Pharmaceutical compositions of cholesteryl ester transfer protein inhibitors

A pharmaceutical composition comprising a solid amorphous dispersion of a cholesteryl ester transfer protein (CETP) inhibitor and a concentration-enhancing polymer, said cholesteryl ester transfer protein inhibitor having a solubility in aqueous solution, in the absence of said concentration-enhancing polymer, of less than 10 μg/ml at any pH of from 1 to 8, said concentration-enhancing polymer selected from the group consisting of hydroxypropyl methyl cellulose acetate, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, methyl cellulose, hydroxyethyl methyl cellulose, hydroxyethyl cellulose acetate, hydroxyethyl ethyl cellulose, hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose succinate, hydroxypropyl cellulose acetate succinate, hydroxyethyl methyl cellulose succinate, hydroxyethyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, hydroxyethyl methyl cellulose acetate succinate, hydroxyethyl methyl cellulose acetate phthalate, carboxyethyl cellulose, carboxymethyl cellulose, cellulose acetate phthalate, methyl cellulose acetate phthalate, ethyl cellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate, hydroxypropyl methyl cellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate succinate, hydroxypropyl methyl cellulose acetate succinate phthalate, hydroxypropyl methyl cellulose succinate phthalate, cellulose propionate phthalate, hydroxypropyl cellulose butyrate phthalate, cellulose acetate trimellitate, methyl cellulose acetate trimellitate, ethyl cellulose acetate trimellitate, hydroxypropyl cellulose acetate trimellitate, hydroxypropyl methyl cellulose acetate trimellitate, hydroxypropyl cellulose acetate trimellitate succinate, cellulose propionate trimellitate, cellulose butyrate trimellitate, cellulose acetate terephthalate, cellulose acetate isophthalate, cellulose acetate pyridinedicarboxylate, salicylic acid cellulose acetate, hydroxypropyl salicylic acid cellulose acetate, ethylbenzoic acid cellulose acetate, hydroxypropyl ethylbenzoic acid cellulose acetate, ethyl phthalic acid cellulose acetate, ethyl nicotinic acid cellulose acetate, and ethyl picolinic acid cellulose acetate;

• wherein said dispersion has a single glass transition temperature and said cholesteryl ester transfer protein inhibitor has the structure of Formula IV
• and pharmaceutically acceptable salts, enantiomers, or stereoisomers of said compounds;
• wherein RIV-1 is hydrogen, YIV, WIV—XIV or WIV—YIV;
• wherein WIV is a carbonyl, thiocarbonyl, sulfinyl or sulfonyl;
• XIV is —O—YIV, —S—YIV, —N(H)—YIV or —N—(YIV)2;
• wherein YIV for each occurrence is independently ZIV or a fully saturated, partially unsaturated or fully unsaturated one to ten membered straight or branched carbon chain wherein the carbons, other than the connecting carbon, may optionally be replaced with one or two heteroatoms selected independently from oxygen, sulfur and nitrogen and said carbon is optionally mono-, di- or tri-substituted independently with halo, said carbon is optionally mono-substituted with hydroxy, said carbon is optionally mono-substituted with oxo, said sulfur is optionally mono- or di-substituted with oxo, said nitrogen is optionally mono-, or di-substituted with oxo, and said carbon chain is optionally mono-substituted with ZIV;
• wherein ZIV is a partially saturated, fully saturated or fully unsaturated three to eight membered ring optionally having one to four heteroatoms selected independently from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated three to six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen;
• wherein said ZIV substituent is optionally mono-, di- or tri-substituted independently with halo, (C2–C6)alkenyl, (C1–C6)alkyl, hydroxy, (C1–C6)alkoxy, (C1–C4)alkylthio, amino, nitro, cyano, oxo, carboxy, (C1–C6)alkyloxycarbonyl, mono-N- or di-N,N-(C1–C6)alkylamino wherein said (C1–C6)alkyl substituent is optionally mono-, di- or tri-substituted independently with halo, hydroxy, (C1–C6)alkoxy, (C1–C4)alkylthio, amino, nitro, cyano, oxo, carboxy, (C1–C6)alkyloxycarbonyl, mono-N- or di-N,N-(C1–C6)alkylamino, said (C1–C6)alkyl substituent is also optionally substituted with from one to nine fluorines;
• RIV-2 is a partially saturated, fully saturated or fully unsaturated one to six membered straight or branched carbon chain wherein the carbons, other than the connecting carbon, may optionally be replaced with one or two heteroatoms selected independently from oxygen, sulfur and nitrogen wherein said carbon atoms are optionally mono-, di- or tri-substituted independently with halo, said carbon is optionally mono-substituted with oxo, said carbon is optionally mono-substituted with hydroxy, said sulfur is optionally mono- or di-substituted with oxo, said nitrogen is optionally mono- or di-substituted with oxo;
• or said RIV-2 is a partially saturated, fully saturated or fully unsaturated three to seven membered ring optionally having one to two heteroatoms selected independently from oxygen, sulfur and nitrogen, wherein said RIV-2 ring is optionally attached through (C1–C4)alkyl;
• wherein said RIV-2 ring is optionally mono-, di- or tri-substituted independently with halo, (C2–C6)alkenyl, (C1–C6)alkyl, hydroxy, (C1–C6)alkoxy, (C1–C4)alkylthio, amino, nitro, cyano, oxo, carboxy, (C1–C6)alkyloxycarbonyl, mono-N- or di-N,N-(C1–C6)alkylamino wherein said (C1–C6)alkyl substituent is optionally mono-, di- or tri-substituted independently with halo, hydroxy, (C1–C6)alkoxy, (C1–C4)alkylthio, oxo or (C1–C6)alkyloxycarbonyl;
• with the proviso that RIV-2 is not methyl;
• RIV-3 is hydrogen or QIV;
• wherein QIV is a fully saturated, partially unsaturated or fully unsaturated one to six membered straight or branched carbon chain wherein the carbons other than the connecting carbon, may optionally be replaced with one heteroatom selected from oxygen, sulfur and nitrogen and said carbon is optionally mono-, di- or tri-substituted independently with halo, said carbon is optionally mono-substituted with hydroxy, said carbon is optionally mono-substituted with oxo, said sulfur is optionally mono- or di-substituted with oxo, said nitrogen is optionally mono- or di-substituted with oxo, and said carbon chain is optionally mono-substituted with VIV;
• wherein VIV is a partially saturated, fully saturated or fully unsaturated three to eight membered ring optionally having one to four heteroatoms selected independently from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated three to six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen;
• wherein said VIV substituent is optionally mono-, di-, tri-, or tetra-substituted independently with halo, (C1–C6)alkyl, (C2–C6)alkenyl, hydroxy, (C1–C6)alkoxy, (C1–C4)alkylthio, amino, nitro, cyano, oxo, carboxamoyl, mono-N- or di-N,N-(C1–C6) alkylcarboxamoyl, carboxy, (C1–C6)alkyloxycarbonyl, mono-N- or di-N,N-(C1–C6)alkylamino wherein said (C1–C6)alkyl or (C2–C6)alkenyl substituent is optionally mono-, di- or tri-substituted independently with hydroxy, (C1–C6)alkoxy, (C1–C4)alkylthio, amino, nitro, cyano, oxo, carboxy, (C1–C6)alkyloxycarbonyl, mono-N- or di-N,N-(C1–C6)alkylamino, said (C1–C6)alkyl or (C2–C6)alkenyl substituents are also optionally substituted with from one to nine fluorines;
• RIV-4 is QIV-1 or VIV-1;
• wherein QIV-1 a fully saturated, partially unsaturated or fully unsaturated one to six membered straight or branched carbon chain wherein the carbons, other than the connecting carbon, may optionally be replaced with one heteroatom selected from oxygen, sulfur and nitrogen and said carbon is optionally mono-, di- or tri-substituted independently with halo, said carbon is optionally mono-substituted with hydroxy, said carbon is optionally mono-substituted with oxo, said sulfur is optionally mono- or di-substituted with oxo, said nitrogen is optionally mono- or di-substituted with oxo, and said carbon chain is optionally mono-substituted with VIV-1;
• wherein VIV-1 is a partially saturated, fully saturated or fully unsaturated three to six membered ring optionally having one to two heteroatoms selected independently from oxygen, sulfur and nitrogen;
• wherein said VIV-1 substituent is optionally mono-;
• di-, tri-, or tetra-substituted independently with halo, (C1–C6)alkyl, (C1–C6)alkoxy, amino, nitro, cyano, (C1–C6)alkyloxycarbonyl, mono-N- or di-N,N-(C1–C6)alkylamino wherein said (C1–C6)alkyl substituent is optionally mono-substituted with oxo, said (C1–C6)alkyl substituent is also optionally substituted with from one to nine fluorines;
• wherein either RIV-3 must contain VIV or RIV-4 must contain VIV-1;
• RIV-5, RIV-6, RIV-7 and RIV-8 are each independently hydrogen, a bond, nitro or halo wherein said bond is substituted with TIV or a partially saturated, fully saturated or fully unsaturated (C1–C12) straight or branched carbon chain wherein carbon, may optionally be replaced with one or two heteroatoms selected independently from oxygen, sulfur and nitrogen wherein said carbon atoms are optionally mono-, di- or tri-substituted independently with halo, said carbon is optionally mono-substituted with hydroxy, said carbon is optionally mono-substituted with oxo, said sulfur is optionally mono- or di-substituted with oxo, said nitrogen is optionally mono- or di-substituted with oxo, and said carbon is optionally mono-substituted with TIV;
• wherein TIV is a partially saturated, fully saturated or fully unsaturated three to eight membered ring optionally having one to four heteroatoms selected independently from oxygen, sulfur and nitrogen, or, a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated three to six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen;
• wherein said TIV substituent is optionally mono-, di- or tri-substituted independently with halo, (C1–C6)alkyl, (C2–C6)alkenyl, hydroxy, (C1–C6)alkoxy, (C1–C4)alkylthio, amino, nitro, cyano, oxo, carboxy, (C1–C6)alkyloxycarbonyl, mono-N- or di-N,N-(C1–C6)alkylamino wherein said (C1–C6)alkyl substituent is optionally mono-, di- or tri-substituted independently with hydroxy, (C1–C6)alkoxy, (C1–C4)alkylthio, amino, nitro, cyano, oxo, carboxy, (C1–C6)alkyloxycarbonyl, mono-N- or di-N,N-(C1–C6)alkylamino, said (C1–C6)alkyl substituent is also optionally substituted with from one to nine fluorines;
• and
• wherein RIV-5 and RIV-6, or RIV-6 and RIV-7, and/or RIV-7 and RIV-8 may also be taken together and can form at least one four to eight membered ring that is partially saturated or fully unsaturated optionally having one to three heteroatoms independently selected from nitrogen, sulfur and oxygen;
• wherein said ring or rings formed by RIV-5 and RIV-6, or RIV-6 and RIV-7, and/or RIV-7 and RIV-8 are optionally mono-, di- or tri-substituted independently with halo, (C1–C6)alkyl, (C1–C4)alkylsulfonyl, (C2–C6)alkenyl, hydroxy, (C1–C6)alkoxy, (C1–C4)alkylthio, amino, nitro, cyano, oxo, carboxy, (C1–C6)alkyloxycarbonyl, mono-N- or di-N,N-(C1–C6)alkylamino wherein said (C1–C6)alkyl substituent is optionally mono-, di- or tri-substituted independently with hydroxy, (C1–C6)alkoxy, (C1–C6)alkylthio, amino, nitro, cyano, oxo, carboxy, (C1–C6)alkyloxycarbonyl, mono-N- or di-N,N-(C1–C6)alkylamino, said (C1–C6)alkyl substituent is also optionally substituted with from one to nine fluorines;
• with the proviso that when RIV-2 is carboxyl or (C1–C4)alkylcarboxyl, then RIV-1 is not hydrogen;
• and
• wherein said composition provides a maximum concentration of the CETP inhibitor in a use environment that is at least about ten-fold the maximum concentration provided by a control composition comprising an equivalent amount of the CETP inhibitor and free from said polymer.

A pharmaceutical composition comprisng a solid amorphous dispersion of a cholesteryl ester transfer protein inhibitor and a concentration-enhancing polymer, said composition providing a maximum concentration of said cholesteryl ester transfer protein inhibitor in a use environment that is at least 10-fold the maximum concentration provided by a control composition comprising an equivalent amount of said cholesteryl ester transfer protein inhibitor and free from said concentration-enhancing polymer, said concentration-enhancing polymer selected from the group consisting of hydroxypropyl methyl cellulose acetate, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, methyl cellulose, hydroxyethyl methyl cellulose, hydroxyethyl cellulose acetate, hydroxyethyl ethyl cellulose, hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose succinate, hydroxypropyl cellulose acetate succinate, hydroxyethyl methyl cellulose succinate, hydroxyethyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, hydroxyethyl methyl cellulose acetate succinate, hydroxyethyl methyl cellulose acetate phthalate, carboxyethyl cellulose, carboxymethyl cellulose, cellulose acetate phthalate, methyl cellulose acetate phthalate, ethyl cellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate, hydroxypropyl methyl cellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate succinate, hydroxypropyl methyl cellulose acetate succinate phthalate, hydroxypropyl methyl cellulose succinate phthalate, cellulose propionate phthalate, hydroxypropyl cellulose butyrate phthalate, cellulose acetate trimellitate, methyl cellulose acetate trimellitate, ethyl cellulose acetate trimellitate, hydroxypropyl cellulose acetate trimellitate, hydroxypropyl methyl cellulose acetate trimellitate, hydroxypropyl cellulose acetate trimellitate succinate, cellulose propionate trimellitate, cellulose butyrate trimellitate, cellulose acetate terephthalate, cellulose acetate isophthalate, cellulose acetate pyridinedicarboxylate, salicylic acid cellulose acetate, hydroxypropyl salicylic acid cellulose acetate, ethylbenzoic acid cellulose acetate, hydroxypropyl ethylbenzoic acid cellulose acetate, ethyl phthalic acid cellulose acetate, ethyl nicotinic acid cellulose acetate, and ethyl picolinic acid cellulose acetate;

• wherein said dispersion has a single glass transition temperature and said cholesteryl ester transfer protein inhibitor has the structure of Formula IV
• and pharmaceutically acceptable salts, enantiomers, or stereoisomers of said compounds:
• wherein RIV-1 is hydrogen, YIV, WIV—XIV or WIV—YIV;
• wherein WIV is a carbonyl, thiocarbonyl, sulfinyl or sulfonyl;
• XIV is —O—YIV, —S—YIV, —N(H)—YIV or —N—(YIV)2;
• wherein YIV for each occurrence is independently ZIV or a fully saturated, partially unsaturated or fully unsaturated one to ten membered straight or branched carbon chain wherein the carbons, other than the connecting carbon, may optionally be replaced with one or two heteroatoms selected independently from oxygen, sulfur and nitrogen and said carbon is optionally mono-, di- or tri-substituted independently with halo, said carbon is optionally mono-substituted with hydroxy, said carbon is optionally mono-substituted with oxo, said sulfur is optionally mono- or di-substituted with oxo, said nitrogen is optionally mono-, or di-substituted with oxo, and said carbon chain is optionally mono-substituted with ZIV;
• wherein ZIV is a partially saturated, fully saturated or fully unsaturated three to eight membered ring optionally having one to four heteroatoms selected independently from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated three to six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen;
• wherein said ZIV substituent is optionally mono-, di- or tri-substituted independently with halo, (C2–C6)alkenyl, (C1–C6)alkyl, hydroxy, (C1–C6)alkoxy, (C1–C4)alkylthio, amino, nitro, cyano, oxo, carboxy, (C1–C6)alkyloxycarbonyl, mono-N- or di-N,N-(C1–C6)alkylamino wherein said (C1–C6)alkyl substituent is optionally mono-, di- or tri-substituted independently with halo, hydroxy, (C1–C6)alkoxy, (C1–C4)alkylthio, amino, nitro, cyano, oxo, carboxy, (C1–C6)alkyloxycarbonyl, mono-N- or di-N,N-(C1–C6)alkylamino, said (C1–C6)alkyl substituent is also optionally substituted with from one to nine fluorines;
• RIV-2 is a partially saturated, fully saturated or fully unsaturated one to six membered straight or branched carbon chain wherein the carbons, other than the connecting carbon, may optionally be replaced with one or two heteroatoms selected independently from oxygen, sulfur and nitrogen wherein said carbon atoms are optionally mono-, di- or tri-substituted independently with halo, said carbon is optionally mono-substituted with oxo, said carbon is optionally mono-substituted with hydroxy, said sulfur is optionally mono- or di-substituted with oxo, said nitrogen is optionally mono- or di-substituted with oxo;
• or said RIV-2 is a partially saturated, fully saturated or fully unsaturated three to seven membered ring optionally having one to two heteroatoms selected independently from oxygen, sulfur and nitrogen, wherein said RIV-2 ring is optionally attached through (C1–C4)alkyl;
• wherein said RIV-2 ring is optionally mono-, di- or tri-substituted independently with halo, (C2–C6)alkenyl, (C1–C6)alkyl, hydroxy, (C1–C6)alkoxy, (C1–C4)alkylthio, amino, nitro, cyano, oxo, carboxy, (C1–C6)alkyloxycarbonyl, mono-N- or di-N,N-(C1–C6)alkylamino wherein said (C1–C6)alkyl substituent is optionally mono-, di- or tri-substituted independently with halo, hydroxy, (C1–C6)alkoxy, (C1–C4)alkylthio, oxo or (C1–C6)alkyloxycarbonyl;
• with the proviso that RIV-2 is not methyl;
• RIV-3 is hydrogen or QIV;
• wherein QIV is a fully saturated, partially unsaturated or fully unsaturated one to six membered straight or branched carbon chain wherein the carbons other than the connecting carbon, may optionally be replaced with one heteroatom selected from oxygen, sulfur and nitrogen and said carbon is optionally mono-, di- or tri-substituted independently with halo, said carbon is optionally mono-substituted with hydroxy, said carbon is optionally mono-substituted with oxo, said sulfur is optionally mono- or di-substituted with oxo, said nitrogen is optionally mono- or di-substituted with oxo, and said carbon chain is optionally mono-substituted with VIV;
• wherein VIV is a partially saturated, fully saturated or fully unsaturated three to eight membered ring optionally having one to four heteroatoms selected independently from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated three to six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen;
• wherein said VIV substituent is optionally mono-, di-, tri-, or tetra-substituted independently with halo, (C1–C6)alkyl, (C2–C6)alkenyl, hydroxy, (C1–C6)alkoxy, (C1–C4)alkylthio, amino, nitro, cyano, oxo, carboxamoyl, mono-N- or di-N,N-(C1–C6) alkylcarboxamoyl, carboxy, (C1–C6)alkyloxycarbonyl, mono-N- or di-N,N-(C1–C6)alkylamino wherein said (C1–C6)alkyl or (C2–C6)alkenyl substituent is optionally mono-, di- or tri-substituted independently with hydroxy, (C1–C6)alkoxy, (C1–C4)alkylthio, amino, nitro, cyano, oxo, carboxy, (C1–C6)alkyloxycarbonyl, mono-N- or di-N,N-(C1–C6)alkylamino, said (C1–C6)alkyl or (C2–C6)alkenyl substituents are also optionally substituted with from one to nine fluorines;
• RIV-4 is QIV-1 or VIV-1;
• wherein QIV-1 a fully saturated, partially unsaturated or fully unsaturated one to six membered straight or branched carbon chain wherein the carbons, other than the connecting carbon, may optionally be replaced with one heteroatom selected from oxygen, sulfur and nitrogen and said carbon is optionally mono-, di- or tri-substituted independently with halo, said carbon is optionally mono-substituted with hydroxy, said carbon is optionally mono-substituted with oxo, said sulfur is optionally mono- or di-substituted with oxo, said nitrogen is optionally mono- or di-substituted with oxo, and said carbon chain is optionally mono-substituted with VIV-1;
• wherein VIV-1 is a partially saturated, fully saturated or fully unsaturated three to six membered ring optionally having one to two heteroatoms selected independently from oxygen, sulfur and nitrogen;
• wherein said VIV-1 substituent is optionally mono-;
• di-, tri-, or tetra-substituted independently with halo, (C1–C6)alkyl, (C1–C6)alkoxy, amino, nitro, cyano, (C1–C6)alkyloxycarbonyl, mono-N- or di-N,N-(C1–C6)alkylamino wherein said (C1–C6)alkyl substituent is optionally mono-substituted with oxo, said (C1–C6)alkyl substituent is also optionally substituted with from one to nine fluorines;
• wherein either RIV-3 must contain VIV or RIV-4 must contain VIV-1;
• RIV-5, RIV-6, RIV-7 and RIV-8 are each independently hydrogen, a bond, nitro or halo wherein said bond is substituted with TIV or a partially saturated, fully saturated or fully unsaturated (C1–C12) straight or branched carbon chain wherein carbon, may optionally be replaced with one or two heteroatoms selected independently from oxygen, sulfur and nitrogen wherein said carbon atoms are optionally mono-, di- or tri-substituted independently with halo, said carbon is optionally mono-substituted with hydroxy, said carbon is optionally mono-substituted with oxo, said sulfur is optionally mono- or di-substituted with oxo, said nitrogen is optionally mono- or di-substituted with oxo, and said carbon is optionally mono-substituted with TIV;
• wherein TIV is a partially saturated, fully saturated or fully unsaturated three to eight membered ring optionally having one to four heteroatoms selected independently from oxygen, sulfur and nitrogen, or, a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated three to six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen;
• wherein said TIV substituent is optionally mono-, di- or tri-substituted independently with halo, (C1–C6)alkyl, (C2–C6)alkenyl, hydroxy, (C1–C6)alkoxy, (C1–C4)alkylthio, amino, nitro, cyano, oxo, carboxy, (C1–C6)alkyloxycarbonyl, mono-N- or di-N,N-(C1–C6)alkylamino wherein said (C1–C6)alkyl substituent is optionally mono-, di- or tri-substituted independently with hydroxy, (C1–C6)alkoxy, (C1–C4)alkylthio, amino, nitro, cyano, oxo, carboxy, (C1–C6)alkyloxycarbonyl, mono-N- or di-N,N-(C1–C6)alkylamino, said (C1–C6)alkyl substituent is also optionally substituted with from one to nine fluorines;
• and
• wherein RIV-5 and RIV-6, or RIV-6 and RIV-7, and/or RIV-7 and RIV-8 may also be taken together and can form at least one four to eight membered ring that is partially saturated or fully unsaturated optionally having one to three heteroatoms independently selected from nitrogen, sulfur and oxygen;
• wherein said ring or rings formed by RIV-5 and RIV-6, or RIV-6 and RIV-7, and/or RIV-7 and RIV-8 are optionally mono-, di- or tri-substituted independently with halo, (C1–C6)alkyl, (C1–C4)alkylsulfonyl, (C2–C6)alkenyl, hydroxy, (C1–C6)alkoxy, (C1–C4)alkylthio, amino, nitro, cyano, oxo, carboxy, (C1–C6)alkyloxycarbonyl, mono-N- or di-N,N-(C1–C6)alkylamino wherein said (C1–C6)alkyl substituent is optionally mono-, di- or tri-substituted independently with hydroxy, (C1–C6)alkoxy, (C1–C6)alkylthio, amino, nitro, cyano, oxo, carboxy, (C1–C6)alkyloxycarbonyl, mono-N- or di-N,N-(C1–C6)alkylamino, said (C1–C6)alkyl substituent is also optionally substituted with from one to nine fluorines;
• with the proviso that when RIV-2 is carboxyl or (C1–C4)alkylcarboxyl, then RIV-1 is not hydrogen.

A pharmaceutical composition comprising a solid amorphous dispersion of a cholesteryl ester transfer protein inhibitor and a polymer, said composition providing a relative bioavailability that is at least 4 relative to a control composition comprising an equivalent amount of said cholesteryl ester transfer protein inhibitor and free from said polymer, said polymer selected from the group consisting of hydroxypropyl methyl cellulose acetate, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, methyl cellulose, hydroxyethyl methyl cellulose, hydroxyethyl cellulose acetate, hydroxyethyl ethyl cellulose, hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose succinate, hydroxypropyl cellulose acetate succinate, hydroxyethyl methyl cellulose succinate, hydroxyethyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, hydroxyethyl methyl cellulose acetate succinate, hydroxyethyl methyl cellulose acetate phthalate, carboxyethyl cellulose, carboxymethyl cellulose, cellulose acetate phthalate, methyl cellulose acetate phthalate, ethyl cellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate, hydroxypropyl methyl cellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate succinate, hydroxypropyl methyl cellulose acetate succinate phthalate, hydroxypropyl methyl cellulose succinate phthalate, cellulose propionate phthalate, hydroxypropyl cellulose butyrate phthalate, cellulose acetate trimellitate, methyl cellulose acetate trimellitate, ethyl cellulose acetate trimellitate, hydroxypropyl cellulose acetate trimellitate, hydroxypropyl methyl cellulose acetate trimellitate, hydroxypropyl cellulose acetate trimellitate succinate, cellulose propionate trimellitate, cellulose butyrate trimellitate, cellulose acetate terephthalate, cellulose acetate isophthalate, cellulose acetate pyridinedicarboxylate, salicylic acid cellulose acetate, hydroxypropyl salicylic acid cellulose acetate, ethylbenzoic acid cellulose acetate, hydroxypropyl ethylbenzoic acid cellulose acetate, ethyl phthalic acid cellulose acetate, ethyl nicotinic acid cellulose acetate, and ethyl picolinic acid cellulose acetate;

• wherein said dispersion has a single glass transition temperature and said cholesteryl ester transfer protein inhibitor has the structure of Formula IV
• and pharmaceutically acceptable salts, enantiomers, or stereoisomers of said compounds:
• wherein RIV-1 is hydrogen, YIV, WIV—XIV or WIV—YIV;
• wherein WIV is a carbonyl, thiocarbonyl, sulfinyl or sulfonyl;
• XIV is —O—YIV, —S—YIV, —N(H)—YIV or —N—(YIV)2;
• wherein YIV for each occurrence is independently ZIV or a fully saturated, partially unsaturated or fully unsaturated one to ten membered straight or branched carbon chain wherein the carbons, other than the connecting carbon, may optionally be replaced with one or two heteroatoms selected independently from oxygen, sulfur and nitrogen and said carbon is optionally mono-, di- or tri-substituted independently with halo, said carbon is optionally mono-substituted with hydroxy, said carbon is optionally mono-substituted with oxo, said sulfur is optionally mono- or di-substituted with oxo, said nitrogen is optionally mono-, or di-substituted with oxo, and said carbon chain is optionally mono-substituted with ZIV;
• wherein ZIV is a partially saturated, fully saturated or fully unsaturated three to eight membered ring optionally having one to four heteroatoms selected independently from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated three to six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen;
• wherein said ZIV substituent is optionally mono-, di- or tri-substituted independently with halo, (C2–C6)alkenyl, (C1–C6)alkyl, hydroxy, (C1–C6)alkoxy, (C1–C4)alkylthio, amino, nitro, cyano, oxo, carboxy, (C1–C6)alkyloxycarbonyl, mono-N- or di-N,N-(C1–C6)alkylamino wherein said (C1–C6)alkyl substituent is optionally mono-, di- or tri-substituted independently with halo, hydroxy, (C1–C6)alkoxy, (C1–C4)alkylthio, amino, nitro, cyano, oxo, carboxy, (C1–C6)alkyloxycarbonyl, mono-N- or di-N,N-(C1–C6)alkylamino, said (C1–C6)alkyl substituent is also optionally substituted with from one to nine fluorines;
• RIV-2 is a partially saturated, fully saturated or fully unsaturated one to six membered straight or branched carbon chain wherein the carbons, other than the connecting carbon, may optionally be replaced with one or two heteroatoms selected independently from oxygen, sulfur and nitrogen wherein said carbon atoms are optionally mono-, di- or tri-substituted independently with halo, said carbon is optionally mono-substituted with oxo, said carbon is optionally mono-substituted with hydroxy, said sulfur is optionally mono- or di-substituted with oxo, said nitrogen is optionally mono- or di-substituted with oxo;
• or said RIV-2 is a partially saturated, fully saturated or fully unsaturated three to seven membered ring optionally having one to two heteroatoms selected independently from oxygen, sulfur and nitrogen, wherein said RIV-2 ring is optionally attached through (C1–C4)alkyl;
• wherein said RIV-2 ring is optionally mono-, di- or tri-substituted independently with halo, (C2–C6)alkenyl, (C1–C6)alkyl, hydroxy, (C1–C6)alkoxy, (C1–C4)alkylthio, amino, nitro, cyano, oxo, carboxy, (C1–C6)alkyloxycarbonyl, mono-N- or di-N,N-(C1–C6)alkylamino wherein said (C1–C6)alkyl substituent is optionally mono-, di- or tri-substituted independently with halo, hydroxy, (C1–C6)alkoxy, (C1–C4)alkylthio, oxo or (C1–C6)alkyloxycarbonyl;
• with the proviso that RIV-2 is not methyl;
• RIV-3 is hydrogen or QIV;
• wherein QIV is a fully saturated, partially unsaturated or fully unsaturated one to six membered straight or branched carbon chain wherein the carbons other than the connecting carbon, may optionally be replaced with one heteroatom selected from oxygen, sulfur and nitrogen and said carbon is optionally mono-, di- or tri-substituted independently with halo, said carbon is optionally mono-substituted with hydroxy, said carbon is optionally mono-substituted with oxo, said sulfur is optionally mono- or di-substituted with oxo, said nitrogen is optionally mono- or di-substituted with oxo, and said carbon chain is optionally mono-substituted with VIV;
• wherein VIV is a partially saturated, fully saturated or fully unsaturated three to eight membered ring optionally having one to four heteroatoms selected independently from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated three to six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen;
• wherein said VIV substituent is optionally mono-, di-, tri-, or tetra-substituted independently with halo, (C1–C6)alkyl, (C2–C6)alkenyl, hydroxy, (C1–C6)alkoxy, (C1–C4)alkylthio, amino, nitro, cyano, oxo, carboxamoyl, mono-N- or di-N,N-(C1–C6) alkylcarboxamoyl, carboxy, (C1–C6)alkyloxycarbonyl, mono-N- or di-N,N-(C1–C6)alkylamino wherein said (C1–C6)alkyl or (C2–C6)alkenyl substituent is optionally mono-, di- or tri-substituted independently with hydroxy, (C1–C6)alkoxy, (C1–C4)alkylthio, amino, nitro, cyano, oxo, carboxy, (C1–C6)alkyloxycarbonyl, mono-N- or di-N,N-(C1–C6)alkylamino, said (C1–C6)alkyl or (C2–C6)alkenyl substituents are also optionally substituted with from one to nine fluorines;
• RIV-4 is QIV-1 or VIV-1;
• wherein QIV-1 a fully saturated, partially unsaturated or fully unsaturated one to six membered straight or branched carbon chain wherein the carbons, other than the connecting carbon, may optionally be replaced with one heteroatom selected from oxygen, sulfur and nitrogen and said carbon is optionally mono-, di- or tri-substituted independently with halo, said carbon is optionally mono-substituted with hydroxy, said carbon is optionally mono-substituted with oxo, said sulfur is optionally mono- or di-substituted with oxo, said nitrogen is optionally mono- or di-substituted with oxo, and said carbon chain is optionally mono-substituted with VIV-1;
• wherein VIV-1 is a partially saturated, fully saturated or fully unsaturated three to six membered ring optionally having one to two heteroatoms selected independently from oxygen, sulfur and nitrogen;
• wherein said VIV-1 substituent is optionally mono-;
• di-, tri-, or tetra-substituted independently with halo, (C1–C6)alkyl, (C1–C6)alkoxy, amino, nitro, cyano, (C1–C6)alkyloxycarbonyl, mono-N- or di-N,N-(C1–C6)alkylamino wherein said (C1–C6)alkyl substituent is optionally mono-substituted with oxo, said (C1–C6)alkyl substituent is also optionally substituted with from one to nine fluorines;
• wherein either RIV-3 must contain VIV or RIV-4 must contain VIV-1;
• RIV-5, RIV-6, RIV-7 and RIV-8 are each independently hydrogen, a bond, nitro or halo wherein said bond is substituted with TIV or a partially saturated, fully saturated or fully unsaturated (C1–C12) straight or branched carbon chain wherein carbon, may optionally be replaced with one or two heteroatoms selected independently from oxygen, sulfur and nitrogen wherein said carbon atoms are optionally mono-, di- or tri-substituted independently with halo, said carbon is optionally mono-substituted with hydroxy, said carbon is optionally mono-substituted with oxo, said sulfur is optionally mono- or di-substituted with oxo, said nitrogen is optionally mono- or di-substituted with oxo, and said carbon is optionally mono-substituted with TIV;
• wherein TIV is a partially saturated, fully saturated or fully unsaturated three to eight membered ring optionally having one to four heteroatoms selected independently from oxygen, sulfur and nitrogen, or, a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated three to six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen;
• wherein said TIV substituent is optionally mono-, di- or tri-substituted independently with halo, (C1–C6)alkyl, (C2–C6)alkenyl, hydroxy, (C1–C6)alkoxy, (C1–C4)alkylthio, amino, nitro, cyano, oxo, carboxy, (C1–C6)alkyloxycarbonyl, mono-N- or di-N,N-(C1–C6)alkylamino wherein said (C1–C6)alkyl substituent is optionally mono-, di- or tri-substituted independently with hydroxy, (C1–C6)alkoxy, (C1–C4)alkylthio, amino, nitro, cyano, oxo, carboxy, (C1–C6)alkyloxycarbonyl, mono-N- or di-N,N-(C1–C6)alkylamino, said (C1–C6)alkyl substituent is also optionally substituted with from one to nine fluorines;
• and
• wherein RIV-5 and RIV-6, or RIV-6 and RIV-7, and/or RIV-7 and RIV-8 may also be taken together and can form at least one four to eight membered ring that is partially saturated or fully unsaturated optionally having one to three heteroatoms independently selected from nitrogen, sulfur and oxygen;
• wherein said ring or rings formed by RIV-5 and RIV-6, or RIV-6 and RIV-7, and/or RIV-7 and RIV-8 are optionally mono-, di- or tri-substituted independently with halo, (C1–C6)alkyl, (C1–C4)alkylsulfonyl, (C2–C6)alkenyl, hydroxy, (C1–C6)alkoxy, (C1–C4)alkylthio, amino, nitro, cyano, oxo, carboxy, (C1–C6)alkyloxycarbonyl, mono-N- or di-N,N-(C1–C6)alkylamino wherein said (C1–C6)alkyl substituent is optionally mono-, di- or tri-substituted independently with hydroxy, (C1–C6)alkoxy, (C1–C6)alkylthio, amino, nitro, cyano, oxo, carboxy, (C1–C6)alkyloxycarbonyl, mono-N- or di-N,N-(C1–C6)alkylamino, said (C1–C6)alkyl substituent is also optionally substituted with from one to nine fluorines;
• with the proviso that when RIV-2 is carboxyl or (C1–C4)alkylcarboxyl, then RIV-1 is not hydrogen.