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US 6,288,234 B1Granted
Multibinding inhibitors of microsomal triglyceride transferase protein
AssigneeAdvanced Medicine, Inc.
InventorJohn H. Griffin
Life of this patent
Estimating the term…
Abstract
Disclosed are multibinding compounds which inhibit microsomal triglyceride transferase protein (MTP), a protein which mediates the transfer of lipids during the assembly of lipoproteins and related biomolecules. The multibinding compounds contain from 2 to 10 ligands covalently attached to one or more linkers. The multibinding compounds of this invention are useful for lowering serum lipid, cholesterol and/or triglyceride levels, and for preventing and treating disorders associated with hyperlipemia, hyperlipidemia, hyperlipoproteinemia, hypercholestrolemia, hypertriglyceridemia and the like, such atherosclerosis.
Claims10
A compound of formula II:
- L′—X′—L′ II
- wherein each L′ is a ligand independently selected from the group consisting of:
- wherein
- each R20 and R21 is independently selected from the group consisting of hydrogen and halo;
- each R22 is independently selected from the group consisting of hydrogen, alkyl and halo;
- each R23 is independently selected from the group consisting of hydrogen and a covalent bond linking the ligand to the linker;
- each R24 is independently selected from the group consisting of hydrogen and a covalent bond linking the ligand to the linker;
- each R25 is independently selected from the group consisting of aryl, heteroaryl, heterocyclic, cycloalkyl, substituted cycloalkyl and a covalent bond linking the ligand to the linker;
- each R26 is independently selected from the group consisting of hydrogen, alkyl and a covalent bond linking the ligand to the linker;
- each Q″ is independently selected from the group consisting of a covalent bond, —O— and —S—;
- each a is independently an integer of from 2 to 6;
- X′ is a linker represented by the formula:
- —Xa—Z—(Ya—Z)m—Yb—Z—Xa—
- wherein
- m is an integer of from 0 to 20;
- Xa at each separate occurrence is selected from the group consisting of —O—, —S—, —NR—, —C(O)—, —C(O)O—, —C(O)NR—, —C(S), —C(S)O—, —C(S)NR— or a covalent bond where R is as defined below;
- Z is at each separate occurrence is selected from the group consisting of alkylene, substituted alkylene, cycloalkylene, substituted cylcoalkylene, alkenylene, substituted alkenylene, alkynylene, substituted alkynylene, cycloalkenylene, substituted cycloalkenylene, arylene, heteroarylene, heterocyclene, or a covalent bond;
- Ya and Yb at each separate occurrence are selected from the group consisting of —C(O)NR′—, —NR′C(O)—, —NR′C(O)NR′, —C(═NR′)—NR′, —NR′—C(═NR′)—, —NR′—C(O)—O—, —N═C(Xa)—NR′—, —P(O)(OR′)—O—, —S(O)nCR′R″—, —S(O)n—NR′—, —S—S— and a covalent bond;
- where n is 0, 1 or 2;
- and
- R, R′ and R″ at each separate occurrence are selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl and heterocyclic;
- and pharmaceutically-acceptable salts or pro-drugs thereof;
- provided that in each ligand only one of R23, R24, R25 and R26 is a covalent bond linking the ligand to the linker.
20 more elements
A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of a multibinding compound of formula II:
- L′—X′—L′ II
- wherein each L′ is a ligand independently selected from the group consisting of:
- wherein
- each R20 and R21 is independently selected from the group consisting of hydrogen and halo;
- each R22 is independently selected from the group consisting of hydrogen, alkyl and halo;
- each R23 is independently selected from the group consisting of hydrogen and a covalent bond linking the ligand to the linker;
- each R24 is independently selected from the group consisting of hydrogen and a covalent bond linking the ligand to the linker;
- each R25 is independently selected from the group consisting of aryl, heteroaryl, heterocyclic, cycloalkyl, substituted cycloalkyl and a covalent bond linking the ligand to the linker;
- each R26 is independently selected from the group consisting of hydrogen, alkyl and a covalent bond linking the ligand to the linker;
- each Q″ is independently selected from the group consisting of a covalent bond, —O— and —S—;
- each a is independently an integer of from 2 to 6;
- X′is a linker represented by the formula:
- —Xa—Z—(Ya—Z)m—Yb—Z—Xa—
- wherein
- m is an integer of from 0 to 20;
- Xa at each separate occurrence is selected from the group consisting of —O—, —S—, —NR—, —C(O)—, —C(O)O—, —C(O)NR—, —C(S), —C(S)O—, —C(S)NR— or a covalent bond where R is as defined below;
- Z is at each separate occurrence is selected from the group consisting of alkylene, substituted alkylene, cycloalkylene, substituted cylcoalkylene, alkenylene, substituted alkenylene, alkynylene, substituted alkynylene, cycloalkenylene, substituted cycloalkenylene, arylene, heteroarylene, heterocyclene, or a covalent bond;
- Ya and Yb at each separate occurrence are selected from the group consisting of —C(O)NR′—, —NR′C(O)—, —NR′C(O)NR′, —C(═NR′)—NR′, —NR′—C(═NR′)—, —NR′—C(O)—O—, —N═C(Xa)—NR′—, —P(O)(OR′)—O—, —S(O)nCR′R″—, —S(O)n—NR′—, —S—S— and a covalent bond;
- where n is 0, 1 or 2;
- and
- R, R′ and R″ at each separate occurrence are selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl and heterocyclic;
- and pharmaceutically-acceptable salts or pro-drugs thereof;
- provided that in each ligand only one of R23, R24, R25, and R26 is a covalent bond linking the ligand to the linker.
20 more elements
Dependencies are inferred from the claim text.