US20030091643A1 - Pharmaceutical compositions of dispersions of drugs and neutral polymers - Google Patents

Pharmaceutical compositions of dispersions of drugs and neutral polymers Download PDF

Info

Publication number
US20030091643A1
US20030091643A1 US10/175,132 US17513202A US2003091643A1 US 20030091643 A1 US20030091643 A1 US 20030091643A1 US 17513202 A US17513202 A US 17513202A US 2003091643 A1 US2003091643 A1 US 2003091643A1
Authority
US
United States
Prior art keywords
composition
phenyl
polymer
amino
methyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US10/175,132
Other languages
English (en)
Inventor
Dwayne Friesen
Michael Gumkowski
Rodney Ketner
Douglas Lorenz
James Nightingale
Ravi Shanker
James West
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bend Research Inc
Original Assignee
Individual
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=23158329&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=US20030091643(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Individual filed Critical Individual
Priority to US10/175,132 priority Critical patent/US20030091643A1/en
Publication of US20030091643A1 publication Critical patent/US20030091643A1/en
Priority to US11/383,520 priority patent/US20060216351A1/en
Assigned to BEND RESEARCH, INC. reassignment BEND RESEARCH, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: PFIZER PRODUCTS INC., PFIZER INC.
Priority to US14/242,141 priority patent/US9468604B2/en
Priority to US15/258,477 priority patent/US20160374945A1/en
Abandoned legal-status Critical Current

Links

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
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • 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
    • A61K9/10—Dispersions; Emulsions
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682—Processes

Definitions

  • This invention relates to pharmaceutical compositions comprised of amorphous dispersions of drugs and neutral polymers that provide either improved chemical stability, concentration-enhancement, or both improved chemical stability and concentration-enhancement.
  • Curatolo, et al., EP 0 901 786 A2 disclose forming pharmaceutical spray dried dispersions of sparingly soluble drugs and the polymer hydroxypropyl methyl cellulose acetate succinate.
  • the spray dried dispersions disclosed in Curatolo et al. provide superior aqueous concentration relative to dispersions formed from other methods and relative to the crystalline drug alone.
  • amorphous dispersions may be formed of drugs which are not low-solubility drugs.
  • the inventors have determined that for some drug and polymer dispersions, the drug is not chemically stable in the dispersion.
  • the inventors have observed that for dispersions containing certain drugs and polymers, the drug degrades in the dispersion over time, resulting in a loss of potency for the composition. The inventors have found this problem to arise especially for acid-sensitive drugs.
  • the present invention relates to, in a first aspect, pharmaceutical compositions comprising a solid amorphous dispersion of an acid-sensitive drug and a neutral dispersion polymer, wherein said composition provides improved chemical stability relative to a control acidic dispersion comprising an equivalent quantity of said drug and an acidic polymer.
  • the acid-sensitive drug has one or more functional groups selected from the group consisting of sulfonyl ureas, hydroxamic acids, hydroxy amides, carbamates, acetals, hydroxy ureas, esters, and amides.
  • the acid-sensitive drug when present in a control acidic dispersion and stored for a period of six months at 40° C. and 75% relative humidity has a degree of degradation of at least 0.01%, preferably at least 0.1%.
  • the drug is quinoxaline-2-carboxylic acid [4(R)-carbamoyl-1(S)-3- fluorobenzyl-2(S),7-dihydroxy-7-methyl-octyl]amide; quinoxaline-2-carboxylic acid[1 -benzyl-4-(4,4-difluoro-cyclohexyl)-2-hydroxy-4-hydroxycarbamoyl-butyl]-amide; quinoxaline-2-carboxylic acid [1-benzyl-4-(4,4-difluoro-1-hydroxy-cyclohexyl)-2-hydroxy-4-hydroxycarbamoyl-butyl]-amide; (+)-N- ⁇ 3-[3-(4-fluorophenoxy)phenyl]-2-cyclopenten-1-yl ⁇ -N-hydroxyurea; omeprazole; etoposide; famotidine; erythromycin; quinapril;
  • the drug in said composition has a relative degree of improvement in chemical stability of at least 1.25, preferably at least 3, more preferably at least 10.
  • drug in said composition has a relative degree of improvement in chemical stability of at least 1.25 when stored at 40° C. and 75% relative humidity for a period of six months.
  • the dispersion polymer is ionizable, non-ionizable, cellulosic, or non-cellulosic.
  • Preferred cellulosic dispersion polymers include hydroxypropyl methyl cellulose acetate, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, methyl cellulose, hydroxyethyl methyl cellulose, hydroxyethyl cellulose acetate, and hydroxyethyl ethyl cellulose.
  • Preferred non-cellulosic dispersion polymers include vinyl polymers and copolymers having one or more substituents comprising hydroxyl-containing repeat units, alkylacyloxy-containing repeat units, or cyclicamido-containing repeat units; polyvinyl alcohols that have at least a portion of their repeat units in the unhydrolyzed form; polyvinyl alcohol polyvinyl acetate copolymers; polyethylene glycol, polyethylene glycol polypropylene glycol copolymers, polyvinyl pyrrolidone; polyethylene polyvinyl alcohol copolymers, and polyoxyethylene-polyoxypropylene block copolymers.
  • the non-cellulosic dispersion polymer comprising a vinyl copolymer having: (1) hydroxyl-containing repeat units; and (2) hydrophobic repeat units.
  • the acid-sensitive drug is also a low-solubility drug and said dispersion polymer is concentration-enhancing.
  • the drug has a minimum solubility in aqueous solution in the absence of said dispersion polymer of less than 1 mg/mL at any pH of from about 1 to about 8, more preferably the minimum aqueous solubility is less than 0.01 mg/mL.
  • the drug has a dose-to-aqueous-solubility ratio of at least 10 mL.
  • the dispersion polymer is present in an amount sufficient to provide a maximum concentration of said acid-sensitive drug in a use environment that is at least 1.25-fold, preferably at least 2-fold, that provided by a second control composition comprising an equivalent quantity of said acid-sensitive drug and free from said dispersion polymer.
  • the dispersion polymer is present in a sufficient amount so that said dispersion provides in a use environment an area under the concentration versus time curve for any period of at least 90 minutes between the time of introduction into the use environment and about 270 minutes following introduction to the use environment that is at least 1.25-fold, preferably at least 2-fold, that provided by a second control composition comprising an equivalent quantity of said acid-sensitive drug and free from said dispersion polymer.
  • the dispersion polymer is present in a sufficient amount so that said dispersion provides a relative bioavailability that is at least 1.25, preferably at least 2, relative to a second control composition comprising an equivalent quantity of said acid-sensitive drug and free from said polymer.
  • the drug is base-sensitive and said dispersion polymer is non-ionizable.
  • the dispersion comprising a buffer.
  • buffers include sodium acetate, ammonium acetate, sodium carbonate, sodium bicarbonate, disodium hydrogen phosphate and trisodium phosphate.
  • the buffer comprises at least 10 wt % of said dispersion.
  • the dispersion has a pH from about 6 to about 10.
  • the composition comprising a base and the dispersion has a pH of from about 6 to about 10.
  • the acid-sensitive drug is a low-solubility drug and the composition comprising a second polymer, said dispersion is free from at least a portion of said second polymer, and said second polymer is concentration-enhancing.
  • the second polymer has at least one hydrophobic portion and at least one hydrophilic portion.
  • the second polymer is a cellulosic, ionizable polymer, comprising hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose succinate, hydroxypropyl cellulose acetate succinate, hydroxyethyl methyl cellulose succinate, hydroxyethyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, hydroxyethyl methyl cellulose acetate succinate, hydroxyethyl methyl cellulose acetate succinate, hydroxyethyl methyl cellulose acetate phthalate, carboxyethyl cellulose, carboxymethyl cellulose, cellulose acetate phthalate, methyl cellulose acetate phthalate, ethyl cellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate, hydroxypropyl methyl cellulose acetate phthalate, hydroxypropyl methyl cellulose acetate phthalate succinate, hydroxypropyl
  • second polymers are non-ionizable cellulosic polymers comprising hydroxypropyl methyl cellulose acetate, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, methyl cellulose, hydroxyethyl methyl cellulose, hydroxyethyl cellulose acetate, and hydroxyethyl ethyl cellulose. Still other more preferably second polymers are ionizable, non-cellulosic polymers comprising carboxylic acid functionalized polymethacrylates, carboxylic acid functionalized polyacrylates, amine-functionalized polyacrylates, amine-fuctinoalized polymethacrylates, proteins, and carboxylic acid functionalized starches.
  • second polymers are non-ionizable, non-cellulosic polymers comprising vinyl polymers and copolymers having one or more substituents such as hydroxyl-containing repeat units, alkylacyloxy-containing repeat units, or cyclicamido-containing repeat units; polyvinyl alcohols that have at least a portion of their repeat units in the unhydrolyzed form; polyvinyl alcohol polyvinyl acetate copolymers; polyethylene glycol, polyethylene glycol polypropylene glycol copolymers, polyvinyl pyrrolidone polyethylene polyvinyl alcohol copolymers, and polyoxyethylene-polyoxypropylene block copolymers.
  • the second polymer has (1) hydroxyl-containing repeat units; and (2) hydrophobic repeat units.
  • the drug in said composition has a relative degree of improvement in chemical stability of at least 1.25, preferably at least 3.
  • the dispersion is mixed with said second polymer.
  • the dispersion and said second polymer occupy separate regions of said composition.
  • the second polymer is present in an amount sufficient to provide a maximum concentration of said acid-sensitive drug in a use environment that is at least 1.25-fold, preferably at least 2-fold, that of a control composition comprising an equivalent quantity of said dispersion and free from said second polymer.
  • the second polymer is present in a sufficient amount so that said composition provides in a use environment an area under the concentration versus time curve for any period of at least 90 minutes between the time of introduction into the use environment and about 270 minutes following introduction to the use environment that is at least 1.25-fold, preferably at least 2-fold, that of a control composition comprising an equivalent quantity of said dispersion and free from said second polymer.
  • the second polymer is present in a sufficient amount so that said composition provides a relative bioavailability that is at least 1.25, preferably at least 2, relative to a control composition comprising an equivalent quantity of said dispersion and free from said second polymer.
  • a second aspect of the present invention relates to methods for treating a condition in an animal comprising by administering to an animal in need of such treatment a therapeutic amount of the above-described composition.
  • a third aspect of the present invention relates to methods of administering a pharmaceutical composition comprising co-administering to a patient: (a) a solid amorphous dispersion comprising an acid-sensitive drug and a neutral polymer; and (b) a second polymer, wherein said dispersion is substantially free from said second polymer and said second polymer is concentration-enhancing.
  • the second polymer is cellulosic, such as hydroxypropyl methyl cellulose acetate succinate, cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate, methyl cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl cellulose acetate phthalate, cellulose acetate terephthalate and cellulose acetate isophthalate.
  • cellulosic such as hydroxypropyl methyl cellulose acetate succinate, cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate, methyl cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl cellulose acetate phthalate, cellulose acetate terephthalate and cellulose acetate isophthalate.
  • the dispersion is administered separately from said second polymer.
  • the dispersion and said second polymer are administered at about the same time.
  • a fourth aspect of the present invention relates to pharmaceutical compositions that a solid amorphous dispersion of a low-solubility drug and a neutral dispersion polymer, wherein said neutral dispersion polymer comprising a vinyl copolymer having hydrophilic hydroxyl-containing repeat units and hydrophobic repeat units.
  • the hydrophobic repeat units include ester-linked alkylate or arylate substituents. More preferably, the hydrophobic repeat unit is an alkylate such as acetate, propionate, and butyrate. More preferably, the hydrophobic repeat units comprise the acetylated form of the hydroxyl-containing repeat units. Preferably, the acetylated form of the hydroxyl-containing repeat units comprise 0.5 to 30% of the repeat units of the polymer.
  • the hydroxyl-containing repeat unit is vinyl alcohol.
  • the dispersion polymer is a vinyl alcohol/vinyl acetate copolymer.
  • a fifth aspect of the present invention relates to pharmaceutical compositions that include a solid amorphous dispersion comprising a low-solubility drug, a neutral dispersion polymer, and an excipient such as a base or a buffer.
  • the neutral dispersion polymer is concentration enhancing.
  • Preferred neutral dispersion polymers are present in an amount sufficient to provide a maximum concentration of said low-solubility drug in a use environment that is at least 1.25-fold, preferably at least 2-fold, that provided by a second control composition comprising an equivalent quantity of said low-solubility drug and free from a concentration-enhancing polymer.
  • the neutral dispersion polymer is present in a sufficient amount so that said composition, when introduced to a use environment, provides an area under the concentration-versus time curve for any period of at least 90 minutes between the time of introduction to the use environment and about 270 minutes following introduction to the use environment that is at least 1.25-fold, preferably at least 2-fold, that of a second control composition comprising an equivalent quantity of said low-solubility drug and free from a concentration-enhancing polymer.
  • the neutral dispersion polymer is present in a sufficient amount so that said composition provides a relative bioavailability that is at least 1.25, preferably at least 2, relative to a second control composition comprising an equivalent quantity of said low-solubility drug and free from a concentration-enhancing polymer.
  • the drug in said composition has a relative degree of improvement in chemical stability of at least 1.25.
  • the composition provides improved chemical stability relative to a control composition, wherein said control comprising an equivalent quantity of a dispersion of said drug and said neutral dispersion polymer but free from said base and said buffer.
  • the term “use environment” may refer to the in vivo environment of the gastrointestinal (GI) tract of an animal, particularly a human, or the in vitro environment of a test solution, such as phosphate buffered saline (PBS) or model fasted duodenal (MFD) solution.
  • GI gastrointestinal
  • PBS phosphate buffered saline
  • MFD model fasted duodenal
  • the composition may be dosed in a variety of dosage forms, including both immediate release and controlled release dosage forms, the latter including both delayed and sustained release forms.
  • the composition may include blends of polymers.
  • the various aspects of the present invention provide one or more of the following advantages.
  • the inventors have recognized that a problem with forming dispersions of acid-sensitive drugs is that for some dispersions, the drug does not remain chemically stable in the dispersion over time.
  • the inventors have found that acid-sensitive drugs dispersed in an acidic polymer, such as hydroxypropyl methyl cellulose acetate succinate (which has carboxylic acid functional groups), have a tendency to chemically degrade over time. It is believed that the presence of acidic ionic groups on the acidic polymer may either catalyze degradation of the drug or react directly with the drug.
  • the inventors have substantially reduced, if not eliminated the problem of drug degradation, by forming dispersions using neutral polymers, i.e. polymers that do not include acidic functional groups.
  • the present invention is able to realize the advantages of forming dispersions of acid-sensitive drugs by improving the chemical stability of the acid-sensitive drug in the dispersion.
  • the invention in some embodiments further provides enhanced aqueous concentration and bioavailability for low-solubility drugs while at the same time minimizing the loss in potency and generation of impurities in the composition resulting from reaction or degradation of the drug when in the presence of an acidic species, such as an acidic dispersion polymer.
  • compositions provide surprisingly effective concentration-enhancement.
  • the polymers may be used with any low-solubility drug to improve the concentration of the drug in a use environment.
  • the pharmaceutical compositions of the present invention comprise solid amorphous dispersions of a drug and a neutral dispersion polymer.
  • the present invention finds utility anytime it is desired to improve either the chemical stability of an acid-sensitive drug, to improve the concentration or bioavailability of a low-solubility drug, or both.
  • the dispersions of the present invention improve the chemical stability of acid-sensitive drugs.
  • the dispersions may be used to prevent degradation of the drug due to interactions with dispersion polymers, acidic dispersion species, or other acidic excipients present in the composition.
  • the dispersions improve the concentration or bioavailability of a low-solubility drug. Suitable acid-sensitive drugs, low-solubility drugs, neutral polymers and methods for making the dispersions are discussed in more detail below.
  • the term “drug” is conventional, denoting a compound having beneficial prophylactic and/or therapeutic properties when administered to an animal, especially humans.
  • the drug is an acid-sensitive drug, meaning that the drug either chemically reacts with or otherwise degrades in the presence of acidic species.
  • Acid-sensitive drugs often include functional groups which are reactive under acidic conditions, such as sulfonyl ureas, hydroxamic acids, hydroxy amides, carbamates, acetals, hydroxy ureas, esters, and amides. Drugs which include such functional groups may be prone to reactions such as hydrolysis, lactonization, or transesterification in the presence of acidic species.
  • Acid-sensitive drugs may be identified experimentally by determining whether the drug chemically reacts or degrades when dispersed in an acidic polymer.
  • the term “acid-sensitive drug” refers to a drug which, when dispersed in a “control acidic dispersion,” degrades when stored under controlled aging conditions either for long storage times at ambient storage conditions or for short storage times under elevated temperature and relative humidity conditions.
  • the “control acidic dispersion” used to determine whether a drug is acid-sensitive is a dispersion of the drug and a pharmaceutically acceptable acidic polymer.
  • a convenient pharmaceutically acceptable acidic polymer for use as the acidic dispersion polymer is the HF grade of hydroxypropyl methyl cellulose acetate succinate (HPMCAS), which is an acidic, or so-called enteric polymer having carboxylic acid functional groups, and a pK a of about 5.
  • the HPMCAS in the control acidic dispersion should have a minimum degree of substitution of succinate groups (O(CO)CH 2 CH 2 (CO)OH) of at least 4 wt % (or at least about 100 milliequivalents of carboxylic acid functional groups per mole of polymer).
  • succinate groups O(CO)CH 2 CH 2 (CO)OH
  • other acidic polymers which are at least as acidic as the HF grade of HPMCAS may be used, such as hydroxypropyl methyl cellulose acetate phthalate (HPMCP) or cellulose acetate phthalate (CAP).
  • HPMCP hydroxypropyl methyl cellulose acetate phthalate
  • CAP cellulose acetate phthalate
  • such polymers should have at least about 100 milliequivalents of carboxylic acid functional groups per mole of polymer.
  • the amount of acidic polymer present in the control acidic dispersion may vary, but should comprise at least 50 wt % or more of the control acidic dispersion.
  • a drug is an acid-sensitive drug if it meets the drug degradation criteria described below in at least one control acidic dispersion comprised of 25 wt % drug and 75 wt % of the dispersion polymer HPMCAS, HPMCP or CAP.
  • drug degradation may be measured using any conventional method for measuring the purity or potency of drug in a pharmaceutical composition.
  • the amount of active drug present in a dispersion may be measured initially using high-performance liquid chromatography (HPLC) or any other analytical technique well known in the art.
  • HPLC high-performance liquid chromatography
  • the amount of drug initially present may be calculated from the amount of drug present in the dispersion formulation.
  • the potency of the dispersion may then be measured after storage at controlled temperature and humidity conditions for an appropriate period of time. A decrease in potency indicates that a chemical reaction has occurred, leading to a decrease in the amount of active drug present in the dispersion, and is an indication of poor chemical stability.
  • An alternative method used to evaluate chemical stability is to analyze the rate of increase in the amount of drug degradant(s) in the dispersion, which would indicate reaction of the drug to form the degradant(s).
  • An HPLC or other analytical technique may be used to determine the concentration of drug degradant(s) in a dispersion.
  • the amount of the degradant(s) is measured before and after storage under controlled aging conditions.
  • the amount of increase in the drug degradant(s) may be used to determine the amount of decrease in “percent drug purity.”
  • the “percent drug purity” is defined as 100 times the total amount of drug present divided by the total amount of drug initially present.
  • the rate at which drug degradation occurs is generally dependent on the storage conditions.
  • the drug when formulated as a composition of the present invention, should be stable at ambient temperature and humidity conditions (e.g., relative humidities of 20% to 60%) for long periods of time, such as months or years.
  • the storage conditions may employ elevated temperature and/or humidity to simulate longer storage times at ambient conditions.
  • the storage time may vary from a few days to weeks or months, depending on the reactivity of the drug and the storage conditions.
  • a “degree of degradation” of drug following storage may be determined by subtracting the final percent drug purity (either determined by measuring the decrease in drug present or an increase in the amount of drug degradants present) from the initial percent drug purity. For example, for a dispersion initially containing 100 mg drug, and no measurable impurities, the initial percent drug purity is 100 wt %. If, after storage, the amount of drug in the dispersion decreases to 95 mg, the final percent drug purity would be 95 wt % and the “degree of degradation” is 5 wt % (100 wt % ⁇ 95 wt %).
  • “degree of degradation” can be determined by subtracting from the amount of one or more specific degradants initially present from the amount of that specific drug degradant present after storage. Such a measure is useful where there are several drug degradants, of which only one (or a few) is of concern. The degree of degradation may be calculated on the basis of only those degradants that are of concern, rather than all of the degradant. For example, if a drug initially contained a specific degradant at a concentration of 1 wt % and after storage the concentration of that degradant was 6 wt %, the degree of degradation would be 5 wt % (6 wt % ⁇ 1 wt %).
  • an “acid-sensitive” drug is one in which the degree of degradation of the drug in a control acidic dispersion (as defined above) is at least 0.01 wt % in a six month period at 40° C. and 75% relative humidity (RH), or alternatively, in which the degree of degradation is at least 0.01 wt % in a one year period at 30° C. at 60% RH, or as defined below with respect to degradation of drug in an acidic aqueous solution.
  • RH relative humidity
  • Dispersions of the present invention are preferred for acid-sensitive drugs having a degree of degradation that is greater than the minimum level when in the presence of an acidic dispersion polymer.
  • the dispersions of the present invention are preferred for “very acid-sensitive drugs.”
  • Very acid-sensitive drugs are those which, when dispersed in a control acidic dispersion, have a degree of degradation of at least 0.1 wt % when stored at 40° C./75% RH for six months.
  • the dispersions are even more preferred for drugs which have a degree of degradation of at least 1 wt %, and are most preferred for drugs which have a degree of degradation of at least 5.0 wt % when stored at 40° C./75% RH for six months.
  • the acid-sensitive drug when present in the control acidic dispersion degrades at a rate that is greater than the rate at which pure drug in the amorphous form, or if the amorphous form is physically unstable, the crystalline form, degrades.
  • a relative degree of degradation of the drug in a control acidic dispersion to the pure form of the drug may be determined by taking the ratio of the degree of degradation of the drug in the control acidic dispersion and the degree of degradation of the pure form of the drug under the same storage conditions for the same storage time period.
  • the relative degree of degradation of the drug in the control acidic dispersion to the pure form of the drug is 50 (5 wt %/0.1 wt %).
  • An acid-sensitive drug is one in which the relative degree of degradation of the drug in the control composition to the pure form of the drug is at least 2. The invention finds increasing utility as the relative degree of degradation increases above this minimum level. Thus, the invention is preferred for drugs having a relative degree of degradation of about 3 or more, and more preferred for drugs having a relative degree of degradation of about 5 or more.
  • Another test to determine whether a drug is an acid sensitive drug as used herein is to administer the drug to an acidic aqueous solution and plot drug concentration versus time.
  • the acidic solution should have a pH of from 1-4.
  • Drugs which are acid sensitive are those for which the drug concentration decreases by at least 1% within 24 hours of administration of the drug to the acidic solution.
  • the drug is “slightly acid-sensitive.” If the drug concentration changes by 1% in the 1-6 hour time period, then the drug is “moderately acid-sensitive.” If the drug concentration changes by 1% in less than 1 hour, then the drug is “highly acid-sensitive.”
  • the present invention finds increasing utility for drugs which are slightly acid-sensitive, moderately acid-sensitive and highly acid-sensitive.
  • acid-sensitive drugs deliverable by the invention are set forth below, by way of example only. Each named drug should be understood to include the neutral form of the drug, pharmaceutically acceptable salts, and prodrugs.
  • acid-sensitive drugs include quinoxaline-2-carboxylic acid [4(R)-carbamoyl-1(S)-3-fluorobenzyl-2(S),7-dihydroxy-7-methyl-octyl]amide; quinoxaline-2-carboxylic acid [1-benzyl-4-(4,4-difluoro-cyclohexyl)-2-hydroxy-4 -hydroxycarbamoyl-butyl]-amide; quinoxaline-2-carboxylic acid [1-benzyl-4-(4,4-difluoro-1-hydroxy-cyclohexyl)-2-hydroxy-4-hydroxycarbamoyl-butyl]-amide; (+)-N- ⁇ 3-[3-(4-fluorophenoxy)phenyl
  • the drug is a “low-solubility drug,” meaning that the drug may be either “substantially water-insoluble,” which means that the drug has a minimum aqueous solubility at physiologically relevant pH (e.g., pH 1-8) of less than 0.01 mg/mL, “sparingly water-soluble,” that is, has an aqueous solubility up to about 1 to 2 mg/mL, or even low to moderate aqueous-solubility, having an aqueous-solubility from about 1 mg/mL to as high as about 20 to 40 mg/mL.
  • physiologically relevant pH e.g., pH 1-8
  • “sparingly water-soluble” that is, has an aqueous solubility up to about 1 to 2 mg/mL, or even low to moderate aqueous-solubility, having an aqueous-solubility from about 1 mg/mL to as high as about 20 to 40 mg/mL.
  • the drug has a dose-to-aqueous solubility ratio greater than 10 mL, and more typically greater than 100 mL, where the drug solubility (mg/mL) is the minimum value observed in any physiologically relevant aqueous solution (e.g., those with pH values between 1 and 8) including USP simulated gastric and intestinal buffers, and dose is in mg.
  • the dose-to-aqueous-solubility-ratio may be determined by simply dividing the dose (in mg) by the aqueous 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, and 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.
  • 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 ;
  • WI is a carbonyl, thiocarbonyl, sulfinyl or sulfonyl
  • X I is —O—Y I , —S—Y O , —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 -C6)alkyl or (C 2 -C 6 )alkenyl substituent is optionally mono-, di- or tri-substituted independently with hydroxy, (C 1 -C 6 )alk
  • 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 ;
  • 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;
  • VI, 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‘,
  • Q II-1 a fully saturated, partially unsaturated or fully unsaturated one to six membered straight or branched carbon chain wherein the carbons, other than the connecting carbon, may optionally be replaced with one heteroatom selected from oxygen, sulfur and nitrogen and said carbon is optionally mono-, di- or tri-substituted independently with halo, said carbon is optionally mono-substituted with hydroxy, said carbon is optionally mono-substituted with oxo, said sulfur is optionally mono- or di-substituted with oxo, said nitrogen is optionally mono- or di-substituted with oxo, and said carbon chain is optionally mono-substituted with V II-1 ;
  • V II-1 is a partially saturated, fully saturated or fully unsaturated three to six membered ring optionally having one to two heteroatoms selected independently from oxygen, sulfur and nitrogen;
  • V II-1 substituent is optionally mono-, di-, tri-, or tetra-substituted independently with halo, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, amino, nitro, cyano, (C 1 -C 6 )alkyloxycarbonyl, mono-N- or di-N,N-(C 1 -C 6 )alkylamino wherein said (C 1 -C 6 )alkyl substituent is optionally mono-substituted with oxo, said (C 1 -C 6 )alkyl substituent is optionally substituted with from one to nine fluorines;
  • R II-5 , R II-6 , R II-7 and R II-8 are each independently hydrogen, a bond, nitro or halo wherein said bond is substituted with T II or a partially saturated, fully saturated or fully unsaturated (C 1 -C 12 ) straight or branched carbon chain wherein carbon may optionally be replaced with one or two heteroatoms selected independently from oxygen, sulfur and nitrogen wherein said carbon atoms are optionally mono-, di- or tri-substituted independently with halo, said carbon is optionally mono-substituted with hydroxy, said carbon is optionally mono-substituted with oxo, said sulfur is optionally mono- or di-substituted with oxo, said nitrogen is optionally mono- or di-substituted with oxo, and said carbon is optionally mono-substituted with T II ;
  • T II is a partially saturated, fully saturated or fully unsaturated three to twelve membered ring optionally having one to four heteroatoms selected independently from oxygen, sulfur and nitrogen, or, a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated three to six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen;
  • T II substituent is optionally mono-, di- or tri-substituted independently with halo, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 4 )alkylthio, amino, nitro, cyano, oxo, carboxy, (C 1 -C 6 )alkyloxycarbonyl, mono-N- or di-N,N-(C 1 -C 6 )alkylamino wherein said (C 1 -C 6 )alkyl substituent is optionally mono-, di- or tri-substituted independently with hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 4 )alkylthio, amino, nitro, cyano, oxo, carboxy, (C 1 -C 6 )alkyloxycarbonyl, mono-N- or
  • the CETP inhibitor is selected from one of the following compounds of Formula II:
  • R III-1 is hydrogen, Y III , W III —X III , W III -Y III :
  • W III is a carbonyl, thiocarbonyl, sulfinyl or sulfonyl
  • X III is —O—Y III , —S—Y III , —N(H)—Y III or —N—(Y III ) 2 ;
  • Y III for each occurrence is independently Z III or a fully saturated, partially unsaturated or fully unsaturated one to ten membered straight or branched carbon chain wherein the carbons, other than the connecting carbon, may optionally be replaced with one or two heteroatoms selected independently from oxygen, sulfur and nitrogen and said carbon is optionally mono-, di- or tri-substituted independently with halo, said carbon is optionally mono-substituted with hydroxy, said carbon is optionally mono-substituted with oxo, said sulfur is optionally mono- or di-substituted with oxo, said nitrogen is optionally mono-, or di-substituted with oxo, and said carbon chain is optionally mono-substituted with Z III ;
  • Z III is a partially saturated, fully saturated or fully unsaturated three to twelve membered ring optionally having one to four heteroatoms selected independently from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated three to six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen;
  • said Z III substituent is optionally mono-, di- or tri-substituted independently with halo, (C 2 -C 6 )alkenyl, (C 1 -C 6 ) alkyl, hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 4 )alkylthio, amino, nitro, cyano, oxo, carboxy, (C 1 -C 6 )alkyloxycarbonyl, mono-N- or di-N,N-(C 1 -C 6 )alkylamino wherein said (C 1 -C 6 )alkyl substituent is optionally mono-, di- or tri-substituted independently with halo, hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 4 )alkylthio, amino, nitro, cyano, oxo, carboxy, (C 1 -C 6 )alkyloxycarbonyl, mono
  • R III-3 is hydrogen or Q III ;
  • Q III is a fully saturated, partially unsaturated or fully unsaturated one to six membered straight or branched carbon chain wherein the carbons, other than the connecting carbon, may optionally be replaced with one heteroatom selected from oxygen, sulfur and nitrogen and said carbon is optionally mono-, di- or tri-substituted independently with halo, said carbon is optionally mono-substituted with hydroxy, said carbon is optionally mono-substituted with oxo, said sulfur is optionally mono- or di-substituted with oxo, said nitrogen is optionally mono- or di-substituted with oxo, and said carbon chain is optionally mono-substituted with V III ;
  • V III is a partially saturated, fully saturated or fully unsaturated three to twelve membered ring optionally having one to four heteroatoms selected independently from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated three to six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen;
  • V III substituent is optionally mono-, di-, tri-, or tetra-substituted independently with halo, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 4 )alkylthio, amino, nitro, cyano, oxo, carboxamoyl, mono-N- or di-N,N-(C 1 -C 6 ) alkylcarboxamoyl, carboxy, (C 1 -C 6 )alkyloxycarbonyl, mono-N- or di-N,N- 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 )alk
  • R III-4 is Q III-1 or V III-1 ;
  • Q III 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 ;
  • 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-4 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 ;
  • V IV 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-(Cl-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 -
  • 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, (Cl-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 )al
  • the CETP inhibitor is selected from one of the following compounds of Formula V:
  • Another class of CETP inhibitors that finds utility with the present invention consists of cycloalkano-pyridines having the Formula VI
  • a VI denotes an aryl containing 6 to 10 carbon atoms, which is optionally substituted with up to five identical or different substituents in the form of a halogen, nitro, hydroxyl, trifluoromethyl, trifluoromethoxy or a straight-chain or branched alkyl, acyl, hydroxyalkyl or alkoxy containing up to 7 carbon atoms each, or in the form of a group according to the formula —BNR VI-3 R VI-4 , wherein
  • R VI-3 and R VI-4 are identical or different and denote a hydrogen, phenyl or a straight-chain or branched alkyl containing up to 6 carbon atoms,
  • D VI denotes an aryl containing 6 to 10 carbon atoms, which is optionally substituted with a phenyl, nitro, halogen, trifluoromethyl or trifluoromethoxy, or a radical according to the formula R VI-5 —L VI —,
  • R VI-5 , R VI-6 and R VI-9 denote, independently from one another, a cycloalkyl containing 3 to 6 carbon atoms, or an aryl containing 6 to 10 carbon atom or a 5- to 7-membered, optionally benzo-condensed, saturated or unsaturated, mono-, bi- or tricyclic heterocycle containing up to 4 heteroatoms from the series of S, N and/or O, wherein the rings are optionally substituted, in the case of the nitrogen-containing rings also via the N function, with up to five identical or different substituents in the form of a halogen, trifluoromethyl, nitro, hydroxyl, cyano, carboxyl, trifluoromethoxy, a straight-chain or branched acyl, alkyl, alkylthio, alkylalkoxy, alkoxy or alkoxycarbonyl containing up to 6 carbon atoms each, an aryl or trifluoromethyl-substituted aryl
  • R VI-10 , R VI-11 and R VI-12 denote, independently from one another, an aryl containing 6 to 10 carbon atoms, which is in turn substituted with up to two identical or different substituents in the form of a phenyl, halogen or a straight-chain or branched alkyl containing up to 6 carbon atoms
  • R VI-13 and R VI-14 are identical or different and have the meaning of R VI-3 and R VI-4 given above, or
  • R VI-5 and/or R VI-6 denote a radical according to the formula
  • R VI-7 denotes a hydrogen or halogen
  • R VI-8 denotes a hydrogen, halogen, azido, trifluoromethyl, hydroxyl, trifluoromethoxy, a straight-chain or branched alkoxy or alkyl containing up to 6 carbon atoms each, or a radical according to the formula
  • R VI-15 and R VI-16 are identical or different and have the meaning of R VI-3 and R VI-4 given above, or
  • R VI-7 and R VI-8 together form a radical according to the formula ⁇ O or ⁇ NR VI-17 , wherein
  • R VI-17 denotes a hydrogen or a straight-chain or branched alkyl, alkoxy or acyl containing up to 6 carbon atoms each,
  • L VI denotes a straight-chain or branched alkylene or alkenylene chain containing up to 8 carbon atoms each, which are optionally substituted with up to two hydroxyl groups,
  • T VI and X VI are identical or different and denote a straight-chain or branched alkylene chain containing up to 8 carbon atoms, or
  • T VI or X VI denotes a bond
  • V VI denotes an oxygen or sulfur atom or an BNR VI-18 group, wherein
  • R VI-18 denotes a hydrogen or a straight-chain or branched alkyl containing up to 6 carbon atoms or a phenyl
  • E VI denotes a cycloalkyl containing 3 to 8 carbon atoms, or a straight-chain or branched alkyl containing up to 8 carbon atoms, which is optionally substituted with a cycloalkyl containing 3 to 8 carbon atoms or a hydroxyl, or a phenyl, which is optionally substituted with a halogen or trifluoromethyl,
  • R VI-1 and R VI-2 together form a straight-chain or branched alkylene chain containing up to 7 carbon atoms, which must be substituted with a carbonyl group and/or a radical according to the formula
  • a and b are identical or different and denote a number equaling 1, 2 or 3,
  • R VI-19 denotes a hydrogen atom, a cycloalkyl containing 3 to 7 carbon atoms, a straight-chain or branched silylalkyl containing up to 8 carbon atoms, or a straight-chain or branched alkyl containing up to 8 carbon atoms, which is optionally substituted with a hydroxyl, a straight-chain or a branched alkoxy containing up to 6 carbon atoms or a phenyl, which may in turn be substituted with a halogen, nitro, trifluoromethyl, trifluoromethoxy or phenyl or tetrazole-substituted phenyl, and an alkyl that is optionally substituted with a group according to the formula BOR VI-22 , wherein
  • R VI-22 denotes a straight-chain or branched acyl containing up to 4 carbon atoms or benzyl, or
  • R VI-19 denotes a straight-chain or branched acyl containing up to 20 carbon atoms or benzoyl, which is optionally substituted with a halogen, trifluoromethyl, nitro or trifluoromethoxy, or a straight-chain or branched fluoroacyl containing up to 8 carbon atoms,
  • R VI-20 and R VI-21 are identical or different and denote a hydrogen, phenyl or a straight-chain or branched alkyl containing up to 6 carbon atoms, or R VI-20 and R VI-21 together form a 3- to 6-membered carbocyclic ring, and 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,
  • c is a number equaling 1, 2, 3 or 4,
  • d is a number equaling 0 or 1
  • R VI-23 and R VI-24 are identical or different and denote a hydrogen, cycloalkyl containing 3 to 6 carbon atoms, a straight-chain or branched alkyl containing up to 6 carbon atoms, benzyl or phenyl, which is optionally substituted with up to two identical or different substituents in the form of halogen, trifluoromethyl, cyano, phenyl or nitro, and/or the carbocyclic rings formed are optionally substituted with a spiro-linked radical according to the formula
  • W VI denotes either an oxygen atom or a sulfur atom
  • e is a number equaling 1, 2, 3, 4, 5, 6 or 7,
  • f is a number equaling 1 or 2
  • R VI-25 , R VI-26 ,R VI-27 , R VI-28 , R VI-29 , R VI-30 , and R VI-31 are identical or different and denote a hydrogen, trifluoromethyl, phenyl, halogen or a straight-chain or branched alkyl or alkoxy containing up to 6 carbon atoms each, or
  • R VI-25 and R VI-26 or R VI-27 and R VI-28 each together denote a straight-chain or branched alkyl chain containing up to 6 carbon atoms or
  • R VI-25 and R VI-26 or R VI-27 and R VI-28 each together form a radical according to the formula
  • W VI has the meaning given above
  • g is a number equaling 1, 2, 3, 4, 5, 6 or 7,
  • R VI-32 and R VI-33 together form a 3- to 7-membered heterocycle, which contains an oxygen or sulfur atom or a group according to the formula SO, SO 2 or BNR VI-34 , wherein
  • R VI-34 denotes a hydrogen atom, a phenyl, benzyl, or a straight-chain or branched alkyl containing up to 4 carbon atoms, and salts and N oxides thereof, with the exception of 5(6H)-quinolones, 3-benzoyl-7,8-dihydro-2,7,7-trimethyl-4-phenyl.
  • the CETP inhibitor is selected from one of the following compounds of Formula VI:
  • Another class of CETP inhibitors that finds utility with the present invention consists of substituted-pyridines having the Formula VII
  • R VII-2 and R VII-6 are independently selected from the group consisting of hydrogen, hydroxy, alkyl, fluorinated alkyl, fluorinated aralkyl, chlorofluorinated alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, alkoxyalkyl, and alkoxycarbonyl; provided that at least one of R VII-2 and R VII-6 is fluorinated alkyl, chlorofluorinated alkyl or alkoxyalkyl;
  • R VII-3 is selected from the group consisting of hydroxy, amido, arylcarbonyl, heteroarylcarbonyl, hydroxymethyl
  • R VII-7 is selected from the group consisting of hydrogen, alkyl and cyanoalkyl
  • R VII-15a is selected from the group consisting of hydroxy, hydrogen, halogen, alkylthio, alkenylthio, alkynylthio, arylthio, heteroarylthio, heterocyclylthio, alkoxy, alkenoxy, alkynoxy, aryloxy, heteroaryloxy and heterocyclyloxy, and
  • R VII-16a is selected from the group consisting of alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, and heterocyclyl, arylalkoxy, trialkylsilyloxy;
  • R VII-4 is selected from the group consisting of hydrogen, hydroxy, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, aryl, heteroaryl, heterocyclyl, cycloalkylalkyl, cycloalkenylalkyl, aralkyl, heteroarylalkyl, heterocyclylalkyl, cycloalkylalkenyl, cycloalkenylalkenyl, aralkenyl, hetereoarylalkenyl, heterocyclylalkenyl, alkoxy, alkenoxy, alkynoxy, aryloxy, heteroaryloxy, heterocyclyloxy, alkanoyloxy, alkenoyloxy, alkynoyloxy, aryloyloxy, heteroaroyloxy, heterocyclyloy
  • R VII-5 is selected from the group consisting of hydrogen, hydroxy, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, aryl, heteroaryl, heterocyclyl, alkoxy, alkenoxy, alkynoxy, aryloxy, heteroaryloxy, heterocyclyloxy, alkylcarbonyloxyalkyl, alkenylcarbonyloxyalkyl, alkynylcarbonyloxyalkyl, arylcarbonyloxyalkyl, heteroarylcarbonyloxyalkyl, heterocyclylcarbonyloxyalkyl, cycloalkylalkyl, cycloalkenylalkyl, aralkyl, heteroarylalkyl, heterocyclylalkyl, cycloalkylalkenyl, cycloalkenylalkenyl, cyclo
  • R VII-15b is selected from the group consisting of hydroxy, hydrogen, halogen, alkylthio, alkenylthio, alkynylthio, arylthio, heteroarylthio, heterocyclylthio, alkoxy, alkenoxy, alkynoxy, aryloxy, heteroaryloxy, heterocyclyloxy, aroyloxy, and alkylsulfonyloxy, and
  • R VII-16b is selected form the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkoxy, and trialkylsilyloxy;
  • R VII-17 and R VII-18 are independently selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl;
  • R VII-19 is selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, —SR VII-20 , —OR VII-21 , and BR VII-22 CO 2 R VII-23 , wherein
  • R VII-20 is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aminoalkyl, aminoalkenyl, aminoalkynyl, aminoaryl, aminoheteroaryl, aminoheterocyclyl, alkylheteroarylamino, arylheteroarylamino,
  • R VII-21 is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl,
  • R VII-22 is selected from the group consisting of alkylene or arylene, and
  • R VII-23 is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl;
  • R VII-24 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, aralkenyl, and aralkynyl;
  • R VII-25 is heterocyclylidenyl
  • R VII-26 and R VII-27 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl;
  • R VII-28 and R VII-29 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl;
  • R VII-30 and R VII-31 are independently alkoxy, alkenoxy, alkynoxy, aryloxy, heteroaryloxy, and heterocyclyloxy;
  • R VII-32 and R VII-33 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl;
  • R VII-36 is selected from the group consisting of alkyl, alkenyl, aryl, heteroaryl and heterocyclyl;
  • R VII-37 and R VII-38 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl;
  • R VII-39 is selected from the group consisting of hydrogen, alkoxy, alkenoxy, alkynoxy, aryloxy, heteroaryloxy, heterocyclyloxy, alkylthio, alkenylthio, alkynylthio, arylthio, heteroarylthio and heterocyclylthio, and
  • R VII-40 is selected from the group consisting of haloalkyl, haloalkenyl, haloalkynyl, haloaryl, haloheteroaryl, haloheterocyclyl, cycloalkyl, cycloalkenyl, heterocyclylalkoxy, heterocyclylalkenoxy, heterocyclylalkynoxy, alkylthio, alkenylthio, alkynylthio, arylthio, heteroarylthio and heterocyclylthio;
  • R VII-41 is heterocyclylidenyl
  • R VII-42 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl, and
  • R VII-43 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, haloaryl, haloheteroaryl, and haloheterocyclyl;
  • R VII-44 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl;
  • R VII-45 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, haloalkyl, haloalkenyl, haloalkynyl, haloaryl, haloheteroaryl, haloheterocyclyl, heterocyclyl, cycloalkylalkyl, cycloalkenylalkyl, aralkyl, heteroarylalkyl, heterocyclylalkyl, cycloalkylalkenyl, cycloalkenylalkenyl, aralkenyl, heteroarylalkenyl, heterocyclylalkenyl, alkylthioalkyl, alkenylthioalkyl, alkynylthioalkyl, arylthioalkyl,heteroarylthioalkyl, heterocyclylthioalkyl, alkylthioalkyl,
  • 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 VIII stands for a radical of the formula
  • R VIII-7 and R VIII-8 are identical or different and denote cycloalkyl with 3 to 8 carbon atoms, or aryl with 6 to 10 carbon atoms, or denote a 5- to 7-member aromatic, optionally benzo-condensed, heterocyclic compound with up to 3 heteroatoms from the series S, N and/or O, which are optionally substituted up to 3 times in an identical manner or differently by trifluoromethyl, trifluoromethoxy, halogen, hydroxy, carboxyl, by straight-chain or branched alkyl, acyl, alkoxy, or alkoxycarbonyl with up to 6 carbon atoms each, or by phenyl, phenoxy, or thiophenyl, which can in turn be substituted by halogen, trifluoromethyl, or trifluoromethoxy, and/or the rings are substituted by a group of the formula
  • R VIII-11 and R VIII-12 are identical or different and have the meaning given above for R VIII-1 and R VIII-2 ,
  • X VIII denotes a straight or branched alkyl chain or alkenyl chain with 2 to 10 carbon atoms each, which are optionally substituted up to 2 times by hydroxy,
  • R VIII-9 denotes hydrogen
  • R VIII-10 denotes hydrogen, halogen, azido, trifluoromethyl, hydroxy, mercapto, trifluoromethoxy, straight-chain or branched alkoxy with up to 5 carbon atoms, or a radical of the formula
  • R VIII-13 and R VIII-14 are identical or different and have the meaning given above for R VIII-1 and R VIII-2 , or
  • R VIII-9 and R VIII-10 form a carbonyl group together with the carbon atom.
  • R IX-1 is selected from higher alkyl, higher alkenyl, higher alkynyl, aryl, aralkyl, aryloxyalkyl, alkoxyalkyl, alkylthioalkyl, arylthioalkyl, and cycloalkylalkyl;
  • R IX-2 is selected from aryl, heteroaryl, cycloalkyl, and cycloalkenyl, wherein R IX-2 is optionally substituted at a substitutable position with one or more radicals independently selected from alkyl, haloalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkoxy, halo, aryloxy, aralkyloxy, aryl, aralkyl, aminosulfonyl, amino, monoalkylamino and dialkylamino; and
  • R IX-3 is selected from hydrido, —SH and halo; provided R IX-2 cannot be phenyl or 4-methylphenyl when R IX-1 is higher alkyl and when R IX-3 is BSH.
  • the CETP inhibitor is selected from the following compounds of Formula IX:
  • Another class of CETP inhibitors that finds utility with the present invention consists of hetero-tetrahydroquinolines having the Formula X
  • a X represents cycloalkyl with 3 to 8 carbon atoms or a 5 to 7-membered, saturated, partially saturated or unsaturated, optionally benzo-condensed heterocyclic ring containing up to 3 heteroatoms from the series comprising S, N and/or O, that in case of a saturated heterocyclic ring is bonded to a nitrogen function, optionally bridged over it, and in which the aromatic systems mentioned above are optionally substituted up to 5-times in an identical or different substituents in the form of halogen, nitro, hydroxy, trifluoromethyl, trifluoromethoxy or by a straight-chain or branched alkyl, acyl, hydroxyalkyl or alkoxy each having up to 7 carbon atoms or by a group of the formula BNR X-3 R X-4 ,
  • R X-3 and R X-4 are identical or different and denote hydrogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms,
  • 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:
  • 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.
  • 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.
  • 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.
  • Another class of CETP inhibitors that finds utility with the present invention consists of 2-aryl-substituted pyridines having the Formula (XII)
  • 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.
  • 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:
  • 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 0, 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 XIV-1 ,
  • D XIV-3 , D XIV-4 J XIV-3 , J XIV-4 and K XIV-2 are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more than one of D XIV-3 , D XIV-4 , J XIV-3 , J XIV-4 and K XIV-2 is a covalent bond, no more than one of D XIV-3 D XIV-4 , J XIV-3 , J XIV-4 and K XIV-2 is O, no more than one of D XIV-3 , D XIV-4 , J XIV-3 , J XlV-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 XIV-2 ,
  • 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,
  • heteroarylsulfonyl heteroarylsulfonyl, heteroarylsulfinylalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl, carboxy, carboxyalkyl, carboalkoxy, carboxamide, carboxamidoalkyl, carboaralkoxy, dialkoxyphosphono, diaralkoxyphosphono, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, a spacer selected from a moiety having a chain length of 3 to 6 atoms connected to the point of bonding selected from the group consisting of R XIV-4 and R XIV-8 to form a ring selected from the
  • group consisting of a cycloalkenyl ring having from 5 through 8 contiguous members and a heterocyclyl ring having from 5 through 8 contiguous members, and a spacer selected from a moiety having a chain length of 2 to 5 atoms connected to the point of bonding selected from the group consisting of R XIV-9 and R XIV-13 to form a heterocyclyl having from 5 through 8 contiguous members;
  • R XIV-15 and R XIV-15 when bonded to the different atoms, are taken together to form a group selected from the group consisting of a covalent bond, alkylene, haloalkylene, and a spacer selected from a group consisting of a moiety having a chain length of 2 to 5 atoms connected to form a ring selected from the group of a saturated cycloalkyl having from 5 through 8 contiguous members, a cycloalkenyl having from 5 through 8 contiguous members, and a heterocyclyl having from 5 through 8 contiguous members;
  • R XIV-15 and R XIV-15 when bonded to the same atom are taken together to form a group selected from the group consisting of oxo, thiono, alkylene, haloalkylene, and a spacer selected from the group consisting of a moiety having a chain length of 3 to 7 atoms connected to form a ring selected from the group consisting of a cycloalkyl having from 4 through 8 contiguous members, a cycloalkenyl having from 4 through 8 contiguous members, and a heterocyclyl having from 4 through 8 contiguous members;
  • R XIV-15 is independently selected, when Z XIV is (CH(R XIV-15 )) jXIV —W—(CH(R XIV-15 )) kXIV wherein jXIV and kXIV are integers independently selected from 0 and 1, from the group consisting of hydrido, halo, cyano, aryloxy, carboxyl, acyl, aroyl, heteroaroyl, hydroxyalkyl, heteroaryloxyalkyl, acylamido, alkoxy, alkylthio, arylthio, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, alkoxyalkyl, heteroaryloxyalkyl, aralkoxyalkyl, heteroaralkoxyalkyl, alkylsulfonylalkyl, alkylsulfinylalkyl, alkenyloxyalkyl, alkyl,
  • R XIV-4 , R XIV-5 , R XIV-6 , R XIV-7 , R XIV-8 , R XIV-9 , R XIV-10 , R XIV-11 , R XIV-12 , and R XIV-13 are independently selected from the group consisting of perhaloaryloxy, alkanoylalkyl, alkanoylalkoxy, alkanoyloxy, N-aryl-N-alkylamino, heterocyclylalkoxy, heterocyclylthio, hydroxyalkoxy, carboxamidoalkoxy, alkoxycarbonylalkoxy, alkoxycarbonylalkenyloxy, aralkanoylalkoxy, aralkenoyl, N-alkylcarboxamido, N-haloalkylcarboxamido, N-cycloalkylcarboxamido, N-arylcarboxamidoalkoxy, cycloalkylcarbon
  • R XIV-4 and R XIV-5 , R XIV-5 and R XIV-6 , R XIV-6 and R XIV-7 , R XIV-7 and R XIV-8 , R XIV-8 and R XIV-9 , R XIV-9 and R XIV-10 , R XIV-10 and R XIV-11 , R XIV-11 and R XIV-12 , and R XIV-12 and R XIV-13 are independently selected to form spacer pairs wherein a spacer pair is taken together to form a linear moiety having from 3 through 6 contiguous atoms connecting the points of bonding of said spacer pair members to form a ring selected from the group consisting of a cycloalkenyl ring having 5 through 8 contiguous members, a partially saturated heterocyclyl ring having 5 through 8 contiguous members, a heteroaryl ring having 5 through 6 contiguous members, and an aryl with the provisos that no more than one of the group
  • R XIV-4 and R XIV-9 , R XIV-4 and R XIV-13 , R XIV-8 and R XIV-9 , and R XIV-8 and R XIV-13 are independently selected to form a spacer pair wherein said spacer pair is taken together to form a linear moiety wherein said linear moiety forms a ring selected from the group consisting of a partially saturated heterocyclyl ring having from 5 through 8 contiguous members and a heteroaryl ring having from 5 through 6 contiguous members with the proviso that no more than one of the group consisting of spacer pairs R XIV-4 and R XIV-9 , R XIV-4 and R XIV-13 , R XIV-8 and R XIV-9 , and R XIV-8 and R XIV-13 is used at the same time.
  • the CETP inhibitor is selected from the following compounds of Formula XIV:
  • n XV is an integer selected from 1 through 2;
  • a XV and Q XV are independently selected from the group consisting of —CH 2 (CR XV-37 R XV-38 ) vXV -(CR XV-33 R XV-34 ) uXV -T XV -(CR XV-35 R XV-36 ) wXV- H,
  • a XV and Q XV must be AQ-1 and that one of A XV and Q XV must be selected from the group consisting of AQ-2 and —CH 2 (CR XV-37 R XV-38 ) vXV —(CR XV-33 R XV-34 ) uXV -T XV -(CR XV-35 R XV-36 ) wXV —H;
  • T XV is selected from the group consisting of a single covalent bond, O, S, S(O), S(O) 2 , C(R XV-33 ) ⁇ C(R XV-35 ) and
  • v XV is an integer selected from 0 through 1 with the proviso that vXV is 1 when any one of R XV-33 , R XV-34 , R XV-35 , and R XV-36 is aryl or heteroaryl;
  • uXV and wXV are integers independently selected from 0 through 6;
  • a XV-1 is C(R XV-30 );
  • D XV-1 , D XV-2 , J XV-1 , J XV-2 , and K XV-1 are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more than one of D XV-1 , D XV-2 , J XV-1 , J XV-2 , and K XV-1 is a covalent bond, no more than one of D XV-1 , D XV-2 , J XV-1 , J XV-2 , and K XV-1 is O,no more than one of D XV-1 , D XV-2 , J XV-1 , J XV-2 , and K XV-1 is S, one of D XV-1 , D XV-2 , J XV-1 , J XV-2 , and K XV-1 must be a covalent bond when two of D XV-1 , D XV
  • B XV-1 , B XV-2 , D XV-3 , D XV-4 , J XV-3 , J XV-4 , and K XV-2 are independently selected from the group consisting of C, C(R XV-30 ), N, O, S and a covalent bond with the provisos that no more than 5 of B XV-1 , B XV-2 , D XV-3 , D XV-4 , J XV-3 , J XV-4 , and K XV-2 are a covalent bond, no more than two of B XV-1 , B XV-2 , D XV-3 , D XV-4 , J XV-3 , J XV-4 , and K XV-2 are O, no more than two of B XV-1 , B XV-2 , D XV-3 , D XV-4 , J XV-3 , J XV-4 , and K XV
  • B XV-1 and D XV-3 , D XV-3 and J XV-3 , J XV-3 and K XV-2 , K XV-2 and J XV-4 , J XV-4 and D XV-4 , and D XV-4 and B XV-2 are independently selected to form an in-ring spacer pair wherein said
  • spacer pair is selected from the group consisting of C(R XV-33 ) ⁇ C(R XV-35 ) and N ⁇ N with the provisos that AQ-2 must be a ring of at least five contiguous members, that no more than two of the group of said spacer pairs are simultaneously C(R XV-33 ) ⁇ C(R XV-35 ) and that no more than one of the group of said spacer pairs can be N ⁇ N unless the other spacer pairs are other than C(R XV-33 ) ⁇ C(R XV-35 ), O, N, and S;
  • R XV-1 is selected from the group consisting of haloalkyl and haloalkoxymethyl
  • R XV-2 is selected from the group consisting of hydrido, aryl, alkyl, alkenyl, haloalkyl, haloalkoxy, haloalkoxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl and heteroaryl;
  • R XV-3 is selected from the group consisting of hydrido, aryl, alkyl, alkenyl, haloalkyl, and haloalkoxyalkyl;
  • Y XV is selected from the group consisting of a covalent single bond, (CH 2 ) q wherein q is an integer selected from 1 through 2 and (CH 2 ) j —O—(CH 2 ) k wherein j and k are integers independently selected from 0 through 1;
  • Z XV is selected from the group consisting of covalent single bond, (CH 2 ) q wherein q is an integer selected from 1 through 2, and (CH 2 ) j —O—(CH 2 ) k wherein j and k are integers independently selected from 0 through 1;
  • R xv-4 , R xv-8 , R xv-9 and R xv-13 are independently selected from the group consisting of hydrido, halo, haloalkyl, and alkyl;
  • R XV-30 is selected from the group consisting of hydrido, alkoxy, alkoxyalkyl, halo, haloalkyl, alkylamino, alkylthio, alkylthioalkyl, alkyl, alkenyl, haloalkoxy, and haloalkoxyalkyl with the proviso that R xv-30 is selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen;
  • R XV-30 when bonded to A XV-1 , is taken together to form an intra-ring linear spacer connecting the A XV-1 -carbon at the point of attachment of R XV-30 to the point of bonding of a group selected from the group consisting of R XV-10 , R XV-11 , R XV-12 , R XV-31 , and R XV-32 wherein said intra-ring linear spacer is selected from the group consisting of a covalent single bond and a spacer moiety having from 1 through 6 contiguous atoms to form a ring selected from the group consisting of a cycloalkyl having from 3 through 10 contiguous members, a cycloalkenyl having from 5 through 10 contiguous members, and a heterocyclyl having from 5 through 10 contiguous members;
  • R XV-30 when bonded to A XV-1 , is taken together to form an intra-ring branched spacer connecting the A XV-1 -carbon at the point of attachment of R XV-30 to the points of bonding of each member of any one of substituent pairs selected from the group consisting of subsitituent pairs R XV-10 and R XV-11 , R XV-10 and R XV-31 , R XV-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 , R XV-34 , R XV-35 , and R XV-36 are independently selected from the group consisting of hydrido, carboxy, heteroaralkylthio, heteroaralkoxy, cycloalkylamino, acylalkyl, acylalkoxy, aroylalkoxy, heterocyclyloxy, aralkylaryl, aralkyl, aralkenyl, aralkynyl, heterocyclyl, perhaloaralkyl, aralkylsulfonyl, aralkylsulfonylalky
  • 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 , D XV-2 , D XV-3 , D XV-4 , J XV-3 , J XV-4 , and K XV-2 are independently selected from the group consisting of C and S, no more than two of R XV-9 , R XV-10 , R XV-11 , R XV-12 , R XV-13 , R XV-31 , and R XV-32 are simultaneously oxo, and that R XV-9 , R XV-10 , R XV-11 , R XV-12 , R XV-13 , R XV-31 , and R XV-32 are each independently selected to maintain the te
  • R XV-4 and R XV-5 , R XV-5 and R XV-6 , R XV-6 and R XV-7 , R XV-7 and R XV-8 , R XV-9 and R XV-10 , R XV-10 and R XV-11 , R XV-11 and R XV-31 , R XV-31 and R XV-32 , R XV-32 and R XV-12 , and R XV-12 and R XV-13 are independently selected to form spacer pairs wherein a spacer pair is taken together to form a linear moiety having from 3 through 6 contiguous atoms connecting the points of bonding of said spacer pair members to form a ring selected from the group consisting of a cycloalkenyl ring having 5 through 8 contiguous members, a partially saturated heterocyclyl ring having 5 through 8 contiguous members, a heteroaryl ring having 5 through 6 contiguous members, and an
  • R XV-37 and R XV-38 are independently selected from the group consisting of hydrido, alkoxy, alkoxyalkyl, hydroxy, amino, thio, halo, haloalkyl, alkylamino, alkylthio, alkylthioalkyl, cyano, alkyl, alkenyl, haloalkoxy, and haloalkoxyalkyl.
  • the CETP inhibitor is selected from the following compounds of Formula XV:
  • n XVI is an integer selected from 1 through 4;
  • X XVI is oxy
  • R XVI-1 is selected from the group consisting of haloalkyl, haloalkenyl, haloalkoxymethyl, and haloalkenyloxymethyl with the proviso that R XVI-1 has a higher Cahn-lngold-Prelog stereochemical system ranking than both R XVI-2 and (CHR XVI-3 ) n —N(A XVI )Q XVI wherein A XVI is Formula XVI-(II) and Q is Formula XVI-(III);
  • R XVI-16 is selected from the group consisting of hydrido, alkyl, acyl, aroyl, heteroaroyl, trialkylsilyl, and a spacer selected from the group consisting of a covalent single bond and a linear spacer moiety having a chain length of 1 to 4 atoms linked to the point of bonding of any aromatic substituent selected from the group consisting of R XVI-4 , R XVI-8 , R XVI-9 , and R XVI-13 to form a heterocyclyl ring having from 5 through 10 contiguous members;
  • D XVI-1 D XVI-2 J XVI-1 , J XVI-2 and K XVI-1 are independently selected from the group consisting of C, N, O, S and covalent bond with the provisos that no more than one of D XVI-1 , D XVI-2 , J XVI-1 , J XVI-2 and K XVI-1 is a covalent bond, no more than one D XVI-1 , D XVI-2 , J XVI-1 , J XVI-2 and K XVI-1 is be O, no more than one of D XVI-1 , D XVI-2 , J XVI-1 , J XVI-2 and K XVI-1 is S, one of D XVI-1 , D XVI-2 , J XVI-1 , J XVI-2 and K XVI-1 must be a covalent bond when two of D XVI-1 , D XVI-2 , J XVI-1 , J XVI-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-Ingold-Prelog system ranking than both R XVI-1 , and (CHR XVI-3 ) n —N(A XVI )Q XVI ;
  • R XVI-3 is selected from the group consisting of hydrido, hydroxy, cyano, aryl, aralkyl, acyl, alkoxy, alkyl, alkenyl, alkoxyalkyl, heteroaryl, alkenyloxyalkyl, haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, monocyanoalkyl, dicyanoalkyl, carboxamide, and carboxamidoalkyl, with the provisos that (CHR XVI-3 ) n —N(A XVI )Q XVI has a lower Cahn-Ingold-Prelog stereochemical system ranking than R XVI-1 and a higher Cahn-Ingold-Prelog stereochemical system ranking than R XVI-2 ;
  • Y XVI is selected from a group consisting of a covalent single bond, (C(R XVI-14 ) 2 ) q wherein q is an integer selected from 1 and 2 and (CH(R XVI-14 )) g —W XVI —(CH(R XVI-14 )) p wherein g and p are integers independently selected from 0 and 1;
  • R XVI-14 is selected from the group consisting of hydrido, hydroxy, cyano, hydroxyalkyl, acyl, alkoxy, alkyl, alkenyl, alkynyl, alkoxyalkyl, haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, monocarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl, carboalkoxy, carboxamide, and carboxamidoalkyl;
  • Z XVI is selected from a group consisting of a covalent single bond, (C(R XVI-15 ) 2 ) q , wherein q is an integer selected from 1 and 2, and (CH(R XVI-15 )) j —W XVI —(CH(R XVI-15 )) k wherein j and k are integers independently selected from 0 and 1;
  • W XVI is selected from the group consisting of O, C(O), C(S),C(O)N(R XVI-14 ), C(S)N(R XVI-14 ),(R XVI-14 )NC(O), (R XVI-14 )NC(S), S, S(O), S(O) 2 , S(O) 2 N(R XVI-14 ), (R XVI-14 )NS(O) 2 , and N(R XVI-14 ) with the proviso that R XVI-14 is other than cyano;
  • R XVI-15 is selected, from the group consisting of hydrido, cyano, hydroxyalkyl, acyl, alkoxy, alkyl, alkenyl, alkynyl, alkoxyalkyl, haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, monocarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl, carboalkoxy, carboxamide, and carboxamidoalkyl;
  • R XVI-4 , R XVI-5 , R XVI-6 , R XVI-7 , R XVI-8 , R XVI-9 , R XVI-10 , R XVI-11 , R XVI-12 , and R XVI-13 are independently selected from the group consisting of hydrido, carboxy, heteroaralkylthio, heteroaralkoxy, cycloalkylamino, acylalkyl, acylalkoxy, aroylalkoxy, heterocyclyloxy, aralkylaryl, aralkyl, aralkenyl, aralkynyl, heterocyclyl, perhaloaralkyl, aralkylsulfonyl, aralkylsulfonylalkyl, aralkylsulfinyl, aralkylsulfinylalkyl, halocycloalkyl, halocycloalkenyl,
  • R XVI-4 and R XVI-5 , R XVI-5 and R XVI-6 , R XVI-6 and R XVI-7 , R XVI-7 and R XVI-8 , R XVI-9 and R XVI-10 , R XVI-10 and R XVI-11 , R XVI-11 and R XVI-12 , and R XVI-12 and R XIV-13 are independently selected to form spacer pairs wherein a spacer pair is taken together to form a linear moiety having from 3 through 6 contiguous atoms connecting the points of bonding of said spacer pair members to form a ring selected from the group consisting of a cycloalkenyl ring having 5 through 8 contiguous members, a partially saturated heterocyclyl ring having 5 through 8 contiguous members, a heteroaryl ring having 5 through 6 contiguous members, and an aryl with the provisos that no more than one of the group consisting of spacer pairs R XVI-4 and R
  • R XVI-4 and R XVI-9 , R XVI-4 and R XVI-13 , R XVI-8 and R XVI-9 , and R XVI-8 and R XVI-13 is independently selected to form a spacer pair wherein said spacer pair is taken together to form a linear moiety wherein said linear moiety forms a ring selected from the group consisting of a partially saturated heterocyclyl ring having from 5 through 8 contiguous members and a heteroaryl ring having from 5 through 6 contiguous members with the proviso that no more than one of the group consisting of spacer pairs R XVI-4 and R XVI-9 , R XVI-4 and R XVI-13 , R XVI-8 and R XVI-9 , and R XVI-8 and R XVI-13 is used at the same time.
  • the CETP inhibitor is selected from the following compounds of Formula XVI:

Landscapes

  • Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Dispersion Chemistry (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Compositions Of Macromolecular Compounds (AREA)
US10/175,132 2001-06-22 2002-06-18 Pharmaceutical compositions of dispersions of drugs and neutral polymers Abandoned US20030091643A1 (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
US10/175,132 US20030091643A1 (en) 2001-06-22 2002-06-18 Pharmaceutical compositions of dispersions of drugs and neutral polymers
US11/383,520 US20060216351A1 (en) 2001-06-22 2006-05-16 Pharmaceutical Compositions of Dispersions of Drugs and Neutral Polymers
US14/242,141 US9468604B2 (en) 2001-06-22 2014-04-01 Pharmaceutical compositions of dispersions of drug and neutral polymers
US15/258,477 US20160374945A1 (en) 2001-06-22 2016-09-07 Pharmaceutical compositions of dispersions of drug and neutral polymers

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US30025501P 2001-06-22 2001-06-22
US10/175,132 US20030091643A1 (en) 2001-06-22 2002-06-18 Pharmaceutical compositions of dispersions of drugs and neutral polymers

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US11/383,520 Continuation US20060216351A1 (en) 2001-06-22 2006-05-16 Pharmaceutical Compositions of Dispersions of Drugs and Neutral Polymers

Publications (1)

Publication Number Publication Date
US20030091643A1 true US20030091643A1 (en) 2003-05-15

Family

ID=23158329

Family Applications (4)

Application Number Title Priority Date Filing Date
US10/175,132 Abandoned US20030091643A1 (en) 2001-06-22 2002-06-18 Pharmaceutical compositions of dispersions of drugs and neutral polymers
US11/383,520 Abandoned US20060216351A1 (en) 2001-06-22 2006-05-16 Pharmaceutical Compositions of Dispersions of Drugs and Neutral Polymers
US14/242,141 Expired - Fee Related US9468604B2 (en) 2001-06-22 2014-04-01 Pharmaceutical compositions of dispersions of drug and neutral polymers
US15/258,477 Abandoned US20160374945A1 (en) 2001-06-22 2016-09-07 Pharmaceutical compositions of dispersions of drug and neutral polymers

Family Applications After (3)

Application Number Title Priority Date Filing Date
US11/383,520 Abandoned US20060216351A1 (en) 2001-06-22 2006-05-16 Pharmaceutical Compositions of Dispersions of Drugs and Neutral Polymers
US14/242,141 Expired - Fee Related US9468604B2 (en) 2001-06-22 2014-04-01 Pharmaceutical compositions of dispersions of drug and neutral polymers
US15/258,477 Abandoned US20160374945A1 (en) 2001-06-22 2016-09-07 Pharmaceutical compositions of dispersions of drug and neutral polymers

Country Status (11)

Country Link
US (4) US20030091643A1 (de)
EP (1) EP1404300B1 (de)
JP (1) JP2004534812A (de)
AT (1) ATE444060T1 (de)
BR (1) BR0210518A (de)
CA (1) CA2450957A1 (de)
DE (1) DE60233874D1 (de)
ES (1) ES2333645T3 (de)
MX (1) MXPA03011784A (de)
PT (1) PT1404300E (de)
WO (1) WO2003000235A1 (de)

Cited By (41)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020103225A1 (en) * 2000-08-03 2002-08-01 Curatolo William J. Pharmaceutical compositions of cholesteryl ester transfer protein inhibitors
US20040248942A1 (en) * 2003-02-20 2004-12-09 Bonnie Hepburn Novel formulation, omeprazole antacid complex-immediate release for rapid and sustained suppression of gastric acid
US20050031700A1 (en) * 2003-07-18 2005-02-10 Sanatarus, Inc. Pharmaceutical formulation and method for treating acid-caused gastrointestinal disorders
US20050038007A1 (en) * 2003-08-04 2005-02-17 Pfizer Inc Dosage forms of cholesteryl ester transfer protein inhibitors and HMG-CoA reductase inhibitors
US20050037070A1 (en) * 2003-07-18 2005-02-17 Santarus, Inc. Pharmaceutical formulatins useful for inhibiting acid secretion and methods for making and using them
US20050042291A1 (en) * 2003-07-01 2005-02-24 Michael Hawley Diffusion layer modulated solids
US20050084529A1 (en) * 2003-08-28 2005-04-21 Joerg Rosenberg Solid pharmaceutical dosage form
WO2005067926A1 (en) * 2004-01-16 2005-07-28 Chong Kun Dang Pharmaceutical Corp. Pharmaceutical composition of amlodipine maleate having enhanced stability
US20050220870A1 (en) * 2003-02-20 2005-10-06 Bonnie Hepburn Novel formulation, omeprazole antacid complex-immediate release for rapid and sustained suppression of gastric acid
US20050239845A1 (en) * 2004-04-16 2005-10-27 Santarus, Inc. Combination of proton pump inhibitor, buffering agent, and prokinetic agent
US20050249806A1 (en) * 2004-02-10 2005-11-10 Santarus, Inc. Combination of proton pump inhibitor, buffering agent, and nonsteroidal anti-inflammatory drug
US20050266071A1 (en) * 2004-05-25 2005-12-01 Santarus, Inc. Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them
US20060014788A1 (en) * 2001-06-21 2006-01-19 Pfizer Inc Self-emulsifying formulations of cholesteryl ester transfer protein inhibitors
US20060134213A1 (en) * 2004-11-05 2006-06-22 Wilson Edward S Stabilized ramipril compositions and methods of making
US20060147522A1 (en) * 2004-05-25 2006-07-06 Santarus, Inc. Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them
US20060204585A1 (en) * 2003-07-18 2006-09-14 Santarus, Inc. Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them
US20070026083A1 (en) * 2005-07-28 2007-02-01 Doney John A Method to improve characteristics of spray dried powders and granulated materials, and the products thereby produced
US20070129402A1 (en) * 2004-12-27 2007-06-07 Eisai Research Institute Sustained release formulations
US7235259B2 (en) 2000-08-03 2007-06-26 Pfizer Inc Pharmaceutical compositions of cholesteryl ester transfer protein inhibitors
US20070178152A1 (en) * 2005-11-04 2007-08-02 Shelton Michael C Carboxyalkylcellulose esters for administration of poorly soluble pharmaceutically active agents
US20070196485A1 (en) * 1999-06-22 2007-08-23 Dexcel Ltd. Stable benzimidazole formulation
WO2007110878A1 (en) * 2006-03-27 2007-10-04 Panacea Biotec Ltd Sustained release pharmaceutical composition on the basis of a release system comprising an acid-soluble polymer and a ph-dependent polymer.
US20070249692A1 (en) * 1999-11-12 2007-10-25 Fort James J Inhibitors of crystallization in a solid dispersion
US20070292498A1 (en) * 2003-11-05 2007-12-20 Warren Hall Combinations of proton pump inhibitors, sleep aids, buffers and pain relievers
US20080085315A1 (en) * 2006-10-10 2008-04-10 John Alfred Doney Amorphous ezetimibe and the production thereof
US7364752B1 (en) 1999-11-12 2008-04-29 Abbott Laboratories Solid dispersion pharamaceutical formulations
US20080152717A1 (en) * 2006-12-14 2008-06-26 Isp Investments, Inc. Amorphous valsartan and the production thereof
US20080181961A1 (en) * 2007-01-26 2008-07-31 Isp Investments, Inc. Amorphous oxcarbazepine and the production thereof
US20080181962A1 (en) * 2007-01-26 2008-07-31 Isp Investments, Inc. Formulation process method to produce spray dried products
US20080213368A1 (en) * 2004-12-27 2008-09-04 Eisai R & D Management Co., Ltd. Method for Stabilizing Anti-Dementia Drug
US20080299203A1 (en) * 2003-08-28 2008-12-04 Joerg Rosenberg Solid Pharmaceutical Dosage Formulation
US20090023778A1 (en) * 2005-04-28 2009-01-22 Eisai R&D Management Co., Ltd. Composition Containing Anti-Dementia Drug
US20090092658A1 (en) * 2007-10-05 2009-04-09 Santarus, Inc. Novel formulations of proton pump inhibitors and methods of using these formulations
US20090208579A1 (en) * 2004-12-27 2009-08-20 Eisai R & D Management Co., Ltd. Matrix Type Sustained-Release Preparation Containing Basic Drug or Salt Thereof, and Method for Manufacturing the Same
US7887840B2 (en) 2001-06-22 2011-02-15 Bend Research, Inc. Pharmaceutical compositions comprising drug and concentration-enhancing polymers
US20110038933A1 (en) * 2008-05-06 2011-02-17 Dexcell Ltd. Stable benzimidazole formulation
US8613946B2 (en) 2006-12-21 2013-12-24 Isp Investment Inc. Carotenoids of enhanced bioavailability
US10245238B2 (en) 2014-05-15 2019-04-02 Theravalues Corporation Composition for oral intake
US10736855B2 (en) 2016-02-25 2020-08-11 Dexcel Pharma Technologies Ltd. Compositions comprising proton pump inhibitors
US10835488B2 (en) 2016-06-16 2020-11-17 Dexcel Pharma Technologies Ltd. Stable orally disintegrating pharmaceutical compositions
US20220125732A1 (en) * 2020-10-23 2022-04-28 Appco Pharma Llc Ibuprofen and famotidine tablet

Families Citing this family (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
MY169670A (en) 2003-09-03 2019-05-08 Tibotec Pharm Ltd Combinations of a pyrimidine containing nnrti with rt inhibitors
PT1603553E (pt) * 2003-03-17 2012-02-03 Japan Tobacco Inc Composições farmacêuticas de inibidores de cetp
CN1761463A (zh) * 2003-03-17 2006-04-19 日本烟草产业株式会社 提高s－[2－([[1－(2－乙基丁基)环己基]羰基]氨基)苯基]－2－甲基丙硫代酸酯口服生物利用度的方法
WO2004082675A1 (en) 2003-03-17 2004-09-30 Japan Tobacco Inc. Method for increasing the oral bioavailability of s-[2- ([[1- (2-ethylbutyl) cyclohexyl] carbonyl] amino) phenyl] 2-methylpropanethioate
EP1827429A4 (de) * 2004-12-20 2009-08-05 Reddys Lab Ltd Dr Pharmatzeutische zusammensetzungen mit amorphen benzimidazolverbindungen
KR100760430B1 (ko) * 2004-12-31 2007-10-04 한미약품 주식회사 당뇨병 치료제의 경구 투여용 서방성 복합 제제 및 이의제조 방법
US8372836B2 (en) * 2006-10-17 2013-02-12 Bend Research, Inc. Spray dried formulation
AR065720A1 (es) 2007-03-14 2009-06-24 Tibotec Pharm Ltd Polvos para reconstitucion que comprenden rilpivirina dispersos en ciertos polimeros. uso. proceso.
EP2105130A1 (de) 2008-03-25 2009-09-30 Ratiopharm GmbH Pharmazeutische Formulierung und Verfahren zu deren Herstellung
KR101004205B1 (ko) * 2008-12-17 2010-12-24 동아제약주식회사 유데나필 함유 서방성 제제를 제조하기 위한 제어방출 조성물
AU2010253578B2 (en) 2009-05-27 2014-01-30 Samyang Biopharmaceuticals Corporation A poorly soluble drug containing microsphere with improved bioavailability and method of preparing the same
CN103271884B (zh) * 2013-06-28 2015-12-09 悦康药业集团有限公司 一种兰索拉唑组合物及其制备方法
US10076512B2 (en) 2014-05-01 2018-09-18 Eiger Biopharmaceuticals, Inc. Treatment of hepatitis delta virus infection
US11311519B2 (en) 2014-05-01 2022-04-26 Eiger Biopharmaceuticals, Inc. Treatment of hepatitis delta virus infection
WO2016067132A1 (en) 2014-10-31 2016-05-06 Bend Research Inc. Process for forming active domains dispersed in a matrix
WO2016172342A1 (en) 2015-04-21 2016-10-27 Eiger Biopharmaceuticals, Inc. Pharmaceutical compositions comprising lonafarnib and ritonavir
EP3525763B1 (de) * 2016-10-12 2025-03-05 Intra-Cellular Therapies, Inc. Amorphe feste dispersionen
RU2767410C2 (ru) 2017-03-24 2022-03-17 Интра-Селлулар Терапиз, Инк. Новые композиции и способы
ES2967689T3 (es) 2018-04-06 2024-05-03 Capsugel Belgium Nv Proceso de secado por aspersión para partículas de baja relación de aspecto que comprenden poli[(metacrilato de metilo)-co-(ácido metacrílico)]
US12144808B2 (en) 2018-08-29 2024-11-19 Intra-Cellular Therapies, Inc. Compositions and methods
BR112021003655A2 (pt) 2018-08-31 2021-05-18 Intra-Cellular Therapies, Inc. métodos novos
WO2020047408A1 (en) 2018-08-31 2020-03-05 Intra-Cellular Therapies, Inc. Novel methods
JP7812785B2 (ja) 2019-09-18 2026-02-10 ブリストル－マイヤーズ スクイブ カンパニー Ｔｙｋ２阻害薬の剤形
US12414948B2 (en) 2022-05-18 2025-09-16 Intra-Cellular Therapies, Inc. Methods
WO2024006539A1 (en) * 2022-07-01 2024-01-04 Vitakey Inc. Nutraceutical particles

Citations (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4540602A (en) * 1979-04-13 1985-09-10 Freund Industry Company, Limited Process for the preparation of activated pharmaceutical compositions
US4753800A (en) * 1985-10-04 1988-06-28 Warner-Lambert Company Medicament adsorbates and their preparation
US4894235A (en) * 1984-10-23 1990-01-16 Dr. Rentschler, Arzneimmittel Gmbh & Co. Nifedipine-containing form of administration and method for its production
US4916138A (en) * 1986-04-02 1990-04-10 Fujisawa Pharmaceutical Co., Ltd. Solid dispersion composition of FR-900506 substance
US4983593A (en) * 1988-05-30 1991-01-08 Zeria Pharmaceutical Co Pharmaceutical composition of dihydropyridine compound
US5320848A (en) * 1991-05-28 1994-06-14 Affinity Biotech, Inc. Chewable drug-delivery composition
US5340591A (en) * 1992-01-24 1994-08-23 Fujisawa Pharmaceutical Co., Ltd. Method of producing a solid dispersion of the sparingly water-soluble drug, nilvadipine
US5368864A (en) * 1988-11-25 1994-11-29 Henning Berlin Gmbh Chemie- Und Pharmawerk Formulation of oxypurinol and/or its alkali and alkaline earth salts
US5456923A (en) * 1991-04-16 1995-10-10 Nippon Shinyaku Company, Limited Method of manufacturing solid dispersion
US5508276A (en) * 1994-07-18 1996-04-16 Eli Lilly And Company Duloxetine enteric pellets
US5658297A (en) * 1995-03-16 1997-08-19 Crainich; Lawrence Surgical staple remover
US5684040A (en) * 1993-05-18 1997-11-04 Basf Aktiengesellschaft Compositions in the form of solid solutions
US5925645A (en) * 1996-03-20 1999-07-20 Bayer Aktiengesellschaft 2-aryl-substituted pyridines
US5935939A (en) * 1995-06-01 1999-08-10 G. D. Searle & Co. Stabilized dispersions of misoprostol
US5939099A (en) * 1995-02-14 1999-08-17 Basf Aktiengesellschaft Solid active extrusion compound preparations containing low-substituted hydroxypropylcellulose
US5968251A (en) * 1996-09-09 1999-10-19 Basf Aktiengesellschaft Production of carotenoid preparations in the form of coldwater-dispersible powders, and the use of the novel carotenoid preparations
US6068856A (en) * 1995-07-05 2000-05-30 Byk Gulden Chemische Fabrik Gmbh Oral pharmaceutical composition with delayed release of active ingredient for pantoprazole
US6077541A (en) * 1997-11-14 2000-06-20 Andrx Pharmaceuticals, Inc. Omeprazole formulation
US6121283A (en) * 1996-11-27 2000-09-19 Pfizer Inc Apo B-secretion/MTP inhibitory amides
US6140343A (en) * 1998-09-17 2000-10-31 Pfizer 4-amino substituted-2-substituted-1,2,3,4-tetrahydroquinolines
US6147089A (en) * 1998-09-17 2000-11-14 Pfizer Inc. Annulated 4-carboxyamino-2-methyl-1,2,3,4,-tetrahydroquinolines
US6184230B1 (en) * 1997-05-16 2001-02-06 Yamanouchi Pharmaceutical Co., Ltd. Anti-helicobacter pylori pharmaceutical composition
US6197786B1 (en) * 1998-09-17 2001-03-06 Pfizer Inc 4-Carboxyamino-2-substituted-1,2,3,4-tetrahydroquinolines
US6221368B1 (en) * 1996-09-13 2001-04-24 Basf Aktiengesellschaft Process for producing solid dosage forms by extrusion
US6254889B1 (en) * 1995-07-26 2001-07-03 Kyowa Hakko Kogyo Co., Ltd. Solid dispersion dosage form of amorphous xanthine derivative and enteric-coating polymer
US6264981B1 (en) * 1999-10-27 2001-07-24 Anesta Corporation Oral transmucosal drug dosage using solid solution
US6395300B1 (en) * 1999-05-27 2002-05-28 Acusphere, Inc. Porous drug matrices and methods of manufacture thereof
US6423345B2 (en) * 1998-04-30 2002-07-23 Acusphere, Inc. Matrices formed of polymer and hydrophobic compounds for use in drug delivery

Family Cites Families (59)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA1146866A (en) * 1979-07-05 1983-05-24 Yamanouchi Pharmaceutical Co. Ltd. Process for the production of sustained release pharmaceutical composition of solid medical material
IE63321B1 (en) 1986-02-03 1995-04-05 Elan Corp Plc Drug delivery system
US5028433A (en) 1988-11-30 1991-07-02 Banyu Pharmaceutical Co., Ltd. Readily absorbable drug formulation of NB-818
EP0462066A1 (de) 1990-06-15 1991-12-18 Warner-Lambert Company Amorphes Gemfibrozil
EP0617612B1 (de) 1991-12-18 1997-09-10 Warner-Lambert Company Verfahren für die herstellung einer festen dispersion
US5656297A (en) 1992-03-12 1997-08-12 Alkermes Controlled Therapeutics, Incorporated Modulated release from biocompatible polymers
US5652332A (en) * 1993-03-12 1997-07-29 Xoma Biologically active peptides from functional domains of bactericidal/permeability-increasing protein and uses thereof
US5968983A (en) * 1994-10-05 1999-10-19 Nitrosystems, Inc Method and formulation for treating vascular disease
TW487582B (en) 1995-08-11 2002-05-21 Nissan Chemical Ind Ltd Method for converting sparingly water-soluble medical substance to amorphous state
CA2231050A1 (en) * 1995-09-07 1997-03-13 Biovail International Ltd. System for rendering substantially non-dissoluble bio-affecting agents bio-available
WO1997044014A1 (en) 1996-05-20 1997-11-27 Janssen Pharmaceutica N.V. Antifungal compositions with improved bioavailability
HRP970330B1 (en) 1996-07-08 2004-06-30 Bayer Ag Cycloalkano pyridines
DE19627431A1 (de) 1996-07-08 1998-01-15 Bayer Ag Heterocyclisch kondensierte Pyridine
DE19627430A1 (de) 1996-07-08 1998-01-15 Bayer Ag Bicyclisch kondensierte Pyridine
DE19627419A1 (de) 1996-07-08 1998-01-15 Bayer Ag Cycloalkano-pyridine
AR008789A1 (es) 1996-07-31 2000-02-23 Bayer Corp Piridinas y bifenilos substituidos
DE19704244A1 (de) 1997-02-05 1998-08-06 Bayer Ag 5-Hydroxy-alkyl substituierte Phenyle
DE19704243A1 (de) 1997-02-05 1998-08-06 Bayer Ag Neue 2-Amino-substituierte Pyridine
JP2894445B2 (ja) 1997-02-12 1999-05-24 日本たばこ産業株式会社 Ｃｅｔｐ活性阻害剤として有効な化合物
DE19709125A1 (de) 1997-03-06 1998-09-10 Bayer Ag Substituierte Chinoline
EP0872233A1 (de) 1997-04-14 1998-10-21 Janssen Pharmaceutica N.V. Antiretrovirale Arzneimittel mit verbesserter Bioverfügbarkeit
ES2287971T3 (es) 1997-08-11 2007-12-16 Pfizer Products Inc. Dispersiones farmaceuticas solidas con biodisponibilidad incrementada.
HN1998000115A (es) 1997-08-21 1999-06-02 Warner Lambert Co Formas de dosificación farmacéuticas sólidas
WO1999014204A1 (en) * 1997-09-16 1999-03-25 G.D. Searle & Co. Substituted 1,2,4-triazoles useful for inhibiting cholesteryl ester transfer protein activity
DE19832159A1 (de) 1997-09-18 1999-03-25 Bayer Ag Substituierte Tetrahydro-naphthaline
DE19741051A1 (de) 1997-09-18 1999-03-25 Bayer Ag Hetero-Tetrahydrochinoline
MA24643A1 (fr) 1997-09-18 1999-04-01 Bayer Ag Tetrahydro-naphtalenes substitues et composes analogues
DE19741400A1 (de) 1997-09-19 1999-03-25 Bayer Ag Benzyl-biphenyle
DE19741399A1 (de) 1997-09-19 1999-03-25 Bayer Ag Tetrahydrochinoline
KR20010023729A (ko) 1997-11-03 2001-03-26 디르크 반테 지질 저하제 조성물
BR9813728A (pt) 1997-12-22 2000-10-10 Schering Corp Composição de dispersão molecular com elevada biodisponibilidade
UA57824C2 (uk) * 1998-02-05 2003-07-15 Пфайзер Продактс Інк. Похідні дигідроксигексанової кислоти, фармацевтична композиція, що їх містить (варіанти), та спосіб лікування (варіанти)
AU3285499A (en) 1998-02-13 1999-08-30 G.D. Searle & Co. Substituted pyridines useful for inhibiting cholesteryl ester transfer protein activity
US6147090A (en) * 1998-09-17 2000-11-14 Pfizer Inc. 4-carboxyamino-2-methyl-1,2,3,4,-tetrahydroquinolines
US6140342A (en) 1998-09-17 2000-10-31 Pfizer Inc. Oxy substituted 4-carboxyamino-2-methyl-1,2,3,4-tetrahydroquinolines
US6350786B1 (en) 1998-09-22 2002-02-26 Hoffmann-La Roche Inc. Stable complexes of poorly soluble compounds in ionic polymers
CA2345108A1 (en) 1998-09-25 2000-04-06 Monsanto Company Substituted n-aliphatic-n-aromatic tertiary-heteroalkylamines useful for inhibiting cholesteryl ester transfer protein activity
JP3924124B2 (ja) 1998-09-25 2007-06-06 ファルマシア・コーポレーション コレステロールエステル輸送タンパク質活性阻害に有効な置換された多環アリールおよびヘテロアリール第三級ヘテロアルキルアミン
US6432426B2 (en) * 1998-11-30 2002-08-13 Symbollon Corporation Non-staining topical iodine composition and method
ATE404178T1 (de) 1999-02-10 2008-08-15 Pfizer Prod Inc Vorrichtung mit matrixgesteuerter wirkstofffreisetzung
ATE433318T1 (de) * 1999-02-10 2009-06-15 Pfizer Prod Inc Osmotisches system zur verabreichung von wirkstoffen, die feste amorphe dispersionen enthalten
US6706283B1 (en) * 1999-02-10 2004-03-16 Pfizer Inc Controlled release by extrusion of solid amorphous dispersions of drugs
ATE400252T1 (de) * 1999-02-10 2008-07-15 Pfizer Prod Inc Pharmazeutische feste dispersionen
DE19918434A1 (de) * 1999-04-23 2000-10-26 Basf Ag Feste Pharmazeutische Formulierungen von säurelabilen Protonenpumpenblockern
GB9920558D0 (en) 1999-08-31 1999-11-03 Bradford Particle Design Ltd Methods for particle formation and their products
TR200200763T2 (tr) 1999-09-24 2003-09-22 Janssen Pharmaceutica N.V. Antiviral bileşimler
US20010036482A1 (en) * 1999-10-15 2001-11-01 Dale Lind Fredell Antimicrobial compositions for mastitis control
HUP0201450A3 (en) 1999-12-08 2003-02-28 Pharmacia Corp Chicago Solid-state form of celecoxib having enhanced bioavailability, pharmaceutical compositions containing it and their preparation
ES2236011T3 (es) 1999-12-08 2005-07-16 Pharmacia Corporation Formas cristalinas polimorficas de celecoxib.
JP2003518487A (ja) 1999-12-23 2003-06-10 ファイザー・プロダクツ・インク ヒドロゲル駆動型積層薬物製剤
PE20011184A1 (es) * 2000-03-16 2001-11-15 Pfizer Prod Inc Composiciones farmaceuticas de inhibidores de la glucogeno-fosforilasa
US20010053791A1 (en) * 2000-03-16 2001-12-20 Babcock Walter C. Glycogen phosphorylase inhibitor
KR20010097244A (ko) 2000-04-21 2001-11-08 유충식 위산도 비의존성 고용해도를 갖는 이트라코나졸 함유약학적 조성물 및 그 제조방법
US7115279B2 (en) * 2000-08-03 2006-10-03 Curatolo William J Pharmaceutical compositions of cholesteryl ester transfer protein inhibitors
TNSN03137A1 (en) * 2001-06-22 2005-12-23 Pfizer Prod Inc PHARMACEUTICAL COMPOSITIONS COMPRISING LOW SOLUBILITY AND / OR ACID SENSITIVE DRUGS AND NEUTRALIZED ACID POLYMERS.
PL372247A1 (en) * 2002-02-01 2005-07-11 Pfizer Products Inc. Method for making homogeneous spray-dried solid amorphous drug dispersions utilizing modified spray-drying apparatus
EP1530457B1 (de) * 2002-08-12 2009-09-09 Bend Research, Inc. Arzneizubereitungen bestehend aus arzneimitteln in halb-geordneter form und polymeren
US20070141150A1 (en) 2003-12-30 2007-06-21 Raghupathi Kandarapu Pharmaceutical composition
CA2568007A1 (en) * 2004-05-28 2005-12-08 Pfizer Products Inc. Pharmaceutical compositions with enhanced performance

Patent Citations (32)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4540602A (en) * 1979-04-13 1985-09-10 Freund Industry Company, Limited Process for the preparation of activated pharmaceutical compositions
US4894235A (en) * 1984-10-23 1990-01-16 Dr. Rentschler, Arzneimmittel Gmbh & Co. Nifedipine-containing form of administration and method for its production
US4753800A (en) * 1985-10-04 1988-06-28 Warner-Lambert Company Medicament adsorbates and their preparation
US4916138A (en) * 1986-04-02 1990-04-10 Fujisawa Pharmaceutical Co., Ltd. Solid dispersion composition of FR-900506 substance
US4983593A (en) * 1988-05-30 1991-01-08 Zeria Pharmaceutical Co Pharmaceutical composition of dihydropyridine compound
US5368864A (en) * 1988-11-25 1994-11-29 Henning Berlin Gmbh Chemie- Und Pharmawerk Formulation of oxypurinol and/or its alkali and alkaline earth salts
US5456923A (en) * 1991-04-16 1995-10-10 Nippon Shinyaku Company, Limited Method of manufacturing solid dispersion
US5320848A (en) * 1991-05-28 1994-06-14 Affinity Biotech, Inc. Chewable drug-delivery composition
US5340591A (en) * 1992-01-24 1994-08-23 Fujisawa Pharmaceutical Co., Ltd. Method of producing a solid dispersion of the sparingly water-soluble drug, nilvadipine
US5684040A (en) * 1993-05-18 1997-11-04 Basf Aktiengesellschaft Compositions in the form of solid solutions
US5508276A (en) * 1994-07-18 1996-04-16 Eli Lilly And Company Duloxetine enteric pellets
US5939099A (en) * 1995-02-14 1999-08-17 Basf Aktiengesellschaft Solid active extrusion compound preparations containing low-substituted hydroxypropylcellulose
US5658297A (en) * 1995-03-16 1997-08-19 Crainich; Lawrence Surgical staple remover
US5935939A (en) * 1995-06-01 1999-08-10 G. D. Searle & Co. Stabilized dispersions of misoprostol
US6068856A (en) * 1995-07-05 2000-05-30 Byk Gulden Chemische Fabrik Gmbh Oral pharmaceutical composition with delayed release of active ingredient for pantoprazole
US6254889B1 (en) * 1995-07-26 2001-07-03 Kyowa Hakko Kogyo Co., Ltd. Solid dispersion dosage form of amorphous xanthine derivative and enteric-coating polymer
US5925645A (en) * 1996-03-20 1999-07-20 Bayer Aktiengesellschaft 2-aryl-substituted pyridines
US6127383A (en) * 1996-03-20 2000-10-03 Bayer Aktiengesellschaft 2-aryl-substituted pyridines
US5968251A (en) * 1996-09-09 1999-10-19 Basf Aktiengesellschaft Production of carotenoid preparations in the form of coldwater-dispersible powders, and the use of the novel carotenoid preparations
US6221368B1 (en) * 1996-09-13 2001-04-24 Basf Aktiengesellschaft Process for producing solid dosage forms by extrusion
US6121283A (en) * 1996-11-27 2000-09-19 Pfizer Inc Apo B-secretion/MTP inhibitory amides
US6184230B1 (en) * 1997-05-16 2001-02-06 Yamanouchi Pharmaceutical Co., Ltd. Anti-helicobacter pylori pharmaceutical composition
US6077541A (en) * 1997-11-14 2000-06-20 Andrx Pharmaceuticals, Inc. Omeprazole formulation
US6689390B2 (en) * 1998-04-30 2004-02-10 Acusphere, Inc. Matrices formed of polymer and hydrophobic compounds for use in drug delivery
US6423345B2 (en) * 1998-04-30 2002-07-23 Acusphere, Inc. Matrices formed of polymer and hydrophobic compounds for use in drug delivery
US6197786B1 (en) * 1998-09-17 2001-03-06 Pfizer Inc 4-Carboxyamino-2-substituted-1,2,3,4-tetrahydroquinolines
US6310075B1 (en) * 1998-09-17 2001-10-30 Pfizer Inc. Annulated 4-carboxyamino-2-methyl-1,2,3,4-tetrahydroquinolines
US6147089A (en) * 1998-09-17 2000-11-14 Pfizer Inc. Annulated 4-carboxyamino-2-methyl-1,2,3,4,-tetrahydroquinolines
US6140343A (en) * 1998-09-17 2000-10-31 Pfizer 4-amino substituted-2-substituted-1,2,3,4-tetrahydroquinolines
US6395300B1 (en) * 1999-05-27 2002-05-28 Acusphere, Inc. Porous drug matrices and methods of manufacture thereof
US6645528B1 (en) * 1999-05-27 2003-11-11 Acusphere, Inc. Porous drug matrices and methods of manufacture thereof
US6264981B1 (en) * 1999-10-27 2001-07-24 Anesta Corporation Oral transmucosal drug dosage using solid solution

Cited By (70)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9023391B2 (en) 1999-06-22 2015-05-05 Dexcel Ltd. Stable benzimidazole formulation
US20070196485A1 (en) * 1999-06-22 2007-08-23 Dexcel Ltd. Stable benzimidazole formulation
US9107830B2 (en) 1999-11-12 2015-08-18 Abbvie, Inc. Inhibitors of crystallization in a solid dispersion
US7364752B1 (en) 1999-11-12 2008-04-29 Abbott Laboratories Solid dispersion pharamaceutical formulations
US20070249692A1 (en) * 1999-11-12 2007-10-25 Fort James J Inhibitors of crystallization in a solid dispersion
US7115279B2 (en) 2000-08-03 2006-10-03 Curatolo William J Pharmaceutical compositions of cholesteryl ester transfer protein inhibitors
US20060211654A1 (en) * 2000-08-03 2006-09-21 Curatolo William J Pharmaceutical Compositions of Cholesteryl Ester Transfer Protein Inhibitor
US8197848B2 (en) 2000-08-03 2012-06-12 Bend Research, Inc. Pharmaceutical compositions of cholesteryl ester transfer protein inhibitors
US7235259B2 (en) 2000-08-03 2007-06-26 Pfizer Inc Pharmaceutical compositions of cholesteryl ester transfer protein inhibitors
US8048452B2 (en) 2000-08-03 2011-11-01 Bend Research, Inc. Pharmaceutical compositions of cholesteryl ester transfer protein inhibitor
US8389011B2 (en) 2000-08-03 2013-03-05 Bend Research, Inc. Pharmaceutical compositions of cholesteryl ester transfer protein inhibitors
US20020103225A1 (en) * 2000-08-03 2002-08-01 Curatolo William J. Pharmaceutical compositions of cholesteryl ester transfer protein inhibitors
US20060014788A1 (en) * 2001-06-21 2006-01-19 Pfizer Inc Self-emulsifying formulations of cholesteryl ester transfer protein inhibitors
US7887840B2 (en) 2001-06-22 2011-02-15 Bend Research, Inc. Pharmaceutical compositions comprising drug and concentration-enhancing polymers
US20050220870A1 (en) * 2003-02-20 2005-10-06 Bonnie Hepburn Novel formulation, omeprazole antacid complex-immediate release for rapid and sustained suppression of gastric acid
US20040248942A1 (en) * 2003-02-20 2004-12-09 Bonnie Hepburn Novel formulation, omeprazole antacid complex-immediate release for rapid and sustained suppression of gastric acid
US20050042291A1 (en) * 2003-07-01 2005-02-24 Michael Hawley Diffusion layer modulated solids
US8993599B2 (en) 2003-07-18 2015-03-31 Santarus, Inc. Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them
US20060204585A1 (en) * 2003-07-18 2006-09-14 Santarus, Inc. Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them
US20050037070A1 (en) * 2003-07-18 2005-02-17 Santarus, Inc. Pharmaceutical formulatins useful for inhibiting acid secretion and methods for making and using them
US20100297220A1 (en) * 2003-07-18 2010-11-25 Santarus, Inc Pharmaceutical Formulation And Method For Treating Acid-Caused Gastrointestinal Disorders
US20050031700A1 (en) * 2003-07-18 2005-02-10 Sanatarus, Inc. Pharmaceutical formulation and method for treating acid-caused gastrointestinal disorders
US20050038007A1 (en) * 2003-08-04 2005-02-17 Pfizer Inc Dosage forms of cholesteryl ester transfer protein inhibitors and HMG-CoA reductase inhibitors
US8377952B2 (en) 2003-08-28 2013-02-19 Abbott Laboratories Solid pharmaceutical dosage formulation
US8333990B2 (en) 2003-08-28 2012-12-18 Abbott Laboratories Solid pharmaceutical dosage form
US20050084529A1 (en) * 2003-08-28 2005-04-21 Joerg Rosenberg Solid pharmaceutical dosage form
US8268349B2 (en) 2003-08-28 2012-09-18 Abbott Laboratories Solid pharmaceutical dosage form
US8309613B2 (en) 2003-08-28 2012-11-13 Abbvie Inc. Solid pharmaceutical dosage form
US8025899B2 (en) 2003-08-28 2011-09-27 Abbott Laboratories Solid pharmaceutical dosage form
US20080299203A1 (en) * 2003-08-28 2008-12-04 Joerg Rosenberg Solid Pharmaceutical Dosage Formulation
US8399015B2 (en) 2003-08-28 2013-03-19 Abbvie Inc. Solid pharmaceutical dosage form
US8691878B2 (en) 2003-08-28 2014-04-08 Abbvie Inc. Solid pharmaceutical dosage form
US20070292498A1 (en) * 2003-11-05 2007-12-20 Warren Hall Combinations of proton pump inhibitors, sleep aids, buffers and pain relievers
WO2005067926A1 (en) * 2004-01-16 2005-07-28 Chong Kun Dang Pharmaceutical Corp. Pharmaceutical composition of amlodipine maleate having enhanced stability
US20050249806A1 (en) * 2004-02-10 2005-11-10 Santarus, Inc. Combination of proton pump inhibitor, buffering agent, and nonsteroidal anti-inflammatory drug
US20050239845A1 (en) * 2004-04-16 2005-10-27 Santarus, Inc. Combination of proton pump inhibitor, buffering agent, and prokinetic agent
US8815916B2 (en) 2004-05-25 2014-08-26 Santarus, Inc. Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them
US8906940B2 (en) 2004-05-25 2014-12-09 Santarus, Inc. Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them
US20050266071A1 (en) * 2004-05-25 2005-12-01 Santarus, Inc. Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them
US20060147522A1 (en) * 2004-05-25 2006-07-06 Santarus, Inc. Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them
US20060134213A1 (en) * 2004-11-05 2006-06-22 Wilson Edward S Stabilized ramipril compositions and methods of making
US20060159742A1 (en) * 2004-11-05 2006-07-20 King Pharmaceutical Research & Development, Inc. Stabilized individually coated ramipril particles, compositions and methods
US8481565B2 (en) * 2004-12-27 2013-07-09 Eisai R&D Management Co., Ltd. Method for stabilizing anti-dementia drug
US20110045074A1 (en) * 2004-12-27 2011-02-24 Eisai R&D Management Co., Ltd. Matrix type sustained-release preparation containing basic drug or salt thereof and, method for manufacturing the same
US20070129402A1 (en) * 2004-12-27 2007-06-07 Eisai Research Institute Sustained release formulations
US20080213368A1 (en) * 2004-12-27 2008-09-04 Eisai R & D Management Co., Ltd. Method for Stabilizing Anti-Dementia Drug
US8507527B2 (en) 2004-12-27 2013-08-13 Eisai R & D Management Co., Ltd. Method for stabilizing anti-dementia drug
US20100152164A1 (en) * 2004-12-27 2010-06-17 Eisai R&D Management Co., Ltd. Method For Stabilizing Anti-Dementia Drug
US20090208579A1 (en) * 2004-12-27 2009-08-20 Eisai R & D Management Co., Ltd. Matrix Type Sustained-Release Preparation Containing Basic Drug or Salt Thereof, and Method for Manufacturing the Same
US20090023778A1 (en) * 2005-04-28 2009-01-22 Eisai R&D Management Co., Ltd. Composition Containing Anti-Dementia Drug
US20070026073A1 (en) * 2005-07-28 2007-02-01 Doney John A Amorphous efavirenz and the production thereof
US20070026083A1 (en) * 2005-07-28 2007-02-01 Doney John A Method to improve characteristics of spray dried powders and granulated materials, and the products thereby produced
US10532028B2 (en) 2005-07-28 2020-01-14 Isp Investments Llc Method to improve characteristics of spray dried powders and granulated materials, and the products thereby produced
US20070178152A1 (en) * 2005-11-04 2007-08-02 Shelton Michael C Carboxyalkylcellulose esters for administration of poorly soluble pharmaceutically active agents
US20100234288A1 (en) * 2006-03-27 2010-09-16 Panacea Biotec Ltd SUSTAINED RELEASE PHARMACEUTICAL COMPOSITION ON THE BASIS OF RELEASE SYSTEM COMPRISING AN ACID-SOLUBLE POLYMER AND A pH-DEPENDENT POLYMER
WO2007110878A1 (en) * 2006-03-27 2007-10-04 Panacea Biotec Ltd Sustained release pharmaceutical composition on the basis of a release system comprising an acid-soluble polymer and a ph-dependent polymer.
US20080085315A1 (en) * 2006-10-10 2008-04-10 John Alfred Doney Amorphous ezetimibe and the production thereof
US20080152717A1 (en) * 2006-12-14 2008-06-26 Isp Investments, Inc. Amorphous valsartan and the production thereof
US8613946B2 (en) 2006-12-21 2013-12-24 Isp Investment Inc. Carotenoids of enhanced bioavailability
US20080181961A1 (en) * 2007-01-26 2008-07-31 Isp Investments, Inc. Amorphous oxcarbazepine and the production thereof
US20080181962A1 (en) * 2007-01-26 2008-07-31 Isp Investments, Inc. Formulation process method to produce spray dried products
US10189957B2 (en) 2007-01-26 2019-01-29 Isp Investments Llc Formulation process method to produce spray dried products
US20090092658A1 (en) * 2007-10-05 2009-04-09 Santarus, Inc. Novel formulations of proton pump inhibitors and methods of using these formulations
US20110038933A1 (en) * 2008-05-06 2011-02-17 Dexcell Ltd. Stable benzimidazole formulation
US12599565B2 (en) 2008-05-06 2026-04-14 Dexcel Pharma Technologies Ltd. Stable benzimidazole formulation
US10245238B2 (en) 2014-05-15 2019-04-02 Theravalues Corporation Composition for oral intake
US10736855B2 (en) 2016-02-25 2020-08-11 Dexcel Pharma Technologies Ltd. Compositions comprising proton pump inhibitors
US10835488B2 (en) 2016-06-16 2020-11-17 Dexcel Pharma Technologies Ltd. Stable orally disintegrating pharmaceutical compositions
US20220125732A1 (en) * 2020-10-23 2022-04-28 Appco Pharma Llc Ibuprofen and famotidine tablet
US12357578B2 (en) * 2020-10-23 2025-07-15 Appco Pharma Llc Ibuprofen and famotidine tablet

Also Published As

Publication number Publication date
ES2333645T3 (es) 2010-02-25
JP2004534812A (ja) 2004-11-18
US20140210117A1 (en) 2014-07-31
BR0210518A (pt) 2004-06-22
US20160374945A1 (en) 2016-12-29
CA2450957A1 (en) 2003-01-03
PT1404300E (pt) 2009-11-09
DE60233874D1 (de) 2009-11-12
ATE444060T1 (de) 2009-10-15
MXPA03011784A (es) 2004-04-02
WO2003000235A9 (en) 2003-12-24
WO2003000235A1 (en) 2003-01-03
US9468604B2 (en) 2016-10-18
US20060216351A1 (en) 2006-09-28
EP1404300A1 (de) 2004-04-07
EP1404300B1 (de) 2009-09-30

Similar Documents

Publication Publication Date Title
US9468604B2 (en) Pharmaceutical compositions of dispersions of drug and neutral polymers
US8173142B2 (en) Pharmaceutical compositions of drugs and neutralized acidic polymers
US8236328B2 (en) Pharmaceutical compositions of dispersions of amorphous drugs mixed with polymers
US8389006B2 (en) Pharmaceutical compositions of adsorbates of amorphous drug
US7887840B2 (en) Pharmaceutical compositions comprising drug and concentration-enhancing polymers
EP2305217B1 (de) Verfahren zur Herstellung von pharmazeutischen Zubereitungen enthaltend eine Feststoffdispersion von Cholesteryl Ester Transfer Protein Inhibitoren
US8197848B2 (en) Pharmaceutical compositions of cholesteryl ester transfer protein inhibitors
US20030170309A1 (en) Pharmaceutical compositions containing polymer and drug assemblies
AU2002302886A1 (en) Pharmaceutical compositions comprising low-solubility and/or acid-sensitive drugs and neutralized acidic polymers

Legal Events

Date Code Title Description
STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION

AS Assignment

Owner name: BEND RESEARCH, INC., OREGON

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:PFIZER INC.;PFIZER PRODUCTS INC.;REEL/FRAME:021998/0880;SIGNING DATES FROM 20081103 TO 20081104

Owner name: BEND RESEARCH, INC.,OREGON

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:PFIZER INC.;PFIZER PRODUCTS INC.;SIGNING DATES FROM 20081103 TO 20081104;REEL/FRAME:021998/0880

Owner name: BEND RESEARCH, INC., OREGON

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:PFIZER INC.;PFIZER PRODUCTS INC.;SIGNING DATES FROM 20081103 TO 20081104;REEL/FRAME:021998/0880