US 2003/0125357 A1Published application

Therapeutic compounds for treating dyslipidemic conditions

AssigneeMerck & Co., Inc.

InventorsAlan D. Adams, Aileen Bouffard, James F. Dropinski, Clare E. Gutteridge, A. Brian Jones, Weiguo Lui, John George Ondeyka, Ali Shiafee, Sheo Bux Singh

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Abstract

Compounds of Formula I 1 and the pharmaceutically acceptable salts and esters thereof, wherein Z is selected from the group consisting of: (a) Formula Ia 2 and (b) Formula Ib 3 are novel LXR agonists and are useful in the treatment of dyslipidemic conditions particularly depressed levels of HDL cholesterol.

Claims25

Dependent claims

A compound of Formula I:

87
and the pharmaceutically acceptable salts and esters thereof, wherein
Z is selected from the group consisting of:
(a) Formula Ia
88
and
(b) Formula Ib
89
wherein Formula Ib represents a saturated heterocyclic ring containing one tertiary nitrogen atom and 5 or 6 carbon atoms, wherein each carbon atom is independently unsubstituted or substituted with at least one substituent selected from the group consisting of:
(i) —C1-4 alkyl,
(ii) phenyl, unsubstituted or substituted with at least one —C1-4 alkyl substituent,
(iii) —CH2-phenyl, wherein phenyl is unsubstituted or substituted with at least one —C1-4 alkyl substituent,
(iv) —COOH and
(v) —COOC1-4 alkyl;
X is selected from the group consisting of:
(a) —NH,
(b) —O— and
(c) —CH2—;
R1 is selected from the group consisting of:
(a) —H,
(b) —OH and
(c) —OC(O)CH3;
R2 and R3 are independently selected from the group consisting of:
(a) —H and
(b) —C1-4 alkyl,
or R2 and R3 together represent ═O;
n is an integer selected from zero and 1;
R4 and R5 represent moieties selected from those defined in the following groups:
(a) R4 and R5 are independently selected from the group consisting of
(i) —H and
(ii) phenyl, unsubstituted or substituted with a group selected from halo, —C1-4 alkyl and —O—C1-4 alkyl,
(b) R4 and R5 together represent —(CH2)m— which joins together with the carbon in Formula Ia to which R4 and R5 are commonly attached to form a cycloalkyl ring, and wherein m is an integer selected from 2 through 5,
(c) R4 and R5 are each alkyl groups joined together with the carbon in Formula Ia to which they are commonly attached to form a carbon-bridged polycycloalkyl ring system selected from isopinylcampheyl and adamantyl, wherein the ring system is unsubstituted or substituted with —C1-4 alkyl,
(d) R4, R5 and R6 are each alkyl groups joined together with the carbon in Formula Ia to which they are commonly attached to form a carbon-bridged polycycloalkyl ring system which is adamantyl, wherein the ring system is unsubstituted or substituted with —C1-4 alkyl, and
(e) R4, R5 and R6 together with the carbon in Formula Ia to which they are commonly attached represent
90
provided R6 is not joined together with R4 and R5 as described above, then R6 is selected from the group consisting of:
(a) —H and
(b) phenyl, unsubstituted or substituted with a group selected from halo, —C1-4 alkyl and —O—C1-4 alkyl,
except that when R4 and R5 are each alkyl groups joined together with the carbon in Formula Ia to which they are commonly attached to form a carbon-bridged polycycloalkyl ring system, then R6 is —H;
R7 is selected from the group consisting of:
(a) —H,
(b) —OH and
(c) —OC(O)CH3;
and
provided that when n is 1, and R2 and R3 together represent ═O, and R4, R5 and R6 together with the carbon in Formula I to which they are commonly attached represent
91
and R1 is —OC(O)CH3 and R7 is —OC(O)CH3, then X is not —O—.

45 more elements

Dependencies are inferred from the claim text.

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Abstract

A compound of Formula I:

87
and the pharmaceutically acceptable salts and esters thereof, wherein
Z is selected from the group consisting of:
(a) Formula Ia
88
and
(b) Formula Ib
89
wherein Formula Ib represents a saturated heterocyclic ring containing one tertiary nitrogen atom and 5 or 6 carbon atoms, wherein each carbon atom is independently unsubstituted or substituted with at least one substituent selected from the group consisting of:
(i) —C1-4 alkyl,
(ii) phenyl, unsubstituted or substituted with at least one —C1-4 alkyl substituent,
(iii) —CH2-phenyl, wherein phenyl is unsubstituted or substituted with at least one —C1-4 alkyl substituent,
(iv) —COOH and
(v) —COOC1-4 alkyl;
X is selected from the group consisting of:
(a) —NH,
(b) —O— and
(c) —CH2—;
R1 is selected from the group consisting of:
(a) —H,
(b) —OH and
(c) —OC(O)CH3;
R2 and R3 are independently selected from the group consisting of:
(a) —H and
(b) —C1-4 alkyl,
or R2 and R3 together represent ═O;
n is an integer selected from zero and 1;
R4 and R5 represent moieties selected from those defined in the following groups:
(a) R4 and R5 are independently selected from the group consisting of
(i) —H and
(ii) phenyl, unsubstituted or substituted with a group selected from halo, —C1-4 alkyl and —O—C1-4 alkyl,
(b) R4 and R5 together represent —(CH2)m— which joins together with the carbon in Formula Ia to which R4 and R5 are commonly attached to form a cycloalkyl ring, and wherein m is an integer selected from 2 through 5,
(c) R4 and R5 are each alkyl groups joined together with the carbon in Formula Ia to which they are commonly attached to form a carbon-bridged polycycloalkyl ring system selected from isopinylcampheyl and adamantyl, wherein the ring system is unsubstituted or substituted with —C1-4 alkyl,
(d) R4, R5 and R6 are each alkyl groups joined together with the carbon in Formula Ia to which they are commonly attached to form a carbon-bridged polycycloalkyl ring system which is adamantyl, wherein the ring system is unsubstituted or substituted with —C1-4 alkyl, and
(e) R4, R5 and R6 together with the carbon in Formula Ia to which they are commonly attached represent
90
provided R6 is not joined together with R4 and R5 as described above, then R6 is selected from the group consisting of:
(a) —H and
(b) phenyl, unsubstituted or substituted with a group selected from halo, —C1-4 alkyl and —O—C1-4 alkyl,
except that when R4 and R5 are each alkyl groups joined together with the carbon in Formula Ia to which they are commonly attached to form a carbon-bridged polycycloalkyl ring system, then R6 is —H;
R7 is selected from the group consisting of:
(a) —H,
(b) —OH and
(c) —OC(O)CH3;
and
provided that when n is 1, and R2 and R3 together represent ═O, and R4, R5 and R6 together with the carbon in Formula I to which they are commonly attached represent
91
and R1 is —OC(O)CH3 and R7 is —OC(O)CH3, then X is not —O—.

45 more elements