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US 6,713,650 B2Granted
ABCA-1 elevating compounds
OwnerPrabha N. Ibrahim, Robert Jiang +4inventors
InventorsPrabha N. Ibrahim, Robert Jiang, Christopher Morrison, Kevin Shenk, Jeff A. Zablocki, Richard Lawn
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Abstract
The present invention provides compounds that elevate cellular expression of the ABCA-1 gene, promoting cholesterol efflux from cells and increasing HDL levels in the plasma of a mammal, in particular humans. The compounds are useful for treating coronary artery disease.
Claims64
A method of treating a disease state in a mammal that is alleviable by treatment with an agent capable of increasing ABCA-1 expression, comprising administering to a mammal in need thereof a therapeutically effective dose of a compound of the Formula I:
- R1—X—Y—Z—NR2R3 Formula I
- wherein:
- R1 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl;
- R2 and R3 are independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;
- or
- R2 and R3 when taken together with the nitrogen atom to which they are attached form a heterocyclic moiety;
- X is oxygen, sulfur, or —NR4—;
- Y is optionally substituted alkylene or a covalent bond;
- wherein R4 is hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, —S(O)2R5, —C(O)R5, or —C(O)NHR5, in which R5 is optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;
- and
- Z is —C(O)—Z1—, —C(S)—Z1—, or —SO2—Z1—;
- in which Z1 is lower alkylene or a covalent bond;
- with the proviso that
- i. when R1, R2, or R3 is alkenyl or alkynyl, the double bond of the alkenyl or the triple bond of the alkynyl is located at least two carbon atoms away from the attachment to the nitrogen;
- ii. when X is NR4, Y and Z1 are not both covalent bonds;
- and
- iii. when X is NR4, R3 and R4 are not both hydrogen.
14 more elements
A compound of the Formula I:
- R1—X—Y—Z—NR2R3 Formula I
- wherein:
- R1 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl;
- R2 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;
- R3 is optionally substituted phenyl;
- or
- R2 and R3 when taken together with the nitrogen atom to which they are attached form a heterocyclic moiety;
- X is oxygen, sulfur, or —NR4—;
- Y is optionally substituted alkylene or a covalent bond;
- wherein R4 is hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, —S(O)2R5,—C(O)R5, or —C(O)NHR5, in which R5 is optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;
- and
- Z is —C(O)—Z1—, —C(S)—Z1—, or —S2—Z1—;
- in which Z1 is lower alkylene or a covalent with bond;
- the proviso that
- i. when R1, or R2 is alkenyl or alkynyl, the double bond of the alkenyl or the triple bond of the alkynyl is located at least two carbon atoms away from the attachment to the nitrogen;
- and
- ii. when R2 is hydrogen, R3 is phenyl, x is —NR4, Y is a covalent bond, and Z is —C(S)—CH2—, then R1 cannot be phenyl optionally substituted by methyl or halo;
- iii. when R2 is hydrogen, R3 is phenyl, X is —NR4, Y is methylene, and Z is —C(S)—, then R4 cannot be methyl or ethyl when R1 is cyclohexyl;
- and
- iv when X is NR4, R3 and R4 are not both hydrogen.
17 more elements
Dependencies are inferred from the claim text.