Triamide-substituted heterobicyclic compounds

Details Triamide-substituted heterobicyclic compounds Triamide-substituted heterobicyclic compounds

2002-06-20

2004-04-13

McKane, Joseph K. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C548S492000

Reexamination Certificate

active

06720351

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to triamide-substituted heterobicyclic compounds. These compounds are inhibitors of microsomal triglyceride transfer protein (MTP) and/or apolipoprotein B (Apo B) secretion and are useful for the treatment of obesity and related diseases. These compounds are also useful for the prevention and treatment of atherosclerosis and its clinical sequelae, for lowering serum lipids, and in the prevention and treatment of related diseases. The invention further relates to pharmaceutical compositions comprising these compounds and to methods of treating obesity, atherosclerosis, and related diseases and/or conditions with said compounds, either alone or in combination with other medicaments, including lipid lowering agents. Further still, the invention relates to certain processes and intermediates related thereto which are useful in the preparation of the compounds of the instant invention.
BACKGROUND OF THE INVENTION
Microsomal triglyceride transfer protein catalyzes the transport of triglyceride, cholesteryl ester, and phospholipids and has been implicated as a putative mediator in the assembly of Apo B-containing lipoproteins, biomolecules which contribute to the formation of atherosclerotic lesions. Specifically, the subcellular (lumen of the microsomal fraction) and tissue distribution (liver and intestine) of MTP have led to speculation that it plays a role in the assembly of plasma lipoproteins, as these are the sites of plasma lipoprotein assembly. The ability of MTP to catalyze the transport of triglyceride between membranes is consistent with this speculation, and suggests that MTP may catalyze the transport of triglyceride from its site of synthesis in the endoplasmic reticulum membrane to nascent lipoprotein particles within the lumen of the endoplasmic reticulum.
Accordingly, compounds which inhibit MTP and/or otherwise inhibit Apo B secretion are useful in the treatment of atherosclerosis and other conditions related thereto. Such compounds are also useful in the treatment of other diseases or conditions in which, by inhibiting MTP and/or Apo B secretion, serum cholesterol and triglyceride levels may be reduced. Such conditions may include, for example, hypercholesterolemia, hypertriglyceridemia, pancreatitis, and obesity; and hypercholesterolemia, hypertriglyceridemia, and hyperlipidemia associated with pancreatitis, obesity, and diabetes. For a detailed discussion, see for example, Wetterau et al., Science, 258, 999-1001, (1992), Wetterau et al., Biochem. Biophys. Acta., 875, 610-617 (1986), European patent application publication Nos. 0 584 446 A2, and 0 643 057 A1, the latter of which refers to certain compounds which have utility as inhibitors of MTP. Other examples of MTP inhibitors may be found in e.g., U.S. Pat. Nos. 5,712,279, 5,741,804, 5,968,950, 6,066,653, and 6,121,283; PCT International Patent Application publications WO 96/40640, WO 97/43257, WO 98/27979, WO 99/33800 and WO 00/05201; and European patent application publications EP 584446 and EP 643,057.
SUMMARY OF THE INVENTION
The present invention relates to compounds of the formula 1:
or a pharmaceutically acceptable salt thereof, wherein:
R
1
is substituted at the 5 or 6 position of formula 1 and has the structure:
m is an integer from 0 to 5;
n is an integer from 0 to 3;
p is an integer from 0 to 3;
L is —C(O)N(R
9
)—, i.e., L has the structure:
X is N or C(R
c
);
R
2
, R
8
, R
11
, R
12
, R
13
and R
16
are each independently selected from halo, cyano, nitro, azido, amino, hydroxy, (C
1
-C
6
)alkyl, (C
2
-C
6
)alkoxy, methoxy, (C
1
-C
6
)alkoxy(C
1
-C
6
)alkyl, mono-, di- or tri-halo(C
2
-C
6
)alkyl, perfluoro(C
2
-C
4
)alkyl, trifluoromethyl, trifluoromethyl(C
1
-C
5
)alkyl, mono-, di- or tri-halo(C
2
-C
6
)alkoxy, trifluoromethyl(C
1
-C
5
)alkoxy, (C
1
-C
6
)alkylthio, hydroxy(C
1
-C
6
)alkyl, (C
3
-C
8
)cycloalkyl(CR
a
R
b
)
q
—, (C
2
-C
6
)alkenyl, (C
2
-C
6
)alkynyl, (C
1
-C
6
)alkylamino-, (C
1
-C
6
)dialkylamino, amino(C
1
-C
6
)alkyl-, —(CR
a
R
b
)
q
NR
a
R
14
, —C(O)NR
a
R
14
, —NR
14
C(O)R
15
, —NR
14
OR
15
, —CH═NOR
15
, —NR
14
C(O)OR
15
, —NR
14
S(O)
j
R
15
, —C(O)R
15
, —C(O)OR
15
, —OC(O)R
15
, —SO
2
NR
a
R
14
, —S(O)
j
R
15
, or —(CR
a
R
b
)
q
S(O)
j
R
15
;
each R
a
and R
b
is independently H or (C
1
-C
6
)alkyl;
R
c
is H or R
11
;
each q is independently an integer from 0 to 6;
each j is independently 0, 1 or 2;
R
3
is H, halo, (C
1
-C
6
)alkyl, or mono-, di- or tri-halo(C
1
-C
6
)alkyl;
R
4
is H, (C
1
-C
6
)alkyl, (C
3
-C
8
)cycloalkyl, —C(O)R
15
, —C(S)R
15
, —(CR
a
R
b
)
t
O(C
1
-C
6
alkyl), —(CR
a
R
b
)
t
S(C
1
-C
6
alkyl), —(CR
a
R
b
)
r
C(O)R
15
, —(CR
a
R
b
)
r
R
15
, —SO
2
R
15
or —(CR
a
R
b
)
q
-phenyl, wherein the phenyl moiety is optionally substituted with from one to five independently selected R
16
;
each r is independently an integer from 2 to 5;
each t is independently an integer from 1 to 6;
R
5
, R
6
and R
9
are each independently H, (C
1
-C
6
)alkyl, (C
3
-C
8
)cycloalkyl, —C(O)R
15
, —C(S)R
15
, —(CR
a
R
b
)
t
O(C
1
-C
6
alkyl), —(CR
a
R
b
)
t
S(C
1
-C
6
alkyl), —(CR
a
R
b
)
r
R
15
or —SO
2
R
15
;
R
7
is phenyl, pyridyl, phenyl-Z
1
— or pyridyl-Z
1
—, wherein the phenyl or pyridyl moiety is optionally substituted with one to five independently selected R
12
;
Z
1
is —SO
2
— or —(CR
a
R
b
)
v
—;
v is independently an integer from 1 to 6;
R
10
is phenyl, pyridyl, phenyl-Z
2
— or pyridyl-Z
2
—, wherein the phenyl or pyridyl moiety is optionally substituted with one to five independently selected R
13
;
Z
2
is —S(O)
j
—, —O—, —(CR
a
R
b
)
w
—, or —(O)
k
(CR
a
R
b
)
w
(O)
k
(CR
a
R
b
)
q
—;
w is independently an integer from 1 to 6;
each k is independently 0 or 1;
each R
14
is independently H, (C
1
-C
6
)alkyl, (C
3
-C
8
)cycloalkyl, —C(O)R
15
, —C(S)R
15
, —(CR
a
R
b
)
t
O(C
1
-C
6
alkyl), —(CR
a
R
b
)
t
S(C
1
-C
6
alkyl), —(CR
a
R
b
)
r
C(O)R
15
, —(CR
a
R
b
)
t
R
15
or —SO
2
R
15
;
each R
15
is independently H, (C
1
-C
6
)alkyl, (C
3
-C
8
)cycloalkyl, trifluoromethyl, trifluoromethyl(C
1
-C
5
)alkyl, wherein the alkyl, moieties of the foregoing R
15
groups are independently optionally substituted with 1 to 3 substituents independently selected from C
1
-C
6
alkyl, C
1
-C
6
alkoxy, amino, hydroxy, halo, cyano, nitro, trifluoromethyl and trifluoromethoxy;
and wherein any of the above “alkyl”, “alkenyl” or “alkynyl” moieties comprising a CH
3
(methyl), CH
2
(methylene), or CH (methine) group which is not substituted with halogen, SO or SO
2
, or attached to a N, O or S atom, optionally bears on said methyl, methylene or methine group a substituent selected from the group consisting of halo, —OR
a
, —SR
a
and —NR
a
R
b
.
In an embodiment of the invention, L is attached to the 2 position of R
1
and to the 5 position of formula 1, i.e., the compound of formula 1 has the structure of formula 1a:
In another embodiment of the invention, L is attached to the 2 position of R
1
and to the 5 position of formula 1, and R
10
is attached at the 3′ position.
In another embodiment of the invention, L is attached to the 3 position of R
1
and to the 5 position formula 1. In another embodiment of the invention, L is attached to the 3 position of R
1
and to the 5 position of formula 1 and X is N. In still another embodiment of the invention, L is attached to the 3 position of R
1
and to the 5 position of formula 1, X is N and R
10
is attached at the 2 position of R
1
. In other embodiments of the invention, the attachment of L to R
1
is selected from the 3, 4, 6 or 6 position and the attachment of L to the compound of formula 1 is selected from the 5 position or 6 position.
In another embodiment of the invention, X is C(R
c
).
In another embodiment of the invention, X is C(R
c
), m is 0, n is 0, and p is 0 or 1.
In another embodiment of the invention, X is C(R
c
), m is 0, n is 0, and p is 0 or 1, and R
10
is phenyl-Z
2
— attached at the 3 position of R
1
, wherein the phenyl moiety of R
10
is optionally substituted with one to five independently selected R
13
.
In another embodiment of the inven

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