Modulators of hepatic lipoprotein metabolism

Patent metadata

Field	Value
Publication number	US-9526720-B2
Application number	US-201314421778-A
Country	US
Kind code	B2
Filing date	Aug 19, 2013
Priority date	Aug 17, 2012
Publication date	Dec 27, 2016
Grant date	Dec 27, 2016

Abstract

The present invention relates to compounds that are useful for modulating hepatic cholesterol metabolism in an animal. The invention includes methods of making and using the compounds of the invention. The invention further provides methods of treating, preventing and/or alleviating a cholesterol related disorder, a cardiovascular disease and/or liver disease in an animal, such as a human, comprising administering compounds of the invention, or pharmaceutically acceptable salts or solvates thereof, to the animal.

First claim

What is claimed:

1. A method of increasing the LDL uptake or the LDL receptor level in at least one cell, the method comprising contacting the at least one cell with a therapeutically effective amount of at least one agent comprising a compound of formula (XV) and at least one pharmaceutically acceptable carrier or excipient; and any pharmaceutically acceptable salts thereof

wherein in the compound of formula (XV):
Q is S(O) p , C(O), bond, C(O)NR 8 , C(O)CH 2 , C(O)O, or C(O)OCH 2 ;
R 12 is halogen, C 1 -C 8 alkyl, CF 3 , N(C 1 -C 8 alkyl) 2 or OR 13 ;
R 13 is C 1 -C 8 alkyl or hydrogen;
R 4 and R 5 are each independently selected from the group consisting of hydrogen, 4-6 membered heterocyclic ring, C 3 -C 8 cycloalkyl ring and (CH 2 ) S -aromatic ring,
further wherein the heterocyclic, cycloalkyl, or aromatic ring is unsubstituted or substituted with one or more R x ;

or R 4 and R 5 taken together form a 4-6 membered heterocyclic ring,
optionally substituted at two adjacent carbon atoms on the heterocylic ring, which can optionally be taken together to form a fused aromatic ring;

R 6 is selected from the group consisting of hydrogen, O(C 1 -C 8 alkyl), O-aromatic ring, O(C 3 -C 8 cycloalkyl ring), and OH;
R x is selected from the group consisting of (CH 2 ) g -aromatic ring and OR 10 , or two R x on adjacent carbon atoms are taken together form a fused aromatic ring;
R 10 is aromatic ring;
R 8 and R 9 are each independently selected from the group consisting of hydrogen, C 1 -C 8 alkyl, (CH 2 ) t -4-8 membered heterocyclic ring, and (CH 2 ) v -aromatic ring,
further where the alkyl, aromatic ring or heterocyclic ring are unsubstituted or substituted with one or more R z ;

R z is selected from halogen, CF 3 , C 1 -C 8 alkyl, and O(C 1 -C 8 alkyl) 2 ;
or two R z on adjacent carbon atoms taken together form a 1,3-dioxole ring;
or R 8 and R 9 taken together form a 4-8 membered heterocyclic ring,
further wherein the heterocyclic ring is unsubstituted or substituted with one or more R m ;

R m is halogen, CF 3 , C 1 -C 8 alkyl, or OR 17 ;
R 17 is hydrogen or C 1 -C 8 alkyl;
s is 0, 1, 2, or 3;
p is 0, 1, or 2;
n is 0, 1, 2, or 3;
j is 0, 1, 2, or 3;
v is 0, 1, 2, or 3;
t is 0, 1, 2, or 3; and
g is 0, 1, 2 or 3;

whereby the at least one agent increases the LDL uptake or the LDL receptor level in the at least one cell.

2. The method of claim 1 , wherein the at least one cell is selected from the group consisting of a hepatic, skin, adrenal gland, muscle, and kidney cell.

3. The method of claim 2 , wherein the at least one cell is a HepG2 cell.

4. A method of treating or preventing a lipoprotein-related or cholesterol-related disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of at least one agent comprising a compound of formula (XV),

wherein in the compound of formula (XV):
Q is S(O) p , C(O), bond, C(O)NR 8 , C(O)CH 2 , C(O)O, or C(O)OCH 2 ;
R 12 is halogen, C 1 -C 8 alkyl, CF 3 , N(C 1 -C 8 alkyl) 2 or OR 13 ;
R 13 is C 1 -C 8 alkyl or hydrogen;
R 4 and R 5 are each independently selected from the group consisting of hydrogen, 4-6 membered heterocyclic ring, C 3 -C 8 cycloalkyl ring and (CH 2 ) S -aromatic ring,
further wherein the heterocyclic, cycloalkyl, or aromatic ring is unsubstituted or substituted with one or more R x ;

or R 4 and R 5 taken together form a 4-6 membered heterocyclic ring,
optionally substituted at two adjacent carbon atoms on the heterocylic ring, which can optionally be taken together to form a fused aromatic ring;

R 6 is selected from the group consisting of hydrogen, O(C 1 -C 8 alkyl), O-aromatic ring, O(C 3 -C 8 cycloalkyl ring), and OH;
R x is selected from the group consisting of (CH 2 ) g -aromatic ring and OR 10 , or two R x on adjacent carbon atoms are taken together form a fused aromatic ring;
R 10 is aromatic ring;
R 8 and R 9 are each independently selected from the group consisting of hydrogen, C 1 -C 8 alkyl, (CH 2 ) t -4-8 membered heterocyclic ring, and (CH 2 ) v -aromatic ring,
further where the alkyl, aromatic ring or heterocyclic ring are unsubstituted or substituted with one or more R z ;

R z is selected from halogen, CF 3 , C 1 -C 8 alkyl, and O(C 1 -C 8 alkyl) 2 ;
or two R z on adjacent carbon atoms taken together form a 1,3-dioxole ring;
or R 8 and R 9 taken together form a 4-8 membered heterocyclic ring,
further wherein the heterocyclic ring is unsubstituted or substituted with one or more R m ;

R m is halogen, CF 3 , C 1 -C 8 alkyl, or OR 17 ;
R 17 is hydrogen or C 1 -C 8 alkyl;
s is 0, 1, 2, or 3;
p is 0, 1, or 2;
n is 0, 1, 2, or 3;
j is 0, 1, 2, or 3;
v is 0, 1, 2, or 3;
t is 0, 1, 2, or 3; and

g is 0, 1, 2 or 3;
or a pharmaceutically acceptable salt or solvate thereof, whereby the lipoprotein-related or cholesterol-related disorder in the subject is treated or prevented.

5. A method of treating or preventing a lipoprotein related liver or cardiovascular disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of at least one agent comprising a compound of formula (XV),

wherein in the compound of formula (XV):
Q is S(O) p , C(O), bond, C(O)NR 8 , C(O)CH 2 , C(O)O, or C(O)OCH 2 ;
R 12 is halogen, C 1 -C 8 alkyl, CF 3 , N(C 1 -C 8 alkyl) 2 or OR 13 ;
R 13 is C 1 -C 8 alkyl or hydrogen;
R 4 and R 5 are each independently selected from the group consisting of hydrogen, 4-6 membered heterocyclic ring, C 3 -C 8 cycloalkyl ring and (CH 2 ) S -aromatic ring,
further wherein the heterocyclic, cycloalkyl, or aromatic ring is unsubstituted or substituted with one or more R x ;

or R 4 and R 5 taken together form a 4-6 membered heterocyclic ring,
optionally substituted at two adjacent carbon atoms on the heterocylic ring, which can optionally be taken together to form a fused aromatic ring;

R 6 is selected from the group consisting of hydrogen, O(C 1 -C 8 alkyl), O-aromatic ring, O(C 3 -C 8 cycloalkyl ring), and OH;
R x is selected from the group consisting of (CH 2 ) g -aromatic ring and OR 10 , or two R x on adjacent carbon atoms are taken together form a fused aromatic ring;
R 10 is aromatic ring;
R 8 and R 9 are each independently selected from the group consisting of hydrogen, C 1 -C 8 alkyl, (CH 2 ) t -4-8 membered heterocyclic ring, and (CH 2 ) v -aromatic ring,
further where the alkyl, aromatic ring or heterocyclic ring are unsubstituted or substituted with one or more R z ;

R z is selected from halogen, CF 3 , C 1 -C 8 alkyl, and O(C 1 -C 8 alkyl) 2 ;
or two R z on adjacent carbon atoms taken together form a 1,3-dioxole ring;
or R 8 and R 9 taken together form a 4-8 membered heterocyclic ring,
further wherein the heterocyclic ring is unsubstituted or substituted with one or more R m ;

R m is halogen, CF 3 , C 1 -C 8 alkyl, or OR 17 ;
R 17 is hydrogen or C 1 -C 8 alkyl;
s is 0, 1, 2, or 3;
p is 0, 1, or 2;
n is 0, 1, 2, or 3;
j is 0, 1, 2, or 3;
v is 0, 1, 2, or 3;
t is 0, 1, 2, or 3; and
g is 0, 1, 2 or 3;

or a pharmaceutically acceptable salt thereof, whereby the liver or cardiovascular disease is treated or prevented in the subject.

6. The method of claim 5 , wherein the cardiovascular disease is myocardial infarction, coronar

Assignees

• Broad Inst Inc

Inventors

• Nagiec Marek Maria
• Perez Jose R
• Palmer Michelle
• Skepner Adam
• Comer Eamon

Classifications

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61K31/35

  having six-membered rings with one oxygen as the only ring hetero atom · CPC title

• A61K31/4025

  not condensed and containing further heterocyclic rings, e.g. cromakalim · CPC title

• C12Q2600/158

  Expression markers · CPC title

• C07D498/04

  Ortho-condensed systems · CPC title