HK1093151A

HK1093151A - Dosage forms providing controlled release of cholesteryl ester transfer protein inhibitors and immediate release of hmg-coa reductase inhibitors

Info

Publication number: HK1093151A
Application number: HK06113968.5A
Authority: HK
Inventors: William John Curatolo; Dwayne Thomas Friesen; Steven C. Sutton
Original assignee: 辉瑞产品公司
Priority date: 2003-08-04
Filing date: 2004-07-21
Publication date: 2007-02-23

Description

Dosage forms providing controlled release cholesteryl ester transfer protein inhibitors and immediate release HMG-CoA reductase inhibitors

Background

The present invention relates to a dosage form comprising (1) a CETP inhibitor in a solubility-improved form and (2) an HMG-CoA reductase inhibitor, wherein the dosage form provides immediate release of the HMG-CoA reductase inhibitor and controlled release of the CETP inhibitor.

It is known that inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme a reductase (HMG-CoA reductase), an important enzyme catalyzing the synthesis of cholesterol in cells, will lead to a decrease in blood cholesterol levels, especially cholesterol in the form of low density lipoprotein (LDL-C). Thus, HMG-CoA reductase inhibitors are considered as potential hypocholesterolemic or hypolipidemic agents.

CETP inhibitors are another class of compounds capable of modulating blood cholesterol levels, such as by increasing high-density lipoprotein (HDL) cholesterol and decreasing low-density lipoprotein (LDL) cholesterol. It is desirable to utilize CETP inhibitors to lower some plasma lipid levels, such as LDL-cholesterol and triglycerides and to raise some other plasma lipid levels, including HDL-cholesterol, and accordingly to treat diseases affected by low levels of HDL cholesterol and/or high levels of LDL-cholesterol and triglycerides, such as atherosclerosis and cardiovascular diseases in some mammals (i.e., those having CETP in their plasma), including humans.

Combination therapy of CETP inhibitors and HMG-CoA reductase inhibitors has been known to treat elevated LDL cholesterol and low HDL cholesterol levels. For example, WO02/13797a2 relates to pharmaceutical combinations of cholesteryl ester transfer protein inhibitors and atorvastatin. The application discloses that the compounds may be administered generally separately or together with a pharmaceutically acceptable carrier, vehicle or diluent. The compounds may be administered individually or together in any conventional oral, parenteral or transdermal dosage form. The combination may be administered in a controlled release dosage form, such as a slow release or fast release dosage form. For oral administration, the dosage form may take the form of solutions, suspensions, tablets, pills, capsules, powders, and the like.

U.S. patent 6,310,075B1 to Dennno et al, relates to CETP inhibitors, pharmaceutical compositions comprising the inhibitors, and uses of the inhibitors. DeNinno et al disclose pharmaceutical combination compositions comprising a CETP inhibitor and an HMG-CoA reductase inhibitor. Dennno discloses that the compounds of this invention can be administered in the form of a pharmaceutical composition comprising at least one compound and a pharmaceutically acceptable vehicle, diluent or carrier. For oral administration, the pharmaceutical compositions can be in the form of solutions, suspensions, tablets, pills, capsules, powders, and the like. Similarly, U.S. Pat. No. 6,197,786B1 to Dennno et al discloses pharmaceutical compositions comprising a CETP inhibitor and an HMG-CoA reductase inhibitor.

U.S. Pat. No. 6,462,091B1 discloses pharmaceutical compositions of CETP inhibitors and HMG-CoA reductase inhibitors for cardiovascular indications. Pharmaceutical compositions include those suitable for oral, rectal, topical, buccal, and parenteral administration. This application discloses solid dosage forms for oral administration, including capsules, tablets, pills, powders, gel caps, and granules.

Another class of CETP inhibitors is disclosed in Schmeck et al, U.S. Pat. No. 5,932,587. Schmeck et al disclose that CETP inhibitors may be used in combination with certain HMG-CoA reductase inhibitors such as statins including atorvastatin.

CETP inhibitors, especially those having high binding activity, are generally hydrophobic, have very low aqueous solubility and have low oral bioavailability when administered in a conventional manner. The compounds have proven difficult to formulate in orally administered forms that give high bioavailability. Thus, CETP inhibitors must be formulated to provide good bioavailability. These formulations are often referred to as "solubility-improved" forms. One method of increasing the bioavailability of CETP inhibitors is to form a solid amorphous dispersion of the drug and concentration-enhancing polymer. See, for example, commonly assigned, co-pending U.S. patent application No. 2002/010325a1 and U.S. patent application No. 10/066,091, the disclosures of which are incorporated herein by reference. Another approach to increasing the bioavailability of CETP inhibitors is to formulate the compounds in a lipid carrier. See, commonly assigned, co-pending U.S. patent application No. 10/175,643, the disclosure of which is incorporated herein by reference. Other methods of increasing the bioavailability of CETP inhibitors include adsorbing CETP inhibitors onto a porous matrix (see co-assigned PCT application No. WO03/00238A1) and providing a stable, amorphous form of CETP inhibitor with a concentration-enhancing polymer (see co-assigned PCT application No. WO03/00294A 1).

Designing dosage forms of CETP inhibitors in a solubility-improved form faces additional challenges. The CETP inhibitors in the solubility-improved form are generally used in increased dosage forms, such as tablets or capsules. Oral dosage forms are of great importance in a size that is easy to swallow, especially for elderly patients. It is also preferred that the number of dosage forms taken per time is small, preferably one unit, since many patients take multiple medications. Furthermore, ease of administration, i.e., once per day or twice per day, is important because patients taking multiple medications have difficulty remembering when and when the medication was taken during the day. In addition, some drugs such as CETP inhibitors are advantageously taken with meals, and the number of times per day is preferably minimized to simplify the requirements for taking with meals.

The above references show that there is a continuing need to find safe and effective methods of delivering a combination of an HMG-CoA reductase inhibitor and a CETP inhibitor.

Summary of The Invention

The present invention provides a dosage form comprising (1) a CETP inhibitor in a solubility-improved form and (2) an HMG-CoA reductase inhibitor, wherein the dosage form provides for immediate release of the HMG-CoA reductase inhibitor and controlled release of the CETP inhibitor.

Immediate release broadly means that at least 70 wt% of the HMG-CoA reductase inhibitor originally present in the dosage form is released within 1 hour or less after introduction into a use environment. Immediate release HMG-CoA reductase inhibitors may be achieved by any means known in the pharmaceutical art, including immediate release coatings, immediate release layers, and immediate release multiparticulates (multiparticulates) or granules.

Controlled release broadly refers to release of the CETP inhibitor at a slower rate than immediate release. Controlled release includes sustained release of the CETP inhibitor and sustained release after a delay period. Controlled release of the CETP inhibitor may be achieved by any means known in the pharmaceutical arts, including the use of matrix controlled release devices, osmotic controlled release devices, and multiparticulate controlled release devices. A device for the controlled release of CETP inhibitors is disclosed in more detail in commonly assigned, co-pending U.S. patent application No. 10/349,600, filed on 23/1/2003, entitled "controlled release pharmaceutical dosage forms of cholesteryl ester transfer protein inhibitors", the disclosure of which is incorporated herein by reference.

In a preferred embodiment, the dosage forms described herein release HMG-CoA reductase inhibitor and CETP inhibitor at a preferred rate.

In one embodiment, the CETP inhibitor is in the form of a matrix controlled release device. The HMG-CoA reductase inhibitor is in the form of an immediate release coating around the controlled release matrix device, or in the form of an immediate release layer associated with the controlled release matrix device.

In another embodiment, the CETP inhibitor is in the form of an osmotic controlled release device. An osmotic controlled release device includes (1) a core including a solubility-improved form of a CETP inhibitor and an osmotic agent, and (2) a non-dissolving, non-eroding coating surrounding the core. The HMG-CoA reductase inhibitor is in the form of an immediate release coating that surrounds the osmotic controlled release device.

In another embodiment, the dosage form comprises a three-layered tablet comprising (1) a composition comprising a CETP inhibitor; (2) a composition comprising an HMG-CoA reductase inhibitor, (3) a swellable-layer composition sandwiched between (1) and (2), and (4) a water permeable coating around (1), (2), and (3), wherein (1) is designed for controlled release of the CETP inhibitor and (2) is designed for immediate release of the HMG-CoA reductase inhibitor.

In another embodiment, the dosage form comprises a plurality of controlled release multiparticulates or granules comprising the solubility-improved form of the CETP inhibitor and a plurality of immediate release multiparticulates or granules comprising the HMG-CoA reductase inhibitor.

In another embodiment, the dosage form comprises a capsule comprising a controlled release device comprising a CETP inhibitor, the device selected from the group consisting of a matrix controlled release device, an osmotic controlled release device, and a controlled release multiparticulate. The capsules also include immediate release compositions containing HMG-CoA reductase inhibitors.

In another embodiment, the dosage form comprises a kit comprising at least two separate compositions: (1) a controlled release containing device comprising a solubility-improved form of a CETP inhibitor, and (2) an HMG-CoA reductase inhibitor comprising an immediate release form. The kit includes a device for containing the separate compositions.

In another aspect, the dosage forms of the present invention may be used to treat any condition that is treated by administration of a CETP inhibitor in combination with an HMG-CoA reductase inhibitor, such as those disclosed in commonly assigned, co-pending U.S. patent application No. 2002/0035125A1, the disclosure of which is incorporated herein by reference.

The foregoing and other objects, features and advantages of the invention will be more readily understood upon consideration of the following description of the invention taken in conjunction with the accompanying drawings.

Brief Description of Drawings

FIGS. 1-7 are schematic drawings of cross-sections of exemplary embodiments of dosage forms of the present invention.

Detailed description of the preferred embodiments

The present invention provides a dosage form comprising (1) a CETP inhibitor in a solubility-improved form and (2) an HMG-CoA reductase inhibitor, wherein the dosage form provides immediate release of the HMG-CoA reductase inhibitor and controlled release of the CETP inhibitor. As used herein, "immediate release" refers to release of at least 70 wt% of the HMG-CoA reductase inhibitor originally present in the dosage form within 1 hour or less after introduction into a use environment. By "controlled release" is meant that the CETP inhibitor is released at a slower rate than the immediate release. Particular embodiments may be in the form of a sustained release oral dosage form, or alternatively, in the form of a delayed release dosage form, or alternatively, an oral dosage form exhibiting a combination of sustained release and delayed release characteristics. The term "control" is a generic term for "sustained release" and "delay". Thus, "controlled release" includes sustained release of the CETP inhibitor as well as sustained release after a delay period. Sustained release features include dosage forms that release the CETP inhibitor in a 0-grade, 1-grade, mixed-grade, or other kinetic form.

"environment of use" may refer to in vivo fluids such as the GI tract, subcutaneous, intranasal, oral, intrathecal, ocular, otic, subcutaneous cavities, vaginal, arterial and venous blood vessels, pulmonary passages, or intramuscular tissues of animals such as mammals and especially humans, or test solutions of an in vitro environment such as Phosphate Buffered Saline (PBS), simulated intestinal buffer without enzymes (SIN), or simulated fasted duodenal (MFD) solutions. Suitable PBS solutions are the following aqueous solutions: comprises 20mM sodium phosphate (Na) ₂HPO₄) 47mM potassium phosphate (KH)₂PO₄) 87mM NaCl, and 0.2mM KCl, adjusted to pH 6.5 with NaOH. A suitable SIN solution is 50mM KH2PO adjusted to pH 7.4₄. A suitable MFD solution is the same PBS solution in which 7.3mM sodium taurocholate and 1.4mM 1-palmitoyl-2-oleyl-sn-glycero-3-phosphocholine are also present.

"administration" to a use environment refers to delivery of a drug by ingestion or swallowing or by other means when the use environment in vivo is the GI tract. One of ordinary skill in the art will appreciate that "administering" to other in vivo use environments refers to contacting the use environment with a composition of the invention using methods known in the art. See, e.g., Remington: the Science and Practice of Pharmacy, 20th edition (2000). Where the environment of use is in vitro, "administering" refers to placing or delivering the dosage form into an in vitro test vehicle.

The release rate, suitable dosage form, CETP inhibitor, solubility-improving form, and HMG-CoA reductase inhibitor are discussed in more detail below.

Release rate

The dosage form of the present invention provides (1) an immediate release HMG-CoA reductase inhibitor and (2) a controlled release solubility-improved form of a CETP inhibitor. As previously mentioned, immediate release refers to release of at least 70 wt% of the HMG-CoA reductase inhibitor originally present in the dosage form within 1 hour or less after introduction into a use environment. The rate at which the HMG-CoA reductase inhibitor is released from the dosage form is expressed as the percentage of HMG-CoA reductase inhibitor that is released 1 hour after administration of the dosage form to the environment of use, relative to that originally present in the dosage form. A dosage form is within the scope of the present invention if, 1 hour after administration of the dosage form to a use environment, the dosage form has released at least 70 wt.% of the HMG-CoA reductase inhibitor originally present in the dosage form. Preferably, the dosage form has released at least 80 wt% 1 hour after administration of the dosage form to a use environment, and more preferably at least 90 wt% 1 hour.

The dosage forms of the present invention provide controlled release of the CETP inhibitor, meaning that the dosage forms release the CETP inhibitor at a slower rate than the immediate release. The release of the CETP inhibitor from a dosage form of the present invention may be expressed as the duration of time between introduction of the dosage form to the environment of use and 70% of the time that the CETP inhibitor remains in the dosage form. The description of the rate of release of CETP inhibitors is complicated by the fact that: the dosage form may have an initial lag time with little or no release occurring, and may release the CETP inhibitor on a 0-order, 1-order, mixed-order, or other kinetic basis. To avoid confusion, we express the release rate as the duration between introduction of the dosage form into the environment of use and 70% of the time that the CETP inhibitor is leaving the dosage form. The description applies to all dosage forms that release a CETP inhibitor, regardless of the morphology of the percent release-time curve and including sustained release dosage forms as well as dosage forms that exhibit sustained release after an initial lag time. Thus, "controlled release" of a CETP inhibitor refers to a dosage form that releases less than 70 wt% of the CETP inhibitor originally present in the dosage form after introduction to a use environment for 1 hour. "sustained release" refers to a dosage form in which the CETP inhibitor is slowly released over time after administration to an environment of use. Dosage forms that release 70 wt% of the CETP inhibitor originally present in the dosage form at any 1 hour period after introduction to the use environment are not considered sustained release dosage forms.

Thus, the time to release 70 wt% of the CETP inhibitor originally present in the dosage form is greater than about 1 hour. In one embodiment, the time to release 70% of the CETP inhibitor initially present in the dosage form is at least about 2 hours, preferably at least about 3 hours, more preferably at least about 4 hours.

However, the release of the CETP inhibitor from the dosage form should not be too slow. Thus, it is also preferred that the time to release 70% of the CETP inhibitor initially present in the dosage form is about 24 hours or less, more preferably about 20 hours or less, and most preferably about 18 hours or less.

The release of CETP inhibitor from a dosage form may also be expressed as the average rate of release of CETP inhibitor per hour over a period of time, defined as the wt% CETP inhibitor in the dosage form released over a period of time divided by the time (hours) sustained over the period of time. For example, if after 16 hours, the dosage form releases 70 wt% of the CETP inhibitor originally present in the dosage form, the average rate of release of the CETP inhibitor is 4.4 wt%/hour (70 wt%/16 hours). Although the average rate of release can be calculated using any period of time introduced into the environment of use, the time generally used is the time required to release 70 wt% of the CETP inhibitor originally present in the dosage form.

Thus, the dosage forms of the present invention have an average CETP inhibitor release rate of less than about 70 wt%/hour. Preferably, the dosage form of the present invention releases the CETP inhibitor at an average rate of about 35 wt%/hour or less, more preferably about 23 wt%/hour or less, and even more preferably about 17.5 wt%/hour or less. It is also preferred that the dosage form of the present invention releases the CETP inhibitor at an average rate of about 2.9 wt%/hour or more, preferably about 3.5 wt%/hour or more, more preferably about 3.9 wt%/hour or more.

The dosage forms of the present invention provide controlled release of the CETP inhibitor relative to an immediate release control dosage form consisting of an equivalent amount of the same solubility-improved form of the CETP inhibitor formulated as an oral powder for reconstitution. In one embodiment, when the use environment is the GI tract of a mammal, the dosage form provides a time to reach a maximum blood concentration (Tmax) in the mammal after administration that is longer than an immediate release control dosage form. Preferably, the Tmax in blood is at least about 1.25-fold longer than the immediate release control dosage form, preferably at least about 1.5-fold longer, and more preferably at least about 2-fold longer. In addition, the maximum drug concentration in blood (Cmax) is less than or equal to 80%, and immediate release control dosage forms that may be less than or equal to 65%, or even less than or equal to 50% provide Cmax. Tmax and Cmax may be compared in fed or fasted conditions, and the dosage form meets the above criteria in at least one of fed or fasted conditions, and preferably in both conditions.

In another aspect, the dosage forms of the present invention provide a controlled release CETP inhibitor that, upon oral administration, causes one or more of the following effects: (a) about 50% or more, preferably about 70% or more, more preferably about 80% or more, even more preferably about 90% or more of plasma CETP over about 12 hours or more, preferably about 16 hours or more; more preferably for about 24 hours or more; (b) a reduction in mean plasma Cmax of 20% or more relative to a dosage form providing an immediate release of an equivalent amount of the solubility-improved form of the CETP inhibitor; (c) (ii) an average increase in HDL cholesterol level of about 20% or more after 8 weeks of administration; and (d) an average decrease in LDL cholesterol levels of about 10% or greater after 8 weeks of administration. In other words, the dosage form, upon administration to an in vivo environment of use, provides at least one of: (i) at least 50% inhibition of plasma cholesteryl ester transfer protein for a period of at least 12 hours; (ii) a maximum plasma concentration of less than or equal to 80% of that provided by a dosage form of an equivalent solubility-improved form of a CETP inhibitor that provides immediate release; (iii) 8 weeks after administration, the mean HDL cholesterol level is at least about 1.2-fold that obtained prior to administration; and (iv) a mean LDL cholesterol level of less than or equal to about 90% prior to administration 8 weeks after administration.

The preferred embodiment exhibits both of the above effects. More preferred embodiments show 3 and 4 of the above effects.

The dosage forms of the present invention may be administered to human patients who are fed or fasted. Preferably in a fed state.

Preferred CETP inhibitor doses and CETP inhibitor release rates from dosage forms of the present invention may be determined using Pharmacokinetic (PK) models for individual CETP inhibitors, or using clinical trials familiar to those of ordinary skill in the art (i.e., in human subjects or patients). The PK model can also be used to predict Cmax and release rate for various doses of CETP inhibitor to determine the dose and release rate that decreases Cmax by 20% or more relative to an equivalent immediate release dosage form.

In one aspect, when the CETP inhibitor is [2R, 4S ]4- [ (3, 5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino ] -2-ethyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (also known as torcetrapib), the dosage forms of the invention, when administered orally, cause one or more of the following effects: (a) plasma concentrations of torcetrapib exceed about 70ng/ml, preferably about 110ng/ml, more preferably about 160ng/ml, even more preferably about 325ng/ml, over a time period of about 12 hours or more, preferably 16 hours or more, more preferably about 24 hours or more; (b) inhibition of plasma CETP by about 50% or more, preferably about 70% or more, more preferably about 80% or more, even more preferably about 90% or more, for a period of about 12 hours or more, preferably about 16 hours or more, more preferably about 24 hours or more; and (c) a 20% or greater decrease in mean plasma Cmax relative to an equivalent solubility-improved form of the torcetrapib dosage form that provides immediate release; (d) (ii) an average increase in HDL cholesterol level of about 20% or greater after 8 weeks of administration; and (e) an average decrease in LDL cholesterol levels of about 10% or greater after 8 weeks of administration.

The preferred embodiment shows both of the above effects. More preferred embodiments exhibit three or more of the above effects.

The dosage form of the invention comprising torcetrapib may be administered to human patients who are fed or fasted. Preferably in a fed state.

The dosage forms of the present invention are administered up to twice a day ("BID"), preferably once a day ("QD"). This aspect is achieved depending on the CETP inhibitor dose and the release rate of the CETP inhibitor from the dosage form

Details of the desired release profile of CETP inhibitors are disclosed in more detail in commonly assigned, co-pending U.S. patent application No. 10/349,600, filed on 23/1/2003, entitled "controlled release pharmaceutical dosage forms for cholesteryl ester transfer protein inhibitors", the disclosure of which is incorporated herein by reference.

In vitro tests can be used to determine whether a dosage form provides release properties within the scope of the present invention. In vitro tests are well known in the art. In vitro tests are designed to mimic the behavior of the dosage form in vivo. An example is the so-called "direct" test, in which the dosage form is placed in a stirred USP type 2 disoette bottle containing 900mL of dissolution vehicle, such as a buffered solution (10mM HCl, 100mM NaCl, pH 2.0, 261mOsm/kg) or the previously described PBS or MFD solution, maintained at 37 ℃. One of ordinary skill in the art will appreciate that in these tests, the dissolution vehicle need not serve as a receptacle for the drug in the dosage form. This is particularly true for osmotic dosage forms in which the rate at which undissolved drug is expressed from the osmotic dosage form is not substantially affected by the drug dissolved in the dissolution vehicle. However, for dosage forms that deliver the drug in a dissolved state, it is preferred to select an elution vehicle in which the drug solubility in the vehicle multiplied by the volume of the vehicle exceeds the total amount of drug administered; that is, the vehicle should act as a receptor for the drug. By "sink" is meant that the composition and volume of the dissolution vehicle is sufficient that an equivalent amount of the drug alone in the dosage form will dissolve in the dissolution vehicle. Preferably, the composition and volume of the dissolution vehicle is sufficient that an amount of drug equivalent to at least about 2-fold of the dosage form will dissolve in the dissolution vehicle. In most cases, the CETP inhibitor is very insoluble in the aqueous vehicle, and a surfactant, such as sodium lauryl sulfate or other excipient, may be added to the dissolution vehicle to increase the solubility of the drug and ensure that the dissolution vehicle acts as a receptor for the drug. The dosage form is placed in the dissolution vehicle and the vehicle is agitated with a paddle at a rotational speed of 50 rpm. When the dosage form is a tablet, capsule or other solid dosage form, the dosage form may be held in a wire support to hold the dosage form off the bottom of the flask so that all of its surface is exposed to the dissolution medium. Samples of dissolved vehicle were taken at intervals using an automated sampling of dissoette with an automated receiving solution replacement of VanKel VK 8000. The concentration of drug dissolved in the dissolution vehicle is then determined by comparing the UV absorption of the sample to the absorption of a drug standard using High Performance Liquid Chromatography (HPLC). From the concentration of drug in the dissolution vehicle and the volume of the vehicle, the amount of drug dissolved in the vehicle is then calculated, taking into account the amount of drug initially present in the dosage form, and this value is used to calculate the actual amount of drug released from the dosage form.

The dosage forms of the present invention may also be evaluated using the "residue test" using the following procedure. Each of the many dosage forms was placed in a separate stirred USP type 2 disoette flask containing 900mL of simulated gastric or intestinal environment buffer solution at 37 ℃. After a given time interval, the dosage form was removed from the flask, the released material was removed from the surface of the dosage form, and the dosage form was cut in half and placed in 100mL of recovery solution described below. For the first 2 hours, the dosage form is stirred in 25mL of acetone or other solvent suitable for dissolving any coating on the dosage form. Next, 125mL of methanol was added and stirring was continued overnight at ambient temperature to dissolve the drug remaining in the dosage form. About 2mL of the recovered solution was removed and centrifuged, and 250mL of the supernatant was added to the HPLC tube and diluted with 750mL of methanol. The residual drug was then analyzed by HPLC. The amount of drug remaining in the dosage form is subtracted from the total amount of drug originally present in the dosage form to yield the released amount at each time interval.

Alternatively, in vivo testing may be used to determine whether a dosage form provides drug release properties within the scope of the present invention. However, due to the difficulties and complexity inherent in vivo procedures, it is preferred that in vitro procedures be used to evaluate dosage forms even though the ultimate environment of use is typically the human GI tract. In vitro testing as described above is expected to approximate in vivo behavior and dosage forms that meet the in vitro release rates described herein are within the scope of the invention. The dosage form is administered to a group of subjects, such as humans, and drug release and drug absorption are monitored by the following routes: (1) periodically drawing blood and measuring the serum or plasma concentration of the drug, or (2) measuring the amount of drug remaining in the dosage form after it is expelled from the anus (residual drug) or (3) both (1) and (2). In the second method, residual drug is determined by the following method: the dosage form is recovered after discharge from the anus of the subject and the drug remaining in the dosage form is measured using the same procedure described above for the in vitro residue test. The difference between the amount of drug in the initial dosage form and the amount of residual drug is a measure of the amount of drug released during the mouth-to-anus passage. This test is limited in use as it provides only a single point in time for drug release, but can be used to demonstrate a correlation between in vitro and in vivo release.

In one method of monitoring drug release and absorption in vivo, serum or plasma drug concentrations are plotted along the ordinate (y-axis) against blood sampling time along the abscissa (x-axis). The data can then be analyzed using conventional analysis to determine the drug release rate, such as Wagner-Nelson or Loo-Riegelman analysis. See also Welling, "Pharmacokinetics: processes and materials "(acsmograph 185, amer. chem. soc., Washington, d.c., 1986). Data processing in this manner yields an apparent in vivo drug release profile.

Dosage forms

The dosage forms of the present invention provide controlled release of a CETP inhibitor in a solubility-improved form and immediate release of an HMG-CoA reductase inhibitor. Controlled release of CETP inhibitors is desirable for several reasons. There is often a need for a method of reducing the maximum CETP inhibitor concentration (Cmax) in plasma after administration, but still providing good bioavailability to reduce undesirable side effects, relative to an immediate release dosage form containing an equivalent amount of CETP inhibitor. Furthermore, it is important to facilitate the administration of CETP inhibitors, i.e. once daily (QD) or twice daily (BID), because it is difficult for patients taking multiple drugs to remember which drug was taken at what time of day. In addition, it is advantageous to administer certain drugs, such as CETP inhibitors, with the meal, and it is preferable to minimize the number of times the drug is administered per day to simplify the requirement for the drug to be administered with the meal.

The CETP inhibitor in a solubility-improved form that provides controlled release may be any device or set of devices known in the pharmaceutical art that delivers a drug in a controlled manner. Controlled release refers to the slow release of a solubility-improved form of a CETP inhibitor into the environment of use. The solubility-improved form of the CETP inhibitor may be delivered to the environment of use in the form of a suspension, i.e., a plurality of small particles comprising a controlled release means for dissolving the drug in the environment of use at a controlled rate. Exemplary controlled release devices include matrix controlled release devices, osmotic controlled release devices, and multiparticulate controlled release devices. The controlled release device may or may not dissolve itself.

Immediate release HMG-CoA reductase inhibitors are also desirable. Many HMG-CoA reductase inhibitors have a half-life of 20 hours or more. Immediate release of the HMG-CoA reductase inhibitor may be achieved by any means known in the pharmaceutical art. Exemplary methods include immediate release coatings, immediate release layers, immediate release multiparticulates or granules, and immediate release tablets, capsules, or pills. The immediate release composition may include HMG-CoA reductase inhibitor alone or in admixture with excipients or other substances to assist in the formation of the dosage form.

The present invention includes any dosage form, controlled release devices in combination with CETP inhibitors and immediate release devices for HMG-CoA reductase inhibitors. The devices described may be combined as desired to achieve the desired release characteristics disclosed herein. Controlled release devices, immediate release devices, and exemplary dosage forms of the present invention are discussed below.

Controlled release device

The device for providing controlled release of the solubility-improved form of the CETP inhibitor may be any device or set of devices known in the pharmaceutical art that delivers a drug in a controlled manner. Exemplary devices include erodible (erodible) and non-erodible matrix controlled release devices, osmotic controlled release devices, and multiparticulate controlled release devices.

Controlled matrix release device

In one embodiment, a solubility-improved form of a CETP inhibitor is incorporated into an eroding or non-eroding polymeric matrix controlled release device. An erodible matrix refers to an aqueous-erodible or water-swellable or aqueous-soluble matrix in the sense of being erodible or swellable or soluble in pure water, or requiring the presence of an acid or base to ionize the polymer matrix sufficiently to cause erosion or dissolution. When contacted with an aqueous use environment, the eroding polymer matrix absorbs water and forms an aqueous-swollen gel or "matrix" that traps the solubility-improved form of the CETP inhibitor. The water-swellable matrix gradually erodes, swells, disintegrates or dissolves in the use environment, thereby controlling the release of the CETP inhibitor into the use environment. Examples of such devices are more fully disclosed in commonly assigned co-pending U.S. patent application No. 09/495,059, filed on month 1 and 31 of 2000, which claims priority from provisional patent application No. 60/119,400 filed on month 2 and 10 of 1999, the relevant disclosure of which is incorporated herein by reference.

The eroding polymer matrix, into which the solubility-improved form of the CETP inhibitor is incorporated, may be generally described as a group of excipients that, upon formation, mix with the solubility-improved form, absorb water upon contact with an aqueous use environment and form a water-swollen gel or "matrix" that entraps the drug form. Drug release can occur by a variety of mechanisms: the matrix may be disintegrated or dissolved around particles (particles) or granules (granules) of the drug in a solubility-improved form; or the drug may dissolve in the absorbed aqueous solution and diffuse from the tablet, bead or granule of the device. The key component of such water-swellable matrices are water-swellable, erodible, or soluble polymers, which may be generally described as osmopolymers, hydrogels, or water-swellable polymers. The geopolymer may be linear, branched, or crosslinked. It may be a homopolymer or a copolymer. Most preferably it is a naturally occurring polymer such as a derivative of a polysaccharide or protein, although it may be a synthetic polymer derived from vinyl, acrylate, methacrylate, urethane, ester and oxide monomers.

The substance includes naturally occurring polysaccharides such as chitin, chitosan, dextran and pullulan; gum agar, gum arabic, karaya gum, locust bean gum, tragacanth gum, carrageenan, ghatti gum, guar gum, xanthan gum, and scleroglucan; starches such as dextrin and maltodextrin; hydrocolloids such as gums; phospholipids such as lecithin; alginates such as ammonium, sodium, potassium or calcium alginate, propylene glycol alginate; gelatin; collagen; and cellulose. "cellulosic" refers to a cellulosic polymer that has been modified by reacting at least a portion of the hydroxyl groups on the saccharide repeat units with a compound to form ester-linked or ether-linked substituents. For example, the ethylcellulose of cellulose has ether-linked ethyl substituents attached to the sugar repeat units, while the cellulose acetate of cellulose has ester-linked acetoxy substituents.

A preferred class of cellulose for the eroding matrix includes aqueously-soluble and aqueously-eroding celluloses such as Ethyl Cellulose (EC), Methyl Ethyl Cellulose (MEC), Carboxy Methyl Cellulose (CMC), CMEC, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), Cellulose Acetate (CA), Cellulose Propionate (CP), Cellulose Butyrate (CB), Cellulose Acetate Butyrate (CAB), CAP, CAT, hydroxypropyl methyl cellulose (HPMC), HPMCP, HPMCAS, hydroxypropyl methyl cellulose acetate trimellitate (HPMCAT), and ethyl hydroxyethyl cellulose (EHEC). A particularly preferred class of cellulose comprises HPMC in various grades of low viscosity (MW less than or equal to 50,000 daltons) and high viscosity (MW greater than 50,000 daltons). Commercially available low viscosity HPMC polymers include the Dow METHOCEL series E5, E15LV, E50LV and K100LY, although high viscosity HPMC polymers include E4MCR, E10MCR, K4M, K15M and K100M; the K series of METHOCEL (trade Mark) is particularly preferred in this group. Other commercially available types of HPMC include Shin Etsu METOLOSE 90SH series.

Although the main role of the eroding matrix material is to control the rate of release of the CETP inhibitor in a solubility-improved form into the environment of use, the inventors have found that the choice of matrix material has a great influence on the maximum concentration achieved by the device as well as on maintaining a high drug concentration. In one embodiment, the matrix material is a concentration-enhancing polymer as defined below.

Other materials that may be used as the matrix material for erosion include, but are not limited to, pullulan, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, glycerol fatty esters, polyacrylamide, polyacrylic acid, copolymers of ethacrylic acid or methacrylic acid (EUDRAGIT ®, Rohmamerica, Inc., Piscataway, New Jersey) and other acrylic acid derivatives such as butyl methacrylate, methyl methacrylate, ethyl acrylate, (2-dimethylaminoethyl) methacrylate, and homopolymers and copolymers of (trimethylaminoethyl) methacrylate chloride.

The eroding matrix polymer may contain a variety of additives and excipients well known in the pharmaceutical art of the same type, including osmopolymers, osmagens, solubility-enhancing or-retarding agents, and excipients that facilitate stability or device processing.

Alternatively, the compositions of the present invention may be administered using or incorporated into a non-eroding matrix device. In such a device, the CETP inhibitor in a solubility-improved form is distributed in an inert matrix. The drug is released by diffusion through an inert matrix. Examples of materials suitable for the inert matrix include insoluble plastic articles such as methacrylate-methylmethacrylate copolymers, polyvinyl chloride, and polyethylene; hydrophilic polymers such as ethyl cellulose, cellulose acetate, and crosslinked polyvinylpyrrolidone (also known as crospovidone); and fatty compounds such as carnauba wax, microcrystalline wax, and triglycerides. The apparatus is also described in Remington: the Science and practice of Pharmacy, 20 th edition (2000).

The matrix controlled release device can be prepared as follows: mixing together the solubility-improved form of the CETP inhibitor and other excipients, and then forming the mixture into a tablet, troche, pill, or other device formed using a compression force. The compression device may be formed using any of a variety of compression apparatus used in the preparation of pharmaceutical devices. Examples include single-punch presses, rotary tablet presses, and multi-layer rotary tablet presses, all of which are well known in the art. See, e.g., Remington: the Science and Practice of Pharmacy, 20 th edition, 2000. The compressed device can be any shape including round, oval, oblong, cylindrical, or triangular. The upper and lower surfaces of the pressing device may be flat, spherical, concave, or convex.

When formed using pressing, the device preferably has a force of at least 5 kilogram force (Kp)/cm²And more preferably at least 7Kp/cm². Here, "strength" is the breaking force, also known as the "hardness" of a broken tablet formed from a substance, the force required to separate the tablet from its largest cross-section perpendicular to the tablet. The breaking force can be measured using a Schleuniger tablet hardness tester Model 6D. The compression force required to achieve this strength depends on the size of the tablet, but is generally greater than about 5kP/cm ². Brittleness is a well-known measure of the resistance of a device to surface wear, and measures the weight loss after the device is subjected to a standard agitation step. The brittleness value of 0.8-1.0% is an acceptable upper limit. The device has a height of more than 5kP/cm²Is generally very hard, has a brittleness of less than 0.5%,

other methods of forming matrix controlled release devices are well known in the pharmaceutical arts. See, e.g., Remington: the Science and Practice of Pharmacy, 20 th edition, 2000.

Osmotic controlled release device

Alternatively, a solubility-improved form of the CETP inhibitor may be incorporated into an osmotic controlled release device. The device has at least two components: (a) a tablet core comprising an osmotic agent and a CETP inhibitor in a solubility-improved form; and (b) a water permeable, non-dissolving and non-eroding coating surrounding the core which controls the flow of water from the aqueous environment of use into the core to cause release of the drug by extruding part or all of the core into the environment of use. The osmotic agent contained in the core of the device may be an aqueous-swellable hydrophilic polymer or it may be osmogen, also known as osmagent. The coating is preferably polymeric, water-permeable, and has at least one delivery opening. Examples of such devices are more fully disclosed in commonly assigned co-pending U.S. patent application No. 09/495,061 filed on 31/1/2000, which claims priority to provisional patent application No. 60/119,406 filed on 10/2/1999, the relevant disclosure of which is incorporated herein by reference.

In addition to the solubility-improved form of the CETP inhibitor, the core of the osmotic device optionally includes an "osmotic agent". "osmotic agent" refers to any agent that generates a driving force to transport water from the environment of use to the core of the device. Exemplary osmotic agents are water-swellable hydrophilic polymers, and osmogens (or osmagens). Thus, the core may comprise water-swellable hydrophilic polymers, ionic as well as non-ionic, commonly known as "osmopolymers" and "hydrogels". The amount of water-swellable hydrophilic polymer in the tablet core ranges from about 5 to about 80 wt%, preferably 10 to 50 wt%. Exemplary materials include hydrophilic vinyl and acrylic polymers, polysaccharides such as calcium alginate, polyethylene oxide (PEO), polyethylene glycol (PEG), polypropylene glycol (PPG), poly (2-hydroxyethyl methacrylate), poly (acrylic acid) acid, poly (methacrylic acid) acid, polyvinylpyrrolidone (PVP), and crosslinked PVP, polyvinyl alcohol (PVA), PVA/PVP copolymers, and PVA/PVP copolymers with hydrophobic monomers such as methyl methacrylate, vinyl acetate, and the like, hydrophilic polyurethanes containing large PEO blocks, crosslinked sodium carboxymethylcellulose, carrageenan, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), carboxymethyl cellulose (CMC), and carboxyethyl cellulose (CEC), sodium alginate, polycarbophil, gelatin, xanthan gum, and sodium starch glycolate. Other materials include hydrogels comprising an interpenetrating network of polymers, which may be formed by addition or condensation polymerization, and whose constituents may include hydrophilic and hydrophobic monomers such as those just mentioned. Preferred polymers for use as the water-swellable hydrophilic polymer include PEO, PEG, PVP, croscarmellose sodium, HPMC, sodium starch glycolate, polyacrylic acid, and cross-linked forms or mixtures thereof.

The core may also comprise osmogen (or osmagent). The amount present in the tablet core ranges from about 2 to about 70 wt%, preferably 10 to 50 wt%. Typical types of suitable osmogens are water-soluble organic acids, salts and sugars which are able to absorb water through the surrounding coating barrier, thereby creating an osmotic pressure gradient. Typical useful osmogens include magnesium sulfate, magnesium chloride, calcium chloride, sodium chloride, lithium chloride, potassium sulfate, sodium carbonate, sodium sulfite, lithium sulfate, potassium chloride, sodium sulfate, mannitol, xylitol, urea, sorbitol, cellophane, raffinose, sucrose, glucose, fructose, lactose, citric acid, succinic acid, tartaric acid, and mixtures thereof. Particularly preferred osmogens are glucose, lactose, sucrose, mannitol, xylitol and sodium chloride.

The core may include various additives and excipients that enhance the performance or stability of the dosage form, tableting or processing. The additives and excipients include tableting aids, surfactants, water-soluble polymers, pH adjusters, fillers, binders, pigments, disintegrants, antioxidants, lubricants, and flavoring agents. Examples of such ingredients are microcrystalline cellulose; metal salts of acids such as aluminum stearate, calcium stearate, magnesium stearate, sodium stearate, and zinc stearate; pH control agents such as buffers, organic acids and organic acid salts, and organic and inorganic bases; fatty acids, hydrocarbons and fatty acids such as stearic acid, palmitic acid, liquid paraffin, stearyl alcohol, and palmitol (palmitol); fatty acid esters such as glyceryl (mono-and di-) stearate, triglycerides, glyceryl (palmitoyl stearyl) ester, sorbitan esters such as sorbitan monostearate, sucrose monopalmitate, and sodium stearyl fumarate; polyoxyethylethylene sorbitan esters; surfactants such as alkyl sulfuric acids such as sodium lauryl sulfate and magnesium lauryl sulfate; polymers such as polyethylene glycol Polyoxyethylene glycol, polyoxyethylene and polyoxypropylene ethers and copolymers thereof, and polytetrafluoroethylene; and inorganic materials such as talc and calcium hydrogen phosphate; a cyclodextrin; sugars such as lactose and xylitol; and sodium starch glycolate. An example of a disintegrant is sodium starch glycolate (e.g., Explotab @)^TM) Microcrystalline cellulose (e.g., Avicel)^TM) Microcrystalline silicified cellulose (e.g., ProSolv)^TM) Croscarmellose sodium (e.g., Ac-Di-Sol)^TM)。

When the solubility-improved form is a solid amorphous dispersion formed by a solvent process, the additive may be added directly to the spray-dried solution to dissolve or suspend the additive in the solution as a slurry when the CETP inhibitor/concentration-enhancing polymer dispersion is formed. Alternatively, the additives may be added after the spray drying step to aid in the formation of the final controlled release device. The solubility-enhancing and other additives may also be combined with other solubility-enhancing forms of CETP inhibitors.

One embodiment of an osmotic device consists of one or more drug layers comprising a solubility-improved form of a CETP inhibitor, such as a solid amorphous drug/polymer dispersion, and an expandable layer comprising a water-swellable polymer, a drug layer, and a coating around the expandable layer. Each layer may contain other excipients such as tableting aids, osmagents, surfactants, water-soluble polymers and water-swellable polymers.

The osmotic delivery device can be manufactured in a variety of geometries, including two layers, wherein the core comprises a drug layer and an expandable layer adjacent to each other; three layers, wherein the core comprises an expandable layer "sandwiched" between two drug layers; and concentric, wherein the core comprises a central expandable composition surrounded by a drug layer.

The coating of the tablet comprises a membrane that is permeable to water but substantially impermeable to the drug and excipients contained therein. The coating comprises one or more outlet channels or outlets for communicating with a drug-containing layer for delivering the pharmaceutical composition. The drug-containing layer of the core comprises the pharmaceutical composition (including optional osmagents and hydrophilic-soluble polymers), while the expandable layer consists of an expandable hydrogel, with or without other osmotic agents.

When placed in an aqueous vehicle, the tablet absorbs water through the membrane, causing the composition to form an unnecessary aqueous composition, and causing the hydrogel layer to swell and push out the drug-containing composition, leaving the composition to exit the outlet channel. The composition is capable of swelling, helping to keep the drug out of the channel. The drug is delivered from this type of delivery system, either dissolved or dispersed in the composition exiting the outlet channel.

The rate of drug delivery is determined by factors such as the permeability and thickness of the coating, the osmotic pressure of the drug-containing layer, the degree of hydrophilicity of the hydrogel layer, and the surface area of the device. One of ordinary skill in the art will recognize that increasing the thickness of the coating will decrease the release rate, while any of the following will increase the release rate: a coating to increase permeability; increasing the hydrophilicity of the hydrogel layer; increasing the osmotic pressure of the drug-containing layer; or to increase the surface area of the device.

Exemplary materials for forming drug-containing compositions include HPMC, PEO, and PVP, as well as other pharmaceutically acceptable carriers, in addition to the solubility-improved form of the CETP inhibitor itself. In addition, osmagents such as sugars or salts, in particular sucrose, lactose, xylitol, mannitol, or sodium chloride, can be added. Materials used to form the hydrogel layer include sodium CMC, PEO, poly (acrylic acid), (polyacrylate) sodium, croscarmellose sodium, sodium starch glycolate, PVP, crosslinked PVP, and other high molecular weight hydrophilic materials. Particularly useful are PEO polymers having a weight average molecular weight of about 5,000,000 to about 7,500,000 daltons.

In the case of a two-layer geometry, the delivery port or exit passage may be located on the side of the tablet containing the pharmaceutical composition, or may be located on both sides of the tablet or even on the sides of the tablet to connect the drug layer and expandable layer to the exterior of the device. The exit passage may be created by mechanical means or laser drilling, or by special processing during tablet compression to create difficult to coat areas on the tablet or by other means.

Osmotic devices may also be prepared using a uniform core surrounded by a semipermeable membrane coating, as described in U.S. patent No. 3,845,770. The CETP inhibitor in a solubility-improved form may be incorporated into the tablet core and the semipermeable membrane coating may be carried out by conventional tablet-coating techniques, such as with a pan-coater. Drug delivery channels in the coating are then formed by drilling holes in the coating, or by laser or mechanical means. Alternatively, the channels may be formed by breaking a portion of the coating or, as described above, in areas of the tablet that are difficult to coat.

Particularly useful embodiments of osmotic devices include: (a) the single-laminate tablet core comprises: (i) a CETP inhibitor in a solubility-improved form, (ii) hydroxyethyl cellulose, and (iii) osmagent, wherein the hydroxyethyl cellulose is present in the core tablet in an amount of about 2.0% to about 35% by weight and the osmagent is present in an amount of about 15% to about 70% by weight; (b) a water-permeable layer surrounding the core; and (c) at least one channel is present in layer (b) to deliver the drug to the fluid environment surrounding the tablet. In a preferred embodiment, the device is shaped so that the surface area to volume ratio (water-expanded tablet) is greater than 0.6mm ^-1(ii) a More preferably greater than 1.0mm^-1. Preferably the channel connecting the core to the fluid environment is located on the side of the tablet (band area). A particularly preferred shape is an oval shape, wherein the ratio of the tablet processing axes, i.e. the ratio of the major and minor axes defining the tablet shape, is between 1.3 and 3; more preferably between 1.5 and 2.5. In one embodiment, the combination of the drug in a solubility-improved form and osmagent has an average ductility of about 100 to about 200MPa, an average tensile strength of about 0.8 to about 2.0MPa, and an average brittle fracture index of less than about 0.2. The single-layer tablet core may optionally include a disintegrant, a bioavailability-enhancing additive, and/or a pharmaceutically acceptable excipient, carrier or diluent. The device is more fully disclosed in co-owned co-pending U.S. provisional patent application No. 60/353,151The title "osmotic delivery system," the disclosure of which is incorporated herein by reference.

Entrainment of particles of the CETP inhibitor in solubility-improved form in the extruded fluid during operation of the osmotic device is highly desirable. For well-entrained particles, the drug form is preferably well dispersed in the fluid before the particles have a chance to settle in the tablet core. One means of achieving this is to add a disintegrant to assist in the disintegration of the compressed tablet core into the granular component. Examples of standard disintegrants include materials such as sodium starch glycolate (e.g., Explotab @) ^TMCLV), microcrystalline cellulose (e.g., Avicel)^TM) Microcrystalline silicified cellulose (e.g., ProSolv)^TM) And croscarmellose sodium (e.g., Ac-Di-Sol)^TM) And other disintegrants known to those of ordinary skill in the art. Depending on the particular formulation, some disintegrants perform better than others. Several disintegrants tend to form gels when they swell in water, thus hindering drug delivery from the device. The non-gelling, non-swelling disintegrant provides faster dispersion of the drug particles in the core when water enters the core. Preferred non-gelling, non-swelling disintegrants are resins, preferably ion exchange resins. A preferred resin is Amberlite^TMIRP 88 (supplied by Rohm and Haas, Philadelphia, Pa.). When used, the disintegrant is present in an amount of about 1-25% of the core composition.

Particles in the form of a solubility-improving drug are suspended in the device by the addition of a water-soluble polymer and can then be delivered through the channels (e.g., pores). High viscosity polymers can be used to prevent settling. However, at relatively low pressures, the polymer-bound drug is extruded out of the channel. At a given extrusion pressure, the rate of extrusion generally slows as the viscosity increases. Some polymers combine particles of the solubility-improving drug form with water to form a high viscosity solution, but still capable of being extruded from a tablet at relatively low forces. In contrast, polymers with low weight-average molecular weights (< about 300,000) do not form solutions of sufficient viscosity inside the tablet core to be completely delivered due to settling of the particles. When the device is made without the addition of polymer, settling of the particles can be problematic, resulting in poor drug delivery unless the tablet is constantly agitated to prevent settling of the particles in the core. Sedimentation also becomes a problem when the particles are large and/or the density is high so that the sedimentation rate increases.

Preferred water-soluble polymers for use in osmotic engines do not interact with the drug. Nonionic polymers are preferred. An example of a non-ionic polymer that forms a solution with high viscosity but is still extrudable at low pressure is Natrosol^TM250H (high molecular weight hydroxyethylcellulose supplied by Hercules Incorporated, Aqualon Division, Wilmington, DE; MW equal to about 1 million daltons and degree of polymerization equal to about 3,700). Natrosol at a concentration of as low as about 3% of the tablet core weight when combined with osmagent^TM250H provides effective drug delivery. Natrosol^TM250H NF is a high-viscosity grade of nonionic cellulose ether, soluble in hot or cold water. 1% Natrosol measured at 25 ℃ using Brookfield LVT (30rpm)^TMThe viscosity of the 250H solution is between about 1,500 and about 2,500 cps.

Preferred hydroxyethylcellulose polymers for use in these single layer osmotic tablets have a weight average molecular weight of about 300,000 to about 1.5 million. Typically the hydroxyethyl cellulose polymer is present in the core in an amount of about 2.0% to about 35% by weight.

Another example of an osmotic device is an osmotic capsule. The capsule shell or a portion of the capsule shell may be semipermeable. The capsules can be filled with a powder or a liquid consisting of: a CETP inhibitor in a solubility-improved form, an excipient that absorbs water to provide osmotic potential, and/or a water-swellable polymer, or optionally a solubilizing excipient. The capsule core may also be prepared to have a two-layer or multi-layer composition, similar to the two-layer, three-layer, or concentric geometries described above.

Another type of osmotic device useful in the present invention comprises a coated expandable tablet, as disclosed in EP 378404, incorporated herein by reference. Coated expandable tablets comprise a tablet core comprising a drug in a solubility-improved form and an expanding substance, preferably a hydrophilic polymer, coated with a film comprising holes, or pores, through which the hydrophilic polymer can extrude and carry out the pharmaceutical composition in an aqueous use environment. Alternatively, the film may comprise a polymer or a low molecular weight water-soluble "porogen". The porogen dissolves in the aqueous use environment, providing pores through which the hydrophilic polymer and drug can be extruded. Examples of pore formers are water-soluble polymers such as HPMC, PEG, and low molecular weight compounds such as glycerol, sucrose, glucose, and sodium chloride. In addition, holes are formed in the coating by drilling holes in the coating using a laser or other mechanical means. In this type of osmotic device, the membrane material may comprise any membrane-forming polymer, including water permeable or impermeable polymers, such that the membrane deposited on the tablet core is porous or contains a water-soluble pore former or has macroscopic pores to facilitate water ingress and drug release. Embodiments of such sustained release devices may also be multilayered, as described in EP 378404 a 2.

When the solubility-improved form of the CETP inhibitor is a liquid or oil, such as the lipid carrier formulations described herein, the osmotic controlled release device may include a soft-gel or gelatin capsule formed with a mixed wall and including a liquid formulation, wherein the wall includes a barrier layer formed on an outer surface of the capsule, an expandable layer formed on the barrier layer, and a semipermeable layer formed on the expandable layer. The delivery port connects the liquid formulation with an aqueous use environment. Such devices are more fully described in U.S. Pat. Nos. 6,419,952, 6,342,249, 5,324,280, 4,672,850, 4,627,850, 4,203,440, and 3,995,631, all of which are incorporated herein by reference.

The osmotic controlled release device of the present invention also includes a coating. The basic limitations for the coating of the osmotic engine are that it is water-permeable, has at least one drug delivery opening, and is insoluble and non-erodible during release of the drug formulation so that the drug is delivered substantially completely through the delivery opening or orifice, rather than primarily through the osmotic delivery of the coating substance itself. "delivery opening" refers to any passageway, opening or hole, whether drilled mechanically, with a laser, or formed by a hole during coating or formed in situ during use or destroyed during use. The coating should be present in an amount of about 5 to 30 wt%, preferably 10 to 20 wt% of the weight of the tablet core.

The preferred form of the coating is a semipermeable polymeric membrane which forms an orifice thereon either before or during use. The polymer film thickness may vary between about 20 and 800 μm, and is preferably in the range of 100 to 500 μm. The size of the delivery opening should generally be in the range of 0.1 to 3000 μm or more, preferably 50 to 3000 μm in diameter. The ports may be formed after coating by mechanical or laser drilling or may be formed in situ by disrupting the coating; the damage is controlled by deliberately adding relatively few weak moieties to the coating. The delivery outlet may also be formed in situ, by erosion of the plug of water-soluble substance or by disruption of the thinner portion of the coating over the breach of the core. In addition, the delivery outlet may be formed during the coating process, as is the case in the asymmetric membrane coating types disclosed in U.S. Pat. Nos. 5,612,059 and 5,698,220, the disclosures of which are incorporated herein by reference.

When the delivery opening is formed in situ by disrupting the coating, a particularly preferred embodiment is in the form of a collection of beads, the latter being essentially the same or different composition. The drug is primarily released from the beads upon disruption of the coating, and the release may be gradual or relatively abrupt after disruption. When the collection of beads has a variable composition, the composition can be selected such that the beads are destroyed at different times after administration, resulting in a sustained release of the overall release of the drug over a desired duration.

The coating may be dense, microporous, or "asymmetric," with dense regions supported by dense pore regions, such as those disclosed in U.S. Pat. nos. 5,612,059 and 5,698,220. When the coating is dense and the coating is formed of a water-permeable substance. When the coating is porous, it may be formed of either a water-permeable or water-impermeable substance. When the coating is formed of a porous water-impermeable material, water permeates through the pores of the coating as a liquid or vapor.

Examples of osmotic devices utilizing a dense coating include U.S. Pat. Nos. 3,995,631 and 3,845,770, the disclosures of which are directed to dense coatings, and which are incorporated herein by reference. The dense coating is permeable to external fluids such as water and may be formed from any of the materials mentioned in these patents as well as other water-permeable polymers disclosed in the art.

The film may also be apertured as disclosed in U.S. patent nos. 5,654,005 and 5,458,887, or even formed from water-resistant polymers. Another suitable method for forming a coating from a mixture of a water-insoluble polymer and a leachable water-soluble additive is described in U.S. patent 5,120,548, the relevant disclosure of which is incorporated herein by reference. Apertured films can also be formed by the addition of an aperture-forming agent, as disclosed in U.S. Pat. No. 4,612,008, the relevant disclosure of which is incorporated herein by reference.

Furthermore, the vapor-permeable coating may even be formed from an extremely hydrophobic material such as polyethylene or polyvinylidene fluoride, and when dense, is substantially water-impermeable, provided that the coating is porous

Substances used to form the coating include acrylic, vinyl, ether, polyamide, polyester and cellulose derivatives of varying grades that are water-permeable and water-insoluble at physiologically relevant pH, or readily rendered water-insoluble by chemical changes such as by cross-linking.

Specific examples of suitable polymers (or cross-linked forms) that can be used to form the coating include plasticized, unplasticized, and reinforced Cellulose Acetate (CA), cellulose diacetate, cellulose triacetate, CA propionate, cellulose nitrate, Cellulose Acetate Butyrate (CAB), CA ethylcarbamate, CAP, CA methylcarbamate, CA succinate, Cellulose Acetate Trimellitate (CAT), CA dimethylglycinate, CA ethylcarbonate, CA chloroacetate, CA ethyl oxalate, CA methylsulfonate, CA butylsulfonate, CA paratoluene sulfonate, agar acetate, amylose triacetate, beta glucan acetate, beta glucan triacetate, acetaldehyde dimethylacetate, locust bean gum triacetate, hydroxylated ethylene-vinylacetate, EC, PEG, PPG, PEG/PPG copolymers, PVP, HEC, HPC, CMC, CMEC, HPMC, HPMCP, HPMCAS, HPMCAT, poly (acrylic) acids and esters and poly- (methacrylic) acids and esters and copolymers thereof, starch, dextran, dextrin, chitosan, collagen, gelatin, polyolefin, polyether, polysulfone, polyethersulfone, polystyrene, polyvinyl halide, polyvinyl ester and ether, natural waxes and synthetic waxes.

Preferred coating compositions include cellulosic polymers, especially cellulose ethers, cellulose esters, and cellulose ester-ethers, i.e., cellulose derivatives having a mixture of ester and ether substituents.

Another preferred class of coating materials are poly (acrylic) acids and esters, poly (methacrylic) acids and esters, and copolymers thereof.

More preferred coating compositions include cellulose acetate. More preferred coatings include cellulosic polymers and PEG. Most preferred coatings include cellulose acetate and PEG.

Coating is carried out in a conventional manner, usually by dissolving or suspending the coating substance in a solvent and then coating by immersion, spray coating or preferably pan-coating. The preferred coating solution contains 5 to 15 wt% polymer. Solvents commonly used with the above-described cellulosic polymers include acetone, methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, methyl isobutyl ketone, methyl propyl ketone, ethylene glycol monoethyl ether, ethylene glycol monoethyl acetate, methylene chloride, ethylene dichloride, propylene dichloride, nitroethane, nitropropane, tetrachloroethane, 1, 4-dioxane, tetrahydrofuran, diglyme, water, and mixtures thereof. Pore formers as well as non-solvents (such as water, glycerol and ethanol) or plasticizers (such as diethyl phthalate) can also be added in any amount as long as the polymer remains soluble at the spray temperature. Pore formers and their use in preparing coatings are described in U.S. Pat. No. 5,612,059, the relevant disclosure of which is incorporated herein by reference.

The coating may also be a hydrophobic microporous layer in which the pores are substantially filled with gas and are not wetted by aqueous media but are permeable to water vapor, as disclosed in U.S. patent 5,798,119, the relevant disclosure of which is incorporated herein by reference. The hydrophobic but water-vapor permeable coating is typically composed of: hydrophobic polymers such as polyolefins, polyacrylic acid derivatives, polyethers, polysulfones, polyether sulfones, polystyrenes, polyvinyl halides, polyvinyl esters and ethers, natural waxes and synthetic waxes. Particularly preferred hydrophobic microporous coating materials include polystyrene, polysulfone, polyethersulfone, polyethylene, polypropylene, polyvinyl chloride, polyvinyl fluoride, and polytetrafluoroethylene. The hydrophobic coating may be prepared by any of the well-known phase inversion methods of steam-chilling, liquid chilling, thermal methods, leaching soluble materials from the coating, or by sintering the coated particles. In the thermal process, the polymer solution in the latent solvent undergoes a liquid-liquid phase separation in a cooling step. When evaporation of the solvent is not prevented, the resulting film is generally porous. The coating process can be utilized in U.S. Pat. Nos. 4,247,498; 4,490,431 and 4,744,906, the disclosures of which are incorporated herein by reference.

The osmotic controlled release device may be prepared using procedures well known in the pharmaceutical arts. See, e.g., Remington: the Science and Practice of Pharmacy, 20 th edition, 2000.

Multi-particle controlled release device

The dosage forms of the present invention may also provide controlled release of CETP inhibitor in a solubility-improved form by utilizing a multiparticulate controlled release device. Multiparticulates generally refer to devices comprising a plurality of particles or granules ranging in diameter from about 10 μm to about 2mm, more typically from about 100 μm to 1 mm. The multiparticulates may be packaged, for example in a capsule such as a gelatin capsule or a capsule formed from an aqueous-soluble polymer such as HPMCAS, HPMC or starch; administration as a suspension or slurry in a liquid; or it may be formed into tablets, troches, or pills using compression or other methods known in the art.

The multiparticulates may be prepared by any known method, such as wet-and dry-granulation methods, extrusion/spheronization, roller-compaction, melt-congealing, or by spray coating seeds (seed cores). For example, in wet-and dry-granulation processes, a composition comprising a solubility-improved form of a CETP inhibitor and optional excipients may be granulated to form multiparticulates of the desired size. Other excipients, such as binders (e.g., microcrystalline cellulose), may be mixed with the composition to aid in processing and formation of multiparticulates. In the case of wet granulation, a binder such as microcrystalline cellulose may be included in the granulation fluid to assist in the formation of suitable multiparticulates. See, for example, Remington: the Science and Practice of Pharmacy, 20 th edition, 2000.

In any case, the resulting particles may themselves constitute a multiparticulate device or they may be coated with various membrane-forming substances such as enteric polymers or water-swellable or water-soluble polymers, or may be combined with other excipients or carriers to facilitate administration to a patient.

Immediate release of HMG CoA reductase inhibitors

The dosage forms of the present invention also provide for the immediate release of the HMG-CoA reductase inhibitor. This means that within 1 hour or less after introduction into a use environment, the dosage form releases at least 70 wt% of the HMG-CoA reductase inhibitor originally present in the dosage form. Preferably, the dosage form releases at least 80 wt% at 1 hour, and most preferably at least 90 wt% at 1 hour after administration of the dosage form to a use environment.

Indeed, any device known in the pharmaceutical arts for providing immediate release of an HMG-CoA reductase inhibitor may be used in the dosage forms of the present invention. In one embodiment, the HMG-CoA reductase inhibitor is in the form of an immediate release coating that surrounds the composition comprising the solubility-improved form of the CETP inhibitor. HMG-CoA reductase inhibitors may be combined with water-soluble or water-dispersible polymers such as HPC, HPMC, HEC, and the like. The coating may be formed using a solvent-based coating process, a powder-coating process, and a hot-melt coating process, all of which are well known in the art. In the solvent-based process, the coating is prepared by: a solution or suspension is first formed comprising a solvent, an HMG-CoA reductase inhibitor, a coating polymer, and optionally a coating additive. Preferably, the HMG-CoA reductase inhibitor is suspended in the coating solvent. The coating material may be completely dissolved in the coating solvent, or merely suspended in the solvent as an emulsion or suspension, or anything in between. Latex dispersions, including aqueous latex dispersions, are specific examples of emulsions or suspensions that can be used as coating solutions. The solvent used in the solution should be inert, not react with or degrade the HMG-CoA reductase inhibitor, and pharmaceutically acceptable. In one aspect, the solvent is a liquid at room temperature. Preferably, the solvent is a volatile solvent. "volatile solvent" refers to materials having a boiling point less than about 150 ℃ at ambient pressure, although small amounts of solvents having higher boiling points may be used and still give acceptable results.

Examples of solvents suitable for coating the core comprising the CETP inhibitor include alcohols such as methanol, ethanol, isomers of propanol and isomers of butanol; ketones such as acetone, methyl ethyl ketone, and methyl isobutyl ketone; hydrocarbons such as pentane, hexane, heptane, cyclohexane, methylcyclohexane, octane, and mineral oil; ethers such as methyl tert-butyl ether, diethyl ether and ethylene glycol monoethyl ether; chlorinated hydrocarbons such as chloroform, dichloromethane, and dichloroethane; tetrahydrofuran; dimethyl sulfone; n-methyl pyrrolidone; acetonitrile; water; and mixtures thereof.

The coating formulation may also include additives to promote the desired immediate release characteristics or ease of application or to improve the durability or stability of the coating. Types of additives include plasticizers, pore formers, and glidants. Examples of coating additives suitable for use in the compositions of the present invention include plasticizers such as mineral oil, petrolatum, lanolin alcohol, polyethylene glycol, polypropylene glycol, triethyl citrate, sorbitol, triethanolamine, diethyl phthalate, dibutyl phthalate, castor oil, glyceryl triacetate, and others known in the art; emulsifiers, such as polysorbate-80; pore formers such as polyethylene glycol, polyvinylpyrrolidone, polyoxyethylene, hydroxyethylcellulose and hydroxypropylmethylcellulose; and glidants such as colloidal silicon dioxide, talc and corn starch. In one embodiment, the HMG-CoA reductase inhibitor is suspended in a commercially available coating formulation, such as Opadry ® clear (available from Colorcon, inc., WestPoint, PA). Coating is carried out in a conventional manner, usually by immersion, fluidized bed coating, spray coating, or pan-coating.

Immediate release coatings may also utilize powder coating techniques well known in the art. In these techniques, an HMG-CoA reductase inhibitor is mixed with optional coating excipients and additives to form an HMG-CoA reductase inhibitor composition. The composition may then be compressed, such as in a tablet press.

Coating may also be performed using a hot-melt coating technique. In this method, a molten mixture comprising an HMG-CoA reductase inhibitor, and optionally coating excipients and additives, is formed and then sprayed onto a composition comprising a solubility-improved form of a CETP inhibitor. Typically, hot-melt coating is carried out in a fluidized bed equipped with a top-spray device.

Another method of applying a heat-melt coating to the core is to use a modified melt-congealing method. In this process, a composition comprising a CETP inhibitor in a solubility-improved form is suspended in a molten mixture, the CETP inhibitor composition having a melting point greater than the melting point of the molten mixture. The suspension is then formed into droplets comprising the CETP inhibitor composition surrounded by the molten mixture. Droplets are typically formed using an atomizer, such as a rotary or rotary-disc atomizer. The droplets are then cooled to coagulate the molten mixture, forming a coating comprising an HMG-CoA reductase inhibitor on the CETP inhibitor composition.

In another embodiment, the HMG-CoA reductase inhibitor is first formed into an HMG-CoA reductase inhibitor composition comprising the HMG-CoA reductase inhibitor and optionally an excipient. The composition is then formed into an immediate release layer, multiparticulates, or granules, which are combined with a controlled release CETP inhibitor device to form a dosage form of the invention. In one aspect, the immediate release HMG-CoA reductase inhibitor composition consists essentially of HMG-CoA reductase inhibitor alone, such as a crystalline drug. In another aspect, the immediate release HMG-CoA reductase inhibitor composition comprises optional excipients such as stabilizers, diluents, disintegrants, and surfactants. The basic excipient, calcium carbonate, has been found to chemically stabilize HMG-CoA reductase inhibitors such as atorvastatin calcium and pharmaceutically acceptable derivatives thereof. Microcrystalline cellulose and hydrated lactose are used as suitable diluents. Croscarmellose sodium is used as a disintegrant. The non-ionic detergent Tween 80 was used as a surfactant. The composition may also comprise hydroxypropyl cellulose as a binder, which may be selected from several applicable substances such as, for example, polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, hydroxymethyl cellulose or hydroxypropyl methyl cellulose. As antioxidants, agents such as butylated hydroxyanisole, sodium ascorbate, ascorbic acid or others may optionally be included in the composition. Magnesium stearate may be selected from the group consisting of other substances such as stearic acid, palmitic acid, talc or similar lubricating compounds.

The immediate release HMG-CoA reductase inhibitor composition can be formed using any conventional method in combination with an HMG-CoA reductase inhibitor and an excipient. Exemplary methods include wet as well as dry granulation. If wet granulation is used, it is preferred to include a stabilizer such as calcium carbonate to keep the chemical degradation of the HMG-CoA reductase inhibitor at an acceptable level.

One exemplary method of forming an HMG-CoA reductase inhibitor composition comprises (a) milling a drug, (b) dissolving at least one binder additive in an aqueous surfactant solution; (c) mixing the milled drug with at least one drug-stabilizing additive and at least one diluent additive with the drug-stabilizing additive and half of the disintegrant additive in a rotating mixing vessel equipped with a chopper apparatus; (d) granulating the blended pharmaceutical ingredient mixture of step (c) and the surfactant/binder solution of step (b) in gradual increments in a mixing vessel equipped with a chopper; (e) drying the granulated drug mixture at about 50 ℃ overnight; (f) sieving the dried granulated drug mixture; (g) rolling and mixing the sieved medicine mixture with the rest of the disintegrant additive; (h) separately blending an aliquot of the drug mixture of step (g) with magnesium stearate, sieving, and returning to the drug mixture of step (g) and tumble blending all of the drug mixture.

In addition to the HMG-CoA reductase inhibitor, the immediate release layer may include other excipients to aid in formulating the composition into tablets, capsules, suspensions, powders for suspending agents, and the like. See, for example, Remington: the Science and Practice of Pharmacy (20th ed.2000). Examples of other excipients include disintegrants, pore formers, matrix materials, fillers, diluents, lubricants, glidants, and the like, such as those described above.

In one embodiment, the HMG-CoA reductase inhibitor composition further comprises a base. The inclusion of a base can improve the chemical stability of the HMG-CoA reductase inhibitor. The term "base" broadly includes not only strong bases such as sodium hydroxide, but also weak bases and buffers as well as buffers that achieve the desired increased chemical stability. Examples of the base include hydroxides such as sodium hydroxide, calcium hydroxide, ammonium hydroxide, and choline hydroxide; bicarbonates such as sodium bicarbonate, potassium bicarbonate, and ammonium bicarbonate; carbonates such as ammonium carbonate, calcium carbonate, and sodium carbonate; amines such as tris (hydroxymethyl) aminomethane, ethanolamine, diethanolamine, N-methylglucamine, glucosamine, ethylenediamine, N' -dibenzylethylenediamine, N-benzyl-2-phenylethylamine, cyclohexylamine, cyclopentylamine, diethylamine, isopropylamine, diisopropylamine, dodecylamine, and triethylamine; proteins, such as gelatin; amino acids such as lysine, arginine, guanine, glycine, and adenine; polymeric amines, such as polyaminomethacrylates, such as Eudragit E; conjugate bases of various acids, such as sodium acetate, sodium benzoate, ammonium acetate, disodium hydrogen phosphate, sodium phosphate, calcium hydrogen phosphate, sodium phenolate, sodium sulfate, ammonium chloride, and ammonium sulfate; salts of EDTA, such as tetrasodium EDTA; and salts of various acidic polymers such as sodium starch glycolate, sodium carboxymethylcellulose, and sodium polyacrylate.

Exemplary embodiments

The dosage forms of the invention include a CETP inhibitor in a solubility-improved form, and an HMG-CoA reductase inhibitor. The amount of CETP inhibitor and HMG-CoA reductase inhibitor present in the dosage form will vary with the dosage required for each compound, which in turn will depend on the potency of the compound and the disease being treated. For example, for the CETP inhibitor torcetrapib, also known as [2R, 4S ] -4- [ (3, 5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino ] -2-ethyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester, the required dosage range is from 1 mg/day to 1000 mg/day, preferably from 5 mg/day to 500 mg/day. For HMG-CoA reductase inhibitor atorvastatin calcium, the dosage range is 1-160 mg/day. For HMG-CoA reductase inhibitors lovastatin, pravastatin sodium, simvastatin, rosuvastatin calcium, and fluvastatin sodium, the dosage range is 2-160 mg/day. For the HMG-CoA reductase inhibitor cilastatin sodium, the dosage range is 0.05-1.2 mg/day. One of ordinary skill in the art will appreciate that the above dosage ranges are exemplary of the listed drugs. Other CETP inhibitors and other HMG-CoA reductase inhibitors, including pharmaceutically acceptable forms of the above drugs, are within the scope of the invention, and the dosage of the compounds should be adjusted based on the potency and bioavailability of the drug.

In a particularly preferred embodiment, the CETP inhibitor is torcetrapib and the HMG-CoA reductase inhibitor is atorvastatin calcium or a pharmaceutically acceptable form thereof. For these compounds, it is preferred that the weight ratio of CETP inhibitor to HMG-CoA reductase inhibitor in the dosage form range from about 0.0.1 to about 36, preferably from about 0.3 to about 20, more preferably from about 0.5 to about 18.

The dosage forms of the present invention provide an immediate release HMG-CoA reductase inhibitor and a controlled release solubility-improved form of a CETP inhibitor. In one aspect, the dosage form is in the form of a unit dosage form. "Unit dosage form" refers to a single dosage form comprising a solubility-improved form of a CETP inhibitor and an HMG-CoA reductase inhibitor, both the CETP inhibitor and the HMG-CoA reductase inhibitor being delivered to the use environment after administration of the unit dosage form to the use environment, the HMG-CoA reductase inhibitor being released in an immediate release form and the CETP inhibitor being released in a controlled release form. The term "unit dosage form" includes single tablets, troches, pills, capsules, sachets, powders, solutions, and kits, including one or more tablets, troches, pills, capsules, sachets, powders, or solutions taken together.

In one embodiment, the unit dosage form comprises a CETP inhibitor composition and an HMG-CoA reductase inhibitor composition, wherein the CETP inhibitor composition is in the form of a matrix controlled release device and the HMG-CoA reductase inhibitor composition is in the form of an immediate release coating. The CETP inhibitor composition includes a solubility-improved form of the CETP inhibitor, a matrix polymer, and optionally an excipient for a matrix controlled release device as previously discussed. The HMG-CoA reductase inhibitor composition comprises an HMG-CoA reductase inhibitor and optionally an excipient. Referring to fig. 1, in one aspect, unit dosage form 10 is in the form of a matrix tablet 12 comprising a solubility-improved form of a CETP inhibitor, coated with an immediate release coating 14 comprising an HMG-CoA reductase inhibitor and optional excipients as discussed above. The immediate release coating 14 may optionally be coated with a conventional coating (not shown in fig. 1).

Alternatively, the unit dosage form includes a CETP inhibitor composition and an HMG-CoA reductase inhibitor composition, schematically shown as dosage form 20 in FIG. 2. The CETP inhibitor composition 22 is in the form of a matrix controlled release device and the HMG-CoA reductase inhibitor composition is in the form of an immediate release layer 24 associated with the matrix device. By bonded, it is meant that the layer 24 comprising the HMG-CoA reductase inhibitor is adjacent to or substantially in contact with the matrix controlled release device 22. The immediate release layer 24 and the matrix controlled release device may also be separated by an intermediate layer (not shown in fig. 2) comprising a binder or diluent as is well known in the art. The unit dosage form 20 may optionally be coated with a conventional coating 26.

In another embodiment, a unit dosage form includes a CETP inhibitor composition and an HMG-CoA reductase inhibitor composition, schematically illustrated as dosage form 30 in FIG. 3. The CETP inhibitor composition is in the form of an osmotic controlled release device 37 and the HMG-CoA reductase inhibitor composition is in the form of an immediate release coating 34. Osmotic controlled release device 37 includes a core 33, a coating 38, and a delivery port 39. The core may be a single composition or may consist of several layers, including several layers comprising the solubility-improved form of the CETP inhibitor and a highly expanded layer for extruding the CETP inhibitor into the environment of use. The immediate release coating 34 may optionally be coated with a conventional coating (not shown in fig. 3).

In another embodiment, the unit dosage form is in the form of a three-layered tablet, schematically illustrated as dosage form 40 in fig. 4. The three-layer tablet includes (1) a CETP inhibitor composition 42, (2) an HMG-CoA reductase inhibitor composition 44, (3) a swellable-layer composition 45 sandwiched between layers (1) and (2), (4) a water permeable coating 48 surrounding layers (1), (2), and (3), and (5) at least two delivery outlets to provide fluid communication between layer (1) and use environment 49a and between layer (2) and use environment 49 b. The dosage form is designed such that upon administration to a use environment, the HMG-CoA reductase inhibitor composition 44 is released immediately, while the CETP inhibitor composition 42 is released slowly over time.

In another embodiment, the unit dosage form is in the form of a three-layered tablet (not shown) comprising (1) an immediate release HMG-CoA reductase inhibitor composition, and (2) a controlled release CETP inhibitor composition. A low-permeability coating is disposed over the controlled release CETP inhibitor composition. Such dosage forms are disclosed in U.S. Pat. Nos. 4,839,177, 5,422,123, 5,464,633, 5,650,169, 5,738,874, and 6,183,778, the disclosures of which are incorporated herein by reference.

In another embodiment, the unit dosage form is in the form of a capsule, schematically illustrated as dosage form 50 in fig. 5. The capsule includes (1) at least one controlled release device 52, such as a matrix controlled release device or an osmotic controlled release device, including a solubility-improved form of the CETP inhibitor, and (2) an immediate release HMG-CoA reductase inhibitor composition 54. In this embodiment, controlled release device 52 including a CETP inhibitor and HMG-CoA reductase inhibitor composition 54 are first prepared using procedures well known in The art, and then combined, such as placed, into a capsule well known in The art, such as a hard gelatin capsule or a soft gelatin capsule (see, e.g., Remington: The Science and practice of Pharmacy, (20th ed. 2000)). In one embodiment, the CETP inhibitor is in the form of a matrix controlled release device as previously discussed. In another embodiment, the CETP inhibitor is in the form of an osmotic controlled release device as previously discussed. The immediate release HMG-CoA reductase inhibitor composition 54 may simply be particles of the active drug alone, or may be combined with optional excipients to make it in the form of a powder, granules, or multiparticulates as previously discussed.

In another embodiment, the unit dosage form is in the form of a capsule, schematically illustrated as dosage form 60 in fig. 6. The capsules include (1) various controlled release devices, such as controlled release multiparticulates or granules 62 comprising a solubility-improved form of a CETP inhibitor, and (2) an immediate release HMG-CoA reductase inhibitor composition 64. Controlled release CETP inhibitor multiparticulates or granules 62 and HMG-CoA reductase inhibitor composition 64 are first prepared using The preceding steps and may then be combined, such as by placing them in a suitable capsule as is well known in The art, such as a hard gelatin capsule or a soft gelatin capsule (see, e.g., Remington: The Science and Practice of Pharmacy, (20th ed. 2000)).

In another embodiment, the unit dosage form is in the form of a compressed tablet, troche, or pill, schematically illustrated as dosage form 70 of fig. 7. The dosage form includes (1) a plurality of controlled release multiparticulates or granules 72 comprising a solubility-improved form of the CETP inhibitor, and (2) a plurality of particles that immediately release the HMG-CoA reductase inhibitor, such as particles of the active drug alone, or multiparticulates or granules 74 comprising the HMG-CoA reductase inhibitor. The unit dosage forms may optionally be coated with a conventional coating 76.

Another embodiment of a unit dosage form is a powder, commonly referred to in the art as a sachet or oral powder for containment OPC. Controlled release granules or multiparticulates of the CETP inhibitor in a solubility-improved form and granules for immediate release of the HMG-CoA reductase inhibitor, such as granules of the active drug alone, or granules or multiparticulates comprising the HMG-CoA reductase inhibitor, are mixed with optional excipients and placed in a suitable container, such as a sachet, bottle, box, pouch, or other container known in the art. The powder dosage form is then administered in dry form or mixed with a liquid to form a paste, suspension or slurry prior to administration.

Another embodiment of a unit dosage form is a kit comprising at least two separate compositions: (1) a controlled release device comprising a CETP inhibitor in a solubility-improved form, and (2) an HMG-CoA reductase inhibitor in an immediate release form. The kit may include means for containing the separate compositions such as separate containers, e.g., bottles, sachets, boxes, bags, or other containers known in the art, or separate foil packs; however, separate compositions may also be contained in a single, undivided container. Typically the kit includes instructions for administering the separate components.

In another embodiment, the solubility-improved form of the CETP inhibitor and the HMG-CoA reductase inhibitor are present in separate dosage forms and administered together to the environment of use. The CETP inhibitor in its solubility-improved form is in the form of a controlled release dosage form, while the HMG-CoA reductase inhibitor is in the form of an immediate release dosage form. By "administered together" is meant that the two dosage forms are administered separately from each other. In one embodiment, the two dosage forms are each administered together in the same general time frame, such as within 60 minutes, preferably within 30 minutes, more preferably within 15 minutes. In another embodiment, the two dosage forms are administered at separate times. For example, a controlled release dosage form comprising a solubility-improved form of the CETP inhibitor may be taken at a meal time, e.g., breakfast, lunch, or dinner time, while an immediate release dosage form comprising an HMG-CoA reductase inhibitor is taken at night. These methods of administration or variations are within the scope of the present invention.

The invention also includes a method of treating a patient in need of a CETP inhibitor and/or HMG-CoA reductase inhibitor therapy comprising administering to a patient in need thereof a dosage form of the invention. The dosage form provides at least one of: (i) at least 50% inhibition of plasma cholesteryl ester transfer protein for at least 12 hours; (ii) (ii) a maximum plasma concentration of less than or equal to 80% of the maximum plasma concentration provided by an immediate release dosage form comprising an equivalent amount of a solubility-improved form of a CETP inhibitor; (iii) after 8 weeks of administration, the mean HDL cholesterol level is at least about 1.2-fold that obtained prior to administration; and (iv) 8 weeks after administration, the mean LDL cholesterol level is less than or equal to about 90% that obtained prior to administration.

The dosage forms of the present invention may optionally be coated with conventional coatings well known in the art. Coatings may be used to modify taste, improve appearance, facilitate swallowing of the dosage form, or to delay, slow release, or control the release of drug from the dosage form. The coating may be formed using any conventional means including fluid bed coating, spray coating, pan-coating and powder-coating using aqueous or organic solvents. Examples of suitable coating materials include sucrose, maltitol, cellulose acetate, ethyl cellulose, methyl cellulose, sodium carboxymethylcellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, polymethacrylates, polyacrylates, polyvinyl alcohol, polyvinyl pyrrolidone, cetyl alcohol, gelatin, maltodextrin, paraffin wax, microcrystalline wax, and carnauba wax. Mixtures of polymers may also be used. Preferred coatings include the commercial aqueous coating formulation Surelease ® and Opadry ® available from Colorcon Inc (West Point, Pennsylvania).

Cholesteryl ester transfer protein inhibitors

The CETP inhibitor may be any compound that inhibits cholesteryl ester transfer protein. CETP inhibitors are typically "poorly water-soluble," meaning that the CETP inhibitor has a minimum aqueous solubility of less than about 1-2 mg/mL at any physiologically relevant pH (e.g., pH 1-8) and at about 22 ℃. Many CETP inhibitors are "substantially water insoluble," meaning that the CETP inhibitor has a minimum solubility in water of less than about 0.01mg/mL (or 10. mu.g/mL) at any physiologically relevant pH (e.g., pH 1-8) and at about 22 ℃. (unless otherwise stated, the solubility in water is determined here and in the claims at about 22 ℃). As the solubility of the CETP inhibitor decreases, the compositions of the present invention find greater utility and are therefore preferred for CETP inhibitors having a solubility of less than about 10 μ g/mL and more preferred for CETP inhibitors having a solubility of less than about 1 μ g/mL. Many CETP inhibitors have even lower solubility (some are even less than 0.1 μ g/mL) and require significant concentration increase to be sufficiently bioavailable when administered orally to achieve effective plasma concentrations at practical doses.

Typically, CETP inhibitors have a dose-to-aqueous solubility ratio greater than about 100mL, where the solubility (mg/mL) is the minimum observed in any physiologically relevant aqueous solution (e.g., those solutions having a pH of 1-8) including USP simulated gastric and intestinal buffers, and the dosage unit is mg. The compositions of the invention as described above have greater applicability as the solubility of CETP inhibitors decreases and as the dosage increases. Thus, as the dose-water solubility increases, the composition is preferred, and thus a dose-solubility ratio greater than 1000mL is preferred, and a dose-solubility ratio greater than about 5000mL is more preferred. Dose-solubility can be determined by dividing the dose (mg) by the solubility in water (mg/ml).

Oral delivery of many CETP inhibitors is particularly difficult because of their generally extremely low solubility in water, typically less than 2 μ g/ml, and often less than 0.1 μ g/ml. This low solubility is a direct result of the specific structural properties of the substance that binds CETP and thus acts as a CETP inhibitor. This low solubility is mainly due to the hydrophobic nature of CETP inhibitors. Clog P, defined as the log base 10 of the ratio of the solubility of a drug in octanol to the solubility of the drug in water, is a widely accepted measure of hydrophobicity. Typically, the Clog P value of CETP inhibitors is greater than 4 and typically greater than 5. Thus, the hydrophobic and insoluble nature of CETP inhibitors as a class of substances presents particular challenges in oral delivery. Achieving therapeutic drug levels in the blood by oral administration of substantial amounts of drug often requires a large increase in drug concentration in the gastrointestinal fluid and results in a large increase in bioavailability. The increase in drug concentration in the gastrointestinal fluid generally needs to be at least about 10-fold and often at least about 50-fold or even at least about 200-fold to achieve the desired blood level.

The present inventors have recognized that a subset of CETP inhibitors, which are substantially aqueous insoluble, highly hydrophobic, and characterized by a set of physical properties. The first property of the essentially insoluble, hydrophobic CETP inhibitors of this subclass is extremely low solubility in water. Extremely low aqueous solubility means a solubility in water of less than about 10 μ g/ml and preferably less than about 1 μ g/ml with the smallest physiological dependence (pH 1-8).

The second property is a very high dose-to-solubility ratio. When a drug is administered orally in a conventional manner, extremely low solubility in water often results in poor or slow absorption of the drug from the gastrointestinal fluids. For extremely low solubility drugs, poor absorption often becomes progressively more difficult as the dosage (total amount of drug administered orally) increases. Thus, a second characteristic of the subclass of substantially insoluble, hydrophobic CETP inhibitors is the very high dose (mg) -solubility (mg/ml) ratio (ml). By "very high dose-to-solubility ratio" is meant a dose-to-solubility ratio of at least 1000ml, and preferably at least 5,000ml, and more preferably at least 10,000 ml.

A third characteristic of this subclass of substantially insoluble, hydrophobic CETP inhibitors is that they are extremely hydrophobic. By extremely hydrophobic is meant that the drug has a Clog P value of at least 4.0, preferably at least 5.0, and more preferably at least 5.5.

A fourth characteristic of this subclass of substantially insoluble CETP inhibitors is that they have a low melting point. Typically, drugs of this subclass have a melting point of about 150 ℃ or less, and preferably about 140 ℃ or less.

In particular, a consequence of some or all of these four properties is that CETP inhibitors of this subclass typically have very low absolute bioavailability. Specifically, the absolute bioavailability of this subclass of drugs is less than about 10% and more typically less than about 5% when administered orally in its undispersed state.

Hereinafter, its "pharmaceutically acceptable form" refers to any pharmaceutically acceptable derivative or variant, including stereoisomers, mixtures of stereoisomers, enantiomers, solvates, hydrates, (homologies) isomorphos, pseudoisomorphos, polymorphs, salt forms and prodrugs.

One class of CETP inhibitors useful in the present invention consists of oxy-substituted 4-carboxyamino-2-methyl-1, 2, 3, 4-tetrahydroquinoline having the formula I

Formula I

And pharmaceutically acceptable forms thereof;

wherein R is_I-1Is hydrogen, Y_I、W_I-X_I、W_I-Y_I；

Wherein W_IIs carbonyl, thiocarbonyl, sulfinyl or sulfonyl;

X_Iis-O-Y_I、-S-Y_I、-N(H)-Y_Ior-N- (Y)_I)₂；

Wherein Y is_IIndependently at each occurrence is Z _IOr a fully saturated, partially unsaturated or fully unsaturated 1-to 10-membered straight or branched carbon chain, wherein the carbons other than the linking carbon may optionally be replaced by 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, and said carbons are optionally mono-, di-or tri-substituted independently with halo, said carbons are optionally mono-substituted with hydroxy, said carbons are 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-, or di-substituted with Z_IMono-substituted;

wherein Z_IIs a partially saturated, fully saturated or fully unsaturated 3-to 8-membered ring, optionally having 1 to 4 heteroatoms independently selected from oxygen, sulfur and nitrogen, or, is a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated 3-to 6-membered rings, each ring being independently selected, optionally having 1 to 4 heteroatoms independently selected from nitrogen, sulfur and oxygen;

wherein Z is_IThe substituents are optionally mono-, di-or tri-substituted independently with a substituent selected from the group consisting of: halogen, (C)₂-C₆) Alkenyl, (C)₁-C₆) Alkyl, hydroxy, (C)₁-C₆) Alkoxy group, (C)₁-C₄) Alkylthio, amino, nitro, cyano, oxo, carboxy, (C) ₁-C₆) Alkoxycarbonyl, mono-N-or di-N, N- (C)₁-C₆) Alkylamino group of the formula (C)₁-C₆) The alkyl substituent is optionally mono-, di-or tri-substituted independently with a substituent selected from the group consisting of: halogen, hydroxy, (C)₁-C₆) Alkoxy group, (C)₁-C₄) Alkylthio, amino, nitro, cyano, oxo, carboxy, (C)₁-C₆) Alkoxycarbonyl, mono-N-or di-N, N- (C)₁-C₆) Alkylamino group of said (C)₁-C₆) The alkyl substituent is further optionally substituted with 1 to 9 fluorines;

R_I-3is hydrogen or Q_I；

Wherein Q_IIs a fully saturated, partially unsaturated or fully unsaturated 1-to 6-membered straight or branched carbon chain, wherein the carbons other than the linking carbon may optionally be replaced by a heteroatom selected from oxygen, sulfur and nitrogen, and said carbons are optionally mono-, di-or tri-substituted independently with halo, said carbons are optionally mono-substituted with hydroxy, said carbons are 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-, or di-substituted with V_IMono-substituted;

wherein V_IIs a partially saturated, fully saturated or fully unsaturated 3-to 8-membered ring optionally having 1 to 4 heteroatoms independently selected from oxygen, sulfur and nitrogen, or is a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated 3-to 6-membered rings, each ring being independently selected, optionally having 1 to 4 heteroatoms independently selected from nitrogen, sulfur and oxygen;

Wherein said V_IThe substituents are optionally mono-, di-, tri-, or tetra-substituted independently with a substituent selected from the group consisting of: halo, (C)₁-C₆) Alkyl, (C)₂-C₆) Alkenyl, hydroxy, (C)₁-C₆) Alkoxy group, (C)₁-C₄) Alkylthio, amino, nitro, cyano, oxo, carbamoyl, mono-N-or di-N, N- (C)₁-C₆) Alkylcarbamoyl, carboxyl, (C)₁-C₆) Alkoxycarbonyl, mono-N-or di-N, N- (C)₁-C₆) Alkylamino group of the formula (C)₁-C₆) Alkyl or (C)₂-C₆) Alkenyl is optionally mono-, di-, tri-substituted independently with a substituent selected from the group consisting of: hydroxy, (C)₁-C₆) Alkoxy group, (C)₁-C₄) Alkylthio, amino, nitro, cyano, oxo, carboxy, (C)₁-C₆) Alkoxycarbonyl, mono-N-or di-N, N- (C)₁-C₆) Alkylamino group of said (C)₁-C₆) Alkyl or (C)₂-C₆) The alkenyl substituent is further optionally substituted with 1 to 9 fluorines;

R_I-4is Q_I-1Or V_I-1

Wherein Q_I-1Is a fully saturated, partially unsaturated or fully unsaturated 1-to 6-membered straight or branched carbon chain, wherein the carbons other than the linking carbon may optionally be replaced by a heteroatom selected from oxygen, sulfur and nitrogen, and said carbons are optionally mono-, di-or tri-substituted independently with halo, said carbons are optionally mono-substituted with hydroxy, said carbons are 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-, or di-substituted with V _I-1Mono-substituted;

wherein V_I-1Is a partially saturated, fully saturated or fully unsaturated 3-to 6-membered ring optionally having 1 to 2 heteroatoms independently selected from oxygen, sulfur and nitrogen;

wherein said V_I-1The substituents are optionally mono-, di-, tri-, or tetra-substituted independently with a substituent selected from the group consisting of: halo, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy, amino, nitro, cyano, (C)₁-C₆) Alkoxycarbonyl, mono-N-or di-N, N- (C)₁-C₆) Alkylamino group of the formula (C)₁-C₆) Alkyl substituents being optionally mono-substituted by oxo, said (C)₁-C₆) The alkyl substituent is further optionally substituted with 1 to 9 fluorines;

wherein either R_I-3Must contain V_IOr R_I-4Must contain V_I-1(ii) a And R_I-5、R_I-6、R_I-7And R_I-8Each independently is hydrogen, hydroxy or oxy, wherein said oxy is T_IOr partially saturated, fully saturated or fully unsaturated 1-to 12-membered straight or branched carbon chain substituted with 1 or 2 carbons other than the linking carbon optionally selected from oxygen, sulfurAnd nitrogen, and said carbons are optionally independently mono-, di-or tri-substituted with halo, said carbons are optionally mono-substituted with hydroxy, said carbons are 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-or di-substituted with T _IMono-substituted;

wherein T is_IIs a partially saturated, fully saturated or fully unsaturated 3-to 8-membered ring optionally having 1 to 4 heteroatoms independently selected from oxygen, sulfur and nitrogen, or is a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated 3-to 6-membered rings, each ring being independently selected, optionally having 1 to 4 heteroatoms independently selected from nitrogen, sulfur and oxygen;

wherein said T_IThe substituents are optionally mono-, di-or tri-substituted independently with a substituent selected from the group consisting of: halogen, (C)₁-C₆) Alkyl, (C)₂-C₆) Alkenyl, hydroxy, (C)₁-C₆) Alkoxy group, (C)₁-C₄) Alkylthio, amino, nitro, cyano, oxo, carboxy, (C)₁-C₆) Alkoxycarbonyl, mono-N-or di-N, N- (C)₁-C₆) Alkylamino group of the formula (C)₁-C₆) Alkyl is optionally mono-, di-, tri-substituted independently with a substituent selected from the group consisting of: hydroxy, (C)₁-C₆) Alkoxy group, (C)₁-C₄) Alkylthio, amino, nitro, cyano, oxo, carboxy, (C)₁-C₆) Alkoxycarbonyl, mono-N-or di-N, N- (C)₁-C₆) Alkylamino group of said (C)₁-C₆) The alkyl substituents are optionally further substituted with 1-9 fluorines.

Compounds of formula I are disclosed in commonly assigned U.S. Pat. No. 6,140,342, the entire disclosure of which is incorporated herein by reference.

In a preferred embodiment, the CETP inhibitor is selected from one of the following compounds of formula I:

[2R, 4S ]4- [ (3, 5-dichloro-benzyl) -methoxycarbonyl-amino ] -6, 7-dimethoxy-2-methyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester;

[2R, 4S ]4- [ (3, 5-dinitro-benzyl) -methoxycarbonyl-amino ] -6, 7-dimethoxy-2-methyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester;

[2R, 4S ]4- [ (2, 6-dichloro-pyridin-4-ylmethyl) -methoxycarbonyl-amino ] -6, 7-dimethoxy-2-methyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester;

[2R, 4S ]4- [ (3, 5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino ] -6, 7-dimethoxy-2-methyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester;

[2R, 4S ]4- [ (3, 5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino ] -6-methoxy-2-methyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester;

[2R, 4S ]4- [ (3, 5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino ] -7-methoxy-2-methyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester,

[2R, 4S ]4- [ (3, 5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino ] -6, 7-dimethoxy-2-methyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester;

[2R, 4S ]4- [ (3, 5-bis-trifluoromethyl-benzyl) -ethoxycarbonyl-amino ] -6, 7-dimethoxy-2-methyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester;

[2R, 4S ]4- [ (3, 5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino ] -6, 7-dimethoxy-2-methyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid 2, 2, 2-trifluoro-ethyl ester;

[2R, 4S ]4- [ (3, 5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino ] -6, 7-dimethoxy-2-methyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid propyl ester;

[2R, 4S ]4- [ (3, 5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino ] -6, 7-dimethoxy-2-methyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester;

[2R, 4S ]4- [ (3, 5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino ] -2-methyl-6-trifluoromethoxy-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester,

[2R, 4S ] (3, 5-bis-trifluoromethyl-benzyl) - (1-butyryl-6, 7-dimethoxy-2-methyl-1, 2, 3, 4-tetrahydro-quinolin-4-yl) -carbamic acid methyl ester;

[2R, 4S ] (3, 5-bis-trifluoromethyl-benzyl) - (1-butyl-6, 7-dimethoxy-2-methyl-1, 2, 3, 4-tetrahydro-quinolin-4-yl) -carbamic acid methyl ester;

[2R, 4S ] (3, 5-bis-trifluoromethyl-benzyl) - [1- (2-ethyl-butyl) -6, 7-dimethoxy-2-methyl-1, 2, 3, 4-tetrahydro-quinolin-4-yl ] -carbamic acid methyl ester, hydrochloride salt

Another class of CETP inhibitors useful in the present invention consists of 4-carboxyamino-2-methyl-1, 2, 3, 4-tetrahydroquinoline having formula II

Formula II

And pharmaceutically acceptable forms thereof;

wherein R is_II-1Is hydrogen, Y_II、W_II-X_II、W_II-Y_II；

Wherein W_IIIs carbonyl, thiocarbonyl, sulfinyl or sulfonyl;

X_IIis-O-Y_II、-S-Y_II、-N(H)-Y_IIor-N- (Y)_II)₂；

Wherein Y is_IIIndependently at each occurrence is Z_IIOr a fully saturated, partially unsaturated or fully unsaturated 1-to 10-membered straight or branched carbon chain, except for the linkageCarbon other than carbon, which may be optionally replaced by 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen and said carbon is optionally independently mono-, di-or tri-substituted by halo, said carbon is optionally mono-substituted by hydroxy, said carbon is optionally mono-substituted by oxo, said sulfur is optionally mono-or di-substituted by oxo, said nitrogen is optionally mono-, or di-substituted by oxo, and said carbon chain is optionally mono-, or di-substituted by Z_IMono-substitution_I；

Z_IIIs a partially saturated, fully saturated or fully unsaturated 3-to 12-membered ring optionally having 1 to 4 heteroatoms independently selected from oxygen, sulfur and nitrogen, or is a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated 3-to 6-membered rings, each ring being independently selected, optionally having 1 to 4 heteroatoms independently selected from nitrogen, sulfur and oxygen;

Wherein Z is_IIThe substituents are optionally mono-, di-or tri-substituted independently with a substituent selected from the group consisting of: halogen, (C)₂-C₆) Alkenyl, (C)₁-C₆) Alkyl, hydroxy, (C)₁-C₆) Alkoxy group, (C)₁-C₄) Alkylthio, amino, nitro, cyano, oxo, carboxy, (C)₁-C₆) Alkoxycarbonyl, mono-N-or di-N, N- (C)₁-C₆) Alkylamino group of the formula (C)₁-C₆) The alkyl substituent is optionally mono-, di-or tri-substituted independently with a substituent selected from the group consisting of: halogen, hydroxy, (C)₁-C₆) Alkoxy group, (C)₁-C₄) Alkylthio, amino, nitro, cyano, oxo, carboxy, (C)₁-C₆) Alkoxycarbonyl, mono-N-or di-N, N- (C)₁-C₆) Alkylamino group of said (C)₁-C₆) Alkyl is optionally substituted with 1-9 fluoro;

R_II-3is hydrogen or Q_II；

Wherein Q_IIIs a fully saturated, partially unsaturated or fully unsaturated 1-to 6-membered straight or branched carbon chainWherein the carbon other than the connecting carbon is optionally replaced by a heteroatom selected from oxygen, sulfur and nitrogen, and said carbon is optionally independently mono-, di-or tri-substituted by halo, said carbon is optionally mono-substituted by hydroxy, said carbon is optionally mono-substituted by oxo, said sulfur is optionally mono-or di-substituted by oxo, said nitrogen is optionally mono-or di-substituted by oxo, and said carbon chain is optionally mono-or di-substituted by V _IIMono-substituted;

wherein V_IIIs a partially saturated, fully saturated or fully unsaturated 3-to 12-membered ring optionally having 1 to 4 heteroatoms independently selected from oxygen, sulfur and nitrogen, or, is a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated 3-to 6-membered rings, each ring being independently selected, optionally having 1 to 4 heteroatoms independently selected from nitrogen, sulfur and oxygen;

wherein said V_IIThe substituents are optionally mono-, di-, tri-, or tetra-substituted independently with a substituent selected from the group consisting of: halo, (C)₁-C₆) Alkyl, (C)₂-C₆) Alkenyl, hydroxy, (C)₁-C₆) Alkoxy group, (C)₁-C₄) Alkylthio, amino, nitro, cyano, oxo, carbamoyl, mono-N-or di-N, N- (C)₁-C₆) Alkylcarbamoyl, carboxyl, (C)₁-C₆) Alkoxycarbonyl, mono-N-or di-N, N- (C)₁-C₆) Alkylamino group of the formula (C)₁-C₆) Alkyl or (C)₂-C₆) Alkenyl is optionally mono-, di-, tri-substituted independently with a substituent selected from the group consisting of: hydroxy, (C)₁-C₆) Alkoxy group, (C)₁-C₄) Alkylthio, amino, nitro, cyano, oxo, carboxy, (C)₁-C₆) Alkoxycarbonyl, mono-N-or di-N, N- (C)₁-C₆) Alkylamino or said (C)₁-C₆) Alkyl or (C)₂-C₆) The alkenyl substituent is optionally substituted with 1 to 9 fluorines;

R_II-4Is Q_II-1Or V_II-1

Wherein Q_II-1Is a fully saturated, partially unsaturated or fully unsaturated 1-to 6-membered straight or branched carbon chain, wherein the carbons other than the linking carbon may optionally be replaced by a heteroatom selected from oxygen, sulfur and nitrogen, and said carbons are optionally mono-, di-or tri-substituted independently with halo, said carbons are optionally mono-substituted with hydroxy, said carbons are 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-or di-substituted with V_II-1Mono-substituted;

wherein V_II-1Is a partially saturated, fully saturated or fully unsaturated 3-to 6-membered ring optionally having 1 to 2 heteroatoms independently selected from oxygen, sulfur and nitrogen;

wherein said V_II-1The substituents are optionally mono-, di-, tri-, or tetra-substituted independently with a substituent selected from the group consisting of: halo, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy, amino, nitro, cyano, (C)₁-C₆) Alkoxycarbonyl, mono-N-or di-N, N- (C)₁-C₆) Alkylamino group of the formula (C)₁-C₆) Alkyl substituents being optionally mono-substituted by oxo, said (C)₁-C₆) The alkyl substituent is optionally substituted with 1 to 9 fluorines;

wherein either R_II-3Must contain V_IIOr R _II-4Must contain V_II-1(ii) a And

R_II-5、R_II-6、R_II-7and R_II-8Each independently being hydrogen, a chemical bond, nitro or halo, wherein the bond is substituted by T_IIOr partially saturated, fully saturated or fully unsaturated (C)₁-C₁2) Linear or branched carbon chain substitution, wherein a carbon may optionally be replaced by 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, and wherein said carbon atoms are optionally mono-, di-or tri-substituted independently by halogen, said carbonOptionally 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-or di-substituted with T_IIMono-substituted;

wherein T is_IIIs a partially saturated, fully saturated or fully unsaturated 3-to 12-membered ring optionally having 1 to 4 heteroatoms independently selected from oxygen, sulfur and nitrogen, or, is a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated 3-to 6-membered rings, each ring being independently selected, optionally having 1 to 4 heteroatoms independently selected from nitrogen, sulfur and oxygen;

wherein said T_IIThe substituents are optionally mono-, di-or tri-substituted independently with a substituent selected from the group consisting of: halogen, (C) ₁-C₆) Alkyl, (C)₂-C₆) Alkenyl, hydroxy, (C)₁-C₆) Alkoxy group, (C)₁-C₄) Alkylthio, amino, nitro, cyano, oxo, carboxy, (C)₁-C₆) Alkoxycarbonyl, mono-N-or di-N, N- (C)₁-C₆) Alkylamino group of the formula (C)₁-C₆) Alkyl is optionally mono-, di-, tri-substituted independently with a substituent selected from the group consisting of: hydroxy, (C)₁-C₆) Alkoxy group, (C)₁-C₄) Alkylthio, amino, nitro, cyano, oxo, carboxy, (C)₁-C₆) Alkoxycarbonyl, mono-N-or di-N, N- (C)₁-C₆) Alkylamino group of said (C)₁-C₆) The alkyl substituent is further optionally substituted with 1 to 9 fluorines; with the proviso that the substituent R_II-5、R_II-6、R_II-7And R_II-8At least one of which is not hydrogen and is not attached to the quinolinyl group via a peroxy group.

Compounds of formula II are disclosed in commonly assigned U.S. Pat. No. 6,147,090, the entire disclosure of which is incorporated herein by reference.

In a preferred embodiment, the CETP inhibitor is selected from one of the following compounds of formula II:

[2R, 4S ]4- [ (3, 5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino ] -2-methyl-7-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester;

[2R, 4S ]4- [ (3, 5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino ] -7-chloro-2-methyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester;

[2R, 4S ]4- [ (3, 5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino ] -6-chloro-2-methyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester;

[2R, 4S ]4- [ (3, 5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino ] -2, 6, 7-trimethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester

[2R, 4S ]4- [ (3, 5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino ] -6, 7-diethyl-2-methyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester;

[2R, 4S ]4- [ (3, 5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino ] -6-ethyl-2-methyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester;

[2R, 4S ]4- [ (3, 5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino ] -2-methyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester;

[2R, 4S ]4- [ (3, 5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino ] -2-methyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester.

Another class of CETP inhibitors useful in the present invention consists of 4-carboxyamino-2-methyl-1, 2, 3, 4-tetrahydroquinoline having formula III

Formula III

And pharmaceutically acceptable forms thereof;

wherein R is_III-1Is hydrogen, Y_III、W_III-X_III、W_III-Y_III；

Wherein W_IIIIs carbonyl, thiocarbonyl, sulfinyl or sulfonyl;

X_IIIis-O-Y_III、-S-Y_III、-N(H)-Y_IIIor-N- (Y)_III)₂；

Y_IIIIndependently at each occurrence is Z_III-or a fully saturated, partially unsaturated or fully unsaturated 1 to 10 membered straight or branched carbon chain wherein the carbons other than the linking carbon may optionally be replaced by 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, and said carbons are optionally mono-, di-or tri-substituted independently by halo, said carbons are optionally mono-substituted by hydroxy, said carbons are optionally mono-substituted by oxo, said sulfur is optionally mono-or di-substituted by oxo, said nitrogen is optionally mono-, or di-substituted by oxo, and said carbon chain is optionally mono-, or di-substituted by Z _IIIMono-substituted;

wherein Z_IIIIs a partially saturated, fully saturated or fully unsaturated 3-to 12-membered ring optionally having 1 to 4 heteroatoms independently selected from oxygen, sulfur and nitrogen, or is a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated 3-to 6-membered rings, each ring being independently selected, optionally having 1 to 4 heteroatoms independently selected from nitrogen, sulfur and oxygen;

wherein Z is_IIIThe substituents are optionally mono-, di-or tri-substituted independently with a substituent selected from the group consisting of: halogen, (C)₂-C₆) Alkenyl, (C)₁-C₆) Alkyl, hydroxy, (C)₁-C₆) Alkoxy group, (C)₁-C₄) Alkylthio, amino, nitro, cyano, oxo, carboxy, (C)₁-C₆) Alkoxycarbonyl, mono-N-or di-N, N- (C)₁-C₆) Alkylamino group of the formula (C)₁-C₆) Alkyl substituents are optionally independentlyIs mono-, di-or tri-substituted, sterically with a substituent selected from the group consisting of: halogen, hydroxy, (C)₁-C₆) Alkoxy group, (C)₁-C₄) Alkylthio, amino, nitro, cyano, oxo, carboxy, (C)₁-C₆) Alkoxycarbonyl, mono-N-or di-N, N- (C)₁-C₆) Alkylamino group of said (C)₁-C₆) Alkyl is optionally substituted with 1-9 fluoro;

R_III-3is hydrogen or Q_III；

Wherein Q_IIIIs a fully saturated, partially unsaturated or fully unsaturated 1-to 6-membered straight or branched carbon chain, wherein the carbons other than the linking carbon may optionally be replaced by a heteroatom selected from oxygen, sulfur and nitrogen, and said carbons are optionally mono-, di-or tri-substituted independently with halo, said carbons are optionally mono-substituted with hydroxy, said carbons are 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-or di-substituted with V _IIIMono-substituted;

wherein V_IIIIs a partially saturated, fully saturated or fully unsaturated 3-to 12-membered ring optionally having 1 to 4 heteroatoms independently selected from oxygen, sulfur and nitrogen, or is a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated 3-to 6-membered rings, each ring being independently selected, optionally having 1 to 4 heteroatoms independently selected from nitrogen, sulfur and oxygen;

wherein said V_IIIThe substituents are optionally mono-, di-, tri-, or tetra-substituted independently with a substituent selected from the group consisting of: halo, (C)₁-C₆) Alkyl, (C)₂-C₆) Alkenyl, hydroxy, (C)₁-C₆) Alkoxy group, (C)₁-C₄) Alkylthio, amino, nitro, cyano, oxo, carbamoyl, mono-N-or di-N, N- (C)₁-C₆) Alkylcarbamoyl, carboxyl, (C)₁-C₆) Alkoxycarbonyl, mono-N-or di-N, N- (C)₁-C₆) Alkylamino group of the formula (C)₁-C₆) Alkyl or (C)₂-C₆) Alkenyl is optionally mono-, di-, tri-substituted independently with a substituent selected from the group consisting of: hydroxy, (C)₁-C₆) Alkoxy group, (C)₁-C₄) Alkylthio, amino, nitro, cyano, oxo, carboxy, (C)₁-C₆) Alkoxycarbonyl, mono-N-or di-N, N- (C)₁-C₆) Alkylamino or said (C)₁-C₆) Alkyl or (C)₂-C₆) Alkenyl is optionally substituted with 1-9 fluorines;

R_III-4Is Q_III-1Or V_III-1；

Wherein Q_III-1Is a fully saturated, partially unsaturated or fully unsaturated 1-to 6-membered straight or branched carbon chain, wherein the carbons other than the linking carbon may optionally be replaced by a heteroatom selected from oxygen, sulfur and nitrogen, and said carbons are optionally mono-, di-or tri-substituted independently with halo, said carbons are optionally mono-substituted with hydroxy, said carbons are 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-or di-substituted with V_III-1Mono-substituted;

wherein V_III-1Is a partially saturated, fully saturated or fully unsaturated 3-to 6-membered ring optionally having 1 to 2 heteroatoms independently selected from oxygen, sulfur and nitrogen;

wherein said V_III-1The substituents are optionally mono-, di-, tri-, or tetra-substituted independently with a substituent selected from the group consisting of: halo, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy, amino, nitro, cyano, (C)₁-C₆) Alkoxycarbonyl, mono-N-or di-N, N- (C)₁-C₆) Alkylamino group of the formula (C)₁-C₆) Alkyl substituents being optionally mono-substituted by oxo, said (C)₁-C₆) The alkyl substituent optionally has 1 to 9 fluorines;

wherein either R_III-3Must contain V_IIIOr R _III-4Must contain V_III-1(ii) a And is

R_III-5And R_III-6Or R is_III-6And R_III-7And/or R_III-7And R_III-8Together and forming at least one 4-to 8-membered ring, said ring being a partially saturated or fully unsaturated ring and optionally having 1 to 3 heteroatoms independently selected from nitrogen, sulfur and oxygen;

wherein said group consisting of R_III-5And R_III-6Or R is_III-6And R_III-7And/or R_III-7And R_III-8The ring or rings formed are optionally mono-, di-or tri-substituted independently with a substituent selected from the group consisting of: halogen, (C)₁-C₆) Alkyl, (C)₁-C₄) Alkylsulfonyl group, (C)₂-C₆) Alkenyl, hydroxy, (C)₁-C₆) Alkoxy group, (C)₁-C₄) Alkylthio, amino, nitro, cyano, oxo, carboxy, (C)₁-C₆) Alkoxycarbonyl, mono-N-or di-N, N- (C)₁-C₆) Alkylamino group of the formula (C)₁-C₆) Alkyl is optionally mono-, di-, tri-substituted independently with a substituent selected from the group consisting of: hydroxy, (C)₁-C₆) Alkoxy group, (C)₁-C₄) Alkylthio, amino, nitro, cyano, oxo, carboxy, (C)₁-C₆) Alkoxycarbonyl, mono-N-or di-N, N- (C)₁-C₆) Alkylamino group of said (C)₁-C₆) The alkyl substituent optionally has 1 to 9 fluorines;

provided that R is_III-5、R_III-6、R_III-7And/or R_III-8Each independently of the other, without forming at least one ring, is hydrogen, halo, (C)₁-C₆) Alkoxy or (C)₁-C₆) Alkyl group, said (C)₁-C₆) The alkyl group optionally has 1 to 9 fluorines.

The compounds of formula III are disclosed in commonly assigned U.S. patent 6,147,089, the entire disclosure of which is incorporated herein by reference.

In a preferred embodiment, the CETP inhibitor is selected from one of the following compounds of formula III:

ethyl [2R, 4S ]4- [ (3, 5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino ] -2-methyl-2, 3, 4, 6, 7, 8-hexahydro-cyclopenta [ g ] quinoline-1-carboxylate;

ethyl [6R, 8S ]8- [ (3, 5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino ] -6-methyl-3, 6, 7, 8-tetrahydro-1H-2-thia-5-aza-cyclopenta [ b ] naphthalene-5-carboxylate;

[6R, 8S ]8- [ (3, 5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino ] -6-methyl-3, 6, 7, 8-tetrahydro-2H-furo [2, 3-g ] quinoline-5-carboxylic acid ethyl ester;

ethyl [2R, 4S ]4- [ (3, 5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino ] -2-methyl-3, 4, 6, 8-tetrahydro-2H-furo [3, 4-g ] quinoline-1-carboxylate;

[2R, 4S ]4- [ (3, 5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino ] -2-methyl-3, 4, 6, 7, 8, 9-hexahydro-2H-benzo [ g ] quinoline-1-carboxylic acid propyl ester;

ethyl [7R, 9S ]9- [ (3, 5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino ] -7-methyl-1, 2, 3, 7, 8, 9-hexahydro-6-aza-cyclopenta [ a ] naphthalene-6-carboxylate; and

[6S, 8R ]6- [ (3, 5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino ] -8-methyl-1, 2, 3, 6, 7, 8-hexahydro-9-aza-cyclopenta [ a ] naphthalene-9-carboxylic acid ethyl ester.

Another class of CETP inhibitors useful in the present invention consists of 4-carboxyamino-2-substituted-1, 2, 3, 4-tetrahydroquinolines having formula IV

Formula IV

And pharmaceutically acceptable forms thereof;

wherein R is_IV-1Is hydrogen, Y_IV、W_IV-X_IVOr W_IV-Y_IV；

Wherein W_IVIs carbonyl, thiocarbonyl, sulfinyl or sulfonyl;

X_IVis-O-Y_IV、-S-Y_IV、-N(H)-Y_IVor-N- (Y)_IV)₂；

Wherein Y is_IVIndependently at each occurrence is Z_IVOr a fully saturated, partially unsaturated or fully unsaturated 1-to 10-membered straight or branched carbon chain, wherein the carbons other than the linking carbon may optionally be replaced by 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen and said carbons are optionally mono-, di-or tri-substituted independently with halo, said carbons are optionally mono-substituted with hydroxy, said carbons are 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-, or di-substituted with Z_IVMono-substituted;

wherein Z_IVIs a partially saturated, fully saturated or fully unsaturated 3-to 8-membered ring optionally having 1 to 4 heteroatoms independently selected from oxygen, sulfur and nitrogen, or is a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated 3-to 6-membered rings, each ring being independently selected, optionally having 1 to 4 heteroatoms independently selected from nitrogen, sulfur and oxygen;

Wherein Z is_IVThe substituents are optionally mono-, di-or tri-substituted independently with a substituent selected from the group consisting of: halogen, (C)₂-C₆) Alkenyl, (C)₁-C₆) Alkyl, hydroxy, (C)₁-C₆) Alkoxy group, (C)₁-C₄) Alkylthio, amino, nitro, cyano, oxoSubstituted, carboxyl, (C)₁-C₆) Alkoxycarbonyl, mono-N-or di-N, N- (C)₁-C₆) Alkylamino group of the formula (C)₁-C₆) The alkyl substituent is optionally mono-, di-or tri-substituted independently with a substituent selected from the group consisting of: halogen, hydroxy, (C)₁-C₆) Alkoxy group, (C)₁-C₄) Alkylthio, amino, nitro, cyano, oxo, carboxy, (C)₁-C₆) Alkoxycarbonyl, mono-N-or di-N, N- (C)₁-C₆) Alkylamino group of said (C)₁-C₆) The alkyl substituent is further optionally substituted with 1 to 9 fluorines;

R_IV-2is a partially saturated, fully saturated or fully unsaturated 1-to 6-membered straight or branched carbon chain, wherein the carbons other than the linking carbon may optionally be replaced by 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, and wherein said carbon atoms are optionally mono-, di-or tri-substituted independently by halo, said carbon is optionally mono-substituted by oxo, said carbon is optionally mono-substituted by hydroxy, said sulfur is optionally mono-or di-substituted by oxo, said nitrogen is optionally mono-or di-substituted by oxo; or said R _IV-2 is a partially saturated, fully saturated or fully unsaturated 3-to 7-membered ring optionally having 1 to 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, wherein said R_IV-2 rings optionally through (C)₁-C₄) An alkyl linkage;

wherein R is_IV-the 2 ring is optionally mono-, di-or tri-substituted independently with a substituent selected from the group consisting of; halogen, (C)₂-C₆) Alkenyl, (C)₁-C₆) Alkyl, hydroxy, (C)₁-C₆) Alkoxy group, (C)₁-C₄) Alkylthio, amino, nitro, cyano, oxo, carboxy, (C)₁-C₆) Alkoxycarbonyl, mono-N-or di-N, N- (C)₁-C₆) Alkylamino group of the formula (C)₁-C₆) The alkyl substituent is optionally mono-, di-or tri-substituted independently with a substituent selected from the group consisting of: halogen, hydroxy, (C)₁-C₆) Alkoxy group, (C)₁-C₄) Alkylthio, oxo or (C)₁-C₆) An alkoxycarbonyl group;

provided that R is_IV-2 is not methyl;

R_IV-3 is hydrogen or Q_IV；

Wherein Q_IVIs a fully saturated, partially unsaturated or fully unsaturated 1-to 6-membered straight or branched carbon chain, wherein the carbons other than the linking carbon may optionally be replaced by a heteroatom selected from oxygen, sulfur and nitrogen, and said carbons are optionally mono-, di-or tri-substituted independently with halo, said carbons are optionally mono-substituted with hydroxy, said carbons are 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 V _IV；

Wherein V_IVIs a partially saturated, fully saturated or fully unsaturated 3-to 8-membered ring optionally having 1 to 4 heteroatoms independently selected from oxygen, sulfur and nitrogen, or is a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated 3-to 6-membered rings, each ring being independently selected, optionally having 1 to 4 heteroatoms independently selected from nitrogen, sulfur and oxygen;

wherein said V_IVThe substituents are optionally mono-, di-, tri-, or tetra-substituted independently with a substituent selected from the group consisting of: halo, (C)₁-C₆) Alkyl, (C)₂-C₆) Alkenyl, hydroxy, (C)₁-C₆) Alkoxy group, (C)₁-C₄) Alkylthio, amino, nitro, cyano, oxo, carboxamoyl, mono-N-or di-N, N- (C)₁-C₆) Alkyl carboxamoyl, carboxyl, (C)₁-C₆) Alkoxycarbonyl, mono-N-or di-N, N- (C)₁-C₆) Alkylamino group of the formula (C)₁-C₆) Alkyl or (C)₂-C₆) Alkenyl is optionally mono-, di-, tri-or mono-substituted independently with a substituent selected from the group consisting ofGeneration: hydroxy, (C)₁-C₆) Alkoxy group, (C)₁-C₄) Alkylthio, amino, nitro, cyano, oxo, carboxy, (C)₁-C₆) Alkoxycarbonyl, mono-N-or di-N, N- (C)₁-C₆) Alkylamino group of said (C)₁-C₆) Alkyl or (C)₂-C₆) The alkenyl substituent is further optionally substituted with 1 to 9 fluorines;

R_IV-4 is Q_IV-1 or V_IV-1；

Wherein Q_IV-1 is a fully saturated, partially unsaturated or fully unsaturated 1-to 6-membered straight or branched carbon chain wherein the carbons other than the linking carbon may optionally be replaced by a heteroatom selected from oxygen, sulfur and nitrogen, and said carbons are optionally mono-, di-or tri-substituted independently with halo, said carbons are optionally mono-substituted with hydroxy, said carbons are 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；

Wherein V_IV-1 is a partially saturated, fully saturated or fully unsaturated 3-to 6-membered ring optionally having 1 to 2 heteroatoms independently selected from oxygen, sulfur and nitrogen;

wherein said V_IV-1 substituent is optionally mono-, di-, tri-, or tetra-substituted independently with a substituent selected from the group consisting of: halo, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy, amino, nitro, cyano, (C)₁-C₆) Alkoxycarbonyl, mono-N-or di-N, N- (C)₁-C₆) Alkylamino group of the formula (C)₁-C₆) Alkyl substituents being optionally mono-substituted by oxo, said (C)₁-C₆) The alkyl substituent is further optionally substituted with 1 to 9 fluorines;

wherein either R_IV-3Must contain V _IVOr R_IV-4Must contain V_IV-1；

R_IV-5、R_IV-6、R_IV-7And R_IV-8Each independently being hydrogen, a chemical bond, nitro or halo, wherein the bond is substituted by T_IVOr partially saturated, fully saturated or fully unsaturated (C)₁-C₁2) A straight or branched carbon chain wherein carbon, optionally substituted with 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, and wherein said carbon atom 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 is optionally mono-or di-substituted with T_IVMono-substituted;

wherein T is_IVIs a partially saturated, fully saturated or fully unsaturated 3-to 8-membered ring optionally having 1 to 4 heteroatoms independently selected from oxygen, sulfur and nitrogen, or, is a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated 3-to 6-membered rings, each ring being independently selected, optionally having 1 to 4 heteroatoms independently selected from nitrogen, sulfur and oxygen;

wherein said T_IVThe substituents are optionally mono-, di-or tri-substituted independently with a substituent selected from the group consisting of: halogen, (C) ₁-C₆) Alkyl, (C)₂-C₆) Alkenyl, hydroxy, (C)₁-C₆) Alkoxy group, (C)₁-C₄) Alkylthio, amino, nitro, cyano, oxo, carboxy, (C)₁-C₆) Alkoxycarbonyl, mono-N-or di-N, N- (C)₁-C₆) Alkylamino group of the formula (C)₁-C₆) Alkyl is optionally mono-, di-, tri-substituted independently with a substituent selected from the group consisting of: hydroxy, (C)₁-C₆) Alkoxy group, (C)₁-C₄) Alkylthio, amino, nitro, cyano, oxo, carboxy, (C)₁-C₆) Alkoxycarbonyl, mono-N-or di-N, N- (C)₁-C₆) Alkylamino group of said (C)₁-C₆) Alkyl substituents are optionally further substituted by 1 to E9 fluoro; and is

Wherein R is_IV-5And R_IV-6Or R is_IV-6And R_IV-7And/or R_IV-7And R_IV-8And may also together form at least one 4-to 8-membered ring which is partially or fully saturated and optionally has 1 to 3 heteroatoms selected from nitrogen, sulfur and oxygen;

wherein said group consisting of R_IV-5And R_IV-6Or R is_IV-6And R_IV-7And/or R_IV-7And R_IV-8The ring or rings formed are optionally mono-, di-or tri-substituted independently with substituents selected from the group consisting of: halogen, (C)₁-C₆) Alkyl, (C)₁-C₄) Alkylsulfonyl group, (C)₂-C₆) Alkenyl, hydroxy, (C)₁-C₆) Alkoxy group, (C)₁-C₄) Alkylthio, amino, nitro, cyano, oxo, carboxy, (C)₁-C₆) Alkoxycarbonyl, mono-N-or di-N, N- (C) ₁-C₆) Alkylamino group of the formula (C)₁-C₆) Alkyl is optionally mono-, di-, tri-substituted independently with a substituent selected from the group consisting of: hydroxy, (C)₁-C₆) Alkoxy group, (C)₁-C₄) Alkylthio, amino, nitro, cyano, oxo, carboxy, (C)₁-C₆) Alkoxycarbonyl, mono-N-or di-N, N- (C)₁-C₆) Alkylamino group of said (C)₁-C₆) The alkyl substituent is further optionally substituted with 1 to 9 fluorines; with the proviso that when R_IV-2 is carboxy or (C)₁-C₄) Alkylcarboxyl radical, then R_IV-1Is not hydrogen.

Compounds of formula IV are disclosed in commonly assigned U.S. patent 6,197,786, the entire disclosure of which is incorporated herein by reference.

In a preferred embodiment, the CETP inhibitor is selected from one of the following compounds of formula IV:

[2S, 4S ]4- [ (3, 5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino ] -2-isopropyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester;

[2S, 4S ]4- [ (3, 5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino ] -6-chloro-2-cyclopropyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester;

[2S, 4S ] 2-cyclopropyl-4- [ (3, 5-dichloro-benzyl) -methoxycarbonyl-amino ] -6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester;

[2S, 4S ]4- [ (3, 5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino ] -2-cyclopropyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester;

[2R, 4R ]4- [ (3, 5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino ] -2-cyclopropyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester;

[2S, 4S ]4- [ (3, 5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino ] -2-cyclopropyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester;

[2S, 4S ]4- [ (3, 5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino ] -2-cyclobutyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester,

[2R, 4S ]4- [ (3, 5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino ] -2-ethyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester;

[2S, 4S ]4- [ (3, 5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino ] -2-methoxymethyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester;

[2R, 4S ]4- [ (3, 5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino ] -2-ethyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid 2-hydroxy-ethyl ester;

[2S, 4S ]4- [ (3, 5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino ] -2-cyclopropyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester;

[2R, 4S ]4- [ (3, 5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino ] -2-ethyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester;

[2S, 4S ]4- [ (3, 5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino ] -2-cyclopropyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid propyl ester; and

[2R, 4S ]4- [ (3, 5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino ] -2-ethyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid propyl ester.

Another class of CETP inhibitors useful in the present invention consists of 4-amino substituted-2-substituted-1, 2, 3, 4-tetrahydroquinolines having the formula V

Formula V

And pharmaceutically acceptable forms thereof;

wherein RV-1 is Y_V、W_V-X_VOr W_V-Y_V；

Wherein W_VIs carbonyl, thiocarbonyl, sulfinyl or sulfonyl;

X_Vis-O-Y_V、-S-Y_V、-N(H)-Y_Vor-N- (Y)_V)₂；

Wherein Y is_VIndependently at each occurrence is Z_VOr a fully saturated, partially unsaturated or fully unsaturated 1-to 10-membered straight or branched carbon chain, wherein the carbons other than the linking carbon may optionally be replaced by 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen and said carbons are optionally mono-, di-or tri-substituted independently with halo, said carbons are optionally mono-substituted with hydroxy, said carbons are 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-, or di-substituted with Z _VMono-substitution；

Wherein Z_VIs a partially saturated, fully saturated or fully unsaturated 3-to 8-membered ring optionally having 1 to 4 heteroatoms independently selected from oxygen, sulfur and nitrogen, or is a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated 3-to 6-membered rings, each ring being independently selected, optionally having 1 to 4 heteroatoms independently selected from nitrogen, sulfur and oxygen;

wherein Z is_VThe substituents are optionally mono-, di-or tri-substituted independently with a substituent selected from the group consisting of: halogen, (C)₂-C₆) Alkenyl, (C)₁-C₆) Alkyl, hydroxy, (C)₁-C₆) Alkoxy group, (C)₁-C₄) Alkylthio, amino, nitro, cyano, oxo, carboxy, (C)₁-C₆) Alkoxycarbonyl, mono-N-or di-N, N- (C)₁-C₆) Alkylamino group of the formula (C)₁-C₆) The alkyl substituent is optionally mono-, di-or tri-substituted independently with a substituent selected from the group consisting of: halogen, hydroxy, (C)₁-C₆) Alkoxy group, (C)₁-C₄) Alkylthio, amino, nitro, cyano, oxo, carboxy, (C)₁-C₆) Alkoxycarbonyl, mono-N-or di-N, N- (C)₁-C₆) Alkylamino group of said (C)₁-C₆) The alkyl substituent is further optionally substituted with 1 to 9 fluorines;

R_V-2is a partially saturated, fully saturated or fully unsaturated 1-to 6-membered straight or branched carbon chain, wherein the carbons other than the linking carbon may optionally be replaced by 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, and wherein said carbon atoms are optionally mono-, di-or tri-substituted independently by halo, said carbon is optionally mono-substituted by oxo, said carbon is optionally mono-substituted by hydroxy, said sulfur is optionally mono-or di-substituted by oxo, said nitrogen is optionally mono-or di-substituted by oxo; or said R _V-2Is partially saturated, fully saturated or fully unsaturated, optionally having 1 to 2 members independently selected from oxygenSulfur and nitrogen, wherein R is_V-2The rings being optionally joined by (C)₁-C₄) An alkyl group;

wherein R is_V-2The ring is optionally mono-, di-or tri-substituted independently with a substituent selected from the group consisting of: halogen, (C)₂-C₆) Alkenyl, (C)₁-C₆) Alkyl, hydroxy, (C)₁-C₆) Alkoxy group, (C)₁-C₄) Alkylthio, amino, nitro, cyano, oxo, carboxy, (C)₁-C₆) Alkoxycarbonyl, mono-N-or di-N, N- (C)₁-C₆) Alkylamino group of the formula (C)₁-C₆) The alkyl substituent is optionally mono-, di-or tri-substituted independently with a substituent selected from the group consisting of: halogen, hydroxy, (C)₁-C₆) Alkoxy group, (C)₁-C₄) Alkylthio, oxo or (C)₁-C₆) An alkoxycarbonyl group;

R_V-3is hydrogen or Q_V；

Wherein Q_VIs a fully saturated, partially unsaturated or fully unsaturated 1-to 6-membered straight or branched carbon chain, wherein the carbons other than the linking carbon may optionally be replaced by a heteroatom selected from oxygen, sulfur and nitrogen, and said carbons are optionally mono-, di-or tri-substituted independently with halo, said carbons are optionally mono-substituted with hydroxy, said carbons are 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-, or di-substituted with V _VMono-substituted;

wherein V_VIs a partially saturated, fully saturated or fully unsaturated 3-to 8-membered ring optionally having 1 to 4 heteroatoms independently selected from oxygen, sulfur and nitrogen, or is a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated 3-to 6-membered rings, each ring being independently selected, optionally having 1 to 4 heteroatoms independently selected from nitrogen, sulfur and oxygen;

wherein saidV of_VThe substituents are optionally mono-, di-, tri-, or tetra-substituted independently with a substituent selected from the group consisting of: halo, (C)₁-C₆) Alkyl, (C)₂-C₆) Alkenyl, hydroxy, (C)₁-C₆) Alkoxy group, (C)₁-C₄) Alkylthio, amino, nitro, cyano, oxo, carbamoyl, mono-N-or di-N, N- (C)₁-C₆) Alkylcarbamoyl (carboxamoyl), carboxyl, (C)₁-C₆) Alkoxycarbonyl, mono-N-or di-N, N- (C)₁-C₆) Alkylamino group of the formula (C)₁-C₆) Alkyl or (C)₂-C₆) Alkenyl is optionally mono-, di-, tri-substituted independently with a substituent selected from the group consisting of: hydroxy, (C)₁-C₆) Alkoxy group, (C)₁-C₄) Alkylthio, amino, nitro, cyano, oxo, carboxy, (C)₁-C₆) Alkoxycarbonyl, mono-N-or di-N, N- (C)₁-C₆) Alkylamino group of said (C)₁-C₆) Alkyl or (C) ₂-C₆) The alkenyl substituent is also optionally substituted with 1 to 9 fluorines;

R_V-4 is cyano, formyl, W_V-1Q_V-1、W_V-1V_V-1、(C₁-C₄) Alkylene radical V_V-1 or V_V-2；

Wherein WV-1 is carbonyl, thiocarbonyl, SO or SO₂，

Wherein Q_V-1 is a fully saturated, partially unsaturated or fully unsaturated 1-to 6-membered straight or branched carbon chain, wherein said carbon may optionally be replaced by a heteroatom selected from oxygen, sulfur and nitrogen, and said carbon is optionally mono-, di-or tri-substituted independently by halogen, said carbon is optionally mono-substituted by hydroxy, said carbon is optionally mono-substituted by oxo, said sulfur is optionally mono-or di-substituted by oxo, said nitrogen is optionally mono-, or di-substituted by oxo, and said carbon chain is optionally mono-, or di-substituted by V_V-1Mono-substituted;

wherein V_V-1Is a partially saturated, fully saturated or fully unsaturated 3-to 6-membered ring optionally having 1 to 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, or is a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated 3-to 6-membered rings, each ring being independently selected, optionally having 1 to 4 heteroatoms independently selected from nitrogen, sulfur and oxygen;

wherein said V_V-1The substituents are optionally mono-, di-, tri-, or tetra-substituted independently with a substituent selected from the group consisting of: halo, (C) ₁-C₆) Alkyl, (C)₁-C₆) Alkoxy, hydroxy, oxo, amino, nitro, cyano, (C)₁-C₆) Alkoxycarbonyl, mono-N-or di-N, N- (C)₁-C₆) Alkylamino group of the formula (C)₁-C₆) Alkyl substituents being optionally mono-substituted by oxo, said (C)₁-C₆) The alkyl substituent is further optionally substituted with 1 to 9 fluorines;

wherein V_V-2A 5-to 7-membered ring that is partially saturated, fully saturated, or fully unsaturated, containing 1-4 heteroatoms independently selected from oxygen, sulfur, and nitrogen;

wherein said V_V-2The substituents are optionally mono-, di-or tri-substituted independently with a substituent selected from the group consisting of: halogen, (C)₁-C₂) Alkyl, (C)₁-C₂) Alkoxy, hydroxy, or oxo, wherein (C) is₁-C₂) The alkyl group optionally has 1 to 5 fluorines; and is

Wherein R is_V-4Not including direct connection C₄An oxycarbonyl group of nitrogen;

wherein either R_V-3Must contain V_VOr R_V-4Must contain V_V-1；

R_V-5、R_V-6、R_V-7And R_V-8Independently hydrogen, a chemical bond, nitro or halo, wherein the bond is substituted by T_VOr partially saturated, completelyFully saturated or fully unsaturated (C)₁-C₁2) A linear or branched carbon chain wherein a carbon may be optionally replaced by 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, wherein said carbon atom is optionally mono-, di-or tri-substituted independently by halogen, said carbon is optionally mono-substituted by hydroxy, said carbon is optionally mono-substituted by oxo, said sulfur is optionally mono-or di-substituted by oxo, said nitrogen is optionally mono-or di-substituted by oxo, and said carbon chain is optionally substituted by T _VMono-substituted;

wherein T is_VIs a partially saturated, fully saturated or fully unsaturated 3-to 12-membered ring optionally having 1 to 4 heteroatoms independently selected from oxygen, sulfur and nitrogen, or is a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated 3-to 6-membered rings, each ring being independently selected, optionally having 1 to 4 heteroatoms independently selected from nitrogen, sulfur and oxygen;

wherein said T_VThe substituents are optionally mono-, di-or tri-substituted independently with a substituent selected from the group consisting of: halogen, (C)₁-C₆) Alkyl, (C)₂-C₆) Alkenyl, hydroxy, (C)₁-C₆) Alkoxy group, (C)₁-C₄) Alkylthio, amino, nitro, cyano, oxo, carboxy, (C)₁-C₆) Alkoxycarbonyl, mono-N-or di-N, N- (C)₁-C₆) Alkylamino group of the formula (C)₁-C₆) Alkyl is optionally mono-, di-, tri-substituted independently with a substituent selected from the group consisting of: hydroxy, (C)₁-C₆) Alkoxy group, (C)₁-C₄) Alkylthio, amino, nitro, cyano, oxo, carboxy, (C)₁-C₆) Alkoxycarbonyl, mono-N-or di-N, N- (C)₁-C₆) Alkylamino group of said (C)₁-C₆) The alkyl substituent optionally further having 1 to 9 fluorines;

wherein R is_V-5And R_V-6Or R is_V-6And R_V-7And/or R_V-7And R_V-8May also be combined together to form at leastA ring which is a partially saturated or fully unsaturated 4-to 8-membered ring and optionally has 1 to 3 heteroatoms selected from nitrogen, sulfur and oxygen;

Wherein said group consisting of R_V-5And R_V-6Or R is_V-6And R_V-7And/or R_V-7And R_V-8The mono-or polycyclic ring formed is optionally mono-, di-or tri-substituted independently with substituents selected from the group consisting of: halogen, (C)₁-C₆) Alkyl, (C)₁-C₄) Alkylsulfonyl group, (C)₂-C₆) Alkenyl, hydroxy, (C)₁-C₆) Alkoxy group, (C)₁-C₄) Alkylthio, amino, nitro, cyano, oxo, carboxy, (C)₁-C₆) Alkoxycarbonyl, mono-N-or di-N, N- (C)₁-C₆) Alkylamino group of the formula (C)₁-C₆) Alkyl is optionally mono-, di-, tri-substituted independently with a substituent selected from the group consisting of: hydroxy, (C)₁-C₆) Alkoxy group, (C)₁-C₄) Alkylthio, amino, nitro, cyano, oxo, carboxy, (C)₁-C₆) Alkoxycarbonyl, mono-N-or di-N, N- (C)₁-C₆) Alkylamino group of said (C)₁-C₆) The alkyl substituent optionally further has 1 to 9 fluorines.

The compounds of formula V are disclosed in commonly assigned U.S. Pat. No. 6,140,343, the entire disclosure of which is incorporated herein by reference.

In a preferred embodiment, the CETP inhibitor is selected from one of the following compounds of formula V:

[2S, 4S ]4- [ (3, 5-bis-trifluoromethyl-benzyl) -formyl-amino ] -2-cyclopropyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester;

[2S, 4S ]4- [ (3, 5-bis-trifluoromethyl-benzyl) -formyl-amino ] -2-cyclopropyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid propyl ester;

[2S, 4S ]4- [ acetyl- (3, 5-bis-trifluoromethyl-benzyl) -amino ] -2-cyclopropyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester;

[2R, 4S ]4- [ acetyl- (3, 5-bis-trifluoromethyl-benzyl) -amino ] -2-ethyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester;

[2R, 4S ]4- [ acetyl- (3, 5-bis-trifluoromethyl-benzyl) -amino ] -2-methyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester,

[2S, 4S ]4- [1- (3, 5-bis-trifluoromethyl-benzyl) -ureido ] -2-cyclopropyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester;

[2R, 4S ]4- [ acetyl- (3, 5-bis-trifluoromethyl-benzyl) -amino ] -2-ethyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester;

[2S, 4S ]4- [ acetyl- (3, 5-bis-trifluoromethyl-benzyl) -amino ] -2-methoxymethyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester;

[2S, 4S ]4- [ acetyl- (3, 5-bis-trifluoromethyl-benzyl) -amino ] -2-cyclopropyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid propyl ester;

[2S, 4S ]4- [ acetyl- (3, 5-bis-trifluoromethyl-benzyl) -amino ] -2-cyclopropyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester;

[2R, 4S ]4- [ (3, 5-bis-trifluoromethyl-benzyl) -formyl-amino ] -2-ethyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester;

[2R, 4S ]4- [ (3, 5-bis-trifluoromethyl-benzyl) -formyl-amino ] -2-methyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester;

[2S, 4S ]4- [ acetyl- (3, 5-bis-trifluoromethyl-benzyl) -amino ] -2-cyclopropyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester;

[2R, 4S ]4- [ (3, 5-bis-trifluoromethyl-benzyl) -formyl-amino ] -2-ethyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester;

[2S, 4S ]4- [ (3, 5-bis-trifluoromethyl-benzyl) -formyl-amino ] -2-cyclopropyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester;

[2R, 4S ]4- [ (3, 5-bis-trifluoromethyl-benzyl) -formyl-amino ] -2-methyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester; and

[2R, 4S ]4- [ acetyl- (3, 5-bis-trifluoromethyl-benzyl) -amino ] -2-methyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester.

Another class of CETP inhibitors useful in the present invention consists of cycloalkyl-pyridines having the formula VI

Formula VI

And pharmaceutically acceptable forms thereof;

Wherein A is_VIRepresents an aryl group containing 6 to 10 carbon atoms, optionally substituted with up to 5 identical or different substituents, which are halogen, nitro, hydroxy, trifluoromethyl, trifluoromethoxy or straight-chain or branched alkyl, acyl, hydroxyalkyl or alkoxy, each substituent containing up to 7 carbon atoms, or of the formula-NR_VI-3R_VI-4A group of the formula (I) wherein

R_VI-3And R_VI-4Identical or different and denotes hydrogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms,

D_VIrepresents an aryl group containing 6 to 10 carbon atoms optionally substituted by phenyl, nitro, halogen, trifluoromethyl or trifluoromethoxy, or of the formula R_VI-5-L_VIGroup of (A) to (B)

Or R_VI-9-T_VI-V_VI-X_VIIs substituted in which

R_VI-5、R_VI-6And R_VI-9Represents, independently of one another, cycloalkyl having 3 to 6 carbon atoms, or aryl having 6 to 10 carbon atoms or a 5-to 7-membered, optionally benzene-fused, saturated or unsaturated, mono-, di-or tricyclic heterocycle having up to 4 heteroatoms from the group S, N and/or O, wherein the ring is optionally substituted, in the case of a nitrogen-containing ring which is also substituted by N, by up to 5 identical or different substituents, halogen, trifluoromethyl, nitro, hydroxyl, cyano, carboxyl, trifluoromethoxy, straight-chain or branched acyl, alkyl, alkylthio, alkylalkoxy, alkoxy or alkoxycarbonyl each having up to 6 carbon atoms, aryl or trifluoromethyl-substituted aryl each having 6 to 10 carbon atoms, or optionally benzene-fused, an aromatic 5-to 7-membered heterocyclic ring containing up to 3 heteroatoms selected from S, N and/OR O, and/OR according to formula-OR _VI-10，-SR_VI-11，-SO₂R_VI-12or-NR_VI-13R_VI-14In the case of the group of (1), wherein

R_VI-10、R_VI-11And R_VI-12Represents, independently of one another, an aryl radical having 6 to 10 carbon atoms, which is substituted by up to 2 identical or different substituents, such as phenyl, halogen or a linear or branched alkyl radical having up to 6 carbon atoms,

R_VI-13and R_VI-14Identical or different and having R given above_VI-3And R_VI-4Has the meaning of, or

R_VI-5And/or R_VI-6Represents a group of the formula

R_VI-7Represents hydrogen or halogen, and

R_VI-8represents hydrogen, halogen, azido, trifluoromethyl, hydroxyl, trifluoromethoxy, straight-chain or branched alkoxy or alkyl (each group containing up to 6 carbon atoms), or a group of the formula

-NR_VI-15R_VI-16

Wherein

R_VI-15And R_VI-16Identical or different and having R given above_VI-3And R_VI-4Has the meaning of (A), or

R_VI-7And R_VI-8Together form a group of formula ═ O or ═ NR_VI-17Wherein

R_VI-17Represents hydrogen or a linear or branched alkyl, alkoxy or acyl radical each containing up to 6 carbon atoms,

L_VIrepresents a linear or branched alkylene or alkenylene chain, each containing up to 8 carbon atoms, optionally substituted by up to 2 hydroxyl groups,

T_VIand X_VIIdentical or different and represent a straight-chain or branched alkylene chain containing up to 8 carbon atoms, or

T_VIOr X_VIA key is represented that is a key of the key,

V_VIrepresents an oxygen or sulfur atom or-NR _VI-18Group (a) in which

R_VI-18Represents hydrogen or a linear or branched alkyl group containing up to 6 carbon atoms or a phenyl group,

E_VIrepresents cycloalkyl having 3 to 8 carbon atoms, or straight-chain or branched alkyl having up to 8 carbon atoms, which is optionally substituted by cycloalkyl having 3 to 8 carbon atoms or by hydroxy, or by phenyl, which is optionally substituted bySubstituted by halogen or trifluoromethyl, and is substituted by halogen or trifluoromethyl,

R_VI-1and R_VI-2Together form a straight-chain or branched alkylene chain containing up to 7 carbon atoms, which must be substituted by carbonyl groups and/or groups of the formula

Wherein

a and b are identical or different and represent a number equal to 1, 2 or 3,

R_VI-19represents a hydrogen atom, a cycloalkyl group containing from 3 to 7 carbon atoms, a linear OR branched silylalkyl group containing up to 8 carbon atoms, OR a linear OR branched alkyl group containing up to 8 carbon atoms, optionally substituted with a hydroxyl group, a linear OR branched alkoxy group containing up to 6 carbon atoms, OR a phenyl group, which substituents may be substituted with halogen, nitro, trifluoromethyl, trifluoromethoxy OR phenyl OR tetrazole-substituted phenyl, and optionally substituted with a compound of formula-OR_VI-22-substituted alkyl, wherein

R_VI-22Represents a straight-chain or branched acyl or benzyl radical having up to 4 carbon atoms, or

R_VI-19Denotes straight-chain or branched acyl or benzoyl containing up to 20 carbon atoms, which is optionally substituted by halogen, trifluoromethyl, nitro or trifluoromethoxy, or straight-chain or branched fluoroacyl containing up to 8 carbon atoms,

R_VI-20And R_VI-21Identical or different and represent hydrogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms, or

R_VI-20And R_VI-21Together form a 3-to 6-membered carbocyclic ring, and said carbocyclic ring is optionally substituted, optionally also in pairs, with up to 6 identical or different substituents, said substituents being trifluoromethyl, hydroxy, nitrile, halogen, carboxy, nitro-a group, an azido group, a cyano group, a cycloalkyl group or cycloalkoxy group each containing 3 to 7 carbon atoms, a linear or branched alkoxycarbonyl group, alkoxy group or alkylthio group each containing up to 6 carbon atoms, or a linear or branched alkyl group containing up to 6 carbon atoms, said substituents being further substituted with up to 2 identical or different substituents as follows: hydroxy, benzyloxy, trifluoromethyl, benzoyl, straight-chain or branched alkoxy, oxyacyl or carboxyl, each containing up to 4 carbon atoms, and/or phenyl, which substituents are further substituted by halogen, trifluoromethyl or trifluoromethoxy, and/or the carbon ring formed is optionally substituted, also in pairs, by up to 5 identical or different substituents: phenyl, benzoyl, thienyl or sulfonylbenzyl, said substituents being further optionally substituted by halogen, trifluoromethyl, trifluoromethoxy or nitro, and/or being optionally a group of formula

-SO₂-C₆H₅、-(CO)dNR_VI-23R_VI-24Or (c) or (O),

wherein

c is a number equal to 1, 2, 3 or 4,

d is a number equal to 0 or 1,

R_VI-23and R_VI-24Identical or different and denotes hydrogen, cycloalkyl having 3 to 6 carbon atoms, straight-chain or branched alkyl having up to 6 carbon atoms, benzyl or phenyl, which is optionally substituted by up to 2 identical or different substituents, halogen, trifluoromethyl, cyano, phenyl or nitro, and/or the carbocycle formed is optionally substituted by a spiro-linked group of the formula

Wherein

W_VIRepresents an oxygen atom or a sulfur atom,

Y_VIand Y'_VITogether form a 2-to 6-membered straight or branched alkylene chain,

e is a number equal to 1, 2, 3, 4, 5, 6 or 7,

f is a number equal to 1 or 2,

R_VI-25、R_VI-26、R_VI-27、R_VI-28、R_VI-29、R_VI-30and R_VI-31Identical or different and represent hydrogen, trifluoromethyl, phenyl, halogen or straight-chain or branched alkyl or alkoxy having in each case up to 6 carbon atoms, or

R_VI-25And R_VI-26Or R_VI-27And R_VI-28Each together representing a straight or branched alkyl chain containing up to 6 carbon atoms or

R_VI-25And R_VI-26Or R_VI-27And R_VI-28Each together forming a radical of the formula

Wherein

W_VIHaving the meaning given above, the use of,

g is a number equal to 1, 2, 3, 4, 5, 6 or 7,

R_VI-32and R_VI-33Together form a 3-to 7-membered heterocyclic ring containing an oxygen or sulfur atom or according to the formulae SO, SO ₂or-NR_VI-34A group of (1), wherein

R_VI-34Representing a hydrogen atom, a phenyl group, a benzyl group, or a linear or branched alkyl group containing up to 4 carbon atoms, and salts and N-oxides thereofWith the proviso that 5(6H) -quinolone and 3-benzoyl-7, 8-dihydro-2, 7, 7-trimethyl-4-phenyl are excluded.

Compounds of formula VI are disclosed in European patent application No. EP 818448A 1, the entire disclosure of which is incorporated herein by reference.

In a preferred embodiment, the CETP inhibitor is selected from one of the following compounds of formula VI:

2-cyclopentyl-4- (4-fluorophenyl) -7, 7-dimethyl-3- (4-trifluoromethylbenzoyl) -4, 6, 7, 8-tetrahydro-1H-quinolin-5-one;

2-cyclopentyl-4- (4-fluorophenyl) -7, 7-dimethyl-3- (4-trifluoromethylbenzoyl) -7, 8-dihydro-6H-quinolin-5-one;

[ 2-cyclopentyl-4- (4-fluorophenyl) -5-hydroxy-7, 7-dimethyl-5, 6, 7, 8-tetrahydroquinolin-3-yl ] - (4-trifluoromethylphenyl) -methanone;

[5- (tert-butyldimethylsilyloxy) -2-cyclopentyl-4- (4-fluorophenyl) -7, 7-dimethyl-5, 6, 7, 8-tetrahydroquinolin-3-yl ] - (4-trifluoromethylphenyl) -methanone;

[5- (tert-butyldimethylsilyloxy) -2-cyclopentyl-4- (4-fluorophenyl) -7, 7-dimethyl-5, 6, 7, 8-tetrahydroquinolin-3-yl ] - (4-trifluoromethylphenyl) -methanol;

5- (tert-butyldimethylsilyloxy) -2-cyclopentyl-4- (4-fluorophenyl) -3- [ fluoro- (4-trifluoromethylphenyl) -methyl ] -7, 7-dimethyl-5, 6, 7, 8-tetrahydroquinoline;

2-cyclopentyl-4- (4-fluorophenyl) -3- [ fluoro- (4-trifluoromethylphenyl) -methyl ] -7, 7-dimethyl-5, 6, 7, 8-tetrahydroquinolin-5-ol. Another class of CETP inhibitors useful in the present invention consists of substituted-pyridines having the formula VII

Formula VII

And pharmaceutically acceptable forms thereof, wherein

R_VII-2And R_VII-6Independently selected from the group consisting of hydrogen, hydroxy, alkyl, fluorinated aralkyl, chlorofluoroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, alkoxyalkyl, and alkoxycarbonyl; provided that R is_VII-2And R_VII-6At least one of which is fluorinated alkyl, chlorofluoro-alkyl or alkoxyalkyl;

R_VII-3selected from the group consisting of hydroxy, amido, arylcarbonyl, heteroarylcarbonyl, hydroxymethyl-CHO, -CO₂R_VII-7Wherein R is_VII-7Selected from hydrogen, alkyl and cyanoalkyl; and

wherein R is_VII-15aSelected from the group consisting of hydroxy, hydrogen, halogen, alkylthio, alkenylthio, alkynylthio, arylthio, heteroarylthio, heterocyclylthio, alkoxy, alkenyloxy, alkynyloxy, aryloxy, heteroaryloxy and heterocyclyloxy, and

R_VII-16aSelected from the group consisting of alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, and heterocyclyl, arylalkoxy, trialkylsiloxy;

R_VII-4selected 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, heteroarylalkenyl, heterocyclylalkenyl, alkoxy, alkenyloxy, alkynyloxy, aryloxy, heteroaryloxy, heterocyclyloxy, alkanoyloxy, arylacyloxy, heteroaroyloxy, heterocyclyloxy, alkoxycarbonyl, alkoxycarbonyloxy, alkoxy,Alkenyloxycarbonyl, alkynyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, heterocyclyloxycarbonyl, thio, alkylthio, alkenylthio, alkynylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, alkylthioalkyl, alkenylthioalkyl, alkynylthioalkyl, arylthioalkyl, heteroarylthioalkyl, heterocyclylthioalkyl, alkylthioalkenyl, alkenylthioalkenyl, alkynylthioalkenyl, arylthioalkenyl, heteroarylthioalkenyl, heterocyclylthioalkenyl, alkylamino, alkenylamino, alkynylamino, arylamino, heteroarylamino, heterocyclylamino, aryldialkylamino, diarylamino, diheteroarylamino, alkylarylamino, alkylheteroarylamino, arylheteroarylamino, trialkylsilyl, trialkenylsilyl, triarylsilyl, alkylthio, arylthio, alkenylthio, alkynylamino, heteroarylthio, heterocyclylthioalkyl, alkenylthio, alkynylthio, -CO (O) N (R) _VII-8aR_VII-8b) Wherein R is_VII-8aAnd R_VII-8bIndependently selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl, -SO₂R_VII-9Wherein R is_VII-9Selected from the group consisting of hydroxy, alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl, -OP (O) (OR)_VII-10a)(OR_VII-10b) Wherein R is_VII-10aAnd R_VII-10bIndependently selected from hydrogen, hydroxyl, alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl, and-OP (S) (OR)_VII-11a)(OR_VII-11b) Wherein R is_VII-11aAnd R_VII-11bIndependently selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl;

R_VII-5selected from the group consisting of hydrogen, hydroxy, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, aryl, heteroaryl, heterocyclyl, alkoxy, alkenyloxy, alkynyloxy, aryloxy, heteroaryloxy, heterocyclyloxy, alkylcarbonyloxyalkyl, alkenylcarbonyloxyalkyl, alkynylcarbonyloxyalkyl, arylcarbonyloxyalkyl, heteroarylcarbonyloxyalkyl, heterocyclylcarbonyloxyalkyl, cycloalkylalkyl, cycloalkenylalkyl, aralkyl, heteroarylalkyl, heterocyclylalkyl, cycloalkylalkenyl, cycloalkenylalkyl, heterocyclylalkyl, and the likeAlkenylalkenyl, aralkenyl, heteroarylalkenyl, heterocyclylalkenyl, alkylthioalkyl, cycloalkylthioalkyl, alkenylthioalkyl, alkynthioalkyl, arylthioalkyl, heteroarylthioalkyl, heterocyclylthioalkyl, alkylthioalkenyl, alkenylthioalkenyl, alkynylthioalkenyl, arylthioalkenyl, heteroarylthioalkenyl, heterocyclylthioalkenyl, alkoxyalkyl, alkenyloxyalkyl, alkynyloxy-1-alkyl, aryloxyalkyl, heteroaryloxyalkyl, heterocyclyloxyalkyl, alkoxyalkenyl, alkenyloxyalkenyl, alkynyloxyalkenyl, aryloxyalkenyl, heteroaryloxyalkenyl, heterocyclyloxyalkenyl, cyano, hydroxymethyl, -CO ₂R_VII-14Wherein R is_VII-14Selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl;

wherein R is_VII-15bSelected from the group consisting of hydroxy, hydrogen, halogen, alkylthio, alkenylthio, alkynylthio, arylthio, heteroarylthio, heterocyclylthio, alkoxy, alkenyloxy, alkynyloxy, aryloxy, heteroaryloxy, heterocyclyloxy, aryloxy, and alkylsulfonyloxy, and

R_VII-16bselected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkoxy, and trialkylsiloxy;

wherein R is_VII-17And R_VII-18Independently selected from alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl;

wherein R is_VII-19Selected from alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, -SR_VII-20、-OR_VII-21and-R_VII-22CO₂R_VII-23Wherein

R_VII-20Selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aminoalkyl, aminoalkenyl, aminoalkynyl, aminoaryl, aminoheteroaryl, aminoheterocyclyl, alkylheteroarylamino, arylheteroarylamino,

R_VII-21selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl,

R_VII-22selected from alkylene or arylene, and

R_VII-23selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl;

Wherein R is_VII-24Selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, aralkenyl, and aralkynyl;

wherein R is_VII-25Is a heterocyclylene group;

wherein R is_VII-26And R_VII-27Independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl;

wherein R is_VII-28And R_VII-29Independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl;

wherein R is_VII-30And R_VII-31Independently alkoxy, alkenyloxy, alkynyloxy, aryloxy, heteroaryloxy, and heterocyclyloxy; and

wherein R is_VII-32And R_VII-33Independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl;

-C≡C-Si(R_VII-36)₃

wherein R is_VII-36Selected from alkyl, alkenyl, aryl, heteroaryl and heterocyclyl;

wherein R is_VII-37And R_VII-38Independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl;

wherein R is_VII-39Selected from the group consisting of hydrogen, alkoxy, alkenyloxy, alkynyloxy, aryloxy, heteroaryloxy, heterocyclyloxy, alkylthio, alkenylthio, alkynylthio, arylthio, heteroarylthio and heterocyclylthio, and

R_VII-40selected from the group consisting of haloalkyl, haloalkenyl, haloalkynyl, heteroaryl, haloheteroaryl, haloheterocyclyl, cycloalkyl, cycloalkenyl, heterocyclylalkoxy, heterocyclylalkenyloxy, heterocyclylalynyloxy, alkylthio, alkenylthio, alkynylthio, arylthio, heteroarylthio, and heterocyclylthio;

-N＝R_VII-41，

Wherein R is_VII-41Is a heterocyclylene group;

wherein R is_VII-42Selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl, and

R_VII-43selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, heteroaryl, haloheteroaryl, and haloheterocyclyl;

wherein R is_VII-44Selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl;

-N＝S＝O；

-N＝C＝S；

-N＝C＝O；

-N₃；

-SR_VII-45

wherein R is_VII-45Selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, haloalkyl, haloalkenyl, haloalkynyl, heteroaryl, haloheteroaryl, haloheterocyclyl, heterocyclyl, cycloalkylalkyl, cycloalkenylalkyl, aralkyl, heteroarylalkyl, heterocyclylalkyl, cycloalkylalkenyl, cycloalkenylalkenyl, aralkenyl, heteroarylalkenyl, heterocyclylalkyl, alkylthioalkyl, alkenylthioalkyl, alkynylthioalkyl, arylthioalkyl, heteroarylthioalkyl, heterocyclylthioalkyl, alkylthioalkenyl, alkenylthioalkenyl, alkynylthioalkenyl, aralkylthioalkenyl, heteroaralkylthioalkenyl, heterocyclylthioalkenyl, aminocarbonylalkyl, aminocarbonylalkenyl, aminocarbonylalkynyl, aminocarbonylaryl, aminocarbonylheteroaryl, and aminocarbonylheterocyclyl,

-SR_VII-46and-CH₂R_VII-47，

Wherein R is_VII-46Selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl, and R_VII-47Selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl; and

wherein R is_VII-48Selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl, and

R_VII-49selected from the group consisting of alkoxy, alkenyloxy, alkynyloxy, aryloxy, heteroaryloxy, heterocyclyloxy, haloalkyl, haloalkenyl, haloalkynyl, heteroaryl, haloheteroaryl and haloheterocyclyl;

wherein R is_VII-50Selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, alkoxy, alkenyloxy, alkynyloxy, aryloxy, heteroaryloxy, and heterocyclyloxy;

wherein R is_VII-51Selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, haloalkyl, haloalkenyl, haloalkynyl, heteroaryl, haloheteroaryl and haloheterocyclyl; and is

Wherein R is_VII-53Selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl;

with the proviso that when R_VII-5When selected from heterocyclylalkyl and heterocyclylalkenyl, the heterocyclyl of the corresponding heterocyclylalkyl or heterocyclylalkenyl is not delta-lactone; and

With the proviso that when R_VII-4Is aryl, heteroaryl or heterocyclyl, and R_VII-2And R_VII-6When one is trifluoromethyl, then R_VII-2And R_VII-6And the other is difluoromethyl.

Compounds of formula VII are disclosed in WO 9941237-A1, the entire disclosure of which is incorporated herein by reference.

In a preferred embodiment, the CETP inhibitor is selected from the following compounds of formula VII:

5, 5' -dithiobis [ 2-difluoromethyl-4- (2-methylpropyl) -6- (trifluoromethyl) -3-pyridine-carboxylic acid dimethyl ester ].

Another class of CETP inhibitors useful in the present invention consists of substituted pyridines having formula VIII and biphenyls

Of the formula VIII

And to pharmaceutically acceptable forms thereof,

wherein

A_VIIIAryl of 6 to 10 carbon atoms, optionally substituted up to 3 times in the same or different manner by halogen, hydroxy, trifluoromethyl, trifluoromethoxy, by straight-chain or branched alkyl, acyl or alkoxy of up to 7 carbon atoms each, or by a group of the formula

-NR_VIII-1R_VIII-2Wherein

R_VIII-1And R_VIII-2Identical or different and denotes hydrogen, phenyl, or straight-chain or branched alkyl having up to 6 carbon atoms,

D_VIIIrepresents a linear or branched alkyl group of up to 8 carbon atoms, substituted by hydroxyl groups,

E_VIIIand L_VIIIIdentical or different and represent a linear or branched alkyl group of up to 8 carbon atoms, optionally substituted by a cycloalkyl group of 3 to 8 carbon atoms, or represent a cycloalkyl group of 3 to 8 carbon atoms, or

E_VIIIHave the meanings indicated above and

L_VIIIin this case, aryl of 6 to 10 carbon atoms, which is optionally substituted up to 3 times in the same or different manner, is halogen, hydroxy, trifluoromethyl, trifluoromethoxy, or is substituted by straight-chain or branched alkyl, acyl or alkoxy of up to 7 carbon atoms each, or is substituted bySubstituted by a group of the formula

-NR_VIII-3R_VIII-4Wherein

R_VIII-3And R_VIII-4Identical or different and having the above-mentioned meanings for R_VIII-1And R_VIII-2In the sense given in the specification, the term "a", "an", "the" or "an" is used,

or

E_VIIIRepresents a linear or branched alkyl group having up to 8 carbon atoms, or an aryl group having 6 to 10 carbon atoms, optionally substituted in the same or different manner up to 3 times by halogen, hydroxy, trifluoromethyl, trifluoromethoxy, or by a linear or branched alkyl, acyl, or alkoxy group, each having up to 7 carbon atoms, or by a group of the formula

-NR_VIII-5R_VIII-6Wherein

R_VIII-5And R_VIII-6Same or different and having the same meanings as above for R_VIII-1And R_VIII-2The meanings given, and

L_VIIIin this case, a straight or branched alkoxy group of up to 8 carbon atoms or a cycloalkoxy group of 3 to 8 carbon atoms,

T_VIIIa group of the formula

R_VIII-7-X_VIII-orWherein

R_VIII-7And R_VIII-8Cycloalkyl of 3 to 8 carbon atoms, or aryl of 6 to 10 carbon atoms, or 5-to 7-membered aromatic, optionally benzo-fused, heterocyclic compounds having up to 3 heteroatoms from the group S, N and/or O, optionally substituted up to 3 times in the same or different manner, the substituents being trifluoromethyl, trifluoromethoxy, halogen, hydroxy, carboxy, by straight-chain or branched alkyl of up to 6 carbon atoms each, acyl, Alkoxy, or alkoxycarbonyl, or by phenyl, phenoxy, or thienyl, which substituents may be further substituted by halogen, trifluoromethyl, or trifluoromethoxy, and/or by rings substituted by

-NR_VIII-11R_VIII-12Wherein

R_VIII-11And R_VIII-12Same or different and having the same meanings as above for R_VIII-1And R_VIII-2The meaning given is that of the compounds,

X_VIIIrepresents a linear or branched alkyl or alkenyl chain of 2 to 10 carbon atoms each, optionally substituted up to 2 times by hydroxyl groups,

R_VIII-9represents hydrogen, and

R_VIII-10represents hydrogen, halogen, azido, trifluoromethyl, hydroxyl, mercapto, trifluoromethoxy, straight-chain or branched alkoxy having up to 5 carbon atoms, or a radical of the formula

-NR_VIII-13R_VIII-14Wherein

R_VIII-13And R_VIII-14Same or different and having the same meanings as above for R_VIII-1And R_VIII-2The meaning given is that of the compounds,

or

R_VIII-9And R_VIII-10Together with the carbon atom, form a carbonyl group.

Formula (II)_VIIIThe compounds are disclosed in WO 9804528. The entire disclosure of which is incorporated herein by reference.

Another class of CETP inhibitors useful in the present invention consists of substituted 1, 2, 4-triazoles having the formula IX

Formula IX

And pharmaceutically acceptable forms thereof;

wherein R is_IX-1Selected from the group consisting of higher alkyl, higher alkenyl, higher alkynyl, aryl, aralkyl, aryloxyalkyl, alkoxyalkyl, alkylthioalkyl, arylthioalkyl, and cycloalkylalkyl;

Wherein R is_IX-2Selected from aryl, heteroaryl, cycloalkyl, and cycloalkenyl, wherein

R_IX-2Optionally substituted at a substitutable position with one or more substituents independently selected from the group consisting of: alkyl, haloalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkoxy, halo, aryloxy, aralkoxy, aryl, aralkyl, aminosulfonyl, amino, monoalkylamino and dialkylamino; and

wherein R is_IX-3Selected from hydrogen, -SH, and halo;

provided that R is_IX-2Not being phenyl or 4-methylphenyl when R_IX-1Is higher alkyl and when R_IX-3and-SH.

The compounds of formula IX are disclosed in WO 9914204, the entire disclosure of which is incorporated herein by reference.

In a preferred embodiment, the CETP inhibitor is selected from the following compounds of formula IX:

2, 4-dihydro-4- (3-methoxyphenyl) -5-tridecyl-3H-1, 2, 4-triazole-3-thione;

2, 4-dihydro-4- (2-fluorophenyl) -5-tridecyl-3H-1, 2, 4-triazole-3-thione;

2, 4-dihydro-4- (2-methylphenyl) -5-tridecyl-3H-1, 2, 4-triazole-3-thione;

2, 4-dihydro-4- (3-chlorophenyl) -5-tridecyl-3H-1, 2, 4-triazole-3-thione;

2, 4-dihydro-4- (2-methoxyphenyl) -5-tridecyl-3H-1, 2, 4-triazole-3-thione;

2, 4-dihydro-4- (3-methylphenyl) -5-tridecyl-3H-1, 2, 4-triazole-3-thione;

4-cyclohexyl-2, 4-dihydro-5-tridecyl-3H-1, 2, 4-triazole-3-thione;

2, 4-dihydro-4- (3-pyridyl) -5-tridecyl-3H-1, 2, 4-triazole-3-thione;

2, 4-dihydro-4- (2-ethoxyphenyl) -5-tridecyl-3H-1, 2, 4-triazole-3-thione;

2, 4-dihydro-4- (2, 6-dimethylphenyl) -5-tridecyl-3H-1, 2, 4-triazole-3-thione;

2, 4-dihydro-4- (4-phenoxyphenyl) -5-tridecyl-3H-1, 2, 4-triazole-3-thione;

4- (1, 3-benzodioxol-5-yl) -2, 4-dihydro-5-tridecyl-3H-1, 2, 4-triazole-3-thione;

4- (2-chlorophenyl) -2, 4-dihydro-5-tridecyl-3H-1, 2, 4-triazole-3-thione;

2, 4-dihydro-4- (4-methoxyphenyl) -5-tridecyl-3H-1, 2, 4-triazole-3-thione;

2, 4-dihydro-5-tridecyl-4- (3-trifluoromethylphenyl) -3H-1, 2, 4-triazole-3-thione;

2, 4-dihydro-5-tridecyl-4- (3-fluorophenyl) -3H-1, 2, 4-triazole-3-thione;

4- (3-chloro-4-methylphenyl) -2, 4-dihydro-5-tridecyl-3H-1, 2, 4-triazole-3-thione;

2, 4-dihydro-4- (2-methylthiophenyl) -5-tridecyl-3H-1, 2, 4-triazole-3-thione;

4- (4-benzyloxyphenyl) -2, 4-dihydro-5-tridecyl-3H-1, 2, 4-triazole-3-thione;

2, 4-dihydro-4- (2-naphthyl) -5-tridecyl-3H-1, 2, 4-triazole-3-thione;

2, 4-dihydro-5-tridecyl-4- (4-trifluoromethylphenyl) -3H-1, 2, 4-triazole-3-thione;

2, 4-dihydro-4- (1-naphthyl) -5-tridecyl-3H-1, 2, 4-triazole-3-thione;

2, 4-dihydro-4- (3-methylthiophenyl) -5-tridecyl-3H-1, 2, 4-triazole-3-thione;

2, 4-dihydro-4- (4-methylthiophenyl) -5-tridecyl-3H-1, 2, 4-triazole-3-thione;

2, 4-dihydro-4- (3, 4-dimethoxyphenyl) -5-tridecyl-3H-1, 2, 4-triazole-3-thione;

2, 4-dihydro-4- (2, 5-dimethoxyphenyl) -5-tridecyl-3H-1, 2, 4-triazole-3-thione;

2, 4-dihydro-4- (2-methoxy-5-chlorophenyl) -5-tridecyl-3H-1, 2, 4-triazole-3-thione;

4- (4-aminosulfonylphenyl) -2, 4-dihydro-5-tridecyl-3H-1, 2, 4-triazole-3-thione;

2, 4-dihydro-5-dodecyl-4- (3-methoxyphenyl) -3H-1, 2, 4-triazole-3-thione;

2, 4-dihydro-4- (3-methoxyphenyl) -5-tetradecyl-3H-1, 2, 4-triazole-3-thione;

2, 4-dihydro-4- (3-methoxyphenyl) -5-undecyl-3H-1, 2, 4-triazole-3-thione;

And

2, 4-dihydro- (4-methoxyphenyl) -5-pentadecyl-3H-1, 2, 4-triazole-3-thione.

Another class of CETP inhibitors useful in the present invention consists of hetero-tetrahydroquinolines having the formula X

Formula X

The compound N-oxide, and pharmaceutically acceptable forms thereof;

wherein

A_XRepresents cycloalkyl of 3 to 8 carbon atoms, or a 5-to 7-membered, saturated, partially saturated or unsaturated, optionally benzo-fused heterocycle containing up to 3 heteroatoms selected from the group consisting of S, N and/or O, optionally bridged through it in the case where the saturated heterocycle is bound to a nitrogen atom, and wherein the above-mentioned aromatic systems are optionally substituted up to 5 times by identical or different substituents, halogen, nitro, hydroxyl, trifluoromethyl, trifluoromethoxy, or by straight-chain or branched alkyl, acyl, hydroxyalkyl or alkoxy, each having up to 7 carbon atoms, or by the formula-NR_X-3R_X-4By substitution of a group of

Wherein

R_X-3And R_X-4Identical or different and denotes hydrogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms,

or

A_XRepresents a group of the formula

D_XRepresents aryl having 6 to 10 carbon atoms, optionally substituted by phenyl, nitro, halogen, trifluoromethyl or trifluoromethoxy, or represents a group of the formula

R_X-5-L_X-、 Or R_X-9-T_X-V_X-X_X-

Wherein

R_X-5，R_X-6And R_X-9Independently of one another, represents cycloalkyl having 3 to 6 carbon atoms, or aryl having 6 to 10 carbon atoms or a 5-to 7-membered aromatic, optionally benzo-fused, saturated or unsaturated, mono-, di-, or tricyclic heterocycle comprising heteroatoms from the group S, N and/or O, wherein the rings are substituted, optionally up to 5 times by N atoms in the case of nitrogen-containing aromatic rings, by identical or different substituents, halogen, trifluoromethyl, nitro, hydroxyl, cyano, carbonyl, trifluoromethoxy, straight-chain, branched or unbranched acyl having up to 6 carbon atoms in each case, alkyl, alkylthio, alkylalkoxy, alkoxy, or alkoxycarbonyl, by aryl or trifluoromethyl-substituted aryl having in each case 6 to 10 carbon atoms, or by optionally benzo-fused, an aromatic 5-to 7-membered heterocyclic ring having up to 3 heteroatoms selected from S, N, and/OR O, and/OR by the formula-OR_X-10，-SR_X-11，SO₂R_X-12or-NR_X-13R_X-14Is substituted with a group (b) of (a),

wherein

R_X-10，R_X-11And R_X-12Independently of one another, an aryl group having 6 to 10 carbon atoms, which is further substituted up to 2 times by identical or different substituents, phenyl, halogen or straight-chain or branched alkyl having up to 6 carbon atoms,

R_X-13And R_X-14Same or different as for R_X-3And R_X-4The meaning of the terms indicated is to be taken,

or

R_X-5And/or R_X-6Represents a group of the formula

R_X-7Represents hydrogen or halogen, and

R_X-8represents hydrogen, halogen, azido, trifluoromethyl, hydroxyl, trifluoromethoxy, straight-chain or branched alkoxy or alkyl having up to 6 carbon atoms or of the formula-NR_X-15R_X-16A group of (1), wherein

R_X-15And R_X-16Identical or different and have R_X-3And R_X-4The meaning of the display is that the display,

or

R_X-7And R_X-8Together form the formula ═ O or ═ NR_X-17The group of (a) or (b),

wherein

R_X-17Represents hydrogen or a linear or branched alkyl, alkoxy or acyl radical having up to 6 carbon atoms,

L_Xdenotes a linear or branched alkylene or alkenylene chain having up to 8 carbon atoms, optionally substituted by up to 2 hydroxyl groups,

T_Xand X_XIdentical or different and represent a linear or branched alkylene chain of up to 8 carbon atoms

Or

T_XOr X_XRepresents a chemical bond of a compound represented by the formula,

V_Xrepresents an oxygen or sulfur atom or-NR_X-18A group in which

R_X-18Represents hydrogen or a linear or branched alkyl group having up to 6 carbon atoms or a phenyl group,

E_Xrepresents cycloalkyl having 3 to 8 carbon atoms, or linear or branched alkyl having up to 8 carbon atoms, optionally substituted by cycloalkyl having 3 to 8 carbon atoms or hydroxyl, or represents phenyl, optionally substituted by halogen or trifluoromethyl,

R_X-1And R_X-2Together form a straight-chain or branched alkylene chain having up to 7 carbon atoms, which must be substituted by carbonyl groups and/or bySubstituted by a group of the formula

Wherein a and b are the same or different and represent a number equal to 1, 2, or 3,

R_X-19represents hydrogen, cycloalkyl having 3 to 7 carbon atoms, straight-chain OR branched silylalkyl having up to 8 carbon atoms OR straight-chain OR branched alkyl having up to 8 carbon atoms, which is optionally substituted by hydroxyl, straight-chain OR branched alkoxy having up to 6 carbon atoms OR by phenyl, which may be substituted by halogen, nitro, trifluoromethyl, trifluoromethoxy OR by phenyl OR by tetrazole-substituted phenyl, and alkyl, optionally by the formula-OR_X-22Is substituted with a group (b) of (a),

wherein

R_X-22Denotes straight-chain or branched acyl having up to 4 carbon atoms or benzyl,

or

R_X-19Denotes straight-chain or branched acyl or benzoyl having up to 20 carbon atoms, which is optionally substituted by halogen, trifluoromethyl, nitro or trifluoromethoxy, or denotes straight-chain or branched fluoroacyl having up to 8 carbon atoms and 9 fluorine atoms,

R_X-20and R_X-21Identical or different and denotes hydrogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms,

Or

R_X-20And R_X-21Together form a 3-to 6-membered carbocyclic ring, and the carbocyclic rings formed are optionally substituted, optionally also substituted in pairs, with up to 6 identical or different substituents, trifluoromethyl, hydroxy, nitrile, halogen, carboxy, nitro, azido, cyano, rings each having 3 to 7 carbon atomsAlkyl or cycloalkoxy, substituted by linear or branched alkoxycarbonyl, alkoxy or alkylthio, each having up to 6 carbon atoms, or by linear or branched alkyl having up to 6 carbon atoms, which substituents are further substituted by up to 2 identical or different substituents, which are hydroxy, benzyloxy, trifluoromethyl, benzoyl, linear or branched alkoxy, each having up to 4 carbon atoms, oxoacyl or carbonyl and/or phenyl, which substituents may further be substituted by halogen, trifluoromethyl or trifluoromethoxy, and/or the carbon rings formed are optionally substituted, also in pairs, by up to 5 identical or different substituents, which are phenyl, benzoyl, thienyl or sulfonylbenzyl, which substituents are optionally substituted by halogen, trifluoromethyl, trifluoromethoxy or nitro, and/or optionally substituted by a group of formula

-SO₂-C₆H₅，-(CO)dNR_X-23R_X-24Or (c) or (O),

wherein

c represents a number equal to 1, 2, 3, or 4,

d represents a number equal to 0 or 1,

R_X-23 and R_X-24Identical or different and denotes hydrogen, cycloalkyl having 3 to 6 carbon atoms, straight-chain or branched alkyl having up to 6 carbon atoms, benzyl or phenyl, which is optionally substituted by up to 2 identical or different substituents, halogen, trifluoromethyl, cyano, phenyl or nitro, and/or the carbocyclic ring formed is optionally substituted by a spiro-linked radical of the formula

Wherein

W_XRepresents either an oxygen or sulfur atom

Y_XAnd Y'_XTogether form a 2-to 6-membered straight or branched alkylene chain,

e represents a number equal to 1, 2, 3, 4, 5, 6, or 7,

f represents a number equal to 1 or 2,

R_X-25，R_X-26，R_X-27，R_X-28，R_X-29，R_X-30and R_X-31Identical or different and denotes hydrogen, trifluoromethyl, phenyl, halogen or straight-chain or branched alkyl or alkoxy having up to 6 carbon atoms each,

or

R_X-25And R_X-26Or R_X-27And R_X-28Together form a straight or branched alkyl chain having up to 6 carbon atoms,

or

R_X-25And R_X-26Or R_X-27And R_X-28Each together forming a radical of the formula

Wherein

W_XHaving the meaning as given above, and which,

g represents a number equal to 1, 2, 3, 4, 5, 6, or 7,

R_X-32and R_X-33Together form a 3-to 7-membered heterocyclic ring containing an oxygen or sulfur atom or a group of formulae SO, SO ₂Or pi-NR_XA group of-34, wherein

R_X-34Representing hydrogen, phenyl, benzyl or straight or branched chain having up to 4 carbon atomsAn alkyl group.

The compounds of formula X are disclosed in WO 9914215, the entire disclosure of which is incorporated herein by reference.

In a preferred embodiment, the CETP inhibitor is selected from the following compounds of formula X:

2-cyclopentyl-5-hydroxy-7, 7-dimethyl-4- (3-thiophenyl) -3- (4-trifluoromethylbenzyloxy) -5, 6, 7, 8-tetrahydroquinoline;

2-cyclopentyl-3- [ fluoro- (4-trifluoromethylphenyl) methyl ] -5-hydroxy-7, 7-dimethyl-4- (3-thienyl) -5, 6, 7, 8-tetrahydroquinoline; and

2-cyclopentyl-5-hydroxy-7, 7-dimethyl-4- (3-thienyl) -3- (trifluoromethylbenzyl) -5, 6, 7, 8-tetrahydroquinoline.

Another class of CETP inhibitors useful in the present invention consists of substituted tetrahydronaphthalenes and analogs having the formula XI

Formula XI

And pharmaceutically acceptable forms thereof, wherein

A_XIRepresents cycloalkyl having 3 to 8 carbon atoms, or represents aryl having 6 to 10 carbon atoms, or represents 5-to 7-membered, saturated, partially unsaturated or unsaturated, possibly benzo-fused, heterocycle having up to 4 heteroatoms selected from S, N and/or O, where the abovementioned aryl and heterocycle systems are substituted up to 5-fold by identical or different substituents from the group consisting of cyano, halogen, nitro, carboxyl, hydroxyl, trifluoromethyl, trifluoro-methoxy, or by straight-chain or branched alkyl, acyl, hydroxyalkyl, alkylthio, alkoxycarbonyl, oxyalkoxycarbonyl or alkoxy, each of which has up to 7 carbon atoms, or by a group of the formula

-NR_XI-3R_XI-4，

Wherein

R_XI-3And R_XI-4Identical or different and denotes hydrogen, phenyl, or straight-chain or branched alkyl having up to 6 carbon atoms,

D_XIrepresents a group of the formula

R_XI-5-L_XI-， Or R_XI-9-T_XI-V_XI-X_XI-

Wherein

R_XI-5，R_XI-6And R_XI-9Independently of one another, represents cycloalkyl having 3 to 6 carbon atoms, or represents aryl having 6 to 10 carbon atoms, or represents 5 to 7-membered, possibly benzo-fused, saturated or unsaturated, mono-, di-or tricyclic heterocycle having up to 4 heteroatoms from the group S, N and/or O, where the rings may be substituted 5-fold-in the case of nitrogen-containing rings also by N-atoms-by identical or different substituents, halogen, trifluoromethyl, nitro, hydroxyl, cyano, carboxyl, trifluoromethoxy, straight-chain or branched acyl having in each case up to 6 carbon atoms, alkyl, alkylthio, alkylalkoxy, alkoxy or alkoxycarbonyl, aryl substituted by aryl having in each case 6 to 10 carbon atoms or trifluoromethyl, or by a possibly benzo-fused aromatic 5-to 7-membered heterocycle having up to 3 heteroatoms from the group consisting of S, N and/or O, and/or by a group of the formula

-OR_XI-10，-SR_XI-11，-SO₂R_XI-12or-NR_XI-13R_XI-14，

Wherein

R_XI-10，R_XI-11And R_XI-12Independently of one another, are aryl having 6 to 10 carbon atoms, which are substituted up to 2-fold by identical or different substituents, phenyl, halogen Or substituted by straight or branched alkyl groups having up to 6 carbon atoms,

R_XI-13and R_XI-14Same or different and having the same meanings as above for R_XI-3And R_XI-4Given meaning

Or

R_XI-5And/or R_XI-6Represents a group of the formula

R_XI-7Represents hydrogen, halogen or a methyl group,

and is

R_XI-8Represents hydrogen, halogen, azido, trifluoromethyl, hydroxyl, trifluoromethoxy, straight-chain or branched alkoxy or alkyl having up to 6 carbon atoms each, or of the formula-NR_XI-15R_XI-16Group (d) of

Wherein

R_XI-15And R_XI-16Same or different and having the same meanings as above for R_XI-3And R_XI-4The meaning given is that of the compounds,

or

R_XI-7And R_XI-8Together form the formula ═ O or ═ NR_XI-17A group of (1), wherein

R_XI-17Represents hydrogen or a linear or branched alkyl, alkoxy or acyl radical having up to 6 carbon atoms each,

L_XIdenotes straight-chain or branched alkylene-or alkenylene chains each having up to 8 carbon atoms, which may possibly be substituted up to 2-fold by hydroxyl groups,

T_XIand X_XIIdentical or different and denotes a straight-chain or branched alkylene chain having up to 8 carbon atoms,

or

T_XIAnd X_XIRepresents a chemical bond of a compound represented by the formula,

V_XIrepresents an oxygen-or sulfur atom or-NR_XI-18，

Wherein

R_XI-18Represents hydrogen or a linear or branched alkyl radical having up to 6 carbon atoms, or a phenyl radical,

E_XIrepresents cycloalkyl having 3 to 8 carbon atoms, or represents straight-chain or branched alkyl having up to 8 carbon atoms, which may be substituted by cycloalkyl having 3 to 8 carbon atoms or by hydroxyl, or represents phenyl, which may be substituted by halogen or trifluoromethyl,

R_XI-1And R_XI-2Together form a straight-chain or branched alkylene chain having up to 7 carbon atoms, which must be substituted by carbonyl groups and/or by groups of the formula

Wherein

a and b are identical or different and represent 1, 2 or 3

R_XI-19Represents hydrogen, cycloalkyl having 3 to 7 carbon atoms, straight-chain OR branched silylalkyl having up to 8 carbon atoms, OR straight-chain OR branched alkyl having up to 8 carbon atoms, which is possibly substituted by hydroxyl, straight-chain OR branched alkoxy having up to 6 carbon atoms, OR by phenyl, which is itself substituted by halogen, nitro, trifluoromethyl, trifluoromethoxy OR by phenyl, by phenyl OR tetrazole, and alkyl may be substituted by the formula-OR_XI-22Is substituted with a group (b) of (a),

wherein

R_XI-22Representing straight or branched chainsAcyl having up to 4 carbon atoms, or benzyl,

or

R_XI-19Denotes straight-chain or branched acyl or benzoyl having up to 20 carbon atoms, which may be substituted by halogen, trifluoromethyl, nitro or trifluoromethoxy, or denotes straight-chain or branched fluoroacyl having up to 8 carbon atoms and 9 fluorine atoms,

R_XI-20and R_XI-21Identical or different, represents hydrogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms,

Or

R_XI-20And R_XI-21Together form a 3-to 6-membered carbocyclic ring, and, possibly also in pairs, from R_XI-1And R_XI-2The alkylene chain formed may be substituted up to 6-fold by identical or different substituents, such as trifluoromethyl, hydroxyl, nitrile, halogen, carboxyl, nitro, azido, cyano, cycloalkyl or cycloalkoxy having in each case 3 to 7 carbon atoms, by straight-chain or branched alkoxycarbonyl, alkoxy or alkoxythio having in each case up to 6 carbon atoms, or by straight-chain or branched alkyl having up to 6 carbon atoms, the substituents themselves being substituted up to 2-fold by identical or different substituents, the substituents being hydroxy, benzyloxy, trifluoromethyl, benzoyl, straight-chain or branched alkoxy having in each case up to 4 carbon atoms, oxoacyl or carboxy, and/or the phenyl-group itself may be substituted by halogen, trifluoromethyl or trifluoromethoxy, and/or by R._XI-1And R_XI-2The alkylene chains formed are substituted, also in pairs, up to 5-fold, possibly by identical or different substituents, phenyl, benzoyl, thienyl or sulfobenzyl-which may themselves be substituted by halogen, trifluoromethyl, trifluoromethoxy or nitro, and/or by R _XI-1And R_XI-2The alkylene chain formed may be substituted by a group of the formula

-SO₂-C₆H₅，-(CO)dNR_XI-23R_XI-24Or (c) or (O),

wherein

c represents the numbers 1, 2, 3 or 4,

d represents the number 0 or 1 and,

R_XI-23and R_XI-24Are the same or different and denote

Hydrogen, cycloalkyl having 3 to 6 carbon atoms, straight-chain or branched alkyl having up to 6 carbon atoms, benzyl or phenyl, which may be substituted up to 2-fold by identical or different substituents, halogen, trifluoromethyl, cyano, phenyl or nitro, and/or from R_XI-1And R_XI-2The alkylene chain formed may be substituted by spiro-linked radicals of the formula

Wherein

W_XIRepresents an oxygen or sulfur atom, and is represented by,

Y_XIand Y'_XITogether form a 2-to 6-membered straight or branched alkylene chain,

e is 1, 2, 3, 4, 5, 6 or 7,

f represents a number of 1 or 2,

R_XI-25，R_XI-26，R_XI-27，R_XI-28，R_XI-29，R_XI-30and R_XI-31Identical or different and denotes hydrogen, trifluoromethyl, phenyl, halogen, or straight-chain or branched alkyl or alkoxy having in each case up to 6 carbon atoms,

or

R_XI-25And R_XI-26Or R_XI-27And R_XI-28Together form a straight or branched alkyl chain having up to 6 carbon atoms,

or

R_XI-25And R_XI-26Or R_XI-27And R_XI-28Together form a radical of the formula

Wherein

W_XIHaving the meaning as given above, and which,

g is the number 1, 2, 3, 4, 5, 6 or 7,

R_XI-32and R_XI-33Together forming a 3-to 7-membered heterocyclic ring containing an oxygen-or sulfur atom or a group of formulae SO, SO ₂or-NR_XI-34The group of (a) or (b),

wherein R is_XI-34Represents hydrogen, phenyl, benzyl, or a linear or branched alkyl group having up to 4 carbon atoms.

The compounds of formula XI are disclosed in WO 9914174, the entire disclosure of which is incorporated herein by reference.

Another class of CETP inhibitors useful in the present invention consists of 2-aryl-substituted pyridines having the formula XII

Formula XII

And pharmaceutically acceptable forms thereof, wherein

A_XIIAnd E_XIIAryl, which is identical or different and represents 6 to 10 carbon atoms, may be substituted up to 5-fold by identical or different substituents, which are halogen, hydroxy, trifluoromethyl, trifluoromethoxy, nitro, or by straight-chain or branched chainsEach of which is substituted by alkyl, acyl, hydroxyalkyl or alkoxy having up to 7 carbon atoms, or by the formula-NR_XII-1R_XII-2By substitution of a group of

Wherein

R_XII-1And R_XII-2Identical or different and denotes hydrogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms,

D_XIIrepresents a straight-chain or branched alkyl group having up to 8 carbon atoms, L, substituted by a hydroxyl group_XIIRepresents cycloalkyl having 3 to 8 carbon atoms or straight-chain or branched alkyl having up to 8 carbon atoms, which may be substituted by cycloalkyl having 3 to 8 carbon atoms, or by hydroxy,

T_XIIis represented by the formula R _XII-3-X_XIIA group of (A) or (B)

Wherein

R_XII-3 and R_XII-4Identical or different and denotes cycloalkyl having 3 to 8 carbon atoms, or aryl having 6 to 10 carbon atoms, or 5-to 7-membered aromatic, possibly benzo-fused, heterocyclic ring having up to 3 heteroatoms from the group S, N and/or O, which may be substituted up to 3-fold by identical or different substituents, trifluoromethyl, trifluoromethoxy, halogen, hydroxyl, carboxyl, nitro, by straight-chain or branched alkyl, acyl, alkoxy or alkoxycarbonyl, each having up to 6 carbon atoms, or by phenyl, phenoxy or phenylthio, which substituents may furthermore be substituted by halotrifluoromethyl or trifluoromethoxy, and/or wherein the ring may be substituted by the formula-NR_XII-7R_XII-8Is substituted with a group (b) of (a),

wherein

R_XII-7And R_XII-8Identical or different and having R as given above_XII-1And R_XII-2The meaning of (a) is given,

X_XIIis a linear or branched alkyl or alkenyl group each having 2 to 10 carbon atoms, possibly substituted up to 2-fold by hydroxyl or halogen,

R_XII-5represents hydrogen, and is represented by the formula,

and is

R_XII-6Is hydrogen, halogen, mercapto, azido, trifluoromethyl, hydroxyl, trifluoromethoxy, straight-chain or branched alkoxy having up to 5 carbon atoms, or of the formula-NR_XII-9R_XII-10The group of (a) or (b),

wherein

R_XII-9And R_XII-10Identical or different and having R as given above_XII-1And R_XII-2The meaning of (a) is given,

or

R_XII-5And R_XII-6Together with the carbon atom, a carbonyl group may be formed.

Compounds of formula XII are disclosed in EP 796846-A1, the entire disclosure of which is incorporated herein by reference.

In a preferred embodiment, the CETP inhibitor is selected from the following compounds of formula XII:

4, 6-bis- (p-fluorophenyl) -2-isopropyl-3- [ (p-trifluoromethylphenyl) - (fluoro) -methyl ] -5- (1-hydroxyethyl) pyridine;

2, 4-bis- (4-fluorophenyl) -6-isopropyl-5- [4- (trifluoromethylphenyl) -fluoromethyl ] -3-hydroxymethyl) pyridine; and

2, 4-bis- (4-fluorophenyl) -6-isopropyl-5- [2- (3-trifluoromethylphenyl) ethenyl ] -3-hydroxymethyl) pyridine.

Another class of CETP inhibitors useful in the present invention consists of compounds having the formula XIII

Formula X_III

And pharmaceutically acceptable forms thereof, wherein

R_XIIIIs straight-chain or branched C₁-10 alkyl; straight or branched C₂-10 alkenyl groups; halogenated C₁-4 lower alkyl; a C3-10 cycloalkyl group which may be substituted; c5-8 cycloalkenyl which may be substituted; c3-10 cycloalkyl C which may be substituted₁-10 alkyl; an aryl group which may be substituted; an aralkyl group which may be substituted; or a 5-or 6-membered heterocyclic group having 1 to 3 nitrogen atoms, oxygen atoms or sulfur atoms which may be substituted,

X_XIII-1、X_XIII-2、X_XIII-3、X_XIII-4May be the same or different and are each a hydrogen atom; a halogen atom; c_1-4A lower alkyl group; halogenated C_1-4A lower alkyl group; c_1-4Lower alkoxy; a cyano group; a nitro group; an acyl group; or an aryl group;

Y_XIIIis-CO-; or-SO₂-; and

Z_XIIIis a hydrogen atom; or a thiol protecting group.

The compounds of formula XIII are disclosed in WO 98/35937, the entire disclosure of which is incorporated herein by reference.

In a preferred embodiment, the CETP inhibitor is selected from the following compounds of formula XIII:

n, N' - (dithiobis-2, 1-phenylene) bis [2, 2-dimethyl-propionamide ];

n, N' - (dithiobis-2, 1-phenylene) bis [ 1-methyl-cyclohexanecarboxamide ];

n, N' - (dithiobis-2, 1-phenylene) bis [1- (3-methylbutyl) -cyclopentanecarboxamide ];

n, N' - (dithiobis-2, 1-phenylene) bis [1- (3-methylbutyl) -cyclohexanecarboxamide ];

n, N' - (dithiobis-2, 1-phenylene) bis [1- (2-ethylbutyl) -cyclohexanecarboxamide ];

n, N' - (dithiobis-2, 1-phenylene) bis-tricyclo [3.3.1.13, 7] decane-1-carboxamide;

thiopropionic acid, 2-methyl-, S- [2[ [ [1- (2-ethylbutyl) cyclohexyl ] carbonyl ] amino ] phenyl ] ester;

thiopropionic acid, 2, 2-dimethyl-, S- [2- [ [ [1- (2-ethylbutyl) cyclohexyl ] carbonyl ] amino ] phenyl ] ester; and

Thioacetic acid, S- [2- [ [ [1- (2-ethylbutyl) cyclohexyl ] carbonyl ] amino ] phenyl ] ester.

Another class of CETP inhibitors useful in the present invention consists of polycyclic aryl and heteroaryl tertiary-heteroalkylamines having the formula XIV

Formula XIV

And pharmaceutically acceptable forms thereof, wherein:

n_XIVis an integer selected from 0 to 5;

R_XIV-1selected from the group consisting of haloalkyl, haloalkenyl, haloalkoxyalkyl, and haloalkenyloxyalkyl;

X_XIVselected from O, H, F, S, S (O), NH, N (OH), N (alkyl), and N (alkoxy);

R_XIV-16selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, alkoxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, aralkoxyalkyl, heteroaryloxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkeneA group, a cycloalkenylalkyl group, a haloalkyl group, a haloalkenyl group, a halocycloalkyl group, a halocycloalkenyl group, a haloalkoxyalkyl group, a haloalkenyloxyalkyl group, a haloaryl group, a perhaloaralkyl group, a perhaloaryloxyalkyl group, a heteroaryl group, a heteroarylalkyl group, a monoalkoxyformylalkyl group, a monoalkoxyformyl group, a dialkoxycarbonylalkyl group, a monocarbamoyl group, a monocyanoalkyl group, a dicyanoalkyl group, an alkoxyformylcyanoalkyl group, an acyl group, an aroyl group, a heteroaryloyl group, a heteroaryloxyalkyl group, a dialkoxyphosphonoalkyl group, a trialkylsilyl group, and a spacer group selected from a covalent single bond and a linear spacer moiety having 1 to 4 atoms attached to a group selected from R _XIV-4，R_XIV-8，R_XIV-9And R_XIV-13With the proviso that the spacer moiety is not a covalent single bond when R is_XIV-2Is alkyl and is free of R_XIV-16Wherein X is H or F;

D_XIV-1、D_XIV-2、J_XIV-1、J_XIV-2and K_XIV-1Independently selected from C, N, O, S and covalent bond conditions are not more than one D_XIV-1、D_XIV-2、J_XIV-1、J_XIV-2And K_XIV-1Is a covalent bond, not more than one D_XIV-1、D_XIV-2、J_XIV-1、J_XIV-2And K_XIV-1Is O, not more than one D_XIV-1、D_XIV-2、J_XIV-1、J_XIV-2And K_XIV-1Is S, D_XIV-1、D_XIV-2、J_XIV-1、J_XIV-2And K_XIV-1One must be a covalent bond when D_XIV-1、D_XIV-2、J_XIV-1、J_XIV-2And K_XIV-1Two of O and S, and not more than 4D_XIV-1、D_XIV-2、J_XIV-1、J_XIV-2And K_XIV-1Is N;

D_XIV-3、D_XIV-4、J_XIV-3、J_XIV-4and K_XIV-2Independently of each otherSelected from C, N, O, S and covalent bond conditions are not more than one D_XIV-3、D_XIV-4、J_XIV-3、J_XIV-4And K_XIV-2Is a covalent bond, not more than one D_XIV-3、D_XIV-4、J_XIV-3、J_XIV-4And K_XIV-2Is O, not more than one D_XIV-3、D_XIV-4、J_XIV-3、J_XIV-4And K_XIV-2Is S, D_XIV-3、D_XIV-4、J_XIV-3、J_XIV-4And K_XIV-2One must be a covalent bond when D_XIV-3、D_XIV-4、J_XIV-3、J_XIV-4And K_XIV-2Two of O and S, and not more than 4D_XIV-3、D_XIV-4、J_XIV-3、J_XIV-4And K_XIV-2And K_XIV-2Is N;

R_XIV-2independently selected from the group consisting of hydrogen, 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, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl, heteroarylthioalkyl, monoalkoxyformylalkyl, dialkylamino, alkyl, alkoxy, haloalkoxy, haloalkenyloxy, haloalkoxy alkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl, heteroarylthioa, Dialkoxycarbonylalkyl, monocyanoalkyl, dicyanoalkyl, alkoxyformylcyanoalkyl, alkylsulfinyl, alkylsulfonyl, alkylsulfinylalkyl, alkylsulfonylalkyl, haloalkylsulfinyl, haloalkylsulfonyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylalkyl, aralkylsulfinyl, aralkylsulfonyl, cycloalkylsulfinyl, cycloalkylsulfonyl Acyl, cycloalkylsulfinylalkyl, cycloalkylsulfonylalkyl, heteroarylsulfonylalkyl, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylsulfinylalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl, carboxy, carboxyalkyl, alkoxyformyl, carboxamide, carbamoylalkyl, aralkylcarbonyloxy, dialkoxyphosphono, diaryloxyphosphono, dialkoxyphosphonoalkyl, and diarylalkoxyphosphonoalkyl;

R_XIV-2and R_XIV-3Together forming a linear spacer moiety selected from a covalent single bond and a moiety having 1 to 6 atoms to form a ring selected from 3 to 8 membered cycloalkyl, 5 to 8 membered cycloalkenyl, and 4 to 8 membered heterocyclyl;

R_XIV-3selected from the group consisting of hydrogen, hydroxy, halogen, cyano, aryloxy, hydroxyalkyl, amino, alkylamino, dialkylamino, acyl, mercapto, acylamido, alkoxy, alkylthio, arylthio, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, alkoxyalkyl, heteroarylthio, aralkylthio, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aroyl, heteroaroyl, aralkylthioalkyl,

Heteroarylthioalkyls, heteroaryloxyalkyls, alkenyloxyalkyls, alkylthioalkyls, arylthioalkyls, cycloalkyls, cycloalkylalkyls, cycloalkylalkenyls, cycloalkenyls, cycloalkenylalkyls, haloalkyls, haloalkenyls, halocycloalkyls, halocycloalkenyls, haloalkoxylalkyls, haloalkenyloxyalkyls, halocycloalkoxylalkyls,

halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl, heteroarylthioalkyl, monoalkoxyformylalkyl, dialkoxycarbonylalkyl, monocyanoalkyl, dicyanoalkyl, alkoxyformylcyanoalkyl, alkylsulfinyl, alkylsulfonyl, haloalkylsulfinyl, haloalkylsulfonyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylalkyl, aralkylsulfinyl, aralkylsulfonyl, cycloalkylsulfinyl, cycloalkylsulfonyl, cycloalkylsulfinylalkyl, cycloalkylsulfonylalkyl, heteroarylsulfonylalkyl, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylsulfinylalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl, halocarbylalkyl, alkoxycarbonylalkyl, haloalkylsulfinyl, haloalkylsulfonylalkyl, haloalkylsulfinyl, arylsulfinyl, aralk, Carboxy, carboxyalkyl, alkoxyformyl, carboxamide, carbamoylalkyl, aralkylcarbonyloxy, dialkoxyphosphono, diarylalkoxyphosphono, dialkoxyphosphonoalkyl, and diarylalkoxyphosphonoalkyl groups;

Y_XIVSelected from covalent single bond, (C (R)_XIV-14)₂)q_XIVWherein q is_XIVIs an integer selected from 1 and 2, and (CH (R)_XIV-14))g_XIV-W_XIV-(CH(R_XIV-14))p_XIVWherein g is_XIVAnd p_XIVIndependently selected from 0 and 1;

R_XIV-14independently selected from the group consisting of hydrogen, hydroxy, halogen, cyano, aryloxy, amino, alkylamino, dialkylamino, hydroxyalkyl, acyl, aroyl, heteroaroyl, heteroaryloxyalkyl, mercapto, acylamido, alkoxy, alkylthio, arylthio, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, aralkoxyalkylalkoxy, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkyloxyalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy, haloalkenyloxy, dialkylamino, hydroxyalkyl, thioalkyl, thioalkoxyalkyl, thioalkoxy, thioalkyl, thioalkoxy, thioa, Halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl, heteroarylthioalkyl, monoalkoxyformylalkyl, halocycloalkoxyalkyl, perhaloaralkyl, perhaloaralkoxyalkyl, perhaloaralkylalkyl, heteroarylthioalkyl, monoalkoxyformylalkyl, halocycloalkoxyalkyl, Dialkoxycarbonylalkyl, monocyanoylalkyl, dicyanoalkyl, alkoxyformylcyanoalkyl, alkylsulfinyl, alkylsulfonyl, haloalkylsulfinyl, haloalkylsulfonyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylalkyl, aralkylsulfinyl, aralkylsulfonyl, cycloalkylsulfinyl, cycloalkylsulfonyl, cycloalkylsulfinylalkyl, cycloalkylsulfonylalkyl, heteroarylsulfonylalkyl, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylsulfinylalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl, carboxy, carboxyalkyl, alkoxycarbonyl, carboxamide, carbamoylalkyl, aralkylcarbonyloxy, dialkoxyphosphono, diarylalkoxyphosphono, dialkoxyphosphonoalkyl, a diarylalkoxyphosphonoalkyl group, the spacer selected from a moiety having a chain length of 3-6 atoms, attached to a group selected from R_XIV-9And R_XIV-13To form a ring selected from 5-to 8-membered cycloalkenyl rings and 5-to 8-membered heterocyclyl rings, and a spacer selected from a moiety having a chain length of 2-5 atoms, attached to a ring selected from R _XIV-4And R_XIV-8With the proviso that when Y is Y, a 5-to 8-membered heterocyclic group is formed_XIVWhen it is a covalent bond, R_XIV-14The substituents not being connected to Y_XIV；

R_XIV-14And R_XIV-14When bound to different atoms, may together form a group selected from: a covalent bond, an alkylene group, a haloalkylene group, and a spacer selected from a moiety having a chain length of 2 to 5 atoms, linked to form a ring selected from a 5 to 8 membered saturated cycloalkyl group, a 5 to 8 membered cycloalkenyl group, and a 5 to 8 membered heterocyclic group;

R_XIV-14and R_XIV-14When bonded to the same atom, may together form a group selected from: oxo, thioxo, alkylene, haloalkylene, and a spacer selected from a moiety having a chain length of 3 to 7 atoms, to form a ring selected from 4 to 8 membered cycloalkyl, 4 to 8 membered cycloalkenyl, and 4 to 8 membered heterocyclyl;

W_XIVselected from 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)₂N(R_XIV-14)，(R_XIV-14)NS(O)₂And N (R)_XIV-14) Provided that R is_XIV-14Not selected from halo and cyano;

Z_XIVindependently selected from covalent single bonds, (C (R)_XIV-15)₂)q_XIV-2Wherein q is_XIV-2Is an integer selected from 1 and 2, (CH (R)_XIV-15))j_XIV-W-(CH(R_XIV-15))k_XIVWherein j is_XIVAnd k_XIVIs an integer independently selected from 0 and 1, with the proviso that when Z is_XIVIn the case of a covalent single bond, R_XIV-15The substituents not being connected to Z_XIV；

R_XIV-15Independently selected when Z_XIVIs (C (R)_XIV-15)₂)q_XIVWherein q is_XIVIs an integer selected from 1 and 2, selected from hydrogen, hydroxy, halogen, cyano, aryloxy, amino, alkylamino, dialkylamino, hydroxyalkyl, acyl, aroyl, heteroaroyl, heteroaryloxyalkyl, mercapto, acylamido, alkoxy, alkylthio, arylthio, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkylthioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxy, haloalkoxyalkyl, halocycloalkoxy, substituted alkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy, substituted cycloalkoxy, or, Halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl, heteroarylthioalkyl, monoalkoxyformylalkyl, dialkoxide Alkoxyformylalkyl, monocyanoalkyl, dicyanoalkyl, alkoxyformylcyanoalkyl, alkylsulfinyl, alkylsulfonyl, haloalkylsulfinyl, haloalkylsulfonyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylalkyl, aralkylsulfinyl, aralkylsulfonyl, cycloalkylsulfinyl, cycloalkylsulfonyl, cycloalkylsulfinylalkyl, cycloalkylsulfonylalkyl, heteroarylsulfonylalkyl, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylsulfinylalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl, carboxy, carboxyalkyl, alkoxycarbonyl, carboxamide, carbamoylalkyl, aralkylcarbonyloxy, dialkoxyphosphono, diaralkoxyphosphonoalkyl, the spacer is selected from moieties having a chain length of 3 to 6 atoms, attached to R_XIV-4And R_XIV-8The bond site forming a ring selected from a 5-to 8-membered cycloalkenyl ring and a 5-to 8-membered heterocyclyl ring, and the spacer is selected from a moiety having a chain length of 2-5 atoms, attached to a group selected from R _XIV-9And R_XIV-13Bonding sites to form 5-to 8-membered heterocyclic groups;

R_XIV-15and R_XIV-15When bound to different atoms, may together form a group selected from: a covalent bond, an alkylene group, a haloalkylene group, and a spacer selected from a moiety having a chain length of 2 to 5 atoms, joined to form a ring selected from a saturated 5-to 8-membered cycloalkyl group, a 5-to 8-membered cycloalkenyl group, and a 5-to 8-membered heterocyclic group;

R_XIV-15and R_XIV-15When bound to the same atom, may together form a group selected from: oxo, thioxo, alkylene, haloalkylene, and a spacer selected from a moiety having a chain length of 3 to 7 atoms, joined to form a ring selected from 4 to 8 membered cycloalkyl, 4 to 8 membered cycloalkenyl, and 4 to 8 membered heterocyclyl;

R_XIV-15independently selected when Z_XIVIs (CH (R)_XIV-15))j_XIV-W-(CH(R_XIV-15))k_XIVIn which j is_XIVAnd k_XIVIs an integer independently selected from 0 and 1, selected from hydrogen, halogen, cyano, aryloxy, carboxy, acyl, aroyl, heteroaroyl, hydroxyalkyl, heteroaryloxyalkyl, acylamido, alkoxy, alkylthio, arylthio, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, alkoxyalkyl, heteroaryloxyalkyl, heteroaralkoxyalkyl, alkylsulfonylalkyl, alkylsulfinylalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, halo, Perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl, heteroarylthioalkyl, monoalkoxyformylalkyl, dialkoxycarbonylalkyl, monocyanoalkyl, dicyanoalkyl, alkoxyformylcyanoalkyl, alkylsulfinyl, alkylsulfonyl, haloalkylsulfinyl, haloalkylsulfonyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonylalkyl, aralkylsulfinyl, aralkylsulfonyl, cycloalkylsulfinyl, cycloalkylsulfonyl, cycloalkylsulfinylalkyl, cycloalkylsulfonylalkyl, heteroarylsulfonylalkyl, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylsulfinylalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl, carboxyalkylalkyl, alkoxyformyl, carboxamide, carbamoylalkyl, aralkylcarbonyloxy, dialkoxyphosphonoalkyl, diarylalkoxyphosphonoalkyl, a spacer selected from a linear moiety having a chain length of 3 to 6 atoms, linked to a linker selected from R _XIV-4And R_XIV-8A bond site to form a ring selected from the group consisting of a 5-to 8-membered cycloalkenyl ring and a 5-to 8-membered heterocyclyl ring, and a linear moiety spacer selected from the group consisting of having a chain length of 2-5 atoms, attached toIs selected from R_XIV-9And R_XIV-13A bonding site to form a 5-to 8-membered heterocyclyl ring;

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-12and R_XIV-13Independently selected from perhaloaryloxy, alkanoylalkyl, alkanoylalkoxy, alkanoyloxy, N-aryl-N-alkylamino, heterocyclylalkoxy, heterocyclylthio, hydroxyalkoxy, carbamoylalkoxy, alkoxycarbonylalkoxy, alkoxycarbonylalkenoxy, aralkanoylalkoxy, aralkenoyl, N-alkylcarbamoyl, N-haloalkylcarbamoyl, N-cycloalkylcarbamoyl, N-arylcarbamoylalkoxy, cycloalkylcarbonyl, cyanoalkoxy, heterocyclylcarbonyl, hydrogen, carboxy, heteroaralkylthio, heteroaralkyloxy, cycloalkylamino, acylalkyl, acylalkoxy, aroylalkoxy, heterocyclooxy, aralkylaryl, aralkyl, aralkenyl, aralkynyl, heterocyclyl, perhaloaralkyl, aralkylsulfonylsulfonyl, aralkyloxy, heterocycloalkylalkoxy, heterocycloalkyloxy, heterocycl, Aralkylsulfonylalkyl, aralkylsulfinyl, aralkylsulfinylalkyl, halocycloalkyl, halocycloalkenyl, cycloalkylsulfinyl, cycloalkylsulfinylalkyl, cycloalkylsulfonyl, cycloalkylsulfonylalkyl, heteroarylamino, N-heteroarylamino-N-alkylamino, heteroarylaminoalkyl, haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxyalkyl, heteroarylalkoxy, cycloalkoxy, cycloalkenyloxy, cycloalkoxyalkyl, cycloalkylalkoxy, cycloalkenyloxyalkyl, cycloalkylenedioxy, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, hydroxy, amino, thio, nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, heteroarylsulfonyl-N-alkylamino, haloalkenylamino-N-alkylamino, haloalkenyloxy, haloalkenyloxyalkyl, hydroxy, amino, thio, nitro, lower alkylamino, alkylthio, alkyl, Arylthioalkyl, heteroaryloxyalkyl, alkylsulfinyl, alkylsulfinylalkyl, arylsulfinylalkyl, arylsulfonylalkyl, heteroarylsulfinylalkyl, heteroarylsulfonylalkyl, alkylsulfonyl, alkylsulfonylalkyl Haloalkylsulfinylalkyl, haloalkylsulfonylalkyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl, amidosulfonyl, dialkylaminosulfonyl, monoarylamidosulfonyl, arylsulfonamido, diarylamidosulfonyl, monoalkyl monoarylamidosulfonyl, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, heterocyclosulfonyl, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkoyl, heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl, alkynyl, alkenyloxy, alkenyloxyalkyl, alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkylalkanoyl, cycloalkenyl, lower cycloalkylalkyl, lower cycloalkenylalkyl, halo, haloalkylsulfonylamino, alkylaminosulfonyl, haloalkylsulfonylalkylsulfonyl, heteroarylsulfonyl, haloalkylthio, haloalkylenedioxy, A haloalkyl group; haloalkenyl, haloalkoxy, hydroxyhaloalkyl, hydroxyalkylalkyl, hydroxyalkyl, hydroxyheteroaralkyl, haloalkoxyalkyl, aryl, heteroaralkynyl, aryloxy, aralkoxy, aryloxyalkyl, saturated heterocyclic groups, partially saturated heterocyclic groups, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkenyl, heteroarylalkenyl, carboxyalkyl, alkoxycarbonyl, alkoxycarbamoyl, alkylamidocarbonylamido, arylamidocarbonylamido, alkoxyformylalkyl, alkoxyformylalkenyl, aralkylcarbonyloxy, carbamoyl, carbamoylalkyl, cyano, haloalkoxycarbonyl, phosphono, phosphonoalkyl, diarylalkoxyphosphono, and diarylalkyloxyphosphonoalkyl provided that 1 to 5 non-hydrogen ring substituents R are present. _XIV-4，R_XIV-5，R_XIV-6，R_XIV-7And R_XIV-8In the presence of 1 to 5 non-hydrogen ring substituents R_XIV-9，R_XIV-10，R_XIV-11，R_XIV-12And R_XIV-13Exist, and 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-12And R_XIV-13Each independently selected fromMaintaining a carbon tetravalent, nitrogen trivalent, sulfur divalent, and oxygen divalent;

R_XIV-4and R_XIV-5，R_XIV-5And R_XIV-6，R_XIV-6And R_XIV-7，R_XIV-7And R_XIV-8，R_XIV-8And R_XIV-9，R_XIV-9And R_XIV-10，R_XIV-10And R_XIV-11，R_XIV-11And R_XIV-12And R_XIV-12And R_XIV-13Independently selected to form a spacer pair, wherein the spacer pairs are joined together to form a linear moiety having 3-6 atoms, the bonding sites of said spacer pair members being linked to form a ring selected from the group consisting of a 5-8 membered cycloalkenyl ring, a partially saturated 5-8 membered heterocyclyl ring, a 5-6 membered heteroaryl ring, and an aryl, with the proviso that no more than one spacer pair R_XIV-4And R_XIV-5，R_XIV-5And R_XIV-6，R_XIV-6And R_XIV-7And R_XIV-7And R_XIV-8Simultaneously, and not more than one spacer pair R_XIV-9And R_XIV-10，R_XIV-10And R_XIV-11，R_XIV-11And R_XIV-12And R_XIV-12And R_XIV-13Simultaneously used;

R_XIV-4and R_XIV-9，R_XIV-4And R_XIV-13，R_XIV-8And R_XIV-9And R_XIV-8And R_XIV-13Independently selected to form a spacer pair, wherein said spacer pair are joined together to form a linear moiety, wherein said linear moiety forms a ring selected from the group consisting of a partially saturated 5-to 8-membered heterocyclyl ring and a 5-to 6-membered heteroaryl ring, with the proviso that no more than one spacer pair R_XIV-4And R_XIV-9，R_XIV-4And R_XIV-13，R_XIV-8And R_XIV-9And R_XIV-8And R_XIV-13And simultaneously used.

The compounds of formula XIV are disclosed in WO 00/18721, the entire disclosure of which is incorporated herein by reference.

In a preferred embodiment, the CETP inhibitor is selected from the following formula X_IVA compound:

3- [ [3- (3-trifluoromethoxy-phenoxy) phenyl ] [ [3- (1, 1, 2, 2-tetrafluoroethoxy) -phenyl ] methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (3-isopropylphenoxy) phenyl ] [ [3- (1, 1, 2, 2-tetrafluoroethoxy) phenyl ] -methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (3-cyclopropylphenoxy) phenyl ] [ [3- (1, 1, 2, 2-tetrafluoroethoxy) phenyl ] -methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (3- (2-furyl) phenoxy) phenyl ] [ [3- (1, 1, 2, 2-tetrafluoroethoxy) phenyl ] -methyl ] amino ]1, 1, 1-trifluoro-2-propanol;

3- [ [3- (2, 3-dichlorophenoxy) phenyl ] [ [3- (1, 1, 2, 2-tetrafluoroethoxy) phenyl ] -methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (4-fluorophenoxy) phenyl ] [ [3- (1, 1, 2, 2-tetrafluoroethoxy) phenyl ] -methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (4-methylphenoxy) phenyl ] [ [3- (1, 1, 2, 2-tetrafluoroethoxy) phenyl ] -methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (2-fluoro-5-bromophenoxy) phenyl ] [ [3- (1, 1, 2, 2-tetrafluoroethoxy) phenyl ] -methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (4-chloro-3-ethylphenoxy) phenyl ] [ [3- (1, 1, 2, 2-tetrafluoroethoxy) phenyl ] -methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- [3- (1, 1, 2, 2-tetrafluoroethoxy) phenoxy ] phenyl ] [ [3- (1, 1, 2, 2-tetrafluoro-ethoxy) phenyl ] methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- [3- (pentafluoroethyl) phenoxy ] phenyl ] [ [3- (1, 1, 2, 2-tetrafluoroethoxy) -phenyl ] methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (3, 5-dimethylphenoxy) phenyl ] [ [3- (1, 1, 2, 2-tetrafluoroethoxy) phenyl ] -methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (3-ethylphenoxy) phenyl ] [ [3- (1, 1, 2, 2-tetrafluoroethoxy) phenyl ] -methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (3-tert-butylphenoxy) phenyl ] [ [3- (1, 1, 2, 2-tetrafluoroethoxy) phenyl ] -methyl ] amino ]1, 1, 1-trifluoro-2-propanol;

3- [ [3- (3-methylphenoxy) phenyl ] [ [3- (1, 1, 2, 2-tetrafluoroethoxy) phenyl ] -methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (5, 6, 7, 8-tetrahydro-2-naphthyloxy) phenyl ] [ [3- (1, 1, 2, 2-tetrafluoroethoxy) phenyl ] methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (phenoxy) phenyl ] [ [3- (1, 1, 2, 2-tetrafluoroethoxy) phenyl ] methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- [3- (N, N-dimethylamino) phenoxy ] phenyl ] [ [3- (1, 1, 2, 2-tetrafluoroethoxy) phenyl ] methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [ [3- (1, 1, 2, 2-tetrafluoroethoxy) phenyl ] methyl ] [3- [ [3- (trifluoromethoxy) -phenyl ] methoxy ] phenyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [ [3- (1, 1, 2, 2-tetrafluoroethoxy) phenyl ] methyl ] [3- [ [3- (trifluoromethyl) -phenyl ] methoxy ] phenyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [ [3- (1, 1, 2, 2-tetrafluoroethoxy) phenyl ] methyl ] [3- [ [3, 5-dimethylphenyl ] -methoxy ] phenyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [ [3- (1, 1, 2, 2-tetrafluoroethoxy) phenyl ] methyl ] [3- [ [3- (trifluoromethylthio) -phenyl ] methoxy ] phenyl ] amino ] -1, 1, -trifluoro-2-propanol;

3- [ [ [3- (1, 1, 2, 2-tetrafluoroethoxy) phenyl ] methyl ] [3- [ [3, 5-difluorophenyl ] -methoxy ] phenyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [ [3- (1, 1, 2, 2-tetrafluoroethoxy) phenyl ] methyl ] [3- [ cyclohexylmethoxy ] -phenyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (2-difluoromethoxy-4-pyridinyloxy) phenyl ] [ [3- (1, 1, 2, 2-tetrafluoroethoxy) -phenyl ] methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (2-trifluoromethyl-4-pyridinyloxy) phenyl ] [ [3- (1, 1, 2, 2-tetrafluoroethoxy) -phenyl ] methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (3-difluoromethoxyphenoxy) phenyl ] [ [3- (1, 1, 2, 2-tetrafluoroethoxy) -phenyl ] methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [ [3- (3-trifluoromethylthio) phenoxy ] phenyl ] [ [3- (1, 1, 2, 2-tetrafluoroethoxy) -phenyl ] methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (4-chloro-3-trifluoromethylphenoxy) phenyl ] [ [3- (1, 1, 2, 2-tetrafluoroethoxy) -phenyl ] methyl ] amino ] -1, 1, 1, -trifluoro-2-propanol;

3- [ [3- (3-trifluoromethoxy-phenoxy) -phenyl ] [ [3- (pentafluoroethylmethyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (3-isopropylphenoxy) phenyl ] [ [3- (pentafluoroethyl) phenyl ] methyl ] -amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (3-cyclopropylphenoxy) phenyl ] [ [3- (pentafluoroethyl) phenyl ] methyl ] -amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (3- (2-furyl) phenoxy) phenyl ] [ [3- (pentafluoroethyl) phenyl ] methyl ] -amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (2, 3-dichlorophenoxy) phenyl ] [ [3- (pentafluoroethyl) phenyl ] methyl ] -amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (4-fluorophenoxy) phenyl ] [ [3- (pentafluoroethyl) phenyl ] methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (4-methylphenoxy) phenyl ] [ [3- (pentafluoroethyl) phenyl ] methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (2-fluoro-5-bromophenoxy) phenyl ] [ [3- (pentafluoroethyl) phenyl ] methyl ] -amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (4-chloro-3-ethylphenoxy) phenyl ] [ [3- (pentafluoroethyl) phenyl ] methyl ] -amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- [3- (1, 1, 2, 2-tetrafluoroethoxy) phenoxy ] phenyl ] [ [3- (pentafluoroethyl) -phenyl ] methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- [3- (pentafluoroethyl) phenoxy ] phenyl ] [ [3- (pentafluoroethyl) phenyl ] -methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (3, 5-dimethylphenoxy) phenyl ] [ [3- (pentafluoroethyl) phenyl ] methyl ] -amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (3-ethylphenoxy) phenyl ] [ [3- (pentafluoroethyl) phenyl ] methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (3-tert-butylphenoxy) phenyl ] [ [3- (pentafluoroethyl) phenyl ] methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (3-methylphenoxy) phenyl ] [ [ 3-pentafluoroethyl) phenyl ] methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (5, 6, 7, 8-tetrahydro-2-naphthyloxy) phenyl ] [ [3- (pentafluoroethyl) phenyl ] -methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (phenoxy) phenyl ] [ [3- (pentafluoroethyl) phenyl ] methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- [3- (N, N-dimethylamino) phenoxy ] phenyl ] [ [3- (pentafluoroethyl) phenyl ] -methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [ [3- (pentafluoroethyl) phenyl ] methyl ] [3- [ [3- (trifluoromethoxy) phenyl ] -methoxy ] phenyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [ [3- (pentafluoroethyl) phenyl ] methyl ] [3- [ [3- (trifluoromethyl) phenyl ] -methoxy ] phenyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [ [3- (pentafluoroethyl) phenyl ] methyl ] [3- [ [3, 5-dimethylphenyl ] methoxy ] -phenyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [ [3- (pentafluoroethyl) phenyl ] methyl ] [3- [ [3- (trifluoromethylthio) phenyl ] -methoxy ] phenyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [ [3- (pentafluoroethyl) phenyl ] methyl ] [3- [ [3, 5-difluorophenyl ] methoxy ] -phenyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [ [3- (pentafluoroethyl) phenyl ] methyl ] [3- [ cyclohexylmethoxy ] phenyl ] -amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (2-difluoromethoxy-4-pyridinyloxy) phenyl ] [ [3- (pentafluoroethyl) phenyl ] -methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (2-trifluoromethyl-4-pyridinyloxy) phenyl ] [ [3- (pentafluoroethyl) phenyl ] -methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (3-difluoromethoxyphenoxy) phenyl ] [ [3- (pentafluoroethyl) phenyl ] -methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [ [3- (3-trifluoromethylthio) phenoxy ] phenyl ] [ [3- (pentafluoroethyl) phenyl ] -methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (4-chloro-3-trifluoromethylphenoxy) phenyl ] [ [3- (pentafluoroethyl) -phenyl ] methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (3-trifluoromethoxy-phenoxy) phenyl ] [ [3- (heptafluoropropyl) phenyl ] -methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (3-isopropylphenoxy) phenyl ] [ [3- (heptafluoropropyl) phenyl ] methyl ] -amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (3-cyclopropylphenoxy) phenyl ] [ [3- (heptafluoropropyl) phenyl ] methyl ] -amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (3- (2-furyl) phenoxy) phenyl ] [ [3- (heptafluoropropyl) phenyl ] methyl ] -amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (2, 3-dichlorophenoxy) phenyl ] [ [3- (heptafluoropropyl) phenyl ] methyl ] -amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (4-fluorophenoxy) phenyl ] [ [3- (heptafluoropropyl) phenyl ] methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (4-methylphenoxy) phenyl ] [ [3- (heptafluoropropyl) phenyl ] methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (2-fluoro-5-bromophenoxy) phenyl ] [ [3- (heptafluoropropyl) phenyl ] -methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (4-chloro-3-ethylphenoxy) phenyl ] [ [3- (heptafluoropropyl) phenyl ] methyl ] -amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- [3- (1, 1, 2, 2-tetrafluoroethoxy) phenoxy ] phenyl ] [ [3- (heptafluoropropyl) -phenyl ] methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- [3- (pentafluoroethyl) phenoxy ] phenyl ] [ [3- (heptafluoropropyl) phenyl ] -methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (3, 5-dimethylphenoxy) phenyl ] [ [3- (heptafluoropropyl) phenyl ] methyl ] -amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (3-ethylphenoxy) phenyl ] [ [3- (heptafluoropropyl) phenyl ] methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (3-tert-butylphenoxy) phenyl ] [ [3- (heptafluoropropyl) phenyl ] methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (3-methylphenoxy) phenyl ] [ [3- (heptafluoropropyl) phenyl ] methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (5, 6, 7, 8-tetrahydro-2-naphthyloxy) phenyl ] [ [3- (heptafluoropropyl) phenyl ] -methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (phenoxy) phenyl ] [ [3- (heptafluoropropyl) phenyl ] methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- [3- (N, N-dimethylamino) phenoxy ] phenyl ] [ [3- (heptafluoropropyl) phenyl ] -methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [ [3- (heptafluoropropyl) phenyl ] methyl ] [3- [ [3- (trifluoromethoxy) phenyl ] -methoxy ] phenyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [ [3- (heptafluoropropyl) phenyl ] methyl ] [3- [ [3- (trifluoromethyl) phenyl ] -methoxy ] phenyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [ [3- (heptafluoropropyl) phenyl ] methyl ] [3- [ [3, 5-dimethylphenyl ] methoxy ] -phenyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [ [3- (heptafluoropropyl) phenyl ] methyl ] [3- [ [3- (trifluoromethylthio) phenyl ] -methoxy ] phenyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [ [3- (heptafluoropropyl) phenyl ] methyl ] [3- [ [3, 5-difluorophenyl ] methoxy ] -phenyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [ [3- (heptafluoropropyl) phenyl ] methyl ] [3- [ cyclohexylmethoxy ] phenyl ] -amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (2-difluoromethoxy-4-pyridinyloxy) phenyl ] [ [3- (heptafluoropropyl) phenyl ] -methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (2-trifluoromethyl-4-pyridinyloxy) phenyl ] [ [3- (heptafluoropropyl) phenyl ] -methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (3-difluoromethoxyphenoxy) phenyl ] [ [3- (heptafluoropropyl) phenyl ] -methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [ [3- (3-trifluoromethylthio) phenoxy ] phenyl ] [ [3- (heptafluoropropyl) phenyl ] -methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (4-chloro-3-trifluoromethylphenoxy) phenyl ] [ [3- (heptafluoropropyl) -phenyl ] -methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (3-trifluoromethoxy-phenoxy) phenyl ] [ [ 2-fluoro-5- (trifluoromethyl) -phenyl ] -methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (3-isopropylphenoxy) phenyl ] [ [ 2-fluoro-5- (trifluoromethyl) phenyl ] -methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (3-cyclopropylphenoxy) phenyl ] [ [ 2-fluoro-5- (trifluoromethyl) phenyl ] -methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (3- (2-furyl) phenoxy) phenyl ] [ [ 2-fluoro-5- (trifluoromethyl) phenyl ] -methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (2, 3-dichlorophenoxy) phenyl ] [ [ 2-fluoro-5- (trifluoromethyl) phenyl ] -methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (4-fluorophenoxy) phenyl ] [ [ 2-fluoro-5- (trifluoromethyl) phenyl ] -methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (4-methylphenoxy) phenyl ] [ [ 2-fluoro-5- (trifluoromethyl) phenyl ] -methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (2-fluoro-5-bromophenoxy) phenyl ] [ [ 2-fluoro-5- (trifluoromethyl) -phenyl ] methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (4-chloro-3-ethylphenoxy) phenyl ] [ [ 2-fluoro-5- (trifluoromethyl) -phenyl ] methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- [3- (1, 1, 2, 2-tetrafluoroethoxy) phenoxy ] phenyl ] [ [ 2-fluoro-5- (trifluoro-methyl) phenyl ] methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- [3- (pentafluoroethyl) phenoxy ] phenyl ] [ [ 2-fluoro-5- (trifluoromethyl) -phenyl ] -methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (3, 5-dimethylphenoxy) phenyl ] [ [ 2-fluoro-5- (trifluoromethyl) phenyl ] -methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (3-ethylphenoxy) phenyl ] [ [ 2-fluoro-5- (trifluoromethyl) phenyl ] methyl ] -amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (3-tert-butylphenoxy) phenyl ] [ [ 2-fluoro-5- (trifluoromethyl) phenyl ] methyl ] -amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (3-methylphenoxy) phenyl ] [ [ 2-fluoro-5- (trifluoromethyl) phenyl ] methyl ] -amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (5, 6, 7, 8-tetrahydro-2-naphthyloxy) phenyl ] [ [ 2-fluoro-5- (trifluoromethyl) -phenyl ] methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (phenoxy) phenyl ] [ [ 2-fluoro-5- (trifluoromethyl) phenyl ] methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- [3- (N, N-dimethylamino) phenoxy ] phenyl ] [ [ 2-fluoro-5- (trifluoromethyl) -phenyl ] methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [ [ 2-fluoro-5- (trifluoromethyl) phenyl ] methyl ] [3- [ [3- (trifluoromethoxy) -phenyl ] methoxy ] phenyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [ [ 2-fluoro-5- (trifluoromethyl) phenyl ] methyl ] [3- [ [3- (trifluoromethyl) -phenyl ] methoxy ] phenyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [ [ 2-fluoro-5- (trifluoromethyl) phenyl ] methyl ] [3- [ [3, 5-dimethylphenyl ] -methoxy ] phenyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [ [ 2-fluoro-5- (trifluoromethyl) phenyl ] methyl ] [3- [ [3- (trifluoromethylthio) -phenyl ] methoxy ] phenyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [ [ 2-fluoro-5- (trifluoromethyl) phenyl ] methyl ] [3- [ [3, 5-difluorophenyl ] -methoxy ] phenyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [ [ 2-fluoro-5- (trifluoromethyl) phenyl ] methyl ] [3- [ cyclohexylmethoxy ] -phenyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (2-difluoromethoxy-4-pyridinyloxy) phenyl ] [ [ 2-fluoro-5- (trifluoromethyl) -phenyl ] methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (2-trifluoromethyl-4-pyridinyloxy) phenyl ] [ [ 2-fluoro-5- (trifluoromethyl) -phenyl ] methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (3-difluoromethoxyphenoxy) phenyl ] [ [ 2-fluoro-5- (trifluoromethyl) -phenyl ] methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [ [3- (3-trifluoromethylthio) phenoxy ] phenyl ] [ [ 2-fluoro-5- (trifluoromethyl) -phenyl ] methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (4-chloro-3-trifluoromethylphenoxy) phenyl ] [ [ 2-fluoro-5- (trifluoromethyl) phenyl ] methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (3-trifluoromethoxy-phenoxy) phenyl ] [ [ 2-fluoro-4- (trifluoromethyl) -phenyl ] methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (3-isopropylphenoxy) phenyl ] [ [ 2-fluoro-4- (trifluoromethyl) phenyl ] -methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (3-cyclopropylphenoxy) phenyl ] [ [ 2-fluoro-4- (trifluoromethyl) phenyl ] -methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (3- (2-furyl) phenoxy) phenyl ] [ [ 2-fluoro-4- (trifluoromethyl) phenyl ] -methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (2, 3-dichlorophenoxy) phenyl ] [ [ 2-fluoro-4- (trifluoromethyl) phenyl ] -methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (4-fluorophenoxy) phenyl ] [ [ 2-fluoro-4- (trifluoromethyl) phenyl ] -methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (4-methylphenoxy) phenyl ] [ [ 2-fluoro-4- (trifluoromethyl) phenyl ] -methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (2-fluoro-5-bromophenoxy) phenyl ] [ [ 2-fluoro-4- (trifluoromethyl) -phenyl ] methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (4-chloro-3-ethylphenoxy) phenyl ] [ [ 2-fluoro-4- (trifluoromethyl) -phenyl ] methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- [3- (1, 1, 2, 2-tetrafluoroethoxy) phenoxy ] phenyl ] [ [ 2-fluoro-4- (trifluoro-methyl) phenyl ] methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- [3- (pentafluoroethyl) phenoxy ] phenyl ] [ [ 2-fluoro-4- (trifluoromethyl) -phenyl ] methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (3, 5-dimethylphenoxy) phenyl ] [ [ 2-fluoro-4- (trifluoromethyl) phenyl ] -methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (3-ethylphenoxy) phenyl ] [ [ 2-fluoro-4- (trifluoromethyl) phenyl ] methyl ] -amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (3-tert-butylphenoxy) phenyl ] [ [ 2-fluoro-4- (trifluoromethyl) phenyl ] methyl ] -amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (3-methylphenoxy) phenyl ] [ [ 2-fluoro-4- (trifluoromethyl) phenyl ] methyl ] -amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (5, 6, 7, 8-tetrahydro-2-naphthyloxy) phenyl ] [ [ 2-fluoro-4- (trifluoromethyl) -phenyl ] methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (phenoxy) phenyl ] [ [ 2-fluoro-4- (trifluoromethyl) phenyl ] methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- [3- (N, N-dimethylamino) phenoxy ] phenyl ] [ [ 2-fluoro-4- (trifluoromethyl) -phenyl ] methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [ [ 2-fluoro-4- (trifluoromethyl) phenyl ] methyl ] [3- [ [3- (trifluoromethoxy) -phenyl ] methoxy ] phenyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [ [ 2-fluoro-4- (trifluoromethyl) phenyl ] methyl ] [3- [ [3- (trifluoromethyl) -phenyl ] methoxy ] phenyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [ [ 2-fluoro-4- (trifluoromethyl) phenyl ] methyl ] [3- [ [3, 5-dimethylphenyl ] -methoxy ] phenyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [ [ 2-fluoro-4- (trifluoromethyl) phenyl ] methyl ] [3- [ [3- (trifluoromethylthio) -phenyl ] methoxy ] phenyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [ [ 2-fluoro-4- (trifluoromethyl) phenyl ] methyl ] [3- [ [3, 5-difluorophenyl ] -methoxy ] phenyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [ [ 2-fluoro-4- (trifluoromethyl) phenyl ] methyl ] [3- [ cyclohexylmethoxy ] -phenyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (2-difluoromethoxy-4-pyridinyloxy) phenyl ] [ [ 2-fluoro-4- (trifluoromethyl) -phenyl ] methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (2-trifluoromethyl-4-pyridinyloxy) phenyl ] [ [ 2-fluoro-4- (trifluoromethyl) -phenyl ] methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (3-difluoromethoxyphenoxy) phenyl ] [ [ 2-fluoro-4- (trifluoromethyl) -phenyl ] methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [ [3- (3-trifluoromethylthio) phenoxy ] phenyl ] [ [ 2-fluoro-4- (trifluoromethyl) -phenyl ] methyl ] amino ] -1, 1, 1-trifluoro-2-propanol; and

3- [ [3- (4-chloro-3-trifluoromethylphenoxy) phenyl ] [ [ 2-fluoro-4- (trifluoro-methyl) phenyl ] methyl ] amino ] -1, 1, 1-trifluoro-2-propanol.

Another class of CETP inhibitors useful in the present invention consists of substituted N-aliphatic-N-aromatic tertiary-heteroalkylamines having the formula XV

Formula XV

And pharmaceutically acceptable forms thereof, wherein:

n_XVis an integer selected from 1 to 2;

A_XVand Q_XVIs independently selected from-CH₂(CR_XV-37R_XV-38)v_XV-(CR_XV-33R_XV-34)u_XV-T_XV-(CR_XV-35R_XV-36)w_XV-H、

With the proviso that A_XVAnd Q_XVMust be AQ-1 and A_XVAnd Q_XVOne of them is selected from AQ-2 and-CH₂(CR_XV-37R_XV-38)v_XV-(CR_XV-33R_XV-34)u_XV-T_XV-(CR_XV-35R_XV-36)w_XV-H；

T_XVSelected from the group consisting of monovalent covalent bonds, O, S, S (O), S (O)₂、C(R_XV-33)＝C(R_XV-35) C ≡ C; and

V_XVis an integer selected from 0 to 1, with the proviso that when R is_XV-33、_XV-34、R_XV-35And R_XV-36When any of them is aryl or heteroaryl, v _XVIs 1;

u_XVand w_XVIs an integer independently selected from 0 to 6;

A_XV-1 is C (R)_XV-30)；

D_XV-1、D_XV-2、J_XV-1、J_XV-2And K_XV-1Independently selected from C, N, O, S and covalent bond conditions are not more than one D_XV-1、D_XV-2、J_XV-1、J_XV-2And K_XV-1Is a covalent bond, not more than one D_XV-1、D_XV-2、J_XV-1、J_XV-2And K_XV-1Is O, not more than one D_XV-1、D_XV-2、J_XV-1、J_XV-2And K_XV-1Is S, D_XV-1、D_XV-2、J_XV-1、J_XV-2And K_XV-1One must be a covalent bond when D_XV-1、D_XV-2、J_XV-1、J_XV-2And K_XV-1Two of which are O and S and not more than 4D_XV-1、D_XV-2、J_XV-1、J_XV-2And K_XV-1When N is present;

B_XV-1、B_XV-2、D_XV-3、D_XV-4、J_XV-3、J_XV-4and K_XV-2Independently selected from C, C (R)_XV-30) N, O, S and covalent bond conditions are not more than 5B_XV-1、B_XV-2、D_XV-3、D_XV-4、J_XV-3、J_XV-4And K_XV-2Is a covalent bond, not more than 2B_XV-1、B_XV-2、D_XV-3、D_XV-4、J_XV-3、J_XV-4And K_XV-2Is O, not more than 2B_XV-1、B_XV-2、D_XV-3、D_XV-4、J_XV-3、J_XV-4And K_XV-2Is S, not more than 2B_XV-1、B_XV-2、D_XV-3、D_XV-4、J_XV-3、J_XV-4And K_XV-2Both O and S, and not more than 2B_XV-1、B_XV-2、D_XV-3、D_XV-3、J_XV-3、J_XV-4And K_XV-2Is N;

B_XV-1and D_XV-3、D_XV-3And J_XV-3、J_XV-3And K_XV-2、K_XV-2And J_XV-4、J_XV-4And D_XV-4And D_XV-4And B_XV-2Independently selected to form a spacer pair within a ring, wherein said spacer pair is selected from C (R)_XV-33)＝C(R_XV-35) And N ═ N with the proviso that AQ-2 must be at least a 5-membered ring, not more than 2 of said spacer pairs being C (R) simultaneously_XV-33)＝C(R_XV-35) And no more than 1 set of said spacer pairs is N ═ N unless the other spacer pairs are other than C (R)_XV-33)＝C(R_XV-35) O, N, and S;

R_XV-1selected from haloalkyl and haloalkoxymethyl;

R_XV-2selected from the group consisting of hydrogen, aryl, alkyl, alkenyl, haloalkyl, haloalkoxy, haloalkoxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl and heteroaryl;

R_XV-3Selected from the group consisting of hydrogen, aryl, alkyl, alkenyl, haloalkyl, and haloalkoxyalkyl;

Y_XVselected from covalent single bond, (CH)₂) q, wherein q is an integer selected from 1 to 2 and (CH)₂)j-O-(CH₂) k, wherein j and k are integers independently selected from 0 to 1;

Z_XVselected from covalent single bond, (CH)₂) q, wherein q is an integer selected from 1 to 2, and (CH)₂)j-O-(CH₂)_kWherein j and k are integers independently selected from 0 to 1;

R_XV-4、R_XV-8、R_XV-9and R_XV-13Independently selected from hydrogen, halo, haloalkyl, and alkyl;

R_XV-30selected from the group consisting of hydrogen, alkoxy, alkoxyalkyl, halo, haloalkyl, alkylamino, alkylthio, alkylthioalkyl, alkyl, alkenyl, haloalkoxy, and haloalkoxyalkyl with the proviso that R is_XV-30Selected from the group consisting of tetravalent to carbon, trivalent to nitrogen, divalent to sulfur, and divalent to oxygen;

R_XV-30when connecting to A_XV-1, joined together to form a linear spacer in a ring, linked to R_XV-30A of the connection point_XV-1-carbon to be selected from R_XV-10，R_XV-11，R_XV-12，R_XV-31And R_XV-32A bonding site for a group, wherein said intra-ring linear spacer is selected from a covalent single bond and a spacer moiety having 1 to 6 atoms to form a ring selected from a 3 to 10 membered cycloalkyl, a 5 to 10 membered cycloalkenyl, and a 5 to 10 membered heterocyclyl;

R_XV-30when connecting to A_XV-1When (3) a spacer group, which combines together to form a branch in a ring, is attached to R _XV-30A of the connection point_XV-1-a point of attachment of a carbon to any member of the group selected from the following substituent pairs: r_XV-10And R_XV-11，R_XV-10And R_XV-31，R_XV-10And R_XV-32，R_XV-10And R_XV-12，R_XV-11And R_XV-31，R_XV-11And R_XV-32，R_XV-11And R_XV-12，R_XV-31And R_XV-32，R_XV-31And R_XV-12And R_XV-32And R_XV-12And wherein the spacers of said intra-ring branches are selected to form two rings selected from 3-to 10-membered cycloalkyl, 5-to 10-membered cycloalkenyl, and 5-to 10-membered heterocyclyl;

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-35and R_XV-36Independently selected from the group consisting of hydrogen, carboxy, heteroarylalkylthio, heteroarylalkoxy, cycloalkylamino, acylalkyl, acylalkoxy, aroylalkoxy, heterocyclooxy, aralkylaryl, aralkyl, aralkenyl, aralkynyl, heterocyclyl, perhaloaralkyl, aralkylsulfonyl, aralkylsulfonylalkyl, aralkylsulfinyl, aralkylsulfinylalkyl, halocycloalkyl, halocycloalkenyl, cycloalkylsulfinyl, cycloalkylsulfinylalkyl, cycloalkylsulfonyl, cycloalkylsulfonylalkyl, heteroarylamino, N-heteroarylamino-N-alkylamino, heteroarylaminoalkyl, haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxyalkyl, heteroarylalkoxy, cycloalkoxy, cycloalkenyloxy, cycloalkoxyalkyl, cycloalkylalkoxy, cycloalkenyloxyalkyl, cycloalkenyloxy, cycloalkylalkoxy, cycloalkenyloxyalkyl, heterocycloalkyloxy, cycloalkyloxy, heterocycloalkyloxy, and the like, Cycloalkylenedioxy, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxy, halocycloalkenyloxyalkyl, hydroxy, amino, thio, nitro, loweralkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, arylthioalkyl, heteroaryloxyalkyl, alkylsulfinyl, alkylsulfinylalkyl, arylsulfinylalkyl, arylsulfonylalkyl, heteroarylsulfinylalkyl, heteroarylsulfonylalkyl, alkylsulfonyl, alkylsulfonylalkyl, haloalkylsulfinylalkyl, haloalkylsulfonylalkyl, alkylsulfonylamino, alkylaminosulfonyl, amidosulfonyl, monoalkylamidosulfonyl, dialkylamiamidosulfonyl, monoarylamidosulfonyl, arylsulfonamido, diarylamidosulfonyl, monoalkylmonoarylamidosulfonyl, monoalkylarylalkylamidosulfonyl, monoalkylarylalkylsulfonylamino, aryl, Arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, heterocyclylsulfonyl, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkoyl, heteroaralkanoyl, haloalkanoyl, alkyl, heteroarylsulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylsulfonyl, Alkenyl, alkynyl, alkenyloxy, alkenyloxyalkyl, alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkylalkanoyl, cycloalkenyl, lower cycloalkylalkyl, lower cycloalkylalkenylalkyl, halo, haloalkyl, haloalkenyl, haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, hydroxyheteroaralkyl, haloalkoxyalkyl, aryl, heteroaralkynyl, aryloxy, aralkoxy, aryloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkenyl, heteroarylalkenyl, carboxyalkyl, alkoxycarbonyl, alkoxycarbamoyl, alkylamidocarbonylamido, alkoxyformylalkenyl, aralkylcarbonyloxy, haloalkenyloxy, hydroxyalkylcarbonyl, haloalkenyloxy, haloalkenyl, Carbamoyl, carbamoylalkyl, cyano, haloalkoxycarbonyl, phosphono, phosphonoalkyl, diarylalkoxyphosphono, and diarylalkoxyphosphonoalkyl groups with the proviso that R is_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-35And R_XV-36Each independently selected from the group consisting of tetravalent with retention of carbon, trivalent with retention of nitrogen, divalent with retention of sulfur, and divalent with retention of oxygen; not more than 3R _XV-33And R_XV-34Substituents are simultaneously not selected from hydrogen and halo, and not more than 3R_XV-35And R_XV-36The substituents are not simultaneously selected from hydrogen and halo;

R_XV-9，R_XV-10，R_XV-11，R_XV-12，R_XV-13，R_XV-31and R_XV-32Independently selected from oxo, provided that B_XV-1，B_XV-2，D_XV-3，D_XV-4，J_XV-3，J_XV-4And K_XV-2Independently selected from C and S, not more than two R_XV-9，R_XV-10，R_XV-11，R_XV-12，R_XV-13，R_XV-31And R_XV-32Simultaneously is oxo, and R_XV-9，R_XV-10，R_XV-11，R_XV-12，R_XV-13，R_XV-31And R_XV-32Each independently selected from the group consisting of tetravalent with retention of carbon, trivalent with retention of nitrogen, divalent with retention of sulfur, and divalent with retention of oxygen;

R_XV-4and R_XV-5，R_XV-5And R_XV-6，R_XV-6And R_XV-7，R_XV-7And R_XV-8，R_XV-9And R_XV-10，R_XV-10And R_XV-11，R_XV-11And R_XV-31，R_XV-31And R_XV-32，R_XV-32And R_XV-12And R_XV-12And R_XV-13Independently selected to form a spacer pair wherein the spacer pair is taken together to form a linear moiety of 3 to 6 atoms, the bonding sites of said spacer pair members being joined to form a ring selected from the group consisting of a 5-8 membered cycloalkenyl ring, a partially saturated 5-8 membered heterocyclyl ring, a 5-6 membered heteroaryl ring, and an aryl, with the proviso that no more than one spacer pair R_XV-4And R_XV-5，R_XV-5And R_XV-6，R_XV-6And R_XV-7，R_XV-7And R_XV-8Simultaneously, and not more than one spacer pair R_XV-9And R_XV-10，R_XV-10And R_XV-11，R_XV-11And R_XV-31，R_XV-31And R_XV-32，R_XV-32And R_XV-12And R_XV-12And R_XV-13Simultaneously used;

R_XV-9and R_XV-11，R_XV-9And R_XV-12，R_XV-9And R_XV-13R_XV-9And R_XV-31，R_XV-9And R_XV-32，R_XV-10And R_XV-12，R_XV-10And R_XV-13，R_XV-10And R_XV-31，R_XV-10And R_XV-32，R_XV-11And R_XV-12，R_XV-11And R_XV-13，R_XV-11And R_XV-32，R_XV-12And R_XV-31，R_XV-13And R_XV-31And R_XV-13And R_XV-32Independently selected to form a spacer pair, wherein said spacer pair is joined together to form a linear spacer moiety selected from the group consisting of a covalent single bond and a moiety having from 1 to 3 atoms to form a ring selected from the group consisting of 3-8 membered cycloalkyl, 5-8 membered cycloalkenyl, 5-8 membered saturated heterocyclyl and partially saturated 5-8 membered heterocyclyl, provided that no more than one spacer pair is used simultaneously;

R_XV-37And R_XV-38Independently selected from the group consisting of hydrogen, alkoxy, alkoxyalkyl, hydroxy, amino, thio, halo, haloalkyl, alkylamino, alkylthio, alkylthioalkyl, cyano, alkyl, alkenyl, haloalkoxy, and haloalkoxyalkyl.

The compounds of formula XV are disclosed in WO 00/18723, the entire disclosure of which is incorporated herein by reference.

In a preferred embodiment, the CETP inhibitor is selected from the following compounds of formula XV:

3- [ [3- (4-chloro-3-ethylphenoxy) phenyl ] (cyclohexylmethyl) amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (4-chloro-3-ethylphenoxy) phenyl ] (cyclopentylmethyl) amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (4-chloro-3-ethylphenoxy) phenyl ] (cyclopropylmethyl) amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (4-chloro-3-ethylphenoxy) phenyl ] [ (3-trifluoromethyl) cyclohexyl-methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (4-chloro-3-ethylphenoxy) phenyl ] [ (3-pentafluoroethyl) cyclohexyl-methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (4-chloro-3-ethylphenoxy) phenyl ] [ (3-trifluoromethoxy) cyclohexyl-methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (4-chloro-3-ethylphenoxy) phenyl ] [ [3- (1, 1, 2, 2-tetrafluoroethoxy) cyclo-hexylmethyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (3-trifluoromethoxy-phenoxy) phenyl ] (cyclohexylmethyl) amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (3-trifluoromethoxy-phenoxy) phenyl ] (cyclopentylmethyl) amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (3-trifluoromethoxy-phenoxy) phenyl ] (cyclopropylmethyl) amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (3-trifluoromethoxy-phenoxy) phenyl ] [ (3-trifluoromethyl) cyclohexyl-methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (3-trifluoromethoxy-phenoxy) phenyl ] (3-pentafluoroethyl) cyclohexyl-methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (3-trifluoromethoxy-phenoxy) phenyl ] [ (3-trifluoromethoxy) cyclohexyl-methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (3-trifluoromethoxy-phenoxy) phenyl ] [ [3- (1, 1, 2, 2-tetrafluoroethoxy) cyclohexyl-methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (3-isopropylphenoxy) phenyl ] (cyclohexylmethyl ] amino ] -1, 1, 1-trifluoro-2-propanol:

3- [ [3- (3-isopropylphenoxy) phenyl ] (cyclopentylmethyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (3-isopropylphenoxy) phenyl ] (cyclopropylmethyl) amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (3-isopropylphenoxy) phenyl ] [ (3-trifluoromethyl) cyclohexyl-methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (3-isopropylphenoxy) phenyl ] [ (3-pentafluoroethyl) cyclohexyl-methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (3-isopropylphenoxy) phenyl ] [ (3-trifluoromethoxy) cyclohexyl-methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (3-isopropylphenoxy) phenyl ] [3- (1, 1, 2, 2-tetrafluoroethoxy) cyclohexyl-methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (2, 3-dichlorophenoxy) phenyl ] (cyclohexylmethyl) amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (2, 3-dichlorophenoxy) phenyl ] (cyclopentylmethyl) amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (2, 3-dichlorophenoxy) phenyl ] (cyclopropylmethyl) amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (2, 3-dichlorophenoxy) phenyl ] [ (3-trifluoromethyl) cyclohexyl-methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (2, 3-dichlorophenoxy) phenyl ] [ (3-pentafluoroethyl) cyclohexyl-methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (2, 3-dichlorophenoxy) phenyl ] [ (3-trifluoromethoxy) cyclohexyl-methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (2, 3-dichlorophenoxy) phenyl ] [3- (1, 1, 2, 2-tetrafluoroethoxy) cyclo-hexyl-methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (4-fluorophenoxy) phenyl ] (cyclohexylmethyl) amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (4-fluorophenoxy) phenyl ] (cyclopentylmethyl) amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (4-fluorophenoxy) phenyl ] (cyclopropylmethyl) amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (4-fluorophenoxy) phenyl ] [ (3-trifluoromethyl) cyclohexyl-methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (4-fluorophenoxy) phenyl ] [ (3-pentafluoroethyl) cyclohexyl-methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (4-fluorophenoxy) phenyl ] [ (3-trifluoromethoxy) cyclohexyl-methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (4-fluorophenoxy) phenyl ] [ [3- (1, 1, 2, 2-tetrafluoroethoxy) cyclohexyl-methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (3-trifluoromethoxy-benzyloxy ] phenyl ] (cyclohexylmethyl) amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (3-trifluoromethoxy-benzyloxy) phenyl ] (cyclopentylmethyl) amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (3-trifluoromethoxy-benzyloxy) phenyl ] (cyclopropylmethyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (3-trifluoromethoxy-benzyloxy) phenyl ] [ (3-trifluoromethyl) cyclohexyl-methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (3-trifluoromethoxy-benzyloxy) phenyl ] [ (3-pentafluoroethyl) cyclohexyl-methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (3-trifluoromethoxy-benzyloxy ] phenyl ] [ (3-trifluoromethoxy) cyclohexyl-methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (3-trifluoromethoxy-benzyloxy) phenyl ] [3- (1, 1, 2, 2-tetrafluoroethoxy) -cyclohexylmethyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (3-trifluoromethylbenzyloxy) phenyl ] (cyclohexylmethyl) amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (3-trifluoromethylbenzyloxy) phenyl ] (cyclopentylmethyl) amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (3-trifluoromethylbenzyloxy) phenyl ] (cyclopropylmethyl) amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (3-trifluoromethylbenzyloxy) phenyl ] [ (3-trifluoromethyl) cyclohexyl-methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (3-trifluoromethylbenzyloxy) phenyl ] [ (3-pentafluoroethyl) cyclohexyl-methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (3-trifluoromethylbenzyloxy) phenyl ] [ (3-trifluoromethoxy) cyclohexyl-methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [3- (3-trifluoromethylbenzyloxy) phenyl ] [3- (1, 1, 2, 2-tetrafluoroethoxy) cyclohexyl-methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [ [ (3-trifluoromethyl) phenyl ] methyl ] (cyclohexyl) amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [ [ (3-pentafluoroethyl) phenyl ] methyl ] (cyclohexyl) amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [ [ (3-trifluoromethoxy) phenyl ] methyl ] (cyclohexyl) amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [ [3- (1, 1, 2, 2-tetrafluoroethoxy) phenyl ] methyl ] (cyclohexyl) amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [ [ (3-trifluoromethyl) phenyl ] methyl ] (4-methylcyclohexyl) amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [ [ (3-pentafluoroethyl) phenyl ] methyl ] (4-methylcyclohexyl) amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [ [ (3-trifluoromethoxy) phenyl ] methyl ] (4-methylcyclohexyl) amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [ [3- (1, 1, 2, 2-tetrafluoroethoxy) phenyl ] methyl ] (4-methylcyclohexyl) amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [ [ (3-trifluoromethyl ] phenyl ] methyl ] (3-trifluoromethylcyclohexyl) amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [ [ (3-pentafluoroethyl) phenyl ] methyl ] (3-trifluoromethylcyclohexyl) amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [ [ (3-trifluoromethoxy) phenyl ] methyl ] (3-trifluoromethylcyclohexyl) amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [ [3- (1, 1, 2, 2-tetrafluoroethoxy) phenyl ] methyl ] (3-trifluoromethylcyclohexyl) amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [ [ (3-trifluoromethyl) phenyl ] methyl ] [3- (4-chloro-3-ethylphenoxy) cyclo-hexyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [ [ (3-pentafluoroethyl) phenyl ] methyl ] [3- (4-chloro-3-ethylphenoxy) cyclo-hexyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [ [ (3-trifluoromethoxy) phenyl ] methyl ] [3- (4-chloro-3-ethylphenoxy) cyclo-hexyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [ [3- (1, 1, 2, 2-tetrafluoroethoxy) phenyl ] methyl ] [3- (4-chloro-3-ethylphenoxy) -cyclohexyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [ [ (3-trifluoromethyl ] phenyl ] methyl ] (3-phenoxycyclohexyl) amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [ [ (3-pentafluoroethyl) phenyl ] methyl ] (3-phenoxycyclohexyl) amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [ [ (3-trifluoromethoxy) phenyl ] methyl ] (3-phenoxycyclohexyl) amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [ [3- (1, 1, 2, 2-tetrafluoroethoxy) phenyl ] methyl ] (3-phenoxycyclohexyl) amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [ [ (3-trifluoromethyl) phenyl ] methyl ] (3-isopropoxycyclohexyl) amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [ [ (3-pentafluoroethyl) phenyl ] methyl ] (3-isopropoxycyclohexyl) amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [ [ (3-trifluoromethoxy) phenyl ] methyl ] (3-isopropoxycyclohexyl) amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [ [3- (1, 1, 2, 2-tetrafluoroethoxy) phenyl ] methyl ] (3-isopropoxycyclohexyl) -amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [ [ (3-trifluoromethyl) phenyl ] methyl ] (3-cyclopentyloxycyclohexyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [ [ (3-pentafluoroethyl ] phenyl ] methyl ] (3-cyclopentyloxycyclohexyl) amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [ [ (3-trifluoromethoxy) phenyl ] methyl ] (3-cyclopentyloxycyclohexyl) amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [ [3- (1, 1, 2, 2-tetrafluoroethoxy) phenyl ] methyl ] (3-cyclopentyloxycyclohexyl) -amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [ [ (2-trifluoromethyl) pyridin-6-yl ] methyl ] (3-isopropoxycyclohexyl) amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [ [ (2-trifluoromethyl) pyridin-6-yl ] methyl ] (3-cyclopentyloxycyclohexyl) -amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [ [ (2-trifluoromethyl) pyridin-6-yl ] methyl ] (3-phenoxycyclohexyl) amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [ [ (2-trifluoromethyl) pyridin-6-yl ] methyl ] (3-trifluoromethylcyclohexyl) amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [ [ (2-trifluoromethyl) pyridin-6-yl ] methyl ] [3- (4-chloro-3-ethylphenoxy) cyclo-hexyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [ [ (2-trifluoromethyl) pyridin-6-yl ] methyl ] [3- (1, 1, 2, 2-tetrafluoroethoxy) cyclo-hexyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [ [ (2-trifluoromethyl) pyridin-6-yl ] methyl ] (3-pentafluoroethylcyclohexyl) -amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [ [ (2-trifluoromethyl) pyridin-6-yl ] methyl ] (3-trifluoromethoxycyclohexyl) -amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [ [ (3-trifluoromethyl) phenyl ] methyl ] [3- (4-chloro-3-ethylphenoxy) propyl ] -amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [ [ (3-pentafluoroethyl) phenyl ] methyl ] [3- (4-chloro-3-ethylphenoxy) propyl ] -amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [ [ (3-trifluoromethoxy) phenyl ] methyl ] [3- (4-chloro-3-ethylphenoxy) propyl ] -amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [ [3- (1, 1, 2, 2-tetrafluoroethoxy) phenyl ] methyl ] [3- (4-chloro-3-ethylphenoxy) -propyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [ [ (3-trifluoromethyl) phenyl ] methyl ] [3- (4-chloro-3-ethylphenoxy) -2, 2, -di-fluoropropyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [ [ (3-pentafluoroethyl) phenyl ] methyl ] [3- (4-chloro-3-ethylphenoxy) -2, 2-di-fluoropropyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [ [ (3-trifluoromethoxy) phenyl ] methyl ] [3- (4-chloro-3-ethylphenoxy) -2, 2, -di-fluoropropyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [ [3- (1, 1, 2, 2-tetrafluoroethoxy) phenyl ] methyl ] [3- (4-chloro-3-ethylphenoxy) -2, 2, -difluoropropyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [ [ (3-trifluoromethyl) phenyl ] methyl ] [3- (isopropoxy) propyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [ [ (3-pentafluoroethyl) phenyl ] methyl ] [3- (isopropoxy) propyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [ [ (3-trifluoromethoxy) phenyl ] methyl ] [3- (isopropoxy) propyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

3- [ [ [3- (1, 1, 2, 2-tetrafluoroethoxy) phenyl ] methyl ]3- (isopropoxy) propyl ] amino ] -1, 1, 1-trifluoro-2-propanol; and

3- [ [ [3- (1, 1, 2, 2-tetrafluoroethoxy) phenyl ] methyl ] [3- (phenoxy) propyl ] amino ] -1, 1, 1-trifluoro-2-propanol.

Another class of CETP inhibitors useful in the present invention consists of halogenated 1-substituted amino- (n +1) -alkanols of (R) -chirality having the formula XVI

Formula XVI

And pharmaceutically acceptable forms thereof, wherein:

n_XVIis an integer selected from 1 to 4;

X_XVIis oxy;

R_XVI-1selected from the group consisting of haloalkyl, haloalkenyl, haloalkoxymethyl, and haloalkenyloxymethyl with the proviso that R is_XVI-1Having a ratio R_XVI-2And (CHR)_XVI-3)n-N(A_XVI)Q_XVIHigher Cahn-Ingold-Prelog stereochemical system alignment, wherein A_XVIIs formula XVI- (II) and Q is formula XVI- (III);

R_XVI-16selected from the group consisting of hydrogen, alkyl, acyl, aroyl, heteroaroyl, trialkylsilyl, and a spacer selected from the group consisting of a single covalent bond and a linear spacer having a chain length of 1 to 4 atoms, the linkage being selected from R_XVI-4、R_XVI-8、R_XVI-9And R_XVI-13Any aromatic substituent to form a 5-to 10-membered heterocyclic ringA base ring;

D_XVI-1、D_XVI-2、J_XVI-1、J_XVI-2and K_XVI-1Independently selected from C, N, O, S and covalent bond conditions is not more than one D_XVI-1、D_XVI-2、J_XVI-1、J_XVI-2And K_XVI-1Is a covalent bond, not more than one D_XVI-1、D_XVI-2、J_XVI-1、J_XVI-2And K_XVI-1Is O, not more than one D_XVI-1、D_XVI-2、J_XVI-1、J_XVI-2And K_XVI-1Is S, D_XVI-1、D_XVI-2、J_XVI-1、J_XVI-2And K_XVI-1One must be a covalent bond when D_XVI-1、D_XVI-2、J_XVI-1、J_XVI-2And K_XVI-1Two of O and S, and not more than 4D_XVI-1、D_XVI-2、J_XVI-1、J_XVI-2And K_XVI-1When N is present;

D_XVI-3、D_XVI-4、J_XVI-3、J_XVI-4and K_XVI-2Independently selected from C, N, O, S and covalent bond conditions are no more than one covalent bond, no more than one D_XVI-3、D_XVI-4、J_XVI-3、J_XVI-4And K_XVI-2Is O, not more than one D_XVI-3、D_XVI-4、J_XVI-3、J_XVI-4And K_XVI-2Is S, not more than two D_XVI-3、D_XVI-4、J_XVI-3、J_XVI-4And K_XVI-2Is O and S, D_XVI-3、D_XVI-4、J_XVI-3、J_XVI-4And K_XVI-2One must be a covalent bond when D _XVI-3、D_XVI-4、J_XVI-3、J_XVI-4And K_XVI-2Two of O and S, and not more than 4D_XVI-3、D_XVI-4、J_XVI-3、J_XVI-4And K_XVI-2Is N;

R_XVI-2selected from hydrogen, aryl, aralkyl, alkyl, alkenyl, alkenyloxyAlkyl, haloalkyl, haloalkenyl, halocycloalkyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy, halocycloalkoxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, dicyanoalkyl, and alkoxyformylcyanoalkyl, provided that R is_XVI-2Ratio R_XVI-1And (CHR)_XVI-3)n-N(A_XVI)Q_XVIBoth have a lower Cahn-Ingold-Prelog system ranking;

R_XVI-3selected from the group consisting of hydrogen, hydroxy, cyano, aryl, aralkyl, acyl, alkoxy, alkyl, alkenyl, alkoxyalkyl, heteroaryl, alkenyloxyalkyl, haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, monocyanoalkyl, di cyanoalkyl, carboxamide, and carbamoylalkyl, with the proviso that (CHR)_XVI-3)n-N(A_XVI)Q_XVIHaving a ratio R_XVI-1Low Cahn-Ingold-Prelog stereochemical system alignment and higher than R_XVI-2The Cahn-Ingold-Prelog stereochemical system is ranked;

Y_XVIselected from covalent single bonds, (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-14selected from the group consisting of hydrogen, hydroxy, cyano, hydroxyalkyl, acyl, alkoxy, alkyl, alkenyl, alkynyl, alkoxyalkyl, haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, monoalkoxyformylalkyl, monocyanoalkyl, dicyanoalkyl, alkoxyformylcyanoalkyl, alkoxyformyl, carboxamide, and carbamoylalkyl;

Z_XVIselected from 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_XVIselected from 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)₂N(R_XVI-14)、(R_XVI-14)NS(O)₂And N (R)_XVI-14) Provided that R is_XVI-14Is not cyano;

R_XVI-15selected from the group consisting of hydrogen, cyano, hydroxyalkyl, acyl, alkoxy, alkyl, alkenyl, alkynyl, alkoxyalkyl, haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, monoalkoxyformylalkyl, monocyanoalkyl, dicyanoalkyl, alkoxyformylcyanoalkyl, alkoxyformyl, carboxamide, and carbamoylalkyl;

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-12and R_XVI-13Independently selected from the group consisting of hydrogen, carboxy, heteroarylalkylthio, heteroarylalkoxy, cycloalkylamino, acylalkyl, acylalkoxy, aroylalkoxy, heterocyclooxy, aralkylaryl, aralkyl, aralkenyl, aralkynyl, heterocyclyl, perhaloaralkyl, aralkylsulfonyl, aralkylsulfonylalkyl, aralkylsulfinyl, aralkylsulfinylalkyl, halocycloalkyl, halocycloalkenyl, cycloalkylsulfinyl, cycloalkylsulfinylalkyl, cycloalkylsulfonyl, cycloalkylsulfonylalkyl, heteroarylamino, N-heteroarylamino-N-alkylamino, heteroaralkyl, heteroarylaminoalkyl, haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxyalkyl, heteroarylalkoxy, cycloalkoxy, cycloalkenyloxy, cycloalkoxyalkyl, cycloalkylalkoxyalkyloxyalkyl, cycloalkylalkoxyalkyloxy, cycloalkylalkyloxy, cycloalkyl, Cycloalkenyloxyalkyl, cycloalkylenedioxy, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxy, halocycloalkene Alkoxyalkyl, hydroxy, amino, thio, nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, arylthioalkyl, heteroaralkoxyalkyl, alkylsulfinyl, alkylsulfinylalkyl, arylsulfinylalkyl, arylsulfonylalkyl, heteroarylsulfinylalkyl, heteroarylsulfonylalkyl, alkylsulfonyl, alkylsulfonylalkyl, haloalkylsulfinylalkyl, haloalkylsulfonylalkyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkylamidosulfonyl, dialkyl, amidosulfonyl, monoarylamidosulfonyl, arylsulfonamido, diarylamidosulfonyl, monoalkylmonoarylamidosulfonyl, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, substituted aryl, Heteroarylsulfonyl, heterocyclylsulfonyl, heterocyclylthio, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkoyl, heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl, alkynyl, alkenyloxy, alkenyloxyalkyl, alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkylalkanoyl, cycloalkenyl, lower cycloalkylalkyl, lower cycloalkenylalkyl, halo, haloalkyl, haloalkenyl, haloalkoxy, hydroxyhaloalkyl, hydroxyalkylalkyl, hydroxyheteroaralkyl, haloalkoxyalkyl, aryl, heteroarylalkynyl, aryloxy, aralkoxy, aryloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkenyl, heteroarylalkenyl, carboxyalkyl, alkoxyformyl, and pharmaceutically acceptable salts thereof, Alkoxycarbamoyl, alkylamidocarbonylamido, arylamidocarbonylamido, alkoxyformylalkyl, alkoxyformylalkenyl, aralkylcarbonyloxy, carbamoyl, carbamoylalkyl, cyano, carbohaloalkoxy, phosphono, phosphonoalkyl, diarylalkoxyphosphono, and diarylalkoxyphosphonoalkyl groups, with the proviso that R is _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-12And R_XVI-13Each independently selected to retain carbon tetravalent, nitrogen trivalent, sulfur divalent, and oxygen divalent;

R_XVI-4and R_XVI-5，R_XVI-5And R_XVI-6，R_XVI-6And R_XVI-7，R_XVI-7And R_XVI-8，R_XVI-9And R_XVI-10，R_XVI-10And R_XVI-11，R_XVI-11And R_XVI-12And R_XVI-12And R_XIV-13Independently selected to form a spacer pair, wherein the spacer pairs are joined together to form a linear moiety having 3 to 6 atoms, the bonding sites of said spacer pair members being joined to form a ring selected from the group consisting of a 5-8 membered cycloalkenyl ring, a partially saturated 5-8 membered heterocyclyl ring, a 5-6 membered heteroaryl ring, and an aryl, with the proviso that no more than one spacer pair R_XVI-4And R_XVI-5，R_XVI-5And R_XVI-6，R_XVI-6And R_XVI-7And R_XVI-7And R_XVI-8Simultaneously and not more than one spacer pair R_XIV-9And R_XVI-10，R_XVI-10And R_XVI-11，R_XVI-11And R_XVI-12And R_XVI-12And R_XVI-13Can be used simultaneously;

R_XVI-4and R_XVI-9，R_XVI-4And R_XVI-13，R_XVI-8And R_XVI-9And R_XVI-8And R_XVI-13Independently selected to form a spacer pair, wherein said spacer pair are joined together to form a linear moiety, wherein said linear moiety forms a ring selected from the group consisting of a partially saturated 5-to 8-membered heterocyclyl ring and a 5-to 6-membered heteroaryl ring, with the proviso that no more than one spacer pair R_XVI-4And R_XVI-9，R_XVI-4And R_XVI-13，R_XVI-8And R_XVI-9And R_XVI-8And R_XVI-13And simultaneously used.

The compounds of formula XVI are disclosed in WO 00/18724, the entire disclosure of which is incorporated herein by reference.

In a preferred embodiment, the CETP inhibitor is selected from the following compounds of formula XVI:

(2R) -3- [ [3- (3-trifluoromethoxy-phenoxy) phenyl ] [ [3- (1, 1, 2, 2-tetrafluoroethoxy) phenyl ] methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [3- (3-isopropylphenoxy) phenyl ] [ [3- (1, 1, 2, 2-tetrafluoroethoxy) phenyl ] -methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [3- (3-cyclopropylphenoxy) phenyl ] [ [3- (1, 1, 2, 2-tetrafluoroethoxy) phenyl ] -methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [3- (3- (2-furanyl) phenoxy) phenyl ] [ [3- (1, 1, 2, 2-tetrafluoroethoxy) phenyl ] -methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [3- (2, 3-dichlorophenoxy) phenyl ] [ [3- (1, 1, 2, 2-tetrafluoroethoxy) phenyl ] -methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [3- (4-fluorophenoxy) phenyl ] [ [3- (1, 1, 2, 2-tetrafluoroethoxy) phenyl ] -methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [3- (4-methylphenoxy) phenyl ] [ [3- (1, 1, 2, 2-tetrafluoroethoxy) phenyl ] -methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [3- (2-fluoro-5-bromophenoxy) phenyl ] [ [3- (1, 1, 2, 2-tetrafluoroethoxy) phenyl ] -methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [3- (4-chloro-3-ethylphenoxy) phenyl ] [ [3- (1, 1, 2, 2-tetrafluoroethoxy) phenyl ] -methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [3- [3- (1, 1, 2, 2-tetrafluoroethoxy) phenoxy ] phenyl ] [ [3- (1, 1, 2, 2-tetrafluoro-ethoxy) phenyl ] methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [3- [3- (pentafluoroethyl) phenoxy ] phenyl ] [ [3- (1, 1, 2, 2-tetrafluoroethoxy) -phenyl ] methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [3- (3, 5-dimethylphenoxy) phenyl ] [ [3- (1, 1, 2, 2-tetrafluoroethoxy) phenyl ] -methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [3- (3-ethylphenoxy) phenyl ] [ [3- (1, 1, 2, 2-tetrafluoroethoxy) phenyl ] -methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [3- (3-tert-butylphenoxy) phenyl ] [ [3- (1, 1, 2, 2-tetrafluoroethoxy) phenyl ] -methyl ] amino ] -1, 1, 1-trifluoro-2-propanol:

(2R) -3- [ [3- (3-methylphenoxy) phenyl ] [ [3- (1, 1, 2, 2-tetrafluoroethoxy) phenyl ] -methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [3- (5, 6, 7, 8-tetrahydro-2-naphthoxy) phenyl ] [ [3- (1, 1, 2, 2-tetrafluoro-ethoxy) phenyl ] methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [3- (phenoxy) phenyl ] [ [3- (1, 1, 2, 2-tetrafluoroethoxy) phenyl ] methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [3- [3- (N, N-dimethylamino) phenoxy ] phenyl ] [ [3- (1, 1, 2, 2-tetrafluoro-ethoxy) phenyl ] methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [ [3- (1, 1, 2, 2, -tetrafluoroethoxy) phenyl ] methyl ] [3- [ [3- (trifluoromethoxy) -phenyl ] methoxy ] phenyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [ [3- (1, 1, 2, 2-tetrafluoroethoxy) phenyl ] methyl ] [3- [ [3- (trifluoro-methyl) phenyl ] methoxy ] phenyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [ [3- (1, 1, 2, 2-tetrafluoroethoxy) phenyl ] methyl ] [3- [ [3, 5-dimethylphenyl ] -methoxy ] phenyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [ [3- (1, 1, 2, 2-tetrafluoroethoxy) phenyl ] methyl ] [3- [ [3- (trifluoromethylthio) -phenyl ] methoxy ] phenyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [ [3- (1, 1, 2, 2-tetrafluoroethoxy) phenyl ] methyl ] [3- [ [3, 5-difluorophenyl ] -methoxy ] phenyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [ [3- (1, 1, 2, 2-tetrafluoroethoxy) phenyl ] methyl ] [3- [ cyclohexylmethoxy ] -phenyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [3- (2-difluoromethoxy-4-pyridinyloxy) phenyl ] [ [3- (1, 1, 2, 2-tetrafluoroethoxy) -phenyl ] methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [3- (2-trifluoromethyl-4-pyridinyloxy) phenyl ] [ [3- (1, 1, 2, 2-tetrafluoroethoxy) -phenyl ] methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [3- (3-difluoromethoxyphenoxy) phenyl ] [ [3- (1, 1, 2, 2-tetrafluoroethoxy) -phenyl ] methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [ [3- (3-trifluoromethylthio) phenoxy ] phenyl ] [ [3- (1, 1, 2, 2-tetrafluoroethoxy) -phenyl ] methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [3- (4-chloro-3-trifluoromethylphenoxy) phenyl ] [ [3- (1, 1, 2, 2-tetrafluoroethoxy) -phenyl ] methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [3- (3-trifluoromethoxy-phenoxy) -phenyl ] [ [3- (pentafluoroethyl) phenyl ] -methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [3- (3-isopropylphenoxy) phenyl ] [ [3- (pentafluoroethyl) phenyl ] methyl ] -amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [3- (3-cyclopropylphenoxy) phenyl ] [ [3- (pentafluoroethyl) phenyl ] methyl ] -amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [3- (3- (2-furanyl) phenoxy) phenyl ] [ [3- (pentafluoroethyl) phenyl ] methyl ] -amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [3- (2, 3-dichlorophenoxy) phenyl ] [ [3- (pentafluoroethyl) phenyl ] methyl ] -amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [3- (4-fluorophenoxy) phenyl ] [ [3- (pentafluoroethyl) phenyl ] methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [3- (4-methylphenoxy) phenyl ] [ [3- (pentafluoroethyl) phenyl ] methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [3- (2-fluoro-5-bromophenoxy) phenyl ] [ [3- (pentafluoroethyl) phenyl ] methyl ] -amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [3- (4-chloro-3-ethylphenoxy) phenyl ] [ [3- (pentafluoroethyl) phenyl ] methyl ] -amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [3- [3- (1, 1, 2, 2-tetrafluoroethoxy) phenoxy ] phenyl ] [ [3- (pentafluoroethyl) -phenyl ] methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [3- [3- (pentafluoroethyl) phenoxy ] phenyl ] [ [3- (pentafluoroethyl) phenyl ] -methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [3- (3, 5-dimethylphenoxy) phenyl ] [ [3- (pentafluoroethyl) phenyl ] methyl ] -amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [3- (3-ethylphenoxy) phenyl ] [ [3- (pentafluoroethyl) phenyl ] methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [3- (3-tert-butylphenoxy) phenyl ] [ [3- (pentafluoroethyl) phenyl ] methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [3- (3-methylphenoxy) phenyl ] [ [3- (pentafluoroethyl) phenyl ] methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [3- (5, 6, 7, 8-tetrahydro-2-naphthyloxy) phenyl ] [ [3- (pentafluoroethyl) phenyl ] -methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [3- (phenoxy) phenyl ] [ [3 (pentafluoroethyl) phenyl ] methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [3- [3- (N, N-dimethylamino) phenoxy ] phenyl ] [ [3- (pentafluoroethyl) phenyl ] -methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [ [3- (pentafluoroethyl) phenyl ] methyl ] [3- [ [3- (trifluoromethoxy) phenyl ] -methoxy ] phenyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [ [3- (pentafluoroethyl) phenyl ] methyl ] [3- [ [3- (trifluoromethyl) -phenyl ] -methoxy ] phenyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [ [3- (pentafluoroethyl) phenyl ] methyl ] [3- [ [3, 5-dimethylphenyl ] methoxy ] -phenyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [ [3- (pentafluoroethyl) phenyl ] methyl ] [3- [ [3- (trifluoromethylthio) phenyl ] -methoxy ] phenyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [ [3- (pentafluoroethyl) phenyl ] methyl ] [3- [ [3, 5-difluorophenyl ] methoxy ] -phenyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [ [3- (pentafluoroethyl) phenyl ] methyl ] [3- [ cyclohexylmethoxy ] phenyl ] -amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [3- (2-difluoromethoxy-4-pyridinyloxy) phenyl ] [ [3- (pentafluoroethyl) phenyl ] -methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [3- (2-trifluoromethyl-4-pyridinyloxy) phenyl ] [ [3- (pentafluoroethyl) phenyl ] -methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [3- (3-difluoromethoxyphenoxy) phenyl ] [ [3- (pentafluoroethyl) phenyl ] -methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [ [3- (3-trifluoromethylthio) phenoxy ] phenyl ] [ [3- (pentafluoroethyl) phenyl ] -methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [3- (4-chloro-3-trifluoromethylphenoxy) phenyl ] [ [3- (pentafluoroethyl) -phenyl ] methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [3- (3-trifluoromethoxy-phenoxy) phenyl ] [ [3- (heptafluoropropyl) phenyl ] -methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [3- (3-isopropylphenoxy) phenyl ] [ [3- (heptafluoropropyl) phenyl ] methyl ] -amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [3- (3-cyclopropylphenoxy) phenyl ] [ [3- (heptafluoropropyl) phenyl ] methyl ] -amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [3- (3- (2-furanyl) phenoxy) phenyl ] [ [3- (heptafluoropropyl) phenyl ] methyl ] -amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [3- (2, 3-dichlorophenoxy) phenyl ] [ [3- (heptafluoropropyl) phenyl ] methyl ] -amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [3- (4-fluorophenoxy) phenyl ] [ [3- (heptafluoropropyl) phenyl ] methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [3- (4-methylphenoxy) phenyl ] [ [3- (heptafluoropropyl) phenyl ] methyl ] amino ] -1, 1, 1, -trifluoro-2-propanol;

(2R) -3- [ [3- (2-fluoro-5-bromophenoxy) phenyl ] [ [3- (heptafluoropropyl) phenyl ] -methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [3- (4-chloro-3-ethylphenoxy) phenyl ] [ [3- (heptafluoropropyl) phenyl ] methyl ] -amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [3- [3- (1, 1, 2, 2-tetrafluoroethoxy) phenoxy ] phenyl ] [ [3- (heptafluoropropyl) -phenyl ] methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [3- [3- (pentafluoroethyl) phenoxy ] phenyl ] [ [3- (heptafluoropropyl) phenyl ] -methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [3- (3, 5-dimethylphenoxy) phenyl ] [ [3- (heptafluoropropyl) phenyl ] methyl ] -amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [3- (3-ethylphenoxy) phenyl ] [ [3- (heptafluoropropyl) phenyl ] methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [3- (3-tert-butylphenoxy) phenyl ] [ [3- (heptafluoropropyl) phenyl ] methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [3- (3-methylphenoxy) phenyl ] [ [3- (heptafluoropropyl) phenyl ] methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [3- (5, 6, 7, 8-tetrahydro-2-naphthyloxy) phenyl ] [ [3- (heptafluoropropyl) phenyl ] -methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [3- (phenoxy) phenyl ] [ [3- (heptafluoropropyl) phenyl ] methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [3- [3- (N, N-dimethylamino) phenoxy ] phenyl ] [ [3- (heptafluoropropyl) phenyl ] -methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [ [3- (heptafluoropropyl) phenyl ] methyl ] [3- [ [3- (trifluoromethoxy) phenyl ] -methoxy ] phenyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [ [3- (heptafluoropropyl) phenyl ] methyl ] [3- [ [3- (trifluoromethyl) phenyl ] -methoxy ] phenyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [ [3- (heptafluoropropyl) phenyl ] methyl ] [3- [ [3, 5-dimethylphenyl ] methoxy ] -phenyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [ [3- (heptafluoropropyl) phenyl ] methyl ] [3- [ [3- (trifluoromethylthio) phenyl ] -methoxy ] phenyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [ [3- (heptafluoropropyl) phenyl ] methyl ] [3- [ [3, 5-difluorophenyl ] methoxy ] -phenyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [ [3- (heptafluoropropyl) phenyl ] methyl ] [3- [ cyclohexylmethoxy ] phenyl ] -amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [3- (2-difluoromethoxy-4-pyridinyloxy) phenyl ] [ [3- (heptafluoropropyl) phenyl ] -methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [3- (2-trifluoromethyl-4-pyridinyloxy) phenyl ] [ [3- (heptafluoropropyl) phenyl ] -methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [3- (3-difluoromethoxyphenoxy) phenyl ] [ [3- (heptafluoropropyl) phenyl ] -methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [ [3- (3-trifluoromethylthio) phenoxy ] phenyl ] [ [3- (heptafluoropropyl) phenyl ] -methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [3- (4-chloro-3-trifluoromethylphenoxy) phenyl ] [ [3- (heptafluoropropyl) -phenyl ] methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [3- (3-trifluoromethoxy-phenoxy) phenyl ] [ [ 2-fluoro-5- (trifluoromethyl) -phenyl ] methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [3- (3-isopropylphenoxy) phenyl ] [ [ 2-fluoro-5- (trifluoromethyl) phenyl ] -methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [3- (3-cyclopropylphenoxy) phenyl ] [ [ 2-fluoro-5- (trifluoromethyl) phenyl ] -methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [3- (3- (2-furanyl) phenoxy) phenyl ] [ [ 2-fluoro-5- (trifluoromethyl) phenyl ] -methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [3- (2, 3-dichlorophenoxy) phenyl ] [ [ 2-fluoro-5- (trifluoromethyl) phenyl ] -methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [3- (4-fluorophenoxy) phenyl ] [ [ 2-fluoro-5- (trifluoromethyl) phenyl ] -methyl ] amino ] -1, 1, 1-trifluoro-3-propanol;

(2R) -3- [ [3- (4-methylphenoxy) phenyl ] [ [ 2-fluoro-5- (trifluoromethyl) phenyl ] -methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [3- (2-fluoro-5-bromophenoxy) phenyl ] [ [ 2-fluoro-5- (trifluoromethyl) -phenyl ] methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3[ [3- (4-chloro-3-ethylphenoxy) phenyl ] [ [ 2-fluoro-5- (trifluoromethyl) -phenyl ] methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [3- [3- (1, 1, 2, 2-tetrafluoroethoxy) phenoxy ] phenyl ] [ [ 2-fluoro-5- (trifluoro-methyl) phenyl ] methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [3- [3- (pentafluoroethyl) phenoxy ] phenyl ] [ [ 2-fluoro-5- (trifluoromethyl) -phenyl ] methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [3- (3, 5-dimethylphenoxy) phenyl ] [ [ 2-fluoro-5- (trifluoromethyl) phenyl ] -methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [3- (3-ethylphenoxy) phenyl ] [ [ 2-fluoro-5- (trifluoromethyl) phenyl ] methyl ] -amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [3- (3-tert-butylphenoxy) phenyl ] [ [ 2-fluoro-5- (trifluoromethyl) phenyl ] methyl ] -amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [3- (3-methylphenoxy) phenyl ] [ [ 2-fluoro-5- (trifluoromethyl) phenyl ] methyl ] -amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [3- (5, 6, 7, 8-tetrahydro-2-naphthyloxy) phenyl ] [ [ 2-fluoro-5- (trifluoromethyl) -phenyl ] methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [3- (phenoxy) phenyl ] [ [ 2-fluoro-5- (trifluoromethyl) phenyl ] methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [3- [3- (N, N-dimethylamino, phenoxy ] phenyl ] [ [ 2-fluoro-5- (trifluoromethyl) -phenyl ] methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [ [ 2-fluoro-5- (trifluoromethyl) phenyl ] methyl ] [3- [ [3- (trifluoromethoxy) -phenyl ] methoxy ] phenyl ] amino ] -1, 1, 1-trifluoro-3-propanol;

(2R) -3- [ [ [ 2-fluoro-5- (trifluoromethyl) phenyl ] methyl ] [3- [ [3- (trifluoromethyl) -phenyl ] methoxy ] phenyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [ [ 2-fluoro-5- (trifluoromethyl) phenyl ] methyl ] [3- [ [3, 5-dimethylphenyl ] -methoxy ] phenyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [ [ 2-fluoro-5- (trifluoromethyl) phenyl ] methyl ] [3- [ [3- (trifluoromethylthio) -phenyl ] methoxy ] phenyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [ [ 2-fluoro-5- (trifluoromethyl) phenyl ] methyl ] [3- [ [3, 5-difluorophenyl ] -methoxy ] phenyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [ [ 2-fluoro-5- (trifluoromethyl) phenyl ] methyl ] [3- [ cyclohexylmethoxy 1-phenyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [3- (2-difluoromethoxy-4-pyridinyloxy) phenyl ] [ [ 2-fluoro-5- (trifluoromethyl) -phenyl ] methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [3- (2-trifluoromethyl-4-pyridinyloxy) phenyl ] [ [ 2-fluoro-5- (trifluoromethyl) -phenyl ] methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [3- (3-difluoromethoxyphenoxy) phenyl ] [ [ 2-fluoro-5- (trifluoromethyl) -phenyl ] methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [ [3- (3-trifluoromethylthio) phenoxy ] phenyl ] [ [ 2-fluoro-5- (trifluoromethyl) -phenyl ] methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [3- (4-chloro-3-trifluoromethylphenoxy) phenyl ] [ [ 2-fluoro-5- (trifluoro-methyl) phenyl ] methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [3- (3-trifluoromethoxy-phenoxy) phenyl ] [ [ 2-fluoro-4- (trifluoromethyl) -phenyl ] methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [3- (3-isopropylphenoxy) phenyl ] [ [ 2-fluoro-4- (trifluoromethyl) phenyl ] -methyl ] amino ]1-1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [3- (3-cyclopropylphenoxy) phenyl ] [ [ 2-fluoro-4- (trifluoromethyl) phenyl ] -methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [3- (3- (2-furanyl) phenoxy) phenyl ] [ [ 2-fluoro-4- (trifluoromethyl) phenyl ] -methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [3- (2, 3-dichlorophenoxy) phenyl ] [ [ 2-fluoro-4- (trifluoromethyl) phenyl ] -methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [3- (4-fluorophenoxy) phenyl ] [ [ 2-fluoro-4- (trifluoromethyl) phenyl ] -methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [3- (4-methylphenoxy) phenyl ] [ [ 2-fluoro-4- (trifluoromethyl) phenyl ] -methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [3- (2-fluoro-5-bromophenoxy) phenyl ] [ [ 2-fluoro-4- (trifluoromethyl) -phenyl ] methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [3- (4-chloro-3-ethylphenoxy) phenyl ] [ [ 2-fluoro-4- (trifluoromethyl) -phenyl ] methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [3- [3- (1, 1, 2, 2-tetrafluoroethoxy) phenoxy ] phenyl ]

[ [ 2-fluoro-4- (trifluoromethyl) phenyl ] methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [3- [3- (pentafluoroethyl) phenoxy ] phenyl ] [ [ 2-fluoro-4- (trifluoromethyl) -phenyl ] methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [3- (3, 5-dimethylphenoxy) phenyl ] [ [ 2-fluoro-4- (trifluoromethyl) phenyl ] -methyl ] amino 1-1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [3- (3-ethylphenoxy) phenyl ] [ [ 2-fluoro-4- (trifluoromethyl) phenyl ] methyl ] -amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [3- (3-tert-butylphenoxy) phenyl ] [ [ 2-fluoro-4- (trifluoromethyl) phenyl ] methyl ] -amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [3- (3-methylphenoxy) phenyl ] [ [ 2-fluoro-4- (trifluoromethyl) phenyl ] methyl ] -amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [3- (5, 6, 7, 8-tetrahydro-2-naphthyloxy) phenyl ] [ [ 2-fluoro-4- (trifluoromethyl) -phenyl ] methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [3- (phenoxy) phenyl ] [ [ 2-fluoro-4- (trifluoromethyl) phenyl ] methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [3- [3- (N, N-dimethylamino) phenoxy ] phenyl ] [ [ 2-fluoro-4- (trifluoromethyl) -phenyl ] methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [ [ 2-fluoro-4- (trifluoromethyl) phenyl ] methyl ] [3- [ [3- (trifluoromethoxy) phenyl ] methoxy ] phenyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(3R) -3- [ [ [ 2-fluoro-4- (trifluoromethyl) phenyl ] methyl ] [3- [ [3- (trifluoromethyl) phenyl ] methoxy ] phenyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [ [ 2-fluoro-4- (trifluoromethyl) phenyl ] methyl ] [3- [ [3, 5-dimethylphenyl ] -methoxy ] phenyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [ [ 2-fluoro-4- (trifluoromethyl) phenyl ] methyl ] [3- [ [3- (trifluoromethylthio) -phenyl ] methoxy ] phenyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [ [ 2-fluoro-4- (trifluoromethyl) phenyl ] methyl ] [3- [ [3, 5-difluorophenyl ] -methoxy ] phenyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [ [ 2-fluoro-4- (trifluoromethyl) phenyl ] methyl ] [3- [ cyclohexylmethoxy ] -phenyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [3- (2-difluoromethoxy-4-pyridinyloxy) phenyl ] [ [ 2-fluoro-4- (trifluoromethyl) -phenyl ] methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [3- (2-trifluoromethyl-4-pyridinyloxy) phenyl ] [ [ 2-fluoro-4- (trifluoromethyl) -phenyl ] methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [3- (3-difluoromethoxyphenoxy) phenyl ] [ [ 2-fluoro-4- (trifluoromethyl) -phenyl ] methyl ] amino ] -1, 1, 1-trifluoro-2-propanol;

(2R) -3- [ [ [3- (3-trifluoromethylthio) phenoxy ] phenyl ] [ [ 2-fluoro-4- (trifluoromethyl) -phenyl ] methyl ] amino ] -1, 1, 1-trifluoro-2-propanol; and

(2R) -3- [ [3- (4-chloro-3-trifluoromethylphenoxy) phenyl ] [ [ 2-fluoro-4- (trifluoromethyl) phenyl ] methyl ] amino ] -1, 1, 1-trifluoro-2-propanol.

Another class of CETP inhibitors useful in the present invention consists of quinolines of the formula XVII

Formula XVII

And pharmaceutically acceptable forms thereof, wherein:

A_XVIIrepresents an aryl group containing 6 to 10 carbon atoms, optionally substituted with up to 5 identical or different substituents, halogen, nitro, hydroxy, trifluoromethylA group, trifluoromethoxy or straight-chain or branched alkyl, acyl, hydroxyalkyl or alkoxy, each containing up to 7 carbon atoms, or is of the formula-NR_XVII-4R_XVII-5In the form of (1), wherein

R_XVII-4And R_XVII-5Identical or different and denotes hydrogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms,

D_XVIIrepresents an aryl group containing 6 to 10 carbon atoms, optionally substituted by phenyl, nitro, halogen, trifluoromethyl or trifluoromethoxy, or a group of the formula

R_XVII-6——L_XVII——，

Or R_XVII10-T_XVII-V_XVII-X_XVII-

Wherein

R_XVII-6、R_XVII-7、R_XVII-10Represents, independently of one another, cycloalkyl having 3 to 6 carbon atoms, or an aryl having 6 to 10 carbon atoms or a 5-to 7-membered, optionally benzo-fused, saturated or unsaturated, mono-, di-or tricyclic heterocycle having up to 4 heteroatoms from the group S, N and/or O, wherein the ring is optionally substituted, in the case of the nitrogen-containing ring, also by N, with up to 5 identical or different substituents, halogen, trifluoromethyl, nitro, hydroxyl, cyano, carboxyl, trifluoromethoxy, straight-chain or branched acyl, alkyl, alkylthio, alkylalkoxy, alkoxy or alkoxycarbonyl having up to 6 carbon atoms in each case, aryl or trifluoromethyl-substituted aryl having 6 to 10 carbon atoms in each case, or an optionally benzo-fused, aromatic 5-to 7-membered heterocycle having up to 3 heteroatoms from the group S, N and/OR O heteroatoms, and/OR of the formula-OR _XVII-11、-SR_XVII-12、-SO₂R_XVII-13or-NR_XVII-14R_XVII-15A group of (a);

R_XVII-11、R_XVII-12and R_XVII-13Which independently of one another, an aryl group having 6 to 10 carbon atoms, which is further substituted by up to 2 identical or different substituents, which are phenyl, halogen or straight-chain or branched alkyl having up to 6 carbon atoms,

R_XVII-14and R_XVII ^-15Identical or different and having R given above_XVII-4And R_XVII-5Has the meaning of, or

R_XVII-6And/or R_XVII-7Represents a group of the formula

R_XVII-8Represents hydrogen or halogen, and

R_XVII-9represents hydrogen, halogen, azido, trifluoromethyl, hydroxyl, trifluoromethoxy, straight-chain or branched alkoxy or alkyl each containing up to 6 carbon atoms, or of the formula NR_XVII-16R_XVII-17A group of (a);

R_XVII-16and R_XVII-17Identical or different and have the abovementioned R_XVII-4And R_XVII-5The meaning of (a); or

R_XVII-8And R_XVII-9Together form a group of formula ═ O or ═ NR_XVII-18；

R_XVII-18Represents hydrogen or a linear or branched alkyl, alkoxy or acyl radical each containing up to 6 carbon atoms;

L_XVIIrepresents a linear or branched alkylene or alkenylene chain each containing up to 8 carbon atoms, optionally substituted with up to 2 hydroxyl groups;

T_XVIIand X_XVIIIdentical or different and representing straight-chain or branchedThe alkylene chain contains up to 8 carbon atoms; or

T_XVIIAnd X_XVIIRepresents a chemical bond;

V_XVIIrepresents an oxygen or sulfur atom or-NR_XVII-19；

R_XVII-19Represents hydrogen or a linear or branched alkyl group containing up to 6 carbon atoms or a phenyl group;

E_XVIIRepresents cycloalkyl containing 3 to 8 carbon atoms, or straight or branched alkyl containing up to 8 carbon atoms, optionally substituted cycloalkyl containing 3 to 8 carbon atoms or hydroxy, or phenyl, optionally substituted by halogen or trifluoromethyl;

R_XVII-1and R_XVII-2Identical or different and denotes cycloalkyl having 3 to 8 carbon atoms, hydrogen, nitro, halogen, trifluoromethyl, trifluoromethoxy, carboxyl, hydroxyl, cyano, a straight-chain or branched acyl, alkoxycarbonyl or alkoxy having up to 6 carbon atoms, or NR_XVII-20R_XVII-21；

R_XVII-20And R_XVII-21Identical or different and represent hydrogen, phenyl, or linear or branched alkyl having up to 6 carbon atoms; and or

R_XVII-1And/or R_XVII-2Is a linear or branched alkyl group having up to 6 carbon atoms, optionally substituted by halogen, trifluoromethoxy, hydroxy, or a linear or branched alkoxy group having up to 4 carbon atoms, an aryl group comprising 6 to 10 carbon atoms optionally substituted with up to 5 identical or different substituents selected from the group consisting of halogen, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, nitro, linear or branched alkyl, acyl, hydroxyalkyl, alkoxy having up to 7 carbon atoms and NR_XVII-22R_XVII-23；

R_XVII-22And R_XVII-23Identical or different and represent hydrogen, phenyl or straight-chain or branched alkyl of up to 6 carbon atoms; and/or

R_XVII-1And R_XVII-2Combined together to form a linear or branched alkene or alkane having up to 6 carbon atoms, optionally substituted with halogen, trifluoromethyl, hydroxy or a linear or branched alkoxy group having up to 5 carbon atoms;

R_XVII-3represents hydrogen, a linear OR branched acyl radical having up to 20 carbon atoms, a benzoyl radical, optionally substituted by halogen, trifluoromethyl, nitro OR trifluoromethoxy, a linear OR branched fluoroacyl radical having up to 8 carbon atoms and 7 fluorine atoms, a cycloalkyl radical having 3 to 7 carbon atoms, a linear OR branched alkyl radical having up to 8 carbon atoms, optionally substituted by hydroxyl, a linear OR branched alkoxy radical having up to 6 carbon atoms, optionally substituted by phenyl, which may be further substituted by halogen, nitro, trifluoromethyl, trifluoromethoxy OR phenyl OR tetrazole, and/OR a phenyl radical, optionally substituted by the formula-OR_XVII-24A substituted alkyl group;

R_XVII-24straight or branched acyl or benzyl of up to 4 carbon atoms.

Compounds of formula XVII are disclosed in WO98/39299, the entire disclosure of which is incorporated herein by reference.

Another class of CETP inhibitors useful in the present invention consists of 4-phenyltetrahydroquinolines of formula XVIII

Formula XVIII

An N-oxide thereof, and pharmaceutically acceptable forms thereof, wherein:

A_XVIIIRepresents phenyl, optionally substituted by up to 2 identical or different substituents, halogen, trifluoromethyl or straight-chain or branched alkyl or alkoxy having up to 3 carbon atoms;

D_XVIIIrepresented by the formula

Or R_XVIII-8-CH₂-O-CH₂-；

R_XVIII-5And R_XVIII-6May together form ═ O; or

R_XVIII-5Represents hydrogen and R_XVIII-6Represents halogen or hydrogen; or

R_XVIII-5And R_XVIII-6Represents hydrogen;

R_XVIII-7and R_XVIII-8Identical or different and denotes phenyl, naphthyl, benzothiazolyl, quinolinyl, pyrimidinyl or pyridyl, having up to 4 identical or different substituents selected from the group consisting of halogen, trifluoromethyl, nitro, cyano, trifluoromethoxy, -SO₂-CH₃Or NR_XVIII-9R_XVIII-10；

R_XVIII-9And R_XVIII-10 are identical or different and represent hydrogen or a linear or branched alkyl group of up to 3 carbon atoms;

E_XVIIIrepresents a cycloalkyl group of 3 to 6 carbon atoms or a straight or branched alkyl group of up to 8 carbon atoms;

R_XVIII-1represents a hydroxyl group;

R_XVIII-2represents hydrogen or methyl;

R_XVIII-3and R_XVIII-4Identical or different and represent a linear or branched alkyl group of up to 3 carbon atoms; or

R_XVIII-3And R_XVIII-4Together form an alkenylene group of 2 to 4 carbon atoms.

The compounds of formula XVIII are disclosed in WO99/15504, the entire disclosure of which is incorporated by reference.

Another class of CETP inhibitors useful in the present invention consists of aminoethanol derivatives of formula XIX

Formula XIX

And pharmaceutically acceptable forms thereof, wherein:

Ar_XIX-1represents an aromatic ring group which may contain a substituent;

Ar_XIX-2represents an aromatic ring group which may contain a substituent;

R_XIXrepresents an acyl group;

R’_XIXrepresents a hydrogen atom or a hydrocarbon group which may contain a substituent; and

OR”_XIXrepresents a hydroxyl group which may be protected.

Compounds of formula XIX are disclosed in WO2002/059077, the entire disclosure of which is incorporated herein by reference.

In a preferred embodiment, the CETP inhibitor is selected from the following compounds of formula XIX or salts thereof:

n- [ (1RS, 2SR) -2- (4-fluorophenyl) -2-hydroxy-1- [4- (trifluoromethyl) benzyl ] ethyl ] -6, 7-dihydro-5H-benzo [ a ] cyclopentene-1-carboxamide,

4-fluoro-N- ((1R, 2S) -2- (4-fluorophenyl) -2-hydroxy-1- ((4- (trifluoromethyl) phenyl) methyl) ethyl) -1-naphthamide;

n- [ (1R, 2S) -2- (4-fluorophenyl) -2-hydroxy-1- [3- (1, 1, 2, 2-tetrafluoroethoxy) benzyl ] ethyl ] -6, 7-dihydro-5H-benzo [ a ] cyclopentene-1-carboxamide;

n- [ (1RS, 2SR) -2- (4-fluorophenyl) -2-hydroxy-1- [3- (1, 1, 2, 2-tetrafluoroethoxy) benzyl ] ethyl ] -5, 6-dihydronaphthalene-1-carboxamide;

n- [ (1RS, 2SR) -2- (4-fluorophenyl) -2-hydroxy-1- [3- (1, 1, 2, 2-tetrafluoroethoxy) benzyl ] ethyl ] -6, 7, 8, 9-tetrahydro-5H-benzo [ a ] cycloheptene-1-carboxamide;

4-fluoro-N- [ (1R, 2S) -2- (4-fluorophenyl) -2-hydroxy-1- [3- (1, 1, 2, 2-tetrafluoroethoxy) benzyl ] ethyl ] naphthalene-1-carboxamide;

n- [ (1RS, 2SR) -2- (4-fluorophenyl) -2-hydroxy-1- [3- (1, 1, 2, 2-tetrafluoroethoxy) benzyl ] ethyl ] -5, 6, 7, 8-tetrahydrobenzo [ a ] cyclooctene-1-carboxamide;

n- [ (1RS, 2SR) -2- (4-fluorophenyl) -2-hydroxy-1- (4-isopropylbenzyl) ethyl ] -6, 7-dihydro-5H-benzo [ a ] cycloheptene-1-carboxamide;

n- ((1RS, 2SR) -2- (3-fluorophenyl) -2-hydroxy-1- ((4- (trifluoromethyl) phenyl) methyl) ethyl) -6, 7-dihydro-5H-benzo [ a ] cycloheptene-1-carboxamide;

n- ((1RS, 2SR) -2-hydroxy-2- (4-phenoxyphenyl) -1- ((4- (trifluoromethyl) phenyl) methyl) ethyl) -6, 7-dihydro-5H-benzo [ a ] cycloheptene-1-carboxamide;

n- [ (1RS, 2SR) -2- (4-chlorophenyl) -2-hydroxy-1- [3- (1, 1, 2, 2-tetrafluoroethoxy) benzyl) ethyl) -6, 7-dihydro-5H-benzo [ a ] cycloheptene-1-carboxamide;

n- ((1RS, 2SR) -2-hydroxy-2- (4-phenoxy) phenyl) -1- ((3- ((1, 1, 2, 2-tetrafluoroethyl) oxy) phenyl) methyl) ethyl) -6, 7-dihydro-5H-benzo [ a ] cycloheptene-1-carboxamide;

n- ((1RS, 2SR) -2- (4- ((4-chloro-3-ethylphenyl) oxy) phenyl) -2-hydroxy-1- ((3- ((1, 1, 2, 2-tetrafluoroethyl) oxy) phenyl) methyl) ethyl) -6, 7-dihydro-5H-benzo [ a ] cycloheptene-1-carboxamide;

N- ((1RS, 2SR) -2- (2-fluoropyridin-4-yl) -2-hydroxy-1- ((3- ((1, 1, 2, 2-tetrafluoroethoxy) phenyl) methyl) ethyl) -6, 7-dihydro-5H-benzo [ a ] cycloheptene-1-carboxamide;

n- ((1RS, 2RS) -2- (6-fluoropyridin-2-yl) -2-hydroxy-1- ((3- ((1, 1, 2, 2-tetrafluoroethoxy) phenyl) methyl) ethyl) -6, 7-dihydro-5H-benzo [ a ] cycloheptene-1-carboxamide;

n- [ (1RS, 2SR) -1- (4-tert-butylbenzyl) -2- (3-chlorophenyl) -2-hydroxyethyl ] -5-chloro-1-naphthamide;

4-fluoro-N- { (1RS, 2SR) -2- (4-fluorophenyl) -2-hydroxy-1- [ (2, 2, 3, 3-tetrafluoro-2, 3-dihydro-1, 4-benzodioxin-6-yl) methyl ] ethyl } -1-naphthamide.

In a preferred embodiment, the CETP inhibitor is [2R, 4S ] -4- [ (3, 5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino ] -2-ethyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester, also known as torcetrapib. Torcetrapib is shown by the following structural formula

CETP inhibitors, particularly torcetrapib, and methods of making the compounds are disclosed in detail in U.S. Pat. Nos. 6,197,786 and 6,313,142, PCT application Nos. WO 01/40190A1, WO02/088085A2, and WO 02/088069A2, the disclosures of which are incorporated herein by reference. Torcetrapib has unusually low solubility in lumenal fluids in aqueous environments such as the human GI tract. The solubility in water of Torcetrapib is less than about 0.04. mu.g/ml. Torcetrapib must be present in the GI tract in a solubility-improved form to achieve sufficient drug concentration in the GI tract to achieve sufficient absorption into the blood to elicit the desired therapeutic effect.

Solubility-improved forms

The solubility-improved form of the CETP inhibitor is any form that is supersaturated in an aqueous use environment and that, at least temporarily, increases the solubility of the CETP inhibitor by about 1.25-fold or more relative to crystalline CETP. That is, the solubility-improved form provides a drug concentration (MDC) that provides maximum dissolution of the CETP inhibitor in the use environment that is at least 1.25-fold the equilibrium drug concentration provided by the CETP inhibitor in its crystalline form alone. Preferably, the solubility-improved form increases the MDC of the CETP inhibitor in aqueous solution by at least 2-fold, more preferably at least 3-fold, and more preferably at least 5-fold, relative to a control composition. Surprisingly, the solubility-improved form can achieve a great increase in concentration in water. In some cases, the solubility-improved form provides an MDC of the CETP inhibitor that is at least 10-fold, at least 50-fold, at least 200-fold, at least 500-fold, to over 1000-fold that of the control.

Alternatively, the solubility-improved form provides an area under the concentration versus time curve ("AUC") of the drug in the use environment that is at least 1.25-fold that provided by the control composition. AUC is the integral of drug concentration plotted against time. AUC is determined by plotting drug concentration versus time in a test solution when the use environment is in vitro or in vivo, for an in vivo test, in an in vivo use environment (e.g., the GI tract of an animal). Calculation of AUC is a well-known procedure in the pharmaceutical arts and is described, for example, in Welling, "pharmaceutical Methods and materials," ACSMonograph 185 (1986). More specifically, in a use environment, the CETP inhibitor in a solubility-improved form, upon introduction to the use environment, provides an AUC over any 90-minute period from about 0 to about 270 minutes that is at least 1.25-fold that of the control composition. The control composition is the conventional lowest-energy crystalline form of the CETP inhibitor alone, without any solubilizing additives. It is understood that the control composition has no co-solvent or other ingredient that substantially affects the solubility of the CETP inhibitor, and that the CETP inhibitor is in the form of a solid in the control composition. The control composition is conventionally the lowest energy or most stable crystalline form of the CETP inhibitor alone, hereinafter and in the claims referred to as the "raw crystalline form (butk crustaline form)". Preferably, the solubility-improved form provides an AUC that is at least 2-fold, more preferably at least 3-fold, greater than the AUC provided by the control composition. For some CETP inhibitors, the solubility-improved form may provide AUC values that are at least 5-fold, at least 25-fold, at least 100-fold, and even more than 250-fold greater than the AUC values provided by the controls described above.

The solubility-improved form can comprise a solid amorphous dispersion of the CETP inhibitor in a concentration-enhancing polymer or a low molecular weight water-soluble material. Solid amorphous dispersions of a CETP inhibitor and a concentration-enhancing polymer are more fully disclosed in commonly assigned U.S. patent application No. 09/918,127 filed on 30.7.2001, and U.S. patent application No. 10/066,091 filed on 1.2.2002, both of which are incorporated herein by reference. Alternatively, the solubility-improved form may comprise an amorphous CETP inhibitor. The solubility-improved form may comprise nanoparticles, i.e., solid CETP inhibitor particles having a diameter of less than about 900nm, optionally stabilized by a small amount of surfactant or polymerization, as described in US patent 5,145,684. The solubility-improved form may include adsorbates of CETP inhibitors in cross-linked polymers, as described in US patent 5,225,192. The solubility-improved form may comprise a nanosuspension, which is a dispersion of a solid-in-liquid or a solid-in-semi-solid, the dispersed phase comprising a neat CETP inhibitor or mixture of CETP inhibitors, as described in U.S. patent No. 5,858,410. The solubility-improved form may include a CETP inhibitor in a supercooled form, as described in us patent 6,197,349. Solubility-improving forms may include CETP inhibitor/cyclodextrin forms, including those described in U.S. Pat. nos. 5,134,127, 6,046,177, 5,874,418, and 5,376,645. Solubility-improving forms can include soft gel forms, such as mixtures of a CETP inhibitor with a lipid or colloidal protein (e.g., gelatin), including those disclosed in U.S. Pat. nos. 5,851,275, 5,834,022, and 5,686,133. Solubility-improving forms may include self-emulsifying forms, including those disclosed in U.S. Pat. nos. 6,054,136 and 5,993,858. Solubility-improving forms may include three-phase pharmaceutical forms, including those described in U.S. patent No. 6,042,847. The solubility-improving forms described above may also be blended with a concentration-enhancing polymer to provide improved solubility enhancement, as disclosed in commonly assigned U.S. patent application No. 10/176,462 filed 6/20 of 2002, which is incorporated by reference in its entirety. The solubility-improved form may also include (1) a crystalline highly soluble form of a CETP inhibitor such as a salt; (2) a CETP inhibitor in a high energy crystalline form; (3) a hydrate or solvate crystalline form of a CETP inhibitor; (4) amorphous forms of the CETP inhibitor (for CETP inhibitors that may exist in amorphous or crystalline forms); (5) a mixture of a CETP inhibitor (amorphous or crystalline) and a solubilizer; or (6) a solution of the CETP inhibitor dissolved in an aqueous or organic liquid. The solubility-improving forms described above may also be blended with a concentration-enhancing polymer to provide improved solubility enhancement, as disclosed in commonly assigned co-assigned U.S. patent application No. 09/742,785 filed on even 12-20.2000, which is incorporated by reference in its entirety. The solubility-improved form can also include (a) a solid dispersion comprising a CETP inhibitor and a matrix, wherein at least a majority of the CETP inhibitor in the dispersion is in amorphous form; and (b) a concentration-enhancing polymer, as disclosed in commonly assigned U.S. provisional patent application No. 60/300,261 filed on 6/22 of 2001, which is incorporated by reference in its entirety. The solubility-improved form may also include a solid adsorbate comprising a low-solubility CETP inhibitor adsorbed onto a substrate, the substrate having a surface area of at least 20m2/g, and wherein at least a majority of the CETP inhibitor in the solid adsorbate is in amorphous form. The solid adsorbate may optionally comprise a concentration-enhancing polymer. The solid adsorbate may also be mixed with a concentration-enhancing polymer. The solid adsorbate is disclosed in commonly assigned co-pending U.S. patent application No. filed on day 6,17, 2002, which is incorporated by reference in its entirety. The solubility-improved form may also include a CETP inhibitor formulated in a lipid carrier, of the type disclosed in commonly assigned co-pending U.S. patent application No. 10/175,643, 7/19/2002, which is also incorporated herein by reference.

The aqueous use environment can be an in vivo environment, such as the GI tract of an animal, particularly a human, or an in vitro environment of a test solution, such as a Phosphate Buffered Saline (PBS) solution or a fasted duodenal Model (MFD) solution.

The solubility-improved form of CETP inhibitor used in the dosage forms of the present invention provides an increased concentration of dissolved CETP inhibitor in an in vitro dissolution test. Has been determined to dissolve in MFDIncreased drug concentration in solution or in an in vitro dissolution test in PBS solution is a good indicator of in vivo performance as well as bioavailability. A suitable PBS solution is an aqueous solution comprising 20mM Na₂HPO₄，47mMKH2PO₄87mM NaCl, and 0.2mM KCl, adjusted to pH 6.5 with NaOH. A suitable MFD solution is the same PBS solution in which 7.3mM sodium taurocholate and 1.4mM 1-palmitoyl-2-oleyl-sn-glycero-3-phosphocholine are also present. Specifically, a solubility-improved form of a CETP inhibitor can be subjected to a dissolution-test by adding it to MFD or PBS solution and agitating to facilitate dissolution.

In vitro tests to assess increased CETP inhibitor concentration in aqueous solution can be carried out by (1) adding a sufficient amount of a control composition, i.e., the CETP inhibitor in crystalline form from the starting material alone, to an in vitro test vehicle, such as MFD or PBS solution, with agitation to achieve an equilibrium concentration of CETP inhibitor; (2) adding a sufficient amount of the test composition (e.g., a solubility-improved form of the CETP inhibitor) to the same test vehicle under agitation in a separate test such that if the CETP inhibitor is dissolved, the theoretical concentration of the CETP inhibitor will exceed the equilibrium concentration of the CETP inhibitor by at least 2, and preferably by at least 10-fold; and (3) comparing the MDC and/or aqueous AUC of the test composition measured in the test vehicle with the equilibrium concentration of the control composition, and/or aqueous AUC. The test or control compositions were used in the dissolution test described in the following amounts: if all of the CETP inhibitor is dissolved, the CETP inhibitor concentration is at least 2-fold, and preferably at least 100-fold, the equilibrium concentration. In fact, for some extremely insoluble CETP inhibitors, in order to determine the MDC achieved, it is necessary to use the amount of test composition that satisfies the following conditions: if all CETP inhibitor is solubilized, the CETP inhibitor concentration is 1000-fold or even more than the equilibrium concentration of CETP inhibitor.

The concentration of dissolved CETP inhibitor is typically measured for different time points, the test vehicle is sampled and the CETP inhibitor concentration in the test vehicle is plotted against time to determine the MDC. MDC is the dissolved CETP inhibitor maximum selected from measurements during the test. AUC in water was calculated as follows: the composition is introduced into the aqueous use environment (when time equals 0) and the integrated concentration-time curve is integrated over any 90 minutes during 270 minutes (when time equals 270 minutes) following introduction into the use environment. Typically, the time interval for calculating the AUC is from 0 to a time equal to 90 minutes when the composition reaches its MDC quickly, e.g., less than about 30 minutes. However, if the AUC of the composition over any of the above 90-minute periods meets the criteria of the present invention, the resulting composition is considered to be within the scope of the present invention.

To avoid large CETP inhibitor particles causing false assays, the test solution is either filtered or centrifuged. "solubilized drug" is generally understood to be either material that passes through a 0.45 μm syringe filter or material that remains in the supernatant after centrifugation. Filtration can be carried out using a 13mm, 0.45 μm, polyvinylidene fluoride syringe filter sold under the trademark TITAN ® by Scientific Resources. Centrifugation is typically performed using polypropylene microcentrifuge tubes at 13,000G for 60 seconds. Other similar filtration or centrifugation methods may be employed and useful results obtained. For example, results somewhat higher or lower (± 10-40%) than those obtained with the filters described above may be obtained with other types of microfilters, but preferred dispersions may still be identified.

Alternatively, the CETP inhibitor in a solubility-improved form, when orally administered to a human or other animal, provides an AUC for CETP inhibitor concentration in blood (serum or plasma) that is at least about 1.25-fold, preferably at least about 2-fold, preferably at least about 3-fold, preferably at least about 4-fold, preferably at least about 6-fold, preferably at least about 10-fold, and even more preferably at least about 20-fold greater than the AUC observed for a control composition consisting of an equivalent amount of the starting crystalline form of the CETP inhibitor. It should be noted that the compositions can also have a relative bioavailability of about 1.25-fold to about 20-fold that of the control composition.

The relative bioavailability of the CETP inhibitor in its solubility-improved form can be determined using in vivo testing in animals or humans using conventional methods. In vivo tests, such as crossover studies, can be used to determine whether a composition of a CETP inhibitor in a solubility-improved form provides increased relative bioavailability as described above relative to a control composition. In an in vivo crossover study, a test composition of a CETP inhibitor in a solubility-improved form is administered to half of the test subjects, and, after a suitable wash period (e.g., one week), the same subjects are administered a control composition consisting of an equivalent amount (as the test composition) of the crystalline CETP inhibitor. The other half was administered first with the control composition and then with the test composition. Relative bioavailability is measured as the area under the curve (AUC) of blood (serum or plasma) concentration versus time determined for the test group divided by the AUC in blood provided by the control composition. Preferably, such test/control ratios are determined for each subject, and then the ratios are averaged over all subjects in the study. The in vivo measurement of AUC can be performed as follows: serum or plasma concentrations of the drug are plotted along the ordinate (y-axis) against time along the abscissa (x-axis). To facilitate administration, the administration vehicle may be used to administer a pharmaceutical dosage. The administration vehicle is preferably water, but may also contain substances for suspending the test or control compositions, so long as the substances do not dissolve the composition or alter the in vivo solubility of the drug.

Solid amorphous dispersions of CETP inhibitors

In one embodiment, the solubility-improved form of the CETP inhibitor comprises a CETP inhibitor in a solid amorphous dispersion and a concentration-enhancing polymer. Solid amorphous dispersion refers to a solid substance wherein at least part of the CETP inhibitor is in amorphous form and is dispersed in the polymer. Preferably, at least a substantial portion of the CETP inhibitor is amorphous in the solid amorphous dispersion. By "amorphous" is simply meant that the CETP inhibitor is in an amorphous state. The term "majority" of the CETP inhibitor as used herein means that at least 60% of the CETP inhibitor is in amorphous form in a solid amorphous dispersion, rather than in crystalline form. Preferably, the CETP inhibitor is substantially amorphous in a solid amorphous dispersion. As used herein, "substantially amorphous" means that the amount of CETP inhibitor in crystalline form does not exceed about 25%. More preferably, the CETP inhibitor is "almost completely amorphous" in the dispersion, meaning that the amount of CETP inhibitor in crystalline form does not exceed about 10%. The amount of the crystallized CETP inhibitor can be measured using X-ray powder diffraction, Scanning Electron Microscope (SEM) analysis, Differential Scanning Calorimetry (DSC), or any other standard quantitative measurement.

The solid amorphous dispersion may contain from about 1 to about 80 wt% CETP inhibitor, depending on the dosage of CETP inhibitor and the effectiveness of the concentration-enhancing polymer. Enhancement of CETP inhibitor concentration and relative bioavailability in water is generally best at low CETP inhibitor levels, typically less than about 25 to 40 wt%. However, due to practical limitations on dosage form size, higher CETP inhibitor levels are often preferred and in many cases perform well.

The amorphous CETP inhibitor may be present in the solid amorphous dispersion in the form of relatively pure amorphous drug domains, as a solid solution with the drug homogeneously distributed throughout the polymer, or any combination thereof intermediate these states and those states. The solid amorphous dispersion is preferably substantially homogeneous so that the amorphous CETP inhibitor is dispersed as uniformly as possible throughout the polymer. As used herein, "substantially homogeneous" means that the fraction of CETP inhibitor present in the relatively pure amorphous regions of the solid dispersion is relatively small, approaching less than 20%, preferably less than 10%, of the total amount of CETP inhibitor. Substantially homogeneous solid amorphous dispersions generally have greater physical stability, improved concentration-enhancing properties and inherently also high bioavailability relative to non-homogeneous dispersions.

In cases where the CETP inhibitor and the polymer have glass transition temperatures that deviate sufficiently (greater than about 20 ℃), the fraction of drug present as relatively pure amorphous drug domains in the solid amorphous dispersion can be determined by measuring the glass transition temperature (Tg) of the solid amorphous dispersion. As used herein, Tg is the characteristic temperature at which a glassy material undergoes a relatively rapid (e.g., 10 to 100 seconds) physical change from a glassy state to a rubbery state during gradual heating. The Tg of an amorphous material, such as a polymer, drug or dispersion, can be measured using several techniques, including a Dynamic Mechanical Analyzer (DMA), dilatometer, dielectric analyzer, and Differential Scanning Calorimeter (DSC). The exact values measured using various techniques may vary somewhat, but are typically 10 to 30 ℃ apart from each other. When the solid amorphous dispersion exhibits a single Tg, the amount of CETP inhibitor in the solid amorphous dispersion as a pure amorphous drug region is generally less than about 10 wt%, confirming that the solid amorphous dispersion is substantially homogeneous. This contrasts with a simple physical mixture of pure amorphous CETP inhibitor particles and pure amorphous polymer particles, which typically exhibit two distinct Tgs, one pharmaceutical and one polymeric. For solid amorphous dispersions exhibiting two distinct tgs, one approximating the Tg of the drug and the other being the remaining drug/polymer dispersion, at least a portion of the drug is present as relatively pure amorphous regions. The amount of CETP inhibitor present as a relatively pure amorphous drug domain can be determined as follows: a calibration standard of substantially uniform dispersion is first formulated to determine the relationship of the Tg of the solid amorphous dispersion to the drug loading in the dispersion. From these calibrated data, and the Tg of the drug/polymer dispersion, the fraction of CETP inhibitor in the region of relatively pure amorphous drug can be determined. Alternatively, the presence of CETP inhibitor in a relatively pure amorphous drug domain can be determined as follows: by comparing the heat capacity strengths for transformations near the drug Tg and with a calibration standard consisting essentially of a physical mixture of amorphous drug and polymer. In either case, a solid amorphous dispersion is considered substantially homogeneous if the fraction of CETP inhibitor present as relatively pure amorphous drug domains in the solid amorphous dispersion is less than 20 wt%, and preferably less than 10 wt% of the total amount of CETP inhibitor.

Concentration-enhancing polymers

Concentration-enhancing polymers suitable for use in the compositions of the present invention should be inert, that is, they do not adversely chemically react with the CETP inhibitor, pharmaceutically acceptable, and have at least some solubility in aqueous solution at physiologically relevant pH's (e.g., 1-8). The polymer may be neutral or ionizable and should have a water solubility of at least 0.1mg/ml over at least a portion of the pH range of 1-8.

The concentration-enhancing polymers suitable for use in the present invention may be cellulosic or non-cellulosic. The polymer may be neutral or ionizable in aqueous solution. Among them, ionizable and cellulose polymers are preferable, and ionizable cellulose polymers are more preferable.

A preferred class of polymers comprises polymers that are "amphiphilic" in nature, meaning that the polymers have both hydrophobic and hydrophilic portions. The hydrophobic portion may comprise an aliphatic or aromatic hydrocarbon group, or the like. The hydrophilic moiety may comprise an ionizable or nonionizable group, but capable of forming a hydrogen bond, such as a hydroxyl, carboxylic acid, ester, amine, or amide.

Amphiphilic and/or ionizable polymers are preferred because it is believed that such polymers may tend to have relatively strong interactions with CETP inhibitors, which may facilitate the formation of various types of polymer/drug assemblies in the environment of use, as previously described. In addition, the same charge repulsion of such polymeric ionized groups can serve to limit the size of the polymer/drug assemblies to the nanometer or submicron scale. For example, while not wishing to be bound by a particular theory, such polymer/drug assemblies may comprise hydrophobic CETP inhibitor clusters surrounded by a polymer, with the hydrophobic regions of the polymer directed inward toward the CETP inhibitor and the hydrophilic regions of the polymer directed outward toward the aqueous environment. Alternatively, depending on the specific chemistry of the CETP inhibitor, the ionizing functional group of the polymer may be associated with an ionic or polar group of the CETP inhibitor, for example, via ion-pair or hydrogen bonding. In the case of ionizable polymers, the hydrophilic regions of the polymer will include ionized functional groups. Such polymer/drug assemblies can closely resemble charged polymeric micelle-like structures in solution. In any event, regardless of the mechanism of action, such amphiphilic polymers, particularly ionizable cellulosic polymers, have been shown to increase the MDC and/or AUC of a CETP inhibitor in aqueous solution relative to a control composition lacking such polymers (described in commonly assigned US patent application No. 09/918,127, filed 7/31/2001, the disclosure of which is incorporated herein by reference).

Such amphiphilic polymers are surprisingly able to greatly enhance the maximum CETP inhibitor concentration obtained by a CETP inhibitor when administered to a use environment. In addition, such amphiphilic polymers interact with the CETP inhibitor to prevent precipitation or crystallization of the CETP inhibitor from solution, even if its concentration is substantially above its equilibrium concentration. Specifically, when the preferred composition is a solid amorphous dispersion of the CETP inhibitor and the concentration-enhancing polymer, the composition provides a greatly enhanced drug concentration, particularly when the dispersion is substantially homogeneous. The maximum drug concentration may be 10-fold, often greater than 50-fold, the equilibrium concentration of the crystalline CETP inhibitor. This enhanced CETP inhibitor concentration also inherently results in a substantial enhancement of the relative bioavailability of the CETP inhibitor.

One class of polymers suitable for use in the present invention comprises neutral, non-cellulosic polymers. Exemplary polymers include: vinyl polymers and copolymers having hydroxy, alkanoyloxy, and cyclic amido polyvinyl alcohol substituents having at least a portion of the repeating units in unhydrolyzed (vinyl acetate) form; polyvinyl alcohol polyvinyl acetate copolymers; polyvinylpyrrolidone; polyoxyethylene-polyoxypropylene copolymers, also known as poloxamers, and polyethylene polyvinyl alcohol copolymers.

Another class of polymers suitable for use in the present invention comprises ionizable non-cellulosic polymers. Exemplary polymers include: carboxylic acid-functionalized vinyl polymers, e.g. carboxylic acid-functionalized polyisobutenoates and carboxylic acid-functionalized polyacrylates, e.g. EUDRAGITS^®Manufactured by Rohm techninc, of Malden, Massachusetts; amine-functionalized polyacrylates and polymethacrylates; a protein; and carboxylic acid functionalized starches, such as starch glycolate.

Amphiphilic non-cellulosic polymers are copolymers of relatively hydrophilic and relatively hydrophobic monomers. Examples include copolymers of acrylates and methacrylates. Exemplary commercial products of this type of copolymer include EUDRAGITS, which are copolymers of methacrylates and acrylates, and PLURONICS, supplied by BASF, which is a polyoxyethylene-polyoxypropylene copolymer.

A preferred class of polymers comprises ionizable and neutral cellulosic polymers having at least one ester and/or ether linked substituent, wherein the polymer has a degree of substitution of at least 0.1 for each substituent.

It should be noted that in the polymer nomenclature used herein, the substituent attached to an ether before "cellulose" denotes the moiety attached to an ether group; for example, "ethyl cellulose benzoate" has an ethoxybenzoic acid substituent. Similarly, a substituent attached to an ester after "cellulose" represents a carboxylic acid ester; for example, in "cellulose phthalate," one carboxylic acid of each phthalate moiety is linked to the polymer as an ester while the other carboxylic acids are unreacted.

It should also be noted that polymer names such as "cellulose acetate phthalate" (CAP) refer to any family of cellulosic polymers in which acetate and phthalate groups are linked via ester bonds to a significant portion of the cellulosic polymer hydroxyl groups. Generally, the degree of substitution per substituent may range from 0.1 to 2.9, as long as the other criteria for the polymer are met. "degree of substitution" means the average number of three hydroxyl groups per saccharide repeat unit on the cellulose chain that have been substituted. For example, if all hydroxyl groups on the cellulose chain have been substituted with a phthalate, the degree of substitution of the phthalate is 3. Also included within each polymer family type are cellulosic polymers incorporating a minor amount of additional substituents that do not substantially alter the polymer properties.

Amphiphilic cellulose includes polymers in which any or all 3 of the hydroxyl substituents on the cellulose per saccharide repeat unit are substituted with at least one relatively hydrophobic substituent. The hydrophobic substituent may be essentially any substituent capable of rendering the cellulosic polymer essentially water insoluble if substituted to a sufficiently high degree or degree. The hydrophilic regions of the polymer can be those portions that are relatively unsubstituted, in that the unsubstituted hydroxyl groups are themselves relatively hydrophilic, or those regions that are substituted with hydrophilic substituents. Examples of hydrophobic substituents include alkyl groups attached to ethers, such as methyl, ethyl, propyl, butyl, and the like; or an ester-linked alkyl group such as acetate, propionate, butyrate, and the like; and aryl groups linked to ethers and/or esters, such as phenyl, benzoate or phenylate. Hydrophilic groups include non-ionizable groups attached to ethers or esters, such as the hydroxyalkyl substituents hydroxyethyl, hydroxypropyl, and alkyl ether groups, such as ethoxyethoxy or methoxyethoxy. Particularly preferred hydrophilic substituents are ionizable groups attached to ethers or esters, such as carboxylic acids, thiocarboxylic acids, substituted phenoxy groups, amines, phosphates or sulfonates.

One class of cellulosic polymers comprises neutral polymers, meaning that the polymers are substantially non-ionizable in aqueous solution. Such polymers contain non-ionizable substituents, which may be ether-linked or ester-linked. Examples of non-ionizable substituents attached to ethers include: alkyl groups such as methyl, ethyl, propyl, butyl, and the like; hydroxyalkyl groups such as hydroxymethyl, hydroxyethyl, hydroxypropyl, and the like; and aryl groups such as phenyl. Examples of non-ionizable substituents attached to esters include: alkyl groups such as acetate, propionate, butyrate, and the like; and aryl groups such as phenyl ether. However, when aryl groups are included, the polymer may need to include sufficient hydrophilic substituents so that the polymer has at least some aqueous solubility at any physiologically relevant pH of 1 to 8.

Exemplary non-ionizable polymers that can be used as the polymer include: hydroxypropyl methylcellulose acetate, hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, hydroxyethyl cellulose acetate, and hydroxyethyl ethylcellulose.

A preferred group of neutral cellulosic polymers are those that are amphiphilic. Exemplary polymers include hydroxypropyl methylcellulose and hydroxypropyl cellulose acetate, wherein the cellulosic repeat units have a relatively high number of methyl or acetate substituents, relative to unsubstituted hydroxyl or hydroxypropyl substituents, constituting hydrophobic regions, relative to other repeat units on the polymer. Neutral polymers suitable for use in the solid amorphous dispersions of the present invention are more fully disclosed in co-assigned co-pending U.S. patent application No. 10/175,132, filed 6/18/2002, which is incorporated herein by reference.

A preferred class of cellulosic polymers comprises polymers that are at least partially ionizable at physiologically relevant pH and that comprise at least one ionizable substituent, which may be ether-linked or ester-linked. Exemplary ether-linked ionizable substituents include: carboxylic acids such as acetic acid, propionic acid, benzoic acid, salicylic acid, alkoxybenzoic acids such as ethoxybenzoic acid or propoxybenzoic acid, various isomers of alkoxyphthalic acids such as ethoxyphthalic acid and ethoxyisophthalic acid, various isomers of alkoxynicotinic acids such as ethoxynicotinic acid, and various isomers of picolinic acid such as ethoxypicolinic acid, and the like; thiocarboxylic acids such as thioacetic acid; substituted phenoxy groups such as hydroxyphenoxy, etc.; amines such as aminoethoxy, diethylaminoethoxy, trimethylaminoethoxy and the like; phosphate esters, such as phosphate ester ethoxy; and sulfonates, such as sulfonate ethoxy. Exemplary ester-linked ionizable substituents include: carboxylic acids such as succinic acid esters, citric acid esters, phthalic acid esters, terephthalic acid esters, isophthalic acid esters, trimellitic acid esters, and various isomers of dipicolinic acid, and the like; thiocarboxylic acids such as thiosuccinate; substituted phenoxy groups, such as aminosalicylic acid; amines, such as natural or synthetic amino acids, e.g., alanine or phenylalanine; phosphates such as acetyl phosphate; and sulfonates, such as acetyl sulfonate. In order for the aromatic-substituted polymer to also have the requisite water solubility, it is also desirable to attach to the polymer groups that are sufficiently hydrophilic, such as hydroxypropyl or carboxylic acid functional groups, to impart water solubility to the polymer, at least at the pH at which any ionizable groups are ionized. In some instances, the aromatic group itself may be ionizable, such as a phthalate or trimellitate substituent.

Exemplary cellulosic polymers that at least partially ionize at physiologically relevant pH include: hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose succinate, hydroxypropyl cellulose acetate succinate, hydroxyethyl methylcellulose succinate, hydroxyethyl cellulose acetate succinate, hydroxypropyl methylcellulose phthalate, hydroxyethyl methylcellulose acetate succinate, hydroxyethyl methylcellulose phthalate, hydroxyethyl methylcellulose acetate phthalate, carboxyethylcellulose, carboxymethylcellulose, cellulose acetate phthalate, methylcellulose acetate phthalate, ethyl cellulose acetate phthalate, hydroxypropyl methylcellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate phthalate, hydroxypropyl methylcellulose acetate phthalate, hydroxypropyl methylcellulose, Cellulose propionate phthalate, hydroxypropyl cellulose butyrate phthalate, cellulose acetate trimellitate, methyl cellulose acetate trimellitate, ethyl cellulose acetate trimellitate, hydroxypropyl methyl cellulose acetate trimellitate, hydroxypropyl cellulose acetate trimellitate succinate, cellulose propionate trimellitate, cellulose butyrate trimellitate, cellulose acetate terephthalate, cellulose acetate isophthalate, cellulose acetate pyridine dicarboxylate, cellulose salicylate acetate, hydroxypropyl salicylate acetate, ethyl benzoate acetate, hydroxypropyl ethyl benzoate acetate, ethyl phthalate acetate, ethyl nicotinate acetate, and ethyl picolinate acetate.

Exemplary cellulosic polymers having hydrophilic and hydrophobic regions that satisfy the definition of amphiphilicity include polymers such as cellulose acetate phthalate and cellulose acetate trimellitate, where cellulosic repeat units having one or more acetate substituents are hydrophobic relative to those having no acetate substituents, or have one or more ionized phthalate or trimellitate substituents.

A particularly desirable subset of cellulosic ionizable polymers are those that have both carboxylic acid functional aromatic and alkylated substituents and are thus amphiphilic. Exemplary polymers include cellulose acetate phthalate, methyl cellulose acetate phthalate, ethyl cellulose acetate phthalate, hydroxypropyl methyl cellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate succinate, cellulose propionate phthalate, hydroxypropyl cellulose butyrate phthalate, cellulose acetate trimellitate, methyl cellulose acetate trimellitate, ethyl cellulose acetate trimellitate, hydroxypropyl methyl cellulose acetate trimellitate, hydroxypropyl cellulose acetate trimellitate succinate, cellulose propionate trimellitate, cellulose butyrate trimellitate, cellulose acetate terephthalate, hydroxypropyl cellulose acetate phthalate, hydroxypropyl, Cellulose acetate isophthalate, cellulose acetate pyridine dicarboxylate, cellulose salicylate acetate, hydroxypropyl salicylate acetate, ethyl benzoate acetate, hydroxypropyl ethyl benzoate acetate, ethyl phthalate acetate, ethyl nicotinate acetate, and ethyl picolinate acetate.

Another particularly desirable subset of cellulosic ionizable polymers are those having a non-aromatic carboxylate substituent. Exemplary polymers include hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose succinate, hydroxypropyl cellulose acetate succinate, hydroxyethyl methylcellulose succinate, and hydroxyethyl cellulose acetate succinate as well as carboxymethyl ethylcellulose.

As listed above, a wide range of polymers can be used to form dispersions of CETP inhibitors, but the present inventors have found that relatively hydrophobic polymers have shown the best performance, as evidenced by high MDC and AUC values. In particular, cellulosic polymers that are water insoluble in the non-ionized state but water soluble in the ionized state perform particularly well. A particular subclass of such polymers are the so-called "enteric" polymers, including, for example, certain grades of hydroxypropyl methylcellulose acetate phthalate and cellulose acetate trimellitate. Dispersions produced from such polymers generally exhibit a very large maximum drug concentration enhancement, in dissolution tests 50-fold to over 1000-fold over the crystalline drug controls. In addition, non-enteric grades of such polymers, as well as closely related cellulosic polymers, are expected to perform well because the physical properties are similar in the CETP inhibitor class.

Thus, particularly preferred polymers are hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose phthalate (HPMCP), Cellulose Acetate Phthalate (CAP), Cellulose Acetate Trimellitate (CAT), methylcellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate, cellulose acetate terephthalate, and cellulose acetate isophthalate. The most preferred polymers are hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, and cellulose acetate trimellitate and carboxymethyl ethylcellulose.

One particularly effective polymer for forming the dispersions of the present invention is carboxymethyl ethyl cellulose (CMEC). Dispersions prepared from CETP inhibitors and CMEC typically have high glass-transition temperatures at relatively high humidity due to the high glass-transition temperature of CMEC. As discussed below, the high Tgs results in a solid amorphous dispersion with excellent physical stability. In addition, CMEC has excellent chemical stability since all substituents on the CMEC are attached to the cellulose backbone via ether linkages. Furthermore, commercial grades of CMEC, as supplied by Freund Industrial Company, Limited (Tokyo, Japan), are amphiphilic, resulting in a high degree of concentration increase. Finally, hydrophobic CETP inhibitors typically have high solubility in CMEC to form physically stable dispersions with high drug loading.

A particularly effective concentration-enhancing polymer for use with CETP inhibitors is HPMCAS.

While specific polymers have been discussed as being suitable for use in the compositions of the present invention, blends of such polymers may also be suitable. Thus, the term "polymer" is meant to include blends of polymers in addition to a single class of polymers.

For best performance, especially over long term storage prior to use, it is preferred that the CETP inhibitor remains amorphous to the extent possible. The inventors have found that the best results are obtained as long as the glass transition temperature Tg of the amorphous CETP inhibitor material is substantially above the storage temperature of the composition. Specifically, it is preferred that the amorphous state CETP inhibitor has a Tg of at least 40 deg.C, preferably at least 60 deg.C. However, this is not always the case. For example, the Tg of torcetrapib is 30 ℃. With respect to those aspects of the invention wherein the composition is a solid, substantially amorphous dispersion of the CETP inhibitor in the concentration-enhancing polymer, it is preferred that the concentration-enhancing polymer have a Tg of at least 40 deg.C, preferably at least 70 deg.C, and more preferably greater than 100 deg.C. Exemplary high Tg polymers include HPMCAS, HPMCP, CAP, CAT, CMEC, and other celluloses having alkylated or aromatic substituents or both alkylated and aromatic substituents.

Another preferred class of polymers consists of neutralized acidic polymers. "neutralized acidic polymer" refers to any acidic polymer in which a substantial fraction of the "acidic moieties" or "acidic substituents" have been "neutralized", i.e., present in their deprotonated form. "acidic polymer" refers to any polymer having a substantial number of acidic groups. Typically, a substantial number of the acidic groups are greater than or equal to about 0.1 milliequivalents of acidic groups per gram of polymer. "acidic groups" include any functional group that is sufficiently acidic when contacted with or dissolved in water to at least partially donate hydrogen ions to the water and thereby increase the concentration of hydrogen ions. This definition includes any functional group or "substituent" when the functional group is covalently attached to a polymer having a pKa of less than about 10. Exemplary functional groups of this class that are included in the above description include carboxylic acid, thiocarboxylic acid, phosphoric acid, and phenolic groups, and sulfonic acids. The functional groups may constitute the main structure of the polymer, as in the case of polyacrylic acid, but are more commonly covalently linked to the backbone of the parent polymer and are therefore referred to as "substituents". The neutralized acidic polymer is described in more detail in co-assigned pending U.S. patent application No. 10/175,566 filed on 6/17/2002, entitled "pharmaceutical compositions of drugs and neutralized acidic polymers", the relevant disclosure of which is incorporated herein by reference.

In addition, the preferred polymers listed above are amphiphilic cellulosic polymers, which tend to have greater thickening properties relative to other polymers of the present invention. Those having ionizable substituents generally tend to perform best. In vitro tests, compositions with such polymers tend to have higher MDC and AUC values than compositions with other polymers of the invention.

Preparation of the Dispersion

Dispersions of CETP inhibitor and concentration-enhancing polymer may be prepared according to any known method that results in at least a majority (at least 60%) of the CETP inhibitor being in an amorphous state. The methods include mechanical, thermal, and solvent methods. Exemplary mechanical methods include milling and extrusion; the melting method comprises high-temperature melting, solvent modified melting and melting solidification; and solvent methods including non-solvent precipitation, spray coating, and spray drying. See, for example, the following U.S. patents, the relevant disclosures of which are incorporated herein by reference: patent nos. 5,456,923 and 5,939,099, which describe forming dispersions using an extrusion process; patent nos. 5,340,591 and 4,673,564, which describe the formation of dispersions using a milling process; and patent nos. 5,707,646 and 4,894,235, which describe forming dispersions using a melt congealing method.

When the CETP inhibitor has a relatively low melting point, typically less than about 200 deg.C and preferably less than about 150 deg.C, it is advantageous to use melt-congealing or melt-extrusion processes. In the process, the molten mixture comprising the CETP inhibitor and the concentration-enhancing polymer is rapidly cooled to solidify the molten mixture to form a solid amorphous dispersion. By "molten mixture" is meant a mixture comprising the CETP inhibitor and the concentration-enhancing polymer heated sufficiently to render it sufficiently liquid to substantially disperse the CETP inhibitor in the one or more concentration-enhancing polymers and other excipients. Typically, it is desirable to heat the mixture to about 10 ℃ or more above the melting point of the lowest melting excipient or CETP inhibitor in the composition. The CETP inhibitor may be present in the molten mixture as a neat phase, as a solution of the CETP inhibitor uniformly dispersed in the molten mixture, or any combination of these states or those intervening therebetween. The molten mixture is preferably substantially homogeneous so that the CETP inhibitor is as homogeneous as possible in the molten mixture. When the temperature of the molten mixture is below the melting points of both the CETP inhibitor and the concentration-enhancing polymer, the molten excipient, concentration-enhancing polymer, and CETP inhibitor are preferably sufficiently soluble in each other so that a substantial portion of the CETP inhibitor is dispersed in the concentration-enhancing polymer or excipient. It is generally preferred to heat the mixture above the lower melting point of the concentration-enhancing polymer and the CETP inhibitor. It should be noted that many concentration-enhancing polymers are amorphous. In such a case, the melting point refers to the softening point of the polymer. Thus, while the term "melting point" generally refers specifically to the temperature at which a crystalline material transforms from a crystalline to a liquid state, the term is used more broadly herein to refer to the heating of any material or mixture of materials sufficiently to cause it to become liquid, in a manner similar to how a crystalline material becomes liquid.

In general, the processing temperature can vary from 50 ℃ up to about 200 ℃ or higher depending on the melting point of the CETP inhibitor and the polymer, the latter being a function of the grade of polymer selected. However, the processing temperature should not be so high that: unacceptable levels of CETP inhibitor or polymer degradation occur. In some cases, the molten mixture should be formed in an inert atmosphere to prevent degradation of the CETP inhibitor and/or polymer at processing temperatures. When relatively high temperatures are used, it is generally preferred to minimize the reduction of the mixture at elevated temperatures to minimize degradation.

The molten mixture may also include excipients that lower the melting temperature of the molten mixture, thereby allowing processing at lower temperatures. When the excipient has low volatility and remains substantially in the mixture while solidifying, it can typically comprise up to 30% by weight of the melted mixture. For example, a plasticizer may be added to the mixture to lower the melting temperature of the polymer. Examples of plasticizers include water, triethyl citrate, triacetin, and dibutyl sebacate. Volatile agents that dissolve or swell the polymer, such as acetone, water, methanol, and ethyl acetate, may also be added to lower the melting point of the molten mixture. When the volatile vehicle is added, at least a portion, up to substantially all of the vehicle may evaporate after processing the molten mixture or the molten mixture is converted to a solid mixture. In this case, processing may be considered to be a combination of solvent processing and melt-congealing or melt-extrusion. Removal of the volatile excipients from the molten mixture may be accomplished by: will break up or spray into droplets and contact the droplets with a liquid to cool the droplets and lose all or part of the volatile excipients. Examples of other excipients that may be added to the mixture to lower the processing temperature include low molecular weight polymers or oligomers, such as polyethylene glycol, polyvinylpyrrolidone, and poloxamers; fats and oils, including mono-, di-, and triglycerides; natural and synthetic waxes such as carnauba wax, beeswax, microcrystalline wax, castor wax, and paraffin wax; long chain alcohols such as cetyl alcohol and stearyl alcohol; and long chain fats, such as stearic acid. When the added excipient is volatile, as described above, it is removed from the mixture after it is still molten or solidifies to form a solid amorphous dispersion.

Virtually any method may be used to form the molten mixture. One method involves melting the concentration-enhancing polymer in a vessel and then adding the CETP inhibitor to the molten polymer. Another method involves melting the CETP inhibitor in a vessel and then adding the concentration-enhancing polymer. In another method, a solid mixture of CETP inhibitor and concentration-enhancing polymer may be added to a vessel and the mixture heated to form a molten mixture.

Once the molten mixture is formed, it may be mixed to ensure that the CETP inhibitor is uniformly distributed in the molten mixture. The mixing can be carried out by mechanical means, such as a suspension mixer, a magnetic mixer and a stirring bar, a planetary mixer, and a homogenizer. Optionally, as the molten mixture is formed in the vessel, the contents of the vessel may be withdrawn from the vessel and passed through a flow line or static mixer and then returned to the vessel. The amount of shear stress used to mix the molten mixture should be sufficiently high to ensure uniform distribution of the CETP inhibitor in the molten mixture. The molten mixture may be mixed for a period of several minutes to several hours, the mixing time depending on the viscosity of the mixture and the solubility of the CETP inhibitor and the presence of optional excipients in the concentration-enhancing polymer.

Another method of preparing a molten mixture is to use two vessels, melting the CETP inhibitor in the first vessel and melting the concentration-enhancing polymer in the second vessel. The two melts are then drawn through an in-line static mixer or extruder to produce a molten mixture that then solidifies rapidly.

Another method of preparing a molten mixture is by using an extruder, such as a single-screw or twin-screw extruder, both of which are well known in the art. In the described apparatus, a solid charge of the composition is fed into an extruder where a combination of heat and shear forces produces a uniformly mixed molten mixture that is then capable of rapidly solidifying to form a solid amorphous dispersion. Solid feeds can be prepared using methods well known in the art to give a solid mixture with a high degree of homogeneity. Alternatively, the extruder may be equipped with two feeders so that the CETP inhibitor is fed into the extruder through one feeder and the polymer is fed through the other feeder. Other excipients that reduce the processing temperature as described above may be included in the solid feed or, in the presence of a liquid excipient such as water, may be injected into the extruder using methods well known in the art.

The extruder should be designed to produce a molten mixture in which the CETP inhibitor is uniformly distributed in the composition. The various zones in the extruder should be heated to the appropriate temperature to obtain the desired extrusion temperature and the desired degree of mixing or shearing, using procedures well known in the art.

When CETP inhibitors have high solubility in the concentration-enhancing polymer, lower amounts of mechanical energy are required to form the solid amorphous dispersion. In the case where the melting point of the undispersed CETP inhibitor is greater than the melting point of the undispersed concentration-enhancing polymer, the processing temperature may be less than the melting temperature of the undispersed CETP inhibitor but greater than the melting point of the polymer, as the CETP inhibitor will dissolve in the molten polymer. When the melting point of the undispersed CETP inhibitor is less than the melting point of the undispersed concentration-enhancing polymer, the processing temperature may be above the melting point of the undispersed CETP inhibitor but below the melting point of the undispersed concentration-enhancing polymer to allow the melted CETP inhibitor to dissolve in or adsorb to the polymer.

When CETP inhibitors have low solubility in the polymer, a greater amount of mechanical energy is required to form a solid amorphous dispersion. In such cases, the processing temperature may need to be above the melting point of the CETP inhibitor as well as the polymer. As noted above, alternatively, a liquid or low-melting excipient may be added to facilitate melting or mutual dissolution of the concentration-enhancing polymer and CETP inhibitor. High amounts of mechanical energy may also be required to mix the CETP inhibitor and polymer to form the dispersion. Generally, the lowest processing temperature and extruder design that delivers the lowest amount of mechanical energy, i.e., shear, is selected to produce a satisfactory dispersion (substantially amorphous and substantially uniform) to minimize exposure of the CETP inhibitor to harsh conditions.

Once the molten mixture of CETP inhibitor and concentration-enhancing polymer is formed, the mixture should rapidly solidify to form a solid amorphous dispersion. "fast cure" means that the molten mixture solidifies fast enough that substantial phase separation of the CETP inhibitor and polymer does not occur. Generally, this means that the mixture should cure in less than about 10 minutes, preferably less than about 5 minutes and more preferably less than about 1 minute. If the mixture does not cure rapidly, phase separation can occur, leading to the formation of CETP inhibitor-rich and polymer-rich phases.

Solidification occurs primarily when the molten mixture is cooled to at least about 10 c and preferably at least about 30 c below its melting point. As noted above, solidification may additionally be facilitated by evaporation of all or part of one or more volatile excipients or solvents. To promote rapid cooling and evaporation of the volatile excipients, the molten mixture is typically formed into a high surface area shape such as a strand or fiber or droplet. For example, the molten mixture can be forced through one or more small orifices to form long fine fibers or rods or a device, such as an atomizer, e.g., a rotating disk, can be fed which breaks the molten mixture into droplets having a diameter of 1 μm to 1 cm. The droplets will then be contacted with a relatively cold fluid such as air or nitrogen to promote cooling and evaporation.

A useful tool for the evaluation and selection of methods for forming substantially uniform, substantially amorphous dispersions by melt-congealing or melt-extrusion methods is a Differential Scanning Calorimeter (DSC). Although the rate of heating and cooling of the sample in a DSC is limited, it allows for precise control of the sample heating process. For example, the CETP inhibitor and the concentration-enhancing polymer may be dry-blended and then placed in a DSC sample pan. The DSC can then be set to heat the sample at a desired rate, hold the sample at a desired temperature for a period of time, and then rapidly cool the sample to ambient or lower temperature. The sample can then be re-analyzed on the DSC to confirm its conversion to a substantially uniform, substantially amorphous dispersion (i.e., the sample has a single Tg). With this procedure, the temperature and time required to obtain a substantially uniform, substantially amorphous dispersion for a given CETP inhibitor and concentration-enhancing polymer can be determined.

Another method of forming solid amorphous dispersions is "solvent treatment", which consists of the dissolution of a CETP inhibitor and one or more polymers in a common solvent. "common" here refers to a solvent, which may be a mixture of compounds, that will dissolve both the CETP inhibitor as well as the polymer. After both the CETP inhibitor and the polymer have dissolved, the solvent is rapidly removed by evaporation or by mixing with a non-solvent. Exemplary methods are spray drying, spray coating (pan-coating, fluidized bed coating, etc.), and by rapidly mixing the polymer and CETP inhibitor solution with CO ₂Water, or some other non-solvent. Preferably, removal of the solvent results in the formation of a substantially uniform, solid amorphous dispersion. In said dispersion, the CETP inhibitor is dispersed as homogeneously as possible in the polymer and can be considered as a solid solution of CETP inhibitor dispersed in the polymer, wherein a solid amorphous dispersion is thermodynamically stable, meaning that the concentration of CETP inhibitor in the polymer is at or below its equilibrium value, or it can be considered as an supersaturated solid solution wherein the concentration of CETP inhibitor in the concentration-enhancing polymer is above its equilibrium value.

The solvent can be removed by spray drying. The term "spray drying" is used conventionally and refers broadly to the following process: involves breaking up a liquid mixture into droplets (atomization) in a spray drying apparatus and rapidly removing solvent from the mixture, where there is a strong driving force to evaporate the solvent from the droplets. The spray drying process and spray drying equipment are generally described in Perry's Chemical Engineers' Handbook, 20-54 to 20-57 (6 th edition, 1984). For more details on the Spray-drying process and equipment see Marshall, "Atomization and Spray-drying," 50 chem. Eng. prog. monogr. series 2(1954), and Masters, Spray-drying Handbook (Fourth Edition 1985). The strong driving force for solvent evaporation is usually achieved by keeping the solvent partial pressure in the spray drying apparatus significantly lower than the vapor pressure of the solvent in the dried droplets at this temperature. This can be achieved by: (1) maintaining the pressure in the spray drying apparatus at a partial vacuum (e.g., 0.01 to 0.50 atm); or (2) mixing the liquid droplets with a warm drying gas; or (3) both (1) and (2). In addition, at least part of the heat required for solvent evaporation is provided by heating the spray solution.

Suitable solvents for spray drying may be any organic compound in which the CETP inhibitor and the polymer are miscible. Preferably, the solvent is also volatile, having a boiling point of 150 ℃ or less. In addition, The solvent should have relatively low toxicity and The level of removal from The dispersion is acceptable according to The guidelines of The International Committee on Harmonization (ICH). Removal of the solvent to this extent may require a processing step after the spray drying or spray coating process, for example, tray drying. Preferred solvents include alcohols such as methanol, ethanol, n-propanol, isopropanol, and butanol; ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone; esters such as ethyl acetate and propyl acetate; and various other solvents such as acetonitrile, dichloromethane, toluene, and 1, 1, 1-trichloroethane. Less volatile solvents such as dimethylacetamide or dimethylsulfoxide can also be used. Mixtures of solvents, such as 50% methanol with 50% acetone, and water, may also be used, provided that the polymer and CETP inhibitor are sufficiently soluble to make a spray-drying process feasible. Generally, non-aqueous solvents are preferred due to the hydrophobicity of the CETP inhibitor, meaning that the solvent comprises less than about 10 wt% water.

The solvent-bearing feed, including the CETP inhibitor and the concentration-enhancing polymer, can be spray dried under a wide variety of conditions and still yield dispersions with acceptable properties. For example, various types of nozzles may be used to atomize the spray solution so that the spray solution is introduced into the spray drying chamber as a collection of droplets. Essentially any type of nozzle can be used to spray the solution so long as the droplets formed are small enough to be sufficiently dry (due to evaporation of the solvent) and they do not adhere to or coat the spray drying chamber walls.

Although the size of the largest droplets varies with the size, shape and flow pattern of the spray dryer, typically the droplets should be less than about 500 μm in diameter as they exit the nozzle. Examples of the types of nozzles that can be used to form the solid amorphous dispersion include two-fluid nozzles, fountain-type nozzles, flat fan-type nozzles, pressure nozzles, and rotary atomizers. In a preferred embodiment, a pressure nozzle is used, as described in detail in commonly assigned co-pending U.S. provisional application 60/353,986, the disclosure of which is incorporated herein by reference.

The spray solution can be delivered to the spray nozzle or nozzles at a wide range of temperatures and flow rates. Generally, the spraying solution temperature can be carried out at any temperature from just above the solvent freezing point to about 20 ℃ above the ambient pressure boiling point (by pressurizing the solution), and even higher at some removals. The spray solution flow rate to the spray nozzle may vary within wide limits depending on the type of nozzle, the size of the spray dryer and the spray drying conditions such as inlet temperature and flow rate of the drying gas. Typically, the energy to evaporate the solvent from the spray solution during spray drying comes primarily from the drying gas.

The drying gas, in principle, can be essentially any gas, but for safety reasons and to minimize the undesired oxidation of CETP inhibitor or other substances in the solid amorphous dispersion, an inert gas such as nitrogen, nitrogen-enriched air or argon is used. The drying gas is generally introduced into the drying chamber at a temperature of between about 60 ° to about 300 ℃ and preferably interposed between about 80 ° and about 240 ℃.

The large surface-to-volume ratio of the droplets and the large driving force for solvent evaporation result in a fast solidification time of the droplets. The cure time should be less than about 20 seconds, preferably less than about 10 seconds, and more preferably less than 1 second. This rapid solidification is generally important for the particles to remain in a uniform, homogeneous dispersion, rather than separating into the CETP inhibitor-rich and polymer-rich phases. In a preferred embodiment, the height and volume of the spray dryer are adjusted to provide sufficient time for droplet drying upon impingement on the interior surfaces of the spray dryer, as described in detail in commonly assigned, co-pending U.S. provisional application No. 60/354,080, incorporated herein by reference. As mentioned above, in order to obtain a large increase in concentration and bioavailability, it is generally desirable to obtain as homogeneous a dispersion as possible.

After solidification, the solid powder is typically left in the spray drying chamber for about 5 to 60 seconds, further evaporating the solvent from the solid powder. The final solvent content in the solid dispersion should be low as it leaves the dryer, since this will reduce the mobility of the CETP inhibitor molecules in the solid amorphous dispersion and thus improve its stability. Generally, the solvent content of the solid amorphous dispersion should be less than 10 wt% and preferably less than 2 wt% as it leaves the spray drying chamber. After formation, the solid amorphous dispersion may be dried to remove residual solvent using suitable drying methods such as tray drying, fluidized bed drying, microwave drying, belt drying, rotary drying, and other drying methods known in the art.

Solid amorphous dispersions are generally in the form of small particles. The particles have an average size of less than 500 μm in diameter, or less than 100 μm in diameter, less than 50 μm in diameter, or less than 25 μm in diameter. When spray drying is used to form a solid amorphous dispersion, the resulting dispersion is in the form of the small particles. When the solid amorphous dispersion is prepared by other methods, such as by melt-congealing or extrusion, the resulting dispersion can be sieved, milled, or subjected to other methods to obtain a plurality of small particles.

Once a solid amorphous dispersion comprising a CETP inhibitor and a concentration-enhancing polymer has been formed, several processing operations may be utilized to facilitate processing of the dispersion into dosage forms. These processing operations include drying, granulation, and grinding.

The solid amorphous dispersion can be granulated to increase particle size and improve handling of the dispersion while forming a suitable dosage form. Preferably, the particles have an average size in the range of 50 to 1000 μm. The granulation process may be carried out either before or after drying of the composition, as described above. Dry or wet granulation methods may be used for this purpose. One example of a dry granulation process is roller compaction. Wet granulation methods may include so-called low shear and high shear granulation and fluid bed granulation. In these methods, after the dry ingredients have been mixed, a granulation fluid is mixed with the composition to help form a granulated composition. Examples of granulation fluids include various isomers of water, ethanol, isopropyl alcohol, n-propanol, butanol, and mixtures thereof.

If wet granulation is used, the granulated composition is typically dried prior to further processing. Examples of suitable drying methods used in conjunction with wet granulation are the same as those described above. Where the solid amorphous dispersion is prepared using a solvent process, the composition may be granulated prior to removal of residual solvent. During the drying process, residual solvent as well as granulation fluid is simultaneously removed from the composition.

Once the composition has been granulated, it may then be milled to achieve the desired particle size. Examples of suitable methods for grinding the composition include hammer milling, ball milling, fluid-energy milling, roller milling, cutting milling, and other grinding methods known in the art.

Methods for forming solid amorphous dispersions of CETP inhibitor and concentration-enhancing polymer are described in more detail in commonly assigned, co-pending U.S. patent application Nos. 09/918,127 and 10/066,091, which are incorporated herein by reference.

Solid amorphous dispersions of CETP inhibitors can be formulated into controlled release devices using the methods described above.

Lipid carrier formulations

In another aspect of the invention, the solubility-improved form of the CETP inhibitor comprises the CETP inhibitor and a lipophilic carrier selected from digestible oils (digestible oils), lipophilic solvents (also referred to herein as "co-solvents", whether or not another solvent is actually present), lipophilic surfactants, and mixtures of any two or more. Embodiments include CETP inhibitors and: (1) a combination of a pharmaceutically acceptable digestible oil and a surfactant; (2) a pharmaceutically acceptable digestible oil and a miscible lipophilic solvent combination; and (3) a combination of a pharmaceutically acceptable digestible oil, a lipophilic solvent, and a surfactant.

In one embodiment, the present invention provides a composition that increases the oral bioavailability of a CETP inhibitor. The composition comprises:

CETP inhibitors;

2. a co-solvent;

3. a surfactant having an HLB of from 1 to no greater than 8;

4. a surfactant having an HLB of greater than 8 up to 20; and

5. optionally, digestible oil.

In the formulation, all excipients are pharmaceutically acceptable. Such compositions are sometimes referred to herein as "pre-concentrates", with reference to their action in forming stable emulsions when gently mixed with water or other aqueous vehicles, often gastrointestinal fluids. Also referred to herein as "filler," to the extent that it acts as a filler in a softgel capsule.

Soft gels are generally used herein as the preferred dosage form of the present invention and "soft gels" is an abbreviation for soft gelatin capsules. It should be understood that when the term "soft gel" is used alone, it should be understood that the present invention is equally applicable to all types of gelatin and non-gelatin capsules, regardless of hardness, softness, etc.

Co-solvent refers to a solvent in which the CETP inhibitor of interest is highly soluble, having a solubility of at least 150mg/mL for any given CETP inhibitor.

As noted above, and as discussed further below, the digestible oil may form part of the pre-concentrate. If no other pre-concentrate ingredients are capable of acting as an emulsifiable oil phase, the digestible oil may include a solvent that acts as an oil, acts as a CETP inhibitor and disperses to form (emulsifiable) oil droplets once the pre-concentrate is added to water. Some surfactants may serve a dual function, however, i.e., act as surfactants and also act as solvents and oily carriers for forming oil-in-water emulsions. In the case where such surfactants are used, and depending on the amount used, a smaller amount of digestible oil may be required, or not at all.

The pre-concentrate may be self-emulsifying or self-microemulsifying.

The term "self-emulsifying" refers to a formulation that, when diluted at least 100-fold with water or other aqueous vehicle and gently mixed, produces an opaque, stable oil/water emulsion with average droplet diameters of less than about 5 microns, but greater than 100nm, and is generally polydisperse. The emulsion is stable for at least a few (i.e., at least 6) hours, meaning that there is no visually discernable phase separation and no visually discernable crystallization of the CETP inhibitor.

The term "self-microemulsifying" refers to pre-concentrates which upon at least 100x dilution with an aqueous vehicle and gentle mixing give clear, stable oil/water emulsions having an average particle size of about 1 micron or less, preferably less than 100 nm. The particle size is predominantly unitary. Most preferably the emulsion is transparent and has a monomodal distribution with a mean diameter of less than 50nm, as determined, for example, by dynamic light scattering. The microemulsion chamber is thermodynamically stable and has no sign of crystallization of the CETP inhibitor.

The above "gentle mixing" is understood in the art to mean the formation of an emulsion by gentle hand (or therewith) mixing, such as by repeated inversion on a standard laboratory mixing machine. High shear mixing is not required to form the emulsion. The pre-concentrate generally emulsifies almost spontaneously when introduced into the gastrointestinal tract of a human (or other animal).

Combinations of 2 surfactants, one low HLB surfactant and one high HLB surfactant with 1-8 HLB, with higher HLB, 8-20, preferably 9-20, can be used to create suitable conditions for effective emulsification. HLB, an acronym for "hydrophilic-lipophilic balance," is a scale ranging from 1 to 20 for nonionic surfactants. The higher the HLB, the more hydrophilic the surfactant. Hydrophilic surfactants (HLB about 8-20), when used alone, provide a fine emulsion that is advantageously more likely to empty consistently from the stomach and provide a higher surface area for absorption. Disadvantageously, however, such limited miscibility of high HLB surfactants with oils limits their effectiveness, and thus low HLB, lipophilic surfactants (HLB of about 1-8) are also included. This combination of surfactants also provides excellent emulsions. A combination of medium chain triglycerides (e.g. Miglyol ® 812), polysorbate 80(HLB 15) and medium chain long mono/diglycerides (Capmul ® MCM, HLB ═ 6) was found to be as effective as Miglyol ® 812 and a surfactant with HLB of 10 (Labrafac ® CM). N.h. shah et al int.j.pharm, vol 106, 15 (1994). The advantages of using high and low HLB surfactants, including promoting lipolysis, for self-emulsifying systems have been demonstrated by Lacy, US 6,096,338.

Suitable digestible oils, which can be used as a carrier alone or in a carrier comprising digestible oils as part of a mixture comprising medium chain triglycerides (MCT, C6-C12) and long chain triglycerides (LCT, C14-C20) and mixtures of mono-, di-, and triglycerides, or lipophilic derivatives of fatty acids such as esters with alkyl alcohols. Examples of preferred MCT's include fractionated coconut oils such as Miglyol ® 81, which is 56% caprylic acid (C8) and 36% caprylic acid (C10) triglycerides, Miglyol ® 810 (68% C8 and 28% C10), Neobee ® M5, Captex ® 300, Captex ® 355, and Crodamol ® GTCC. Miglyols is supplied by Condea Vista inc. (Huls), Neobee ® is supplied by Stepan Europe, Voreppe, France, Captex ® is supplied by Abitec corp., and Crodamol ® is supplied by Croda corp. Examples of LCTs include vegetable oils such as soybean, safflower, corn, olive, cottonseed, arachis, sunflower, palm, or rapeseed. Examples of fatty acid esters of alkyl alcohols include ethyl oleate and glyceryl monooleate. MCT's are preferred in digestible oils, and Miglyol ® 812 is most preferred.

The carrier may also be a pharmaceutically acceptable solvent, used alone or as a co-solvent in a mixture. Suitable solvents include any solvent that serves to increase the solubility of the CETP inhibitor in the formulation such that the desired dose is delivered per unit of administration. It is generally not possible to predict the solubility of CETP inhibitors in a single solvent, but these are readily determined by "testing". Suitable solvents include glyceryl triacetate (1, 2, 3-propanetriacetate or glyceryl triacetate, supplied by Eastman Chemical corp., inc.) or other polyhydroxy esters of fatty acids, trialkyl citrates, propylene carbonates, dimethyl isosorbide, ethyl lactate, N-methylpyrrolidone, transcutol, glycofurol, peppermint oil, 1, 2-propanediol, ethanol, and polyethylene glycols. Preferred solvents are glyceryl triacetate, propylene carbonate (huntsman Corp.), transcutol (Gattefose), ethyl lactate (Purac, Lincolnshire, NE) and dimethyl sorbitol (sold under the registered trademark ARLASOLVE DMI, ICI America). The hydrophilic solvent is more likely to migrate to the capsule shell and soften the shell and, if volatile, its concentration in the composition can be reduced, but has a potentially negative effect on the solubility of the active ingredient (CETP inhibitor). More preferred are the lipophilic solvents glyceryl triacetate, ethyl lactate, and propylene carbonate.

Hydrophilic surfactants having an HLB of 8 to 20, preferably greater than 10, are particularly effective in reducing the size of emulsified droplets. Suitable choices include non-ionic surfactants such as polyoxyethylene 20 sorbitan monooleate, polysorbate 80, sold under the trademark TWEEN 80, available from ICI trade; polyoxyethylene 20 sorbitan monolaurate (polysorbate 20, TWEEN 20); polyethylene (40 or 60) hydrogenated castor oil (supplied by BASF under the registered trade marks CREMOPHOR ® RH40 and RH 60); polyoxyethylene (35) castor oil (CREMOPHOR ® EL); polyethylene (60) hydrogenated castor oil (Nikkol ® HCO-60); alpha tocopherol polyethylene glycol 1000 succinate (vitamin E TPGS); glyceryl PEG 8 caprylate/caprate (commercially available from Gattefosse under the registered trademark LABRASOL ®); PEG 32 glyceryl laurate (sold by Gattefosse under the registered trademark gel UCIRE ® 44/14), polyoxyethylene fatty esters (commercially available from ICI under the registered trademark MYRJ), polyoxyethylene fatty ethers (provided from ICI under the registered trademark BRIJ). Preferred are polysorbate 80, CREMOPHOR ® RH40(BASF), and vitamin etpgs (eastman).

Lipophilic surfactants having an HLB of less than 8 can be used to achieve balanced polarity to provide stable emulsions, and have been used to reverse the fat degradation inhibition of hydrophilic surfactants. Suitable lipophilic surfactants include the mono-and diglycerides of capric and caprylic acids under the following registered trade marks: capmul ® MCM, MCM 8, and MCM 10, commercially available from Abitec; and Imwitor ® 988, 742 or 308, commercially available from Condea Vista; polyoxyethylene 6 almond oil supplied under the registered trade mark Labrafil ® M1944 CS by Gattefosse; polyoxyethylene corn oil, supplied as Labrafil ® M2125; propylene glycol monolaurate, supplied as Lauroglycol by Gattefosse; propylene glycol dicaprylate/caprate, supplied by Abitec as Captex ® 200 or Miglyol ® 840 supplied by CondeaVista, polyglyceryl oleic acid, commercially available as Plurol oleique from Gattefosse, sorbitan esters of fatty acids (e.g., Span ® 20, Crill ® 1, Crill ® 4, commercially available from ICI and Croda), and glyceryl monooleate (Maisine, Peceol). Preferred of this type are Capmul ® MCM (Abitec Corp.) and Labrafil ® M1944 CS (Gattefose).

In addition to the major liquid formulation ingredients explained above, other stabilizing additives, as conventionally known in the art of soft gel formulations, may be incorporated into the bulking agent as needed, usually in relatively small amounts, such as antioxidants (BHA, BHT, tocopherol, propyl gallate, etc.) and other preservatives such as benzyl alcohol or parabens.

The compositions may be formulated as a fill material for encapsulation in a soft gelatin capsule, a hard gelatin capsule, a non-gelatin capsule such as a hydroxypropyl methylcellulose capsule with a suitable seal, or as a liquid or emulsion for oral administration using methods commonly used in the art. The filling is prepared by mixing the excipient and CETP inhibitor, and heating if necessary.

The proportions of CETP inhibitor, digestible oil, co-solvent, and surfactant depend on the efficiency of emulsification and solubility, and the solubility depends on the desired dosage per capsule. Self-emulsifying formulations are generally useful if the primary goal is to deliver a high dose/soft gel (at least 60mg), typically with a much lower food effect than oil solutions alone. Generally, soft gel pre-concentrates have a solubility of at least 140mg/mL CETP inhibitor in the pre-concentrate, and therefore require higher co-solvent usage and lower levels of surfactant and oil, which is preferred.

Typically, the self-emulsifying formulation ingredients of the CETP inhibitor are in the ranges (expressed as weight percent):

1-50% CETP inhibitor

5-60% of cosolvent

5-75% of high HLB surfactant

5-75% of a low HLB surfactant

Preferred ranges having a favorable low food effect include those expressed below:

1-33% CETP inhibitor

0-30% digestible oil

15-55% of cosolvent

5-40% high HLB surfactant

10-50% low HLB surfactant

General ranges (in weight percent) for the self-microemulsifying formulation ingredients of CETP inhibitors are

1-40% CETP inhibitor

5-65% digestible oil

5-60% of cosolvent

10-75% of high HLB surfactant

5-75% of low HLB surfactant

Additional details of such lipid carrier formulations are disclosed in commonly assigned co-pending U.S. patent application No. 10/175,643 filed 6/19/2002, which is incorporated by reference in its entirety.

The lipid carrier formulations can be formulated as controlled release devices, such as those described above.

HMG-CoA reductase inhibitors

The HMG-CoA reductase inhibitor may be any HMG-CoA reductase inhibitor that lowers plasma concentrations of low-density lipoprotein, total cholesterol, or both. In one aspect, the HMG-CoA reductase inhibitor is selected from a class of therapeutic agents commonly referred to as statins. Examples of HMG-CoA reductase inhibitors that may be used include, but are not limited to, lovastatin (MEVACOR ®; see U.S. Pat. No. 4,231,938; 4,294,926; 4,319,039), simvastatin (ZOCOR ®; see U.S. Pat. No. 4,444,784; 4,450,171, 4,820,850; 4,916,239), pravastatin (PRAVACHOL ®; see U.S. Pat. No. 4,346,227; 4,537,859; 4,410,629; 5,030,447 and 5,180,589), the lactone of pravastatin (see U.S. Pat. No. 4,448,979), fluvastatin (LESCOL ®; see U.S. Pat. No. 5,354,772; 4,911,165; 4,cre739,073; 4,929,437; 5,189,164; 5,118,853; 5,290,946; 5,356,896), the lactone of fluvastatin, atorvastatin (LIPIOR ®; see U.S. Pat. No. 5,273,681; 4,893; 5,489,691; the lactone of atorvastatin, 5,342,952), the lactone of atorvastatin (see EP 465,177; and the European patent publication No. EP ®; see EP ®; the European patent No. EP 4680; the publication of rosuvastatin (see EP ®; see EP 4611; the European patent No. Pat. 4,177; the publication of European patent No. Nos. 5,440,440; see European patent No. 5; see European patent publication of rosuvastatin; see European patent No. 5,440, The lactones of rosuvastatin, itavastatin, nisvastatin, visastatin, atavastatin, bervastatin, compactin, dihydrocompactin, dalvastatin, fluindostatin, pitavastatin, mevastatin (see U.S. Pat. No. 3,983,140), and velostatin (also known as synvinolin). Other example HMG-CoA reductase inhibitors are described in U.S. patent nos. 5,217,992; 5,196,440, respectively; 5,189,180, respectively; 5,166,364, respectively; 5,157,134, respectively; 5,110,940, respectively; 5,106,992, respectively; 5,099,035, respectively; 5,081,136, respectively; 5,049,696, respectively; 5,049,577, respectively; 5,025,017, respectively; 5,011,947, respectively; 5,010,105, respectively; 4,970,221, respectively; 4,940,800, respectively; 4,866,058, respectively; 4,686,237, respectively; 4,647,576, respectively; european application nos. 0142146a2 and 0221025a 1; and PCT application nos. WO 86/03488 and WO 86/07054. Also included are pharmaceutically acceptable forms of the above medicaments. All of the above documents are incorporated herein by reference. Preferably the HMG-CoA reductase inhibitor is selected from fluvastatin, lovastatin, pravastatin, atorvastatin, simvastatin, cerivastatin, rivastatin, mevastatin, velostatin, compactin, dalvastatin, fluindostatin, rosuvastatin, pitavastatin, dihydrocompactin, and pharmaceutically acceptable forms thereof. "pharmaceutically acceptable form" refers to any pharmaceutically acceptable derivative or variant, including stereoisomers, mixtures of stereoisomers, enantiomers, solvates, hydrates, (homo) polymorphs, pseudopolymorphs, polymorphs, salt forms, and prodrugs.

In one embodiment, the HMG-CoA reductase inhibitor is selected from trans-6- [2- (3 or 4-carbamoyl-substituted pyrrol-1-yl) alkyl ] -4-hydroxypyran-2-one and corresponding pyran ring-opening-hydroxy acid derivatives. These compounds are described in U.S. Pat. No. 4,681,893, which is incorporated herein by reference. Pyran ring-opening-hydroxy acid derivatives, which are intermediates in the synthesis of lactone compounds, may be used as the free acid or in the form of a pharmaceutically acceptable metal or amine salt. Specifically, these compounds can be represented by the following structures:

wherein X is-CH₂--、--CH₂CH₂--、--CH₂CH₂CH₂- - (O) - -or- - -CH₂CH(CH₃)--；R₁Is 1-naphthyl; 2-naphthyl; cyclohexyl, norbornenyl; 2-, 3-, or 4-pyridyl; a phenyl group; phenyl substituted with: fluorine, chlorine, bromine, hydroxyl, trifluoromethyl, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, or alkanoylalkoxy of 2 to 8 carbon atoms; or R₂Or R₃is-CONR₅R₆Wherein R is₅And R₆Independently is hydrogen; an alkyl group having 1 to 6 carbon atoms; 2-, 3-, or 4-pyridyl; a phenyl group; phenyl substituted with: fluorine, chlorine, bromine, cyano, trifluoromethyl, or an alkoxyformyl group having 3 to 8 carbon atoms; and R is ₂Or R₃The other is hydrogen; an alkyl group having 1 to 6 carbon atoms; a cyclopropyl group; a cyclobutyl group; a cyclopentyl group; a cyclohexyl group; a phenyl group; or phenyl substituted with: fluorine, chlorine, bromine, hydroxyl, trifluoromethyl, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, or alkanoyloxy of 2 to 8 carbon atoms; r₄Is an alkyl group having 1 to 6 carbon atoms; a cyclopropyl group; a cyclobutyl group; a cyclopentyl group; a cyclohexyl group; or trifluoromethyl; and M is a pharmaceutically acceptable salt (e.g., a counter ion) including a pharmaceutically acceptable metal salt or a pharmaceutically acceptable amine salt.

Among the stereospecific isomers, one preferred HMG-CoA reductase inhibitor is atorvastatinThe hemihydrate hemi-calcium salt. A preferred compound is (2R-trans) -5- (4-fluorophenyl) -2- (1 methylethyl) -N, 4-diphenyl-1- [2- (tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl) ethyl]The ring-opened form of (E) -1H-pyrrole-3-carboxamide, i.e., the enantiomer [ R- (R) ]^*，R^*)]-2- (4-fluorophenyl-. beta.,. delta. dihydroxy-5- (1-methylethyl) -3-phenyl-4- [ (phenylamino) carbonyl)]-1H-pyrrole-1-heptanoic acid hemicalcium salt. The chemical structure can be represented by the following structure:

formula A

Specific isomers have been described in U.S. Pat. No. 5,273,995, which is incorporated herein by reference. In a preferred embodiment, the HMG-CoA reductase inhibitor is selected from atorvastatin, the cyclic lactone forms of atorvastatin, the 2-hydroxy, 3-hydroxy or 4-hydroxy derivatives of said compounds, and the pharmaceutically acceptable salts thereof.

In practice, the salt form may be used instead of the acid or lactone form. Suitable pharmaceutically acceptable salts within the scope of the present invention are those derived from the following bases: such as sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, 1-deoxy-2- (methylamino) -D-sorbitol, magnesium hydroxide, zinc hydroxide, aluminum hydroxide, ferrous or ferric hydroxide, ammonium hydroxide or organic amines such as N-methylglucamine, choline, arginine and the like. Preferably, lithium, calcium, magnesium, aluminium and ferrous or ferric salts are prepared from sodium or potassium salts, the calcium salts of which are obtained by adding the appropriate reagents to a solution of the sodium or potassium salt, i.e. calcium chloride to a solution of the sodium or potassium salt of the compound of formula a.

Method of treatment

The dosage forms of the present invention may be used to treat any condition treatable by the administration of a CETP inhibitor in combination with an HMG-CoA reductase inhibitor as disclosed in commonly assigned, co-pending U.S. patent application No. 2002/0035125A1, the disclosure of which is incorporated herein by reference.

In one aspect, the dosage form of the invention is used for anti-atherosclerotic treatment.

In another aspect, the dosage form of the invention is used to delay and/or control the progression of (atherosclerotic) plaques.

In another aspect, the dosage form of the invention is used for delaying the progression of (arterial) atherosclerotic plaques in coronary arteries.

In another aspect, the dosage form of the invention is used to delay the progression of carotid (arterial) atherosclerotic plaques

In another aspect, the dosage form of the invention is used for delaying the progression of (atherosclerotic) plaques of the peripheral arterial system.

In another aspect, the dosage form of the invention, when used for the treatment of atherosclerosis, causes regression of (atherosclerotic) plaques.

In another aspect, the dosage form of the invention is used for regression of atherosclerotic plaques in coronary arteries

In another aspect, the dosage form of the invention is used for regression of (arterial) atherosclerotic plaques of the carotid artery.

In another aspect, the dosage form of the invention is used for regression of (arterial) atherosclerotic plaques of the peripheral arterial system.

In another aspect, the dosage form of the invention is used for HDL-raising therapy and anti-hyperlipidemic therapy (including LDL lowering).

In another aspect, the dosage form of the invention is used for anti-angina treatment.

In another aspect, the dosage form of the present invention is used for cardiac risk control.

Other features and embodiments of the present invention will become apparent from the following examples, which are given for the purpose of illustration and are not intended to limit the scope of the invention.

Example 1

This example demonstrates the dosage form of the present invention, providing controlled release of the CETP inhibitor [2R, 4S ]4- [ (3, 5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino ] -2-ethyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (torcetrapib) in a solubility-improved form, and immediate release of the HMG-CoA reductase inhibitor atorvastatin hemi calcium trihydrate (hereinafter "atorvastatin").

Formation of CETP inhibitors in improved solubility form

The solubility-improved form of torcetrapib is prepared by forming a solid amorphous dispersion of torcetrapib in hydroxypropyl methylcellulose acetate succinate (HPMCAS). The dispersion was prepared as follows: spray-drying a solution comprising 4.0 wt% torcetrapib, 12.0 wt% HPMCAS-MG (AQUOT-MG, prepared by Shin Etsu (Tokyo, Japan)), and 84 wt% acetone. The solution was spray dried using a pressure spray nozzle (Delavan SDX III): an inlet temperature of about 110 c and an outlet temperature of about 45 c was maintained at a spray pressure of 48atm (700 psig) with a liquid feed rate of about 100 kg/hour into the stainless steel chamber of a Niro PSD-4 spray dryer. Secondary drying was carried out using an Aeromatic MP-6 fluid bed dryer: the drying bed temperature was 40 ℃ and the drying time was 360 minutes.

Controlled release CETP inhibitor compositions

A two-layer osmotic controlled release device was prepared from a solubility-improved form of torcetrapib according to the following procedure. Drug-containing compositions were formed by blending 48 wt% torcetrapib solid amorphous dispersion (25 wt% torcetrapib: HPMCAS-MG), 23 wt% PEO having a weight average molecular weight of 600,000, 23 wt% xylitol (trade name XYLITAB 200), 5 wt% sodium starch glycolate (trade name EXPLOTAB), and 1 wt% magnesium stearate. Drug-containing composition ingredients were first combined without magnesium stearate and mixed in a TURBULA mixer for 20 minutes. The mixture was press-screened (screen size 0.165cm 0.065 inch) and then mixed in the same mixer for an additional 20 minutes. Next, magnesium stearate was added and the drug-containing composition was mixed in the same mixer for an additional 4 minutes.

Forming a water-swellable composition by mixing: 75 wt% croscarmellose sodium (trade name AcDiSol), 24.4 wt% tableting aid silicified microcrystalline cellulose (trade name PROSOLV 90), 0.5 wt% magnesium stearate, and 0.1 wt% Red Lake # 40. AcDiSol, PROSOLV, and Red Lake dyes were combined and mixed in a TURBULA mixer for 20 minutes. Next, magnesium stearate was added. All ingredients were push-screened (screen size 0.084cm [0.033 inch ]), and then remixed for 20 minutes in the same mixer.

The tablet core is formed as follows: the drug-containing composition was prepared by placing 375mg of the drug-containing composition into a standard 13/32 inch standard spherical concave (SRC) die and gently flattening with a punch press. Then, 125mg of the water-swellable composition was placed in the mold on top of the drug-containing composition. The tablet cores were then compressed to a hardness of about 16 Kp. A two-layer tablet core was obtained weighing 500MG total and comprising a total amount of 9.0 wt% torcetrapib (45MG), 27.0 wt% HPMCAS-MG, 17.25 wt% XYLITAB 200, 17.25 wt% PEO 600,000, 3.75 wt% EXPLOTAB, 18.75 wt% AcDiSol, 6.1 wt% pro solv 90, 0.875 wt% magnesium stearate, and 0.025 wt% Red Lake dye.

The water-permeable coating was applied to the core using a Vector LDCS-20 pan coater. The coating solution contained cellulose acetate (CA 398-10, available from Eastman Fine Chemical, Kingsport, Tennessee), polyethylene glycol (PEG 3350, Union Carbide), water, and acetone in a weight ratio of 3.5/1.5/3/92 (wt%). The flow rate of the inlet heated drying air of the pan coater was set to 40ft³Per minute, the outlet temperature was set at 25 ℃. 2.4 atmospheres (20 psig) of nitrogen was used to atomize the coating solution for the spray nozzle, and the nozzle-bed distance was 2 inches. The rotation of the pan was set at 20 rpm. The so-coated tablets were redried at 50 ℃ in a convection oven to remove substantially all of the acetone and water. The final dry coating weight (75mg) was 15 wt% of the tablet core and consisted of about 52.5mg of CA, to And 22.5mg of PEG 3350. A hole of 900 μm in diameter was then laser-drilled in the coating on the drug-containing composition side of the tablet to provide 1 delivery opening per tablet.

Immediate release atorvastatin coating

The osmotic controlled release device described above was coated with an immediate release layer of atorvastatin by dipping each tablet into the following weight of solution: 92.5 wt% water, 1.5 wt% Opadry ® clear (supplied by Colorcon, Inc., WestPoint, PA), 2.0 wt% lactose monohydrate, and 4.0 wt% atorvastatin. The coating solution was formed as follows: the Opadry ® clear polymer was added to a rapidly stirring water weight and stirred in a 37 ℃ temperature-controlled chamber for about 1 hour. Then, lactose monohydrate was added to the polymer solution and the mixture was stirred for about 30 minutes. Atorvastatin is then added to the coating solution to form a suspension. Each tablet was immersed in the stirred suspension, in a 37 ℃ temperature-controlled chamber, and dried at 37 ℃ for about 1 hour, after which the tablets were coated again. Several coatings were applied to each tablet and the tablets were dried overnight at 37 ℃ and then weighed to determine the total amount of immediate release coating applied. An average of 36mg of coating substance (22mg of atorvastatin) was applied to each tablet.

In vitro dissolution test

In vitro tests were performed to measure the release of torcetrapib and atorvastatin from the dosage forms of example 1. For in vitro dissolution testing, each dosage form was first placed in a stirred USP type 2 disoette flask containing 500mL of a buffer solution simulating intestinal contents (50mM KH2 PO)₄pH 7.4). The solution was stirred with a paddle rotating at 50 rpm. Samples were taken at regular intervals and a setup program periodically removed samples of the receiver solution using an automated sampling disoette apparatus. Drug concentrations were analyzed by HPLC: a Hypersil BDS CN column was used and the mobile phase was 50/50 (vol.%) acetonitrile/50 mM ammonium citrate buffer, pH 4. UV absorption was measured at 244 nm. The results are shown in table 1.

TABLE 1

Time (hours)	Torcetrapib (wt% released)	Atorvastatin (wt% release)
Time (hours)	Torcetrapib (wt% released)	Atorvastatin (wt% release)	0	0	0
0.5	0	69	0	0	0
0.5	0	69	1	0	93
2	0	94	1	0	93
2	0	94	4	4	96
8	30	97	4	4	96
8	30	97	10	46	101
12	56	101	10	46	101
12	56	101	16	75	100
18	79	100	16	75	100
18	79	100	20	84	100

The data shows that the dosage form of example 1 provides immediate release of atorvastatin, providing 93% release at 1 hour. In addition, the dosage form of example 1 provided controlled release torcetrapib, with a time taken to release 70 wt% of the drug from the dosage form of about 15 hours. The mean rate of release of torcetrapib from the dosage form during the first 15 hours after administration to the test vehicle was 4.7 wt%/hour.

Example 2

This example demonstrates a second dosage form of the invention that provides controlled release delivery of torcetrapib and immediate release delivery of atorvastatin calcium. torcetrapib is in the form of a solid amorphous dispersion prepared according to example 1.

Controlled release device

The osmotic controlled release device included a solid amorphous dispersion of torcetrapib in HPMCAS-MG, prepared as follows. A mixture was prepared containing 29.0 wt% of the torcetrapib of example 1: HPMCAS-MG dispersion, 55.0 wt% sorbitol (NEOSORB 30/60 DC, supplied by Roquette), 5.0 wt% hydroxypropyl cellulose (KLUCEL EXF, supplied by Hercules), 10 wt% hydroxyethyl cellulose (NATROSOL 250H, supplied by Hercules), and 1 wt% magnesium stearate. All ingredients except magnesium stearate were mixed in a TURBULA mixer for 20 minutes, pushed through a 20-mesh screen, and then blended in the same mixer for an additional 20 minutes. Next, magnesium stearate was added and the composition was mixed in the same mixer for an additional 4 minutes. Tablet cores were formed according to the following procedure: 629mg of the tablet mixture was placed in a ingot mold (0.8 cm. times.1.6 cm [ 0.315. times.0.630 inch ]) and pressed by using an F-punch. The water-permeable coating was applied using a VectorLDCS-20 pan coater as described in example 1. The coating solution comprised CA 398-10, PEG 3350, water, and acetone in a weight ratio of 4/2/5/89. The tablet core (50mg, including about 33mg CA and about 17mg PEG 3350) was at 8 wt% of the final dry coating weight and a 900 μm diameter hole was made in the coating by mechanical-drilling to provide a delivery opening. The delivery opening is drilled at one end of the ingot, in which the longest axis of the ingot is near the intersection with the ingot surface. The final monolayer osmotic controlled release device contained 45mg of torcetrapib.

Immediate release atorvastatin granules

The immediate release atorvastatin granules were prepared by mixing the granulation ingredients, roller-compacting, and grinding. The granule contained 13.9 wt% atorvastatin trihydrate hemicalcium salt, 42.3 wt% calcium carbonate, 17.7 wt% microcrystalline cellulose, 3.8 wt% croscarmellose sodium, 0.5 wt% polysorbate 80, 2.6 wt% hydroxypropyl cellulose, and 19.2 wt% pregelatinized starch.

Dosage forms of the invention

To prepare each dosage form of example 2, Quali-V HPMC capsules (supplied by Shionogi), model 00, were loaded with a single layer osmotic controlled release device as described above and 432mg of immediate release atorvastatin granules. The final dosage form contained 45mg of torcetrapib and 60mg of atorvastatin.

In vitro dissolution test

The in vitro test was performed according to the procedure described in example 1. The results are shown in table 2.

TABLE 2

Time (hours)	torcetrapib (wt% released)	Atorvastatin (wt% release)
Time (hours)	torcetrapib (wt% released)	Atorvastatin (wt% release)	0	0	0
0.5	0	70	0	0	0
0.5	0	70	1	0	80
2	2	82	1	0	80
2	2	82	4	22	82
8	56	93	4	22	82
8	56	93	10	64	97
12	69	98	10	64	97
12	69	98	16	71	100
18	72	100	16	71	100
18	72	100	20	71	100

The data indicate that the dosage form of example 2 provides immediate release of atorvastatin, providing 80% release within 1 hour. In addition, the dosage form of example 1 provides controlled release of torcetrapib, with a time to release 70 wt% of the drug from the dosage form of about 14 hours. After administration of the test vehicle, the dosage form released torcetrapib at an average rate of about 5.0 wt%/hour over the initial 14 hours.

The terms and expressions which have been employed in the foregoing specification are used as terms of description and not of limitation, and there is no intention, in the use of such terms and expressions, of excluding equivalents of the features shown and described or portions thereof, it being recognized that the scope of the invention is defined and limited only by the claims which follow.

Claims

1. A dosage form, comprising:

(a) a cholesteryl ester transfer protein inhibitor in a solubility-improved form, and

(b) HMG-CoA reductase inhibitors; wherein said dosage form provides immediate release of said HMG-CoA reductase inhibitor and controlled release of said cholesteryl ester transfer protein inhibitor.

2. The dosage form of claim 1, wherein said dosage form is a sustained release dosage form that releases 70 wt% of said cholesteryl ester transfer protein inhibitor in vivo or in vitro over a period of 2 hours or more after administration of the dosage form to an aqueous use environment.

3. The dosage form of claim 1, wherein upon administration to an in vivo use environment, said dosage form provides at least one of:

(i) inhibits at least 50% of plasma cholesteryl ester transfer protein for at least 12 hours;

(ii) (ii) a maximum blood concentration of less than or equal to 80% of the maximum blood concentration provided by an immediate release dosage form comprising an equivalent amount of a cholesteryl ester transfer protein inhibitor in a solubility-improved form;

(iii) 8 weeks after administration, the mean HDL cholesterol level is at least about 1.2-fold the level prior to administration; and

(iv) after 8 weeks of administration, the mean LDL cholesterol level was less than or equal to 90% of the level prior to administration.

4. The dosage form of claim 3, wherein upon administration to an in vivo environment of use, said dosage form provides at least two of:

(i) inhibiting at least 50% of plasma cholesteryl ester transfer protein for at least 12 hours;

5. The dosage form of any one of claims 1-4, wherein said dosage form comprises an immediate release composition comprising said HMG-CoA reductase inhibitor.

6. The dosage form of claim 1, wherein said dosage form comprises a kit.

7. The dosage form of any one of claims 1-6, wherein the cholesteryl ester transfer protein inhibitor is selected from compounds of formula I, formula II, formula III, formula IV, formula V, formula VI, formula VII, formula VIII, formula IX, formula X, formula XI, formula XII, formula XIII, formula XIV, formula XV, formula XVI, formula XVII, formula XVIII, and formula XIX.

8. The dosage form of any one of claims 1-6 wherein said cholesteryl ester transfer protein inhibitor is torcetrapib.

9. The dosage form of any of claims 1-6, wherein the HMG-CoA reductase inhibitor is selected from the group consisting of fluvastatin, lovastatin, pravastatin, atorvastatin, simvastatin, cerivastatin, rivastatin, mevastatin, velostatin, compactin, dalvastatin, fluindostatin, rosuvastatin, pitavastatin, dihydrocompactin and pharmaceutically acceptable forms thereof.

10. The dosage form of any one of claims 1-6, wherein said HMG-CoA reductase inhibitor is selected from the group consisting of atorvastatin, the cyclic lactone form of atorvastatin, a 2-hydroxy, 3-hydroxy or 4-hydroxy derivative of said compound, and pharmaceutically acceptable salts thereof.

11. The dosage form of claim 10, wherein the HMG-CoA reductase inhibitor is atorvastatin hemi-calcium trihydrate.

12. The dosage form of any one of claims 1 to 6 comprising torcetrapib and atorvastatin, or a pharmaceutically acceptable form thereof.

13. The dosage form of claim 12, wherein the dosage form provides a plasma concentration of torcetrapib of about 70ng/mL or more for about 12 hours or more after administration to an in vivo use environment.

14. The dosage form of any one of claims 1-13 wherein said solubility-improved form is a solid amorphous dispersion comprising said cholesteryl ester transfer protein inhibitor and a polymer.

15. The dosage form of any one of claims 1-13, wherein said solubility-improved form is selected from the group consisting of a lipid carrier comprising said cholesteryl ester transfer protein inhibitor, a solid adsorbate comprising a low solubility drug adsorbed to a matrix, a nanoparticle, a drug adsorbate in a cross-linked polymer, a nanosuspension, a supercooled form, a drug/cyclodextrin drug form, a soft gel form, a self-emulsifying form, a triphasic drug form, a crystalline highly soluble form, a high energy crystalline form, a hydrate or solvate crystalline form, an amorphous form, a mixture of said cholesteryl ester transfer protein inhibitor and a solubilizing agent, and a solution of said cholesteryl ester transfer protein inhibitor dissolved in a liquid.