihydroxy-pyrrolidin-1-yl-)-3-oxypropyl]amide.
• the drug is a cholesterol ester transfer protein inhibitor selected from the group consisting of [2R,4S]-4-[acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester, [2R,4S]-4-[3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester, and [2R, 4S] 4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid iso
• the present invention relates to methods of administering a drug comprising co-administering to a patient in need of said drug: (a) a solid dispersion comprising a low-solubility drug and a matrix, wherein at least a major portion of said drug in said dispersion is amorphous; and (b) a concentration-enhancing polymer, said dispersion being free from at least a portion of said concentration-enhancing polymer; wherein said dispersion provides improved stability of said drug relative to at least one of a first control composition consisting of a mixture of said low-solubility drug in undispersed amorphous form and said concentration-enhancing polymer, and a second control composition consisting of a dispersion of said low-solubility drug and said concentration-enhancing polymer.
• the dispersion is administered separately from said concentration-enhancing polymer.
• the dispersion and said concentration-enhancing polymer are administered at approximately the same time.
• the dispersion and said concentration-enhancing polymer are present in a single dosage form.
• the present invention also relates to, in an eighth aspect, methods of administering a drug comprising co-administering to a patient in need of said drug: (a) a solid dispersion comprising a low-solubility drug and a matrix, wherein at least a major portion of said drug in said dispersion is amorphous; and (b) a concentration-enhancing polymer, said dispersion being free from at least a portion of said concentration-enhancing polymer;
• the present invention relates to methods of administering a drug comprising co-administering to a patient in need of said drug: (a) a solid dispersion comprising a low-solubility drug and a matrix, wherein at least a major portion of said drug in said dispersion is amorphous; and (b) a concentration-enhancing polymer, said dispersion being free from at least a portion of said concentration-enhancing polymer; wherein said concentration-enhancing polymer is non-cellulosic.
• the present invention relates to methods of administering a drug comprising co-administering to a patient in need of said drug: (a) a solid dispersion comprising a low-solubility drug and a matrix, wherein at least a major portion of said drug in said dispersion is amorphous; and (b) a concentration-enhancing polymer, said dispersion being free from at least a portion of said concentration-enhancing polymer, wherein said concentration-enhancing polymer is selected from the group consisting of non-ionizable cellulosic polymers and neutralized acidic polymers.
• the present invention relates to methods of administering a drug comprising co-administering to a patient in need of said drug: (a) a solid dispersion comprising a low-solubility drug and a matrix, wherein at least a major portion of said drug in said dispersion is amorphous; and (b) a concentration-enhancing polymer, said dispersion being free from at least a portion of said concentration-enhancing polymer, wherein said concentration-enhancing polymer is an ionizable cellulosic polymer having at least one of an ester-linked carboxylic acid-functional aromatic substituent and an ether-linked carboxylic acid-functional aromatic substituent.
• the present invention relates to methods of administering a drug comprising co-administering to a patient in need of said drug: (a) a solid dispersion comprising a low-solubility drug and a matrix, wherein at least a major portion of said drug in said dispersion is amorphous; (b) an amphiphilic, cellulosic concentration-enhancing polymer, said dispersion being free from at least a portion of said amphiphilic, cellulosic concentration-enhancing polymer; (c) said amphiphilic cellulosic concentration-enhancing polymer having at least one hydrophobic substituent selected from the group consisting of ether-linked alkyl substituents, ester-linked alkyl substituents, ether-linked aryl substituents and ester-linked aryl substituents; (d) said amphiphilic cellulosic concentration-enhancing polymer having at least one hydrophilic substituent selected from the group consisting of ether-linked
• compositions of the present invention are combinations comprising (1) a dispersion of a low-solubility drug and matrix and (2) concentration-enhancing polymer(s).
• “Combination” as used herein means that the drug/matrix dispersion and concentration-enhancing polymer may be in physical contact with each other or in close proximity but are not mixed at the molecular level so as to form a solid molecular dispersion.
• the drug/matrix dispersion and the concentration-enhancing polymer may be mixed, they remain as separate phases retaining their own physical properties such as melting points or glass-transition temperatures.
• the dispersion of the drug and matrix is free from at least a portion, if not all, of the concentration-enhancing polymer.
• the drug/matrix dispersion and concentration-enhancing polymer may be co-administered to a patient in need of the drug.
• the dispersion and concentration-enhancing polymer may be administered in separate or the same dosage forms, and may also be administered at essentially the same time or at different times.
• the present invention achieves its advantages by combining a dispersed amorphous drug with a concentration-enhancing polymer.
• One key to the present invention was the recognition by the inventors that the initially enhanced concentration of the drug in solution provided by the amorphous drug could be maintained, and in some cases enhanced by the interaction of the drug and concentration-enhancing polymer being present together in the use environment.
• the concentration-enhancing polymers of this invention may be viewed as acting as crystallization or precipitation inhibitors.
• the concentration-enhancing polymers may also interact to form various types of polymer-drug assemblies such as aggregates or colloids. Surprisingly, this may be accomplished by simply combining the concentration-enhancing polymer with the dispersion, in contrast to forming a molecular dispersion of the drug, matrix and concentration-enhancing polymer.
• the compositions provide improved concentration of drug in the use environment.
• the drug/matrix dispersion when introduced to a use environment, provides an initial concentration of drug that exceeds the equilibrium concentration of drug, while the concentration-enhancing polymer retards the rate at which the initially enhanced drug concentration falls to the equilibrium concentration.
• the compositions of the present invention provide a dissolution area-under-the-concentration-versus-time-curve (“AUC”) that is greater than that provided by crystalline drug alone.
• the compositions of the present invention provide an AUC that is greater than that provided by either the drug/matrix dispersion itself or by the drug in undispersed amorphous form and concentration-enhancing polymer.
• the compositions provide a maximum drug concentration that exceeds the maximum drug concentration provided by either a control consisting of the dispersion itself or by a control consisting of the undispersed amorphous drug plus concentration-enhancing polymer. Nevertheless, the advantages of the invention may be obtained by merely retarding the rate at which the enhanced drug concentration falls to the equilibrium concentration, even without increasing the maximum drug concentration relative to a control composition.
• the compositions of the present invention may also provide enhanced bioavailability of the drug by increasing the concentration of drug which remains dissolved in the use environment, particularly in the GI tract. Improving the concentration of the drug in solution allows more rapid absorption of drug and, as a result, higher blood levels to be achieved. In some cases this enhanced absorption rate enables an effective level of drug to be reached that might not be reached by administration of conventional forms of the drug. In other cases, administration of the compositions of the invention allows effective blood levels to be reached at lower drug dosage levels, which in turn decreases the amount of drug that must be dosed, and reduces the blood level variability. Such compositions may also allow the size of the dosage form to be decreased, depending on the amount of polymer needed.
• compositions of the present invention provide for a higher concentration of drug dissolved in the use environment, and because once a high drug concentration is achieved the concentration tends to remain high due to inhibition of precipitation or crystallization of the drug, the compositions may have a number of positive effects.
• the compositions of the present invention may show less variability in drug absorption as a result of variation in the fed/fasted state of the GI tract of the human or animal.
• absorption of drug may continue over a longer time period and an effective concentration of drug in the blood may be maintained over a longer time period.
• Stabilizing the drug in a dispersion of the drug and matrix and then combining the dispersion with the concentration-enhancing polymer provides another of the advantages of the present invention, which is to allow the use of concentration-enhancing polymers which, for whatever reason, are not suitable for forming a molecular dispersion with the particular drug.
• the invention solves the problem presented where it is difficult to combine the preferred concentration-enhancing polymer and drug to form a stable molecular dispersion.
• the difficulty in forming a stable dispersion may be due to adverse interactions between the drug and polymer in the dispersion, resulting in chemical and/or physical instability of the drug in the dispersion.
• an acidic cellulosic polymer may provide superior concentration-enhancement for some drugs, such polymers may chemically degrade acid-sensitive drugs when present in the dispersion.
• the preferred concentration-enhancing polymer may not be amenable to the preferred process used to form dispersions of the drug.
• cellulosic polymers do not readily melt, and thus are not suitable for use in forming dispersions of drug and the cellulosic polymer by use of most melt-fusion processes.
• the mobility of polymers having a high glass transition temperature is too low to allow use of mechanical processes, such as ball milling, to form dispersions.
• the drug and concentration-enhancing polymer may not share a common solvent, thus precluding the formation of a dispersion of the drug and concentration-enhancing polymer using solvent processing.
• the present invention solves these problems by forming an amorphous dispersion of the drug in an alternative matrix material to form a drug/matrix dispersion, and then combines the drug/matrix dispersion with the concentration-enhancing polymer to form the composition.
• This provides the benefit of either improved drug stability or use of a preferred processing method while at the same time providing the additional level of concentration-enhancement conferred by the presence of the concentration-enhancing polymer.
• the present invention provides in one aspect a composition
• a composition comprising (1) a solid dispersion comprising a low-solubility drug and matrix, wherein at least a major portion of the drug in the dispersion is amorphous and (2) a concentration-enhancing polymer, wherein the drug in the composition has improved chemical or physical stability relative to an appropriate control composition.
• the invention comprises (1) a solid dispersion comprising a low-solubility drug and a matrix, wherein at least a major portion of the drug in the dispersion is amorphous and (2) a concentration-enhancing polymer, wherein the concentration-enhancing polymer is present in a sufficient amount so that the composition improves the concentration of the drug in a use environment relative to an appropriate control composition.
• the invention provides a method for co-administering (1) a solid amorphous dispersion comprising a low-solubility drug and a matrix, and (2) a concentration-enhancing polymer.
• a concentration-enhancing polymer Suitable drug(s), matrices, and concentration-enhancing polymer(s), as well as methods for preparing the compositions, are discussed in detail below.
• the present invention is useful with any drug capable of being formulated as an amorphous drug.
• drug is conventional, denoting a compound having beneficial prophylactic and/or therapeutic properties when administered to an animal, especially humans.
• the drug does not need to be a low-solubility drug in order to benefit from this invention, although low-solubility drugs represent a preferred class for use with the invention.
• Even a drug that nonetheless exhibits appreciable solubility in the desired environment of use can benefit from the increased solubility/bioavailability made possible by this invention if the addition of the concentration-enhancing polymer can reduce the size of the dose needed for therapeutic efficacy or increase the rate of drug absorption in cases where a rapid onset of the drug's effectiveness is desired.
• the drug is a “low-solubility drug,” meaning that the drug may be either “substantially water-insoluble,” which means that the drug has a minimum aqueous solubility at physiologically relevant pH (e.g., pH 1-8) of less than 0.01 mg/mL, “sparingly water-soluble,” that is, has an aqueous solubility up to about 1 to 2 mg/mL, or even low to moderate aqueous-solubility, having an aqueous-solubility from about 1 mg/mL to as high as about 20 to 40 mg/mL.
• the invention finds greater utility as the solubility of the drug decreases.
• compositions of the present invention are preferred for low-solubility drugs having a solubility of less than 10 mg/mL, more preferred for low-solubility drugs having a solubility of less than 1 mg/mL, and even more preferred for low-solubility drugs having a solubility of less than 0.1 mg/mL.
• the drug has a dose-to-aqueous solubility ratio greater than 10 mL, and more typically greater than 100 mL, where the drug solubility (mg/mL) is the minimum value observed in any physiologically relevant aqueous solution (e.g., those with pH values between 1 and 8) including USP simulated gastric and intestinal buffers, and the dose is in mg.
• a dose-to-aqueous-solubility ratio may be calculated by dividing the dose (in mg) by the solubility (in mg/mL).
• Preferred classes of drugs include, but are not limited to, antihypertensives, antianxiety agents, anticlotting agents, anticonvulsants, blood glucose-lowering agents, decongestants, antihistamines, antitussives, antineoplastics, beta blockers, anti-inflammatories, antipsychotic agents, cognitive enhancers, anti-atherosclerotic agents, 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, glycogen phosphorylase inhibitors, and cholesterol ester transfer protein inhibitors.
• Each named drug should be understood to include the neutral form of the drug, pharmaceutically acceptable salts, as well as prodrugs.
• antihypertensives include prazosin, nifedipine, amlodipine besylate, trimazosin and doxazosin; specific examples of a blood glucose-lowering agent are glipizide and chlorpropamide; a specific example of an anti-impotence agent is sildenafil and sildenafil citrate; specific examples of antineoplastics include chlorambucil, lomustine and echinomycin; a specific example of an imidazole-type antineoplastic is tubulazole; a specific example of an anti-hypercholesterolemic is atorvastatin calcium; specific examples of anxiolytics include hydroxyzine hydrochloride and doxepin hydrochloride; specific examples of anti-inflammatory agents include betamethasone, prednisolone, aspirin, piroxicam, valdecoxi
• the invention is not limited by any particular structure or group of CETP inhibitors. Rather, the invention has general applicability to CETP inhibitors as a class, the class tending to be composed of compounds having low solubility.
• Compounds which may be the subject of the invention may be found in a number of patents and published applications, including DE 19741400 A1; DE 19741399 A1; WO 9914215 A1; WO 9914174; DE 19709125 A1; DE 19704244 A1; DE 19704243 A1; EP 818448 A1; WO 9804528 A2; DE 19627431 A1; DE 19627430 A1; DE 19627419 A1; EP 796846 A1; DE 19832159; DE 818197; DE 19741051; WO 9941237 A1; WO 9914204 A1; WO 9835937 A1; JP 11049743; WO 200018721; WO 200018723; WO 200018724; WO 200017164; WO 200017165;
• the invention is useful for CETP inhibitors that have sufficiently low aqueous solubility, low bioavailability or slow rate of absorption such that it is desirable to increase their concentration in an aqueous environment of use. Therefore, anytime one finds it desirable to raise the aqueous concentration of the CETP inhibitor in a use environment, the invention will find utility.
• the CETP inhibitor is “substantially water-insoluble” which means that the CETP inhibitor has a minimum aqueous solubility of less than about 0.01 mg/mL (or 10 ⁇ g/ml) at any physiologically relevant pH (e.g., pH 1-8) and at about 22° C.
• compositions of the present invention find greater utility as the solubility of the CETP inhibitors decreases, and thus are preferred for CETP inhibitors with solubilities less than about 2 ⁇ g/mL, and even more preferred for CETP inhibitors with solubilities less than about 0.5 ⁇ g/mL.
• Many CETP inhibitors have even lower solubilities (some even less than 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
• 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-3 must contain V II or R II-4 must contain V II-1 ; and R II-5 , R II-6 , R II-7 and R II-8 are each independently hydrogen, a bond, nitro or halo wherein said bond is substituted with T II or a partially saturated, fully saturated or fully unsaturated (C 1 -C 12 ) straight or branched carbon chain wherein carbon may optionally be replaced with one or two heteroatoms selected independently from oxygen, sulfur and nitrogen wherein said carbon atoms are optionally mono-, di- or tri-substituted independently with halo, said carbon is optionally mono-substituted with hydroxy, said carbon is optionally mono-substituted with oxo, said sulfur is optionally mono- or di-substituted with oxo, said nitrogen is optionally mono- or di-substituted with oxo, and said carbon is optionally mono-substituted with T II ;
• T II is a partially saturated, fully saturated or fully unsaturated three to twelve membered ring optionally having one to four heteroatoms selected independently from oxygen, sulfur and nitrogen, or, a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated three to six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen;
• T II substituent is optionally mono-, di- or tri-substituted independently with halo, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 4 )alkylthio, amino, nitro, cyano, oxo, carboxy, (C 1 -C 6 )alkyloxycarbonyl, mono-N- or di-N,N-(C 1 -C 6 )alkylamino wherein said (C 1 -C 6 )alkyl substituent is optionally mono-, di- or tri-substituted independently with hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 4 )alkylthio, amino, nitro, cyano, oxo, carboxy, (C 1 -C 6 )alkyloxycarbonyl, mono-N- or
• the CETP inhibitor is selected from one of the following compounds of Formula II:
• [0155] [2R,4S] 4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester.
• R III-1 is hydrogen, Y III , W III —X III , W III—Y III ;
• W III is a carbonyl, thiocarbonyl, sulfinyl or sulfonyl
• X III is —O—Y III , —S—Y III , —N(H)—Y III or —N—(Y III ) 2 ;
• Y III for each occurrence is independently Z III or a fully saturated, partially unsaturated or fully unsaturated one to ten membered straight or branched carbon chain wherein the carbons, other than the connecting carbon, may optionally be replaced with one or two heteroatoms selected independently from oxygen, sulfur and nitrogen and said carbon is optionally mono-, di- or tri-substituted independently with halo, said carbon is optionally mono-substituted with hydroxy, said carbon is optionally mono-substituted with oxo, said sulfur is optionally mono- or di-substituted with oxo, said nitrogen is optionally mono-, or di-substituted with oxo, and said carbon chain is optionally mono-substituted with Z III ;
• Z III is a partially saturated, fully saturated or fully unsaturated three to twelve membered ring optionally having one to four heteroatoms selected independently from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated three to six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen;
• said Z III substituent is optionally mono-, di- or tri-substituted independently with halo, (C 2 -C 6 )alkenyl, (C 1 -C 6 ) alkyl, hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 4 )alkylthio, amino, nitro, cyano, oxo, carboxy, (C 1 -C 6 )alkyloxycarbonyl, mono-N- or di-N,N-(C 1 -C 6 )alkylamino wherein said (C 1 -C 6 )alkyl substituent is optionally mono-, di- or tri-substituted independently with halo, hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 4 )alkylthio, amino, nitro, cyano, oxo, carboxy, (C 1 -C 6 )alkyloxycarbonyl, mono
• R III-3 is hydrogen or Q III ;
• Q III is a fully saturated, partially unsaturated or fully unsaturated one to six membered straight or branched carbon chain wherein the carbons, other than the connecting carbon, may optionally be replaced with one heteroatom selected from oxygen, sulfur and nitrogen and said carbon is optionally mono-, di- or tri-substituted independently with halo, said carbon is optionally mono-substituted with hydroxy, said carbon is optionally mono-substituted with oxo, said sulfur is optionally mono- or di-substituted with oxo, said nitrogen is optionally mono- or di-substituted with oxo, and said carbon chain is optionally mono-substituted with V III ;
• V III is a partially saturated, fully saturated or fully unsaturated three to twelve membered ring optionally having one to four heteroatoms selected independently from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated three to six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen;
• V III substituent is optionally mono-, di-, tri-, or tetra-substituted independently with halo, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 4 )alkylthio, amino, nitro, cyano, oxo, carboxamoyl, mono-N- or di-N,N-(C 1 -C 6 ) alkylcarboxamoyl, carboxy, (C 1 -C 6 )alkyloxycarbonyl, mono-N- or di-N,N-(C 1 -C 6 )alkylamino wherein said (C 1 -C 6 )alkyl or (C 2 -C 6 )alkenyl substituent is optionally mono-, di- or tri-substituted independently with hydroxy, (C 1 -C 6 )
• R III-4 is Q III-1 or V III-1 ;
• Q III-1 a fully saturated, partially unsaturated or fully unsaturated one to six membered straight or branched carbon chain wherein the carbons, other than the connecting carbon, may optionally be replaced with one heteroatom selected from oxygen, sulfur and nitrogen and said carbon is optionally mono-, di- or tri-substituted independently with halo, said carbon is optionally mono-substituted with hydroxy, said carbon is optionally mono- substituted with oxo, said sulfur is optionally mono- or di-substituted with oxo, said nitrogen is optionally mono- or di-substituted with oxo, and said carbon chain is optionally mono-substituted with
• V III-1 is a partially saturated, fully saturated or fully unsaturated three to six membered ring optionally having one to two heteroatoms selected independently from oxygen, sulfur and nitrogen;
• V III-1 substituent is optionally mono-, di-, tri-, or tetra-substituted independently with halo, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, amino, nitro, cyano, (C 1 -C 6 )alkyloxycarbonyl, mono-N- or di-N,N-(C 1 -C 6 )alkylamino wherein said (C 1 -C 6 )alkyl substituent is optionally mono-substituted with oxo, said (C 1 -C 6 )alkyl substituent optionally having from one to nine fluorines;
• R III-3 must contain V III or R III-4 must contain V III-1 ; and R III-5 and R III-6 , or R III-6 and R III-7 , and/or R III-7 and R III-8 are taken together and form at least one four to eight membered ring that is partially saturated or fully unsaturated optionally having one to three heteroatoms independently selected from nitrogen, sulfur and oxygen;
• said ring or rings formed by R III-5 and R III-6 , or R III-6 and R III-7 , and/or R III-7 and R III-8 are optionally mono-, di- or tri-substituted independently with halo, (C 1 -C 6 )alkyl, (C 1 -C 4 )alkylsulfonyl, (C 2 -C 6 )alkenyl, hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 4 )alkylthio, amino, nitro, cyano, oxo, carboxy, (C 1 -C 6 )alkyloxycarbonyl, mono-N- or di-N,N-(C 1 -C 6 )alkylamino wherein said (C 1 -C 6 )alkyl substituent is optionally mono-, di- or tri-substituted independently with hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 6 )
• R III-5 , R III-6 , R III-7 and/or R III-8 are each independently hydrogen, halo, (C 1 -C 6 )alkoxy or (C 1 -C 6 )alkyl, said (C 1 -C 6 )alkyl optionally having from one to nine fluorines.
• the CETP inhibitor is selected from one of the following compounds of Formula III:
• R IV-1 is hydrogen, Y IV , W IV —X IV or W IV —Y IV ;
• W IV is a carbonyl, thiocarbonyl, sulfinyl or sulfonyl
• X IV is —O—Y IV , —S—Y IV , —N(H)—Y IV or —N—(Y IV ) 2 ;
• Y IV for each occurrence is independently Z IV or a fully saturated, partially unsaturated or fully unsaturated one to ten membered straight or branched carbon chain wherein the carbons, other than the connecting carbon, may optionally be replaced with one or two heteroatoms selected independently from oxygen, sulfur and nitrogen and said carbon is optionally mono-, di- or tri-substituted independently with halo, said carbon is optionally mono-substituted with hydroxy, said carbon is optionally mono-substituted with oxo, said sulfur is optionally mono- or di-substituted with oxo, said nitrogen is optionally mono-, or di-substituted with oxo, and said carbon chain is optionally mono-substituted with Z IV ;
• Z IV is a partially saturated, fully saturated or fully unsaturated three to eight membered ring optionally having one to four heteroatoms selected independently from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated three to six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen;
• said Z IV substituent is optionally mono-, di- or tri-substituted independently with halo, (C 2 -C 6 )alkenyl, (C 1 -C 6 ) alkyl, hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 4 )alkylthio, amino, nitro, cyano, oxo, carboxy, (C 1 -C 6 )alkyloxycarbonyl, mono-N- or di-N,N-(C 1 -C 6 )alkylamino wherein said (C 1 -C 6 )alkyl substituent is optionally mono-, di- or tri-substituted independently with halo, hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 4 )alkylthio, amino, nitro, cyano, oxo, carboxy, (C 1 -C 6 )alkyloxycarbonyl, mono
• R IV-2 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 )
• 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:
• [2S,4S] 4-[acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester;
• 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 a the carbocyclic rings formed are optionally substituted, optionally also geminally, with up to six identical or different substituents in the form of trifluoromethyl, hydroxyl, nitrile, halogen, carboxyl, nitro, azido, cyano, cycloalkyl or cycloalkyloxy containing 3 to 7 carbon atoms each, a straight-chain or branched alkoxycarbonyl, alkoxy or alkylthio containing up to 6 carbon atoms each, or a straight-chain or branched alkyl containing up to 6 carbon atoms, which is in turn substituted with up to two identical or different substituents in the form of a hydroxyl, benzyloxy, trifluoromethyl, benzoyl, a straight-chain or branched alkoxy, oxyacyl or carboxyl containing up to 4 carbon atom
• c is a number equaling 1, 2, 3 or 4,
• d is a number equaling 0 or 1
• R VI-23 and R VI-24 are identical or different and denote a hydrogen, cycloalkyl containing 3 to 6 carbon atoms, a straight-chain or branched alkyl containing up to 6 carbon atoms, benzyl or phenyl, which is optionally substituted with up to two identical or different substituents in the form of halogen, trifluoromethyl, cyano, phenyl or nitro, and/or the carbocyclic rings formed are optionally substituted with a spiro-linked radical according to the formula
• W VI denotes either an oxygen atom or a sulfur atom
• Y VI and Y ⁇ VI together form a 2- to 6-membered straight-chain or branched alkylene chain
• e is a number equaling 1, 2, 3, 4, 5, 6 or 7,
• f is a number equaling 1 or 2
• R VI-25 , R VI-26 , R VI-27 , R VI-28 , R VI-29 , R VI-30 and R VI-31 are identical or different and denote a hydrogen, trifluoromethyl, phenyl, halogen or a straight-chain or branched alkyl or alkoxy containing up to 6 carbon atoms each, or
• R VI-25 and R VI-26 or R VI-27 and R VI-28 each together denote a straight-chain or branched alkyl chain containing up to 6 carbon atoms or
• R VI-25 and R VI-26 or R VI-27 and R VI-28 each together form a radical according to the formula
• W VI has the meaning given above
• g is a number equaling 1, 2, 3, 4, 5, 6 or 7,
• R VI-32 and R VI-33 together form a 3- to 7-membered heterocycle, which contains an oxygen or sulfur atom or a group according to the formula SO, SO 2 or BNR VI-34 , wherein
• R VI-34 denotes a hydrogen atom, a phenyl, benzyl, or a straight-chain or branched alkyl containing up to 4 carbon atoms, and salts and N oxides thereof, with the exception of 5(6H)-quinolones, 3-benzoyl-7,8-dihydro-2,7,7-trimethyl-4-phenyl.
• the CETP inhibitor is selected from one of the following compounds of Formula VI:
• Another class of CETP inhibitors that finds utility with the present invention consists of substituted-pyridines having the Formula VII
• R VII-2 and R VII-6 are independently selected from the group consisting of hydrogen, hydroxy, alkyl, fluorinated alkyl, fluorinated aralkyl, chlorofluorinated alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, alkoxyalkyl, and alkoxycarbonyl; provided that at least one of R VII-2 and R VII-6 is fluorinated alkyl, chlorofluorinated alkyl or alkoxyalkyl;
• R VII-3 is selected from the group consisting of hydroxy, amido, arylcarbonyl, heteroarylcarbonyl, hydroxymethyl
• 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-30 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,
• 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 ⁇ -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 VII stands for a radical of the formula
• R VIII-7 and R VIII-8 are identical or different and denote cycloalkyl with 3 to 8 carbon atoms, or aryl with 6 to 10 carbon atoms, or denote a 5- to 7-member aromatic, optionally benzo-condensed, heterocyclic compound with up to 3 heteroatoms from the series S, N and/or O, which are optionally substituted up to 3 times in an identical manner or differently by trifluoromethyl, trifluoromethoxy, halogen, hydroxy, carboxyl, by straight-chain or branched alkyl, acyl, alkoxy, or alkoxycarbonyl with up to 6 carbon atoms each, or by phenyl, phenoxy, or thiophenyl, which can in turn be substituted by halogen, trifluoromethyl, or trifluoromethoxy, and/or the rings are substituted by a group of the formula
• R VIII-11 and R VIII-12 are identical or different and have the meaning given above for R VIII-1 and R VIII-2 ,
• X VIII denotes a straight or branched alkyl chain or alkenyl chain with 2 to 10 carbon atoms each, which are optionally substituted up to 2 times by hydroxy,
• R VIII-9 denotes hydrogen
• R VIII-10 denotes hydrogen, halogen, azido, trifluoromethyl, hydroxy, mercapto, trifluoromethoxy, straight-chain or branched alkoxy with up to 5 carbon atoms, or a radical of the formula
• R VIII-13 and R VIII-14 are identical or different and have the meaning given above for R VIII-1 and R VIII-2 , or
• R VIII-9 and R VIII-10 form a carbonyl group together with the carbon atom.
• R IX-1 is selected from higher alkyl, higher alkenyl, higher alkynyl, aryl, aralkyl, aryloxyalkyl, alkoxyalkyl, alkylthioalkyl, arylthioalkyl, and cycloalkylalkyl;
• R IX-2 is selected from aryl, heteroaryl, cycloalkyl, and cycloalkenyl, wherein
• R IX-2 is optionally substituted at a substitutable position with one or more radicals independently selected from alkyl, haloalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkoxy, halo, aryloxy, aralkyloxy, aryl, aralkyl, aminosulfonyl, amino, monoalkylamino and dialkylamino; and
• R IX-3 is selected from hydrido, —SH and halo
• R IX-2 cannot be phenyl or 4-methylphenyl when R IX-1 is higher alkyl and when R IX-3 is BSH.
• the CETP inhibitor is selected from the following compounds of Formula IX:
• Another class of CETP inhibitors that finds utility with the present invention consists of hetero-tetrahydroquinolines having the Formula X
• a X represents cycloalkyl with 3 to 8 carbon atoms or a 5 to 7-membered, saturated, partially saturated or unsaturated, optionally benzo-condensed heterocyclic ring containing up to 3 heteroatoms from the series comprising S, N and/or O, that in case of a saturated heterocyclic ring is bonded to a nitrogen function, optionally bridged over it, and in which the aromatic systems mentioned above are optionally substituted up to 5-times in an identical or different substituents in the form of halogen, nitro, hydroxy, trifluoromethyl, trifluoromethoxy or by a straight-chain or branched alkyl, acyl, hydroxyalkyl or alkoxy each having up to 7 carbon atoms or by a group of the formula BNR X-3 R X-4 ,
• R X-3 and R X-4 are identical or different and denote hydrogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms,
• 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,
• 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,
• 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
• 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
• 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,
• 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,
• 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
• 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:
• Another class of CETP inhibitors that finds utility with the present invention consists of substituted tetrahydro naphthalines and analogous compound having the Formula XI
• a XI stands for cycloalkyl with 3 to 8 carbon atoms, or stands for aryl with 6 to 10 carbon atoms, or stands for a 5- to 7-membered, saturated, partially unsaturated or unsaturated, possibly benzocondensated, heterocycle with up to 4 heteroatoms from the series S, N and/or O, where aryl and the heterocyclic ring systems mentioned above are substituted up to 5-fold, identical or different, by cyano, halogen, nitro, carboxyl, hydroxy, trifluoromethyl, trifluoro- methoxy, or by straight-chain or branched alkyl, acyl, hydroxyalkyl, alkylthio, alkoxycarbonyl, oxyalkoxycarbonyl or alkoxy each with up to 7 carbon atoms, or by a group of the formula
• R XI-3 and R XI-4 are identical or different and denote hydrogen, phenyl, or straight-chain or branched alkyl with up to 6 carbon atoms
• D XI stands for a radical of the formula
• R XI-5 , R XI-6 and R XI-9 independent of each other, denote cycloalkyl with 3 to 6 carbon atoms, or denote aryl with 6 to 10 carbon atoms, or denote a 5- to 7-membered, possibly benzocondensated, saturated or unsaturated, mono-, bi- or tricyclic heterocycle with up to 4 heteroatoms of the series S, N and/or O, where the cycles are possibly substitutedCin the case of the nitrogen-containing rings also via the N-functionCup to 5-fold, identical or different, by halogen, trifluoromethyl, nitro, hydroxy, cyano, carboxyl, trifluoromethoxy, straight-chain or branched acyl, alkyl, alkylthio, alkylalkoxy, alkoxy or alkoxycarbonyl with up to 6 carbon atoms each.
• 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 ,
• 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 ,
• 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,
• 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,
• 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,
• R XI-20 and R XI-21 together form a 3- to 6-membered carbocycle, and, possibly also geminally, the alkylene chain formed by R XI-1 and R XI-2 , is possibly substituted up to 6-fold, identical or different, by trifluoromethyl, hydroxy, nitrile, halogen, carboxyl, nitro, azido, cyano, cycloalkyl or cycloalkyloxy with 3 to 7 carbon atoms each, by straight-chain or branched alkoxycarbonyl, alkoxy or alkoxythio with up to 6 carbon atoms each, or by straight- chain or branched alkyl with up to 6 carbon atoms, which itself is substituted up to 2-fold, identical or different.
• 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. identical or different, by halogen, trifluoromethyl, cyano, phenyl or nitro, and/or the alkylene chain formed by R XI-1 and R XI-2 is possibly substituted by a spiro-jointed radical of the formula
• W XI denotes either an oxygen or a sulfur atom
• Y XI and Y′ XI together form a 2- to 6-membered straight-chain or branched alkylene chain
• e is a number 1, 2, 3, 4, 5, 6 or 7,
• f denotes a number 1 or 2
• R XI-25 , R XI-26 , R XI-27 , R XI-28 , R XI-29 , R XI-30 and R XI-31 are identical or different and denote hydrogen, trifluoromethyl, phenyl, halogen, or straight-chain or branched alkyl or alkoxy with up to 6 carbon atoms each,
• 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,
• 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, or aryl with 6 to 10 carbon atoms, or a 5- to 7-membered aromatic, possibly benzocondensated heterocycle with up to 3 heteroatoms from the series S, N and/or O, which are possibly substituted up to 3-fold identical or different, by trifluoromethyl, trifluoromethoxy, halogen, hydroxy, carboxyl, nitro, by straight-chain or branched alkyl, acyl, alkoxy or alkoxycarbonyl with up to 6 carbon atoms each or by phenyl, phenoxy or phenylthio which in turn can be substituted by halogen. trifluoromethyl or trifluoromethoxy, and/or where the cycles are possibly substituted by a group of the formula —NR XII-7 R XII-8 ,
• R XII-7 and R XII-8 are identical or different and have the meaning of R XII-1 and R XII-2 given above,
• X XII is a straight-chain or branched alkyl or alkenyl with 2 to 10 carbon atoms each, possibly substituted up to 2-fold by hydroxy or halogen,
• R XII-5 stands for hydrogen
• R XII-6 means to be hydrogen, halogen, mercapto, azido, trifluoromethyl, hydroxy, trifluoromethoxy, straight-chain or branched alkoxy with up to 5 carbon atoms, or a radical of the formula BNR XII-9 R XII-10 ,
• R XII-9 and R XII-10 are identical or different and have the meaning of R XII-1 and R XII-2 given above,
• R XII-5 and R XII-6 together with the carbon atom, form a carbonyl group.
• the CETP inhibitor is selected from the following compounds of Formula XII:
• Another class of CETP inhibitors that finds utility with the present invention consists of compounds having the Formula (XIII)
• R XIII is a straight chain or branched C 1-10 alkyl; straight chain or branched C 2-10 alkenyl; halogenated C 1-4 lower alkyl; C 3-10 cycloalkyl that may be substituted; C 5-8 cycloalkenyl that may be substituted; C 3-10 cycloalkyl C 1-10 alkyl that may be substituted; aryl that may be substituted; aralkyl that may be substituted; or a 5- or 6-membered heterocyclic group having 1 to 3 nitrogen atoms, oxygen atoms or sulfur atoms that may be substituted,
• X XIII-1 , X XIII-2 , X XIII-3 , X XIII-4 may be the same or different and are a hydrogen atom; halogen atom; C 1-4 lower alkyl; halogenated C 1-4 lower alkyl; C 1-4 lower alkoxy; cyano group; nitro group; acyl; or aryl, respectively;
• Y XIII is —CO—; or BSO 2 —;
• Z XIII is a hydrogen atom; or mercapto protective group.
• the CETP inhibitor is selected from the following compounds of Formula XIII:
• n XIV is an integer selected from 0 through 5;
• R XIV-1 is selected from the group consisting of haloalkyl, haloalkenyl, haloalkoxyalkyl, and haloalkenyloxyalkyl;
• X XIV is selected from the group consisting of O, H, F, S, S(O),NH, N(OH), N(alkyl), and N(alkoxy);
• R XIV-16 is selected from the group consisting of hydrido, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, alkoxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, aralkoxyalkyl, heteroaralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxyalkyl, haloalkenyloxyal
• D XIV-1 , D XIV-2 , J XIV-1 , J XIV-2 and K XIV-1 are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more than one of D XIV-1 , D XIV-2 , J XIV-1 , J XIV-2 and K XIV-1 is a covalent bond, no more than one of D XIV-1 , D XIV-2 , J XIV-1 , J XIV-2 and K XIV-1 is O, no more than one of D XIV-1 , D XIV-2 , J XIV-1 , J XIV-2 and K XIV-1 is S, one of D XIV-1 , D XIV-2 , J XIV-1 , J XIV-2 and K XIV-1 must be a covalent bond when two of D XIV-1 , D XIV-2 , J XIV-1 , J
• D XIV-3 , D XIV-4 , J XIV-3 , J XIV-4 and K XIV-2 are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more than one of D XIV-3 , D XLV-4 , J XIV-3 , J XIV-4 and K XIV-2 is a covalent bond, no more than one of D XIV-3 , D XIV-4 , J XIV-3 , J XIV-4 and K XIV-2 is O, no more than one of D XIV-3 , D XIV-4 , J XIV-3 , J XIV-4 and K XIV-2 is S, one of D XIV-3 , D XIV-4 , J XIV-3 , J XIV-4 and K XIV-2 must be a covalent bond when two of D XIV-3 , D XIV-4 , J XIV-3 , J
• R XIV-2 is independently selected from the group consisting of hydrido, hydroxy, hydroxyalkyl, amino, aminoalkyl, alkylamino, dialkylamino, alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkoxyalkyl, aryloxyalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, aralkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxy, aloalkoxyalkyl, haloalkenyloxyalkyl
• R XIV-2 and R XIV-3 are taken together to form a linear spacer moiety selected from the group consisting of a covalent single bond and a moiety having from 1 through 6 contiguous atoms to form a ring selected from the group consisting of a cycloalkyl having from 3 through 8 contiguous members, a cycloalkenyl having from 5 through 8 contiguous members, and a heterocyclyl having from 4 through 8 contiguous members;
• R XIV-3 is selected from the group consisting of hydrido, hydroxy, halo, cyano, aryloxy, hydroxyalkyl, amino, alkylamino, dialkylamino, acyl, sulfhydryl, acylamido, alkoxy, alkylthio, arylthio, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, alkoxyalkyl, heteroarylthio, aralkylthio, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aroyl, heteroaroyl, aralkylthioalkyl, heteroaralkylthioalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, alken
• Y XIV is selected from a group consisting of a covalent single bond,(C(R XIV-14 ) 2 ) qXIV wherein qXIV is an integer selected from 1 and 2 and (CH(R XIV-14 )) gXIV —W XIV —(CH(R XIV-14 )) pXIV wherein gXIV and pXIV are integers independently selected from 0 and 1;
• R XIV-14 is independently selected from the group consisting of hydrido, hydroxy, halo, cyano, aryloxy, amino, alkylamino, dialkylamino, hydroxyalkyl, acyl, aroyl, heteroaroyl, heteroaryloxyalkyl, sulfhydryl, acylamido, alkoxy, alkylthio, arylthio, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, aralkoxyalkylalkoxy, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkoxythioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl,
• R XIV-14 and R XIV-14 when bonded to the different atoms, are taken together to form a group selected from the group consisting of a covalent bond, alkylene, haloalkylene, and a spacer selected from a group consisting of a moiety having a chain length of 2 to 5 atoms connected to form a ring selected from the group of a saturated cycloalkyl having from 5 through 8 contiguous members, a cycloalkenyl having from 5 through 8 contiguous members, and a heterocyclyl having from 5 through 8 contiguous members;
• R XIV-14 and R XIV-14 when bonded to the same atom are taken together to form a group selected from the group consisting of oxo, thiono, alkylene, haloalkylene, and a spacer selected from the group consisting of a moiety having a chain length of 3 to 7 atoms connected to form a ring selected from the group consisting of a cycloalkyl having from 4 through 8 contiguous members, a cycloalkenyl having from 4 through 8 contiguous members, and a heterocyclyl having from 4 through 8 contiguous members;
• W XIV is selected from the group consisting of O,C(O), C(S), C(O)N(R XIV-14 ), C(S)N(R XIV-14 ), (R XIV-14 )NC(O), (R XIV-14 )NC(S), S, S(O), S(O) 2 , S(O) 2 N(R XIV-14 ), (R XIV-14 )NS(O) 2 , and N(R XIV-14 ) with the proviso that R XIV-14 is selected from other than halo and cyano;
• Z XIV is independently selected from a group consisting of a covalent single bond, (C(R XIV-15 ) 2 ) qXIV-2 wherein qXIV-2 is an integer selected from 1 and 2, (CH(R XIV-15 )) jXIV —W—(CH(R XIV-15 )) kXIV wherein jXIV and kXIV are integers independently selected from 0 and 1 with the proviso that, when Z XIV is a covalent single bond, an R XIV-15 substituent is not attached to Z XIV ;
• R XIV-15 is independently selected, when Z XIV is (C(R XIV-15 ) 2 ) qXIV wherein qXIV is an integer selected from 1 and 2, from the group consisting of hydrido, hydroxy, halo, cyano, aryloxy, amino, alkylamino, dialkylamino, hydroxyalkyl, acyl, aroyl, heteroaroyl, heteroaryloxyalkyl, sulfhydryl, acylamido, alkoxy, alkylthio, arylthio, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkylthioalkyl, alkoxyalkyl, heteroaryloxyalkyl,
• R XIV-15 and R XIV-15 when bonded to the different atoms, are taken together to form a group selected from the group consisting of a covalent bond, alkylene, haloalkylene, and a spacer selected from a group consisting of a moiety having a chain length of 2 to 5 atoms connected to form a ring selected from the group of a saturated cycloalkyl having from 5 through 8 contiguous members, a cycloalkenyl having from 5 through 8 contiguous members, and a heterocyclyl having from 5 through 8 contiguous members;
• R XIV-15 and R XIV-15 when bonded to the same atom are taken together to form a group selected from the group consisting of oxo, thiono, alkylene, haloalkylene, and a spacer selected from the group consisting of a moiety having a chain length of 3 to 7 atoms connected to form a ring selected from the group consisting of a cycloalkyl having from 4 through 8 contiguous members, a cycloalkenyl having from 4 through 8 contiguous members, and a heterocyclyl having from 4 through 8 contiguous members;
• R XIV-15 is independently selected, when Z XIV is (CH(R XIV-15 )) jXIV —W—(CH(R XIV-15 )) kXIV wherein jXIV and kXIV are integers independently selected from 0 and 1, from the group consisting of hydrido, halo, cyano, aryloxy, carboxyl, acyl, aroyl, heteroaroyl, hydroxyalkyl, heteroaryloxyalkyl, acylamido, alkoxy, alkylthio, arylthio, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, alkoxyalkyl, heteroaryloxyalkyl, aralkoxyalkyl, heteroaralkoxyalkyl, alkylsulfonylalkyl, alkylsulfinylalkyl, alkenyloxyalkyl, alkyl,
• R XIV-4 , R XIV-5 , R XIV-6 , R XIV-7 , R XIV-8 , R XIV-9 , R XIV-10 , R XIV-11 , R XIV-12 , and R XIV-13 are independently selected from the group consisting of perhaloaryloxy, alkanoylalkyl, alkanoylalkoxy, alkanoyloxy, N-aryl-N-alkylamino, heterocyclylalkoxy, heterocyclylthio, hydroxyalkoxy, carboxamidoalkoxy, alkoxycarbonylalkoxy, alkoxycarbonylalkenyloxy, aralkanoylalkoxy, aralkenoyl, N-alkylcarboxamido, N-haloalkylcarboxamido, N-cycloalkylcarboxamido, N-arylcarboxamidoalkoxy, cycloalkylcarbon
• R XIV-4 and R XIV-5 , R XIV-5 and R XIV-6 , R XIV-6 and R XIV-7 , R XIV-7 and R XIV-8 , R XIV-8 and R XIV-9 , R XIV-9 and R XIV-10 , R XIV-10 and R XIV-11 , R XIV-11 and R XIV-12 , and R XIV-12 and R XIV-13 are independently selected to form spacer pairs wherein a spacer pair is taken together to form a linear moiety having from 3 through 6 contiguous atoms connecting the points of bonding of said spacer pair members to form a ring selected from the group consisting of a cycloalkenyl ring having 5 through 8 contiguous members, a partially saturated heterocyclyl ring having 5 through 8 contiguous members, a heteroaryl ring having 5 through 6 contiguous members, and an aryl with the provisos that no more than one of the group
• R XIV-4 and R XIV-9 , R XIV-4 and R XIV-13 R XIV-8 and R XIV-9 , and R XIV-8 and R XIV-13 are independently selected to form a spacer pair wherein said spacer pair is taken together to form a linear moiety wherein said linear moiety forms a ring selected from the group consisting of a partially saturated heterocyclyl ring having from 5 through 8 contiguous members and a heteroaryl ring having from 5 through 6 contiguous members with the proviso that no more than one of the group consisting of spacer pairs R XIV-4 and R XIV-9 , R XIV-4 and R XIV-13 , R XIV-8 and R XIV-9 , and R XIV-8 and R XIV-13 is used at the same time.
• the CETP inhibitor is selected from the following compounds of Formula XIV:
• 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
• 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-3 R XV-36 ) uXV -H;
• 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- J XV-1 , J XV-2 , and K XV-1 are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more than one of D XV-1 , D XV-2 , J XV-1 , J XV-2 , and K XV-1 is a covalent bond, no more than one of D XV-1 , D XV-2 , J XV-1 , J XV- 2 , and K XV-1 is O, no more than one of D XV-1 , D XV-2 , J XV-1 , J XV-2 , and K XV-1 is S, one of D XV-1 , D XV-2 , J XV-1 , J XV-2 , and K XV-1 must be a covalent bond when two of D XV-1 , D XV-2 , and K
• 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-2 are O,
• 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 )—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 )—O—(CH 2 ) k wherein j and k are integers independently selected from 0 through 1;
• R XV-4 , R XV-8 , R XV-1 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-10 and R XV-32 , R XV-10 and R XV-12 , R XV-11 and R XV-31 , R XV-11 and R XV-32 , R XV-11 and R XV-12 , R XV-31 and R XV-32 , R XV-31 and R XV-12 , and R XV-32 and R XV-12 and wherein said intra-ring branched spacer is selected to form two rings selected from the group consisting of cycloalkyl
• 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 , RXv- 34 , R XV-35 , and R XV-36 are independently selected from the group consisting of hydrido, carboxy, heteroaralkylthio, heteroaralkoxy, cycloalkylamino, acylalkyl, acylalkoxy, aroylalkoxy, heterocyclyloxy, aralkylaryl, aralkyl, aralkenyl, aralkynyl, heterocyclyl, perhaloaralkyl, aralkylsulfonyl, aralkylsulfonylalkyl
• R XV-9 , R XV-10 , R XV-11 , R XV-12 , R XV-13 , R XV-31 , and R XV-32 are independently selected to be oxo with the provisos that B XV-1 , B XV-2 , D XV-3 , D XV-4 , J XV-3 , J XV-4 , and K XV-2 are independently selected from the group consisting of C and S, no more than two of R XV-9 , R XV-10 , R XV-11 , R XV-12 , R XV-13 , R XV-31 , and R XV-32 are simultaneously oxo, and that R XV-9 , R XV-10 , R XV-11 , R XV-12 , R XV-13 , R XV-31 , and R XV-32 are each independently selected to maintain the te
• R XV-4 and R XV-5 , R XV-5 and R XV-6 , R XV-6 and R XV-7 , R XV-7 and R XV-8 , R XV-9 and R XV-10 , RXv- 10 and R XV-11 , R XV-11 and R XV-31 , R XV 31 and R XV-32 , R XV-32 and R XV-12 , and R XV-12 and R XV-13 are independently selected to form spacer pairs wherein a spacer pair is taken together to form a linear moiety having from 3 through 6 contiguous atoms connecting the points of bonding of said spacer pair members to form a ring selected from the group consisting of a cycloalkenyl ring having 5 through 8 contiguous members, a partially saturated heterocyclyl ring having 5 through 8 contiguous members, a heteroaryl ring having 5 through 6 contiguous members, and an
• R XV-37 and R XV-38 are independently selected from the group consisting of hydrido, alkoxy, alkoxyalkyl, hydroxy, amino, thio, halo, haloalkyl, alkylamino, alkylthio, alkylthioalkyl, cyano, alkyl, alkenyl, haloalkoxy, and haloalkoxyalkyl.
• the CETP inhibitor is selected from the following compounds of Formula XV:
• n XVI is an integer selected from 1 through 4.
• R XVI-1 is selected from the group consisting of haloalkyl, haloalkenyl, haloalkoxymethyl, and haloalkenyloxymethyl with the proviso that R XV 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-(II);
• 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-2 and K
• 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 than two of D XVI-3 , D XVI-4 , J XVI-3 , J XVI-4 and K XVI-2 is 0 and S, one of D XVI-3 , D XVI-4 , J XVI-3 , J XVI-4 and K XVI-2 must be a covalent bond when two of D XVI-3 , D XVI-4 ,
• R XVI-2 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-lngold-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-lngold-Prelog stereochemical system ranking than R XVI-1 and a higher Cahn-lngold-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 )) 9 -W XVI -(CH(R XVI-14 )) p wherein g and p are integers independently selected from 0 and 1;
• R XVI-14 is selected from the group consisting of hydrido, hydroxy, cyano, hydroxyalkyl, acyl, alkoxy, alkyl, alkenyl, alkynyl, alkoxyalkyl, haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, monocarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl, carboalkoxy, carboxamide, and carboxamidoalkyl;
• Z XVI is selected from a group consisting of a covalent single bond, (C(R XVI-15 ) 2 ) q , wherein q is an integer selected from 1 and 2, and (CH(R XVI-15 )) j -W XVI -(CH(R XVI-15 )) k wherein j and k are integers independently selected from 0 and 1;
• W XVI is selected from the group consisting of O, C(O), C(S),C(O)N(R XVI-14 ), C(S)N(R XVI-14 ),(R XVI-14 )NC(O), (R XVI-14 )NC(S), S, S(O), S(O) 2 , S(O) 2 N(R XVI-14 ), (R XVI-14 )NS(O) 2 , and N(R XVI-14 ) with the proviso that R XVI-14 is other than cyano;
• R XVI-15 is selected, from the group consisting of hydrido, cyano, hydroxyalkyl, acyl, alkoxy, alkyl, alkenyl, alkynyl, alkoxyalkyl, haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, monocarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl, carboalkoxy, carboxamide, and carboxamidoalkyl;
• R XVI-4 , R XVI-5 , R XVI-6 , R XVI-8 , R XVI-9 , R XVI-10 , R XVI-11 , R XVI-12 , and R XVI-13 are independently selected from the group consisting of hydrido, carboxy, heteroaralkylthio, heteroaralkoxy, cycloalkylamino, acylalkyl, acylalkoxy, aroylalkoxy, heterocyclyloxy, aralkylaryl, aralkyl, aralkenyl, aralkynyl, heterocyclyl, perhaloaralkyl, aralkylsulfonyl, aralkylsulfonylalkyl, aralkylsulfinyl, aralkylsulfinylalkyl, halocycloalkyl, halocycloalkenyl, cycloalkyls
• R XVI-4 and R XVI-5 , R XVI-5 and R XVI-6 , R XVI-6 and R XV-7 , R XVI-7 and R XVI-8, R XVI-9 and R XVI-10 , R XVI-10 and R XVI-11 , R XVI-11 and R XVI-12 and R XVI-12 and R XIV-13 are independently selected to form spacer pairs wherein a spacer pair is taken together to form a linear moiety having from 3 through 6 contiguous atoms connecting the points of bonding of said spacer pair members to form a ring selected from the group consisting of a cycloalkenyl ring having 5 through 8 contiguous members, a partially saturated heterocyclyl ring having 5 through 8 contiguous members, a heteroaryl ring having 5 through 6 contiguous members, and an aryl with the provisos that no more than one of the group consisting of spacer pairs R XVI-4 and R XVI
• R XVI-4 and R XVI-9 , R XVI-4 and R XVI-13 , R XVI-8 and R XVI-9 , and R XVI-8 and R XVI-13 is independently selected to form a spacer pair wherein said spacer pair is taken together to form a linear moiety wherein said linear moiety forms a ring selected from the group consisting of a partially saturated heterocyclyl ring having from 5 through 8 contiguous members and a heteroaryl ring having from 5 through 6 contiguous members with the proviso that no more than one of the group consisting of spacer pairs R XVI-4 and R XVI-9 , R XVI-4 and R XVI-13 , R XVI-8 and R XVI-9 , and R XVI-8 and R XVI-13 is used at the same time.
• the CETP inhibitor is selected from the following compounds of Formula XVI:

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