Amide inhibitors of microsomal triglyceride transfer protein

Details Amide inhibitors of microsomal triglyceride transfer protein Amide inhibitors of microsomal triglyceride transfer protein

2001-12-12

2004-08-24

Morris, Patricia L. (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C546S309000

Reexamination Certificate

active

06780883

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to compounds that are inhibitors of the microsomal triglyceride transfer protein. The invention also relates to methods of treatment of atherosclerosis, obesity, restenosis, coronary heart disease, hyperlipoproteinemia, hypercholesterolemia, and hypertriglyceridemia, and to pharmaceutical compositions containing the inhibitors.
BACKGROUND OF THE INVENTION
The microsomal triglyceride transfer protein (MTP) is required for the assembly of lipoproteins containing apolipoprotein B (apoB). Examples of lipoproteins that contain apoB, include chylomicrons, very low density lipoproteins (VLDL), intermediate density lipoproteins (IDL), high density lipoproteins (HDL), low density lipoproteins (LDL), and lipoprotein a [Lp(a)]. MTP is a heterodimer composed of a unique large subunit of 97 kDA and an ubiquitous multifunctional protein called protein disulfide isomerase.
The function of MTP has been discovered, in part, through the investigation of the disease abetalipoproteinemia, which is a rare autosomal recessive disease that is characterized by defective apoB lipoprotein assembly and secretion. Studies have now shown that persons having abetalipoproteinemia have mutations in the MTP large subunit gene. As a result of this mutation, persons afflicted with abetalipoproteinemia have only trace levels of apoB in plasma and total plasma levels of cholesterol of about 40 mg/dL.
Abnormal plasma lipid and/or lipoprotein concentrations plays a role in diseases such as atherosclerosis, obesity, restenosis, coronary heart disease, hyperlipoproteinemia, hypercholesterolemia, and hypertriglyceridemia. Thus, it would be beneficial to obtain compounds that can inhibit MTP.
U.S. Pat. Nos. 5,712,279 and 5,739,135, which are hereby incorporated by reference in their entirety, relate to compounds that inhibit MTP. The compounds disclosed in these patents are structurally different from the compounds of the present invention.
SUMMARY OF THE INVENTION
The present invention provides compounds having the Formula I
wherein
R
1
is pyridyl, —CH
2
-pyridyl, substituted pyridyl, —CH
2
-substituted pyridyl, phenyl, substituted phenyl,
each R
a
and R
b
are independently hydrogen or C
1
-C
6
alkyl;
m is 0 to 4;
n is 0, 1, or 2;
R
2
is substituted phenyl, phenyl,
 phenyl or substituted phenyl, a pharmaceutically acceptable salt thereof.
In a preferred embodiment of the compounds of Formula I,
In another preferred embodiment of the compounds of Formula I,
R
3
is
In another preferred embodiment of the compounds of Formula I, R
1
is pyridyl, or —CH
2
-pyridyl.
In another preferred embodiment of the compounds of Formula I, R
1
is substituted phenyl or substituted pyridyl.
In another preferred embodiment of the compounds of Formula I, R
2
is substituted phenyl, or phenyl.
In another preferred embodiment, the present invention provides compounds having the Formula I
wherein
R
1
is pyridyl, substituted phenyl, phenyl
 —CH
2
-pyridyl,
 substituted pyridyl, or
R
2
is substituted phenyl, phenyl,
 substituted phenyl, or the pharmaceutically acceptable salt thereof.
In a more preferred embodiment of the compounds of Formula I, the present invention provides the compounds:
2-Benzylsulfanyl-N-(4-methoxy-benzyl)-N-(4-methoxy-phenyl)-benzamide;
N-(3,5-Di-tert-butyl-benzyl)-3,4-dimethoxy-N-phenyl-benzamide;
N-(3,5-Bis-trifluoromethyl-benzyl)-3,4-dimethoxy-N-phenyl-benzamide;
N-(3,5-Dibromo-benzyl)-3,4-dimethoxy-N-phenyl-benzamide;
3,4-Dimethoxy-N-(4-methoxy-benzyl)-N-phenyl-benzamide;
3,4-Dimethoxy-N-(3-methoxy-benzyl)-N-phenyl-benzamide;
N-(3,4-Dichloro-benzyl)-3,4-dimethoxy-N-phenyl-benzamide;
3,4-Dimethoxy-N-naphthalen-2-ylmethyl-N-phenyl-benzamide;
N-(4-tert-Butyl-benzyl)-3,4-dimethoxy-N-phenyl-benzamide; or
N-Biphenyl-2-ylmethyl-3,4-dimethoxy-N-phenyl-benzamide.
In a more preferred embodiment of the compounds of Formula I, the present invention provides the compounds:
N-(3,4-Dichloro-benzyl)-N-(2-methoxy-phenyl)-benzamide;
N-(3,5-Di-tert-butyl-benzyl)-N-[4-(3-diethylamino-propyl)-phenyl]-benzamide;
N-(3,5-Bis-trifluoromethyl-benzyl)-N-[4-(3-diethylamino-propyl)-phenyl]-benzamide;
N-(3,5-Dibromo-benzyl)-N-[4-(3-diethylamino-propyl)-phenyl]-benzamide;
N-[4-(3-Diethylamino-propyl)-phenyl]-N-(4-methoxy-benzyl)-benzamide;
N-[4-(3-Diethylamino-propyl)-phenyl]-N-(3-methoxy-benzyl)-benzamide;
N-(3,4-Dichloro-benzyl)-N-[4-(3-diethylamino-propyl)-phenyl]-benzamide;
N-[4-(3-Diethylamino-propyl)-phenyl]-N-naphthalen-2-ylmethyl-benzamide;
N-Biphenyl-2-ylmethyl-N-[4-(3-diethylamino-propyl)-phenyl]-benzamide; or
3-Methyl-thiophene-2-carboxylic acid (4-iodo-phenyl)-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-ylmethyl)-amide.
In a more preferred embodiment of the compounds of Formula I, the present invention provides the compounds:
N-(4-Methoxy-benzyl)-N-phenyl-benzamide;
N-(3-Methoxy-benzyl)-N-phenyl-benzamide;
3,4,5-Trimethoxy-N-naphthalen-2-ylmethyl-N-quinolin-3-yl-benzamide;
N-(4-tert-Butyl-benzyl)-3,4,5-trimethoxy-N-quinolin-3-yl-benzamide;
N-Biphenyl-2-ylmethyl-3,4,5-trimethoxy-N-quinolin-3-yl-benzamide;
3,4,5-Trimethoxy-N-(6-methoxy-pyridin-3-yl)-N-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-ylmethyl)-benzamide;
N-(3,5-Di-tert-butyl-benzyl)-3,4,5-trimethoxy-N-(6-methoxy-pyridin-3-yl)-benzamide;
N-(3,4-Dichloro-benzyl)-3,4,5-trimethoxy-N-(6-methoxy-pyridin-3-yl)-benzamide;
4-Isopropyl-N-pyridin-3-yl-N-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-ylmethyl)-benzamide; or
4-Isopropyl-N-(3-methoxy-benzyl)-N-pyridin-3-yl-benzamide.
In a more preferred embodiment of the compounds of Formula I, the present invention provides the compounds:
4-Isopropyl-N-naphthalen-2-ylmethyl-N-pyridin-3-yl-benzamide;
′N-(4-tert-Butyl-benzyl)-4-isopropyl-N-pyridin-3-yl-benzamide;
N-Biphenyl-2-ylmethyl-4-isopropyl-N-pyridin-3-yl-benzamide;
2-Ethoxy-N-pyridin-3-yl-N-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-ylmethyl)-benzamide;
N-(3,5-Di-tert-butyl-benzyl)-2-ethoxy-N-pyridin-3-yl-benzamide;
N-(3,5-Dibromo-benzyl)-2-ethoxy-N-pyridin-3-yl-benzamide;
2-Ethoxy-N-(4-methoxy-benzyl)-N-pyridin-3-yl-benzamide;
2-Ethoxy-N-(3-methoxy-benzyl)-N-pyridin-3-yl-benzamide;
N-(3,4-Dichloro-benzyl)-2-ethoxy-N-pyridin-3-yl-benzamide; or
2-Ethoxy-N-naphthalen-2-ylmethyl-N-pyridin-3-yl-benzamide.
In a more preferred embodiment of the compounds of Formula I, the present invention provides the compounds:
N-(4-tert-Butyl-benzyl)-2-ethoxy-N-pyridin-3-yl-benzamide;
N-Biphenyl-2-ylmethyl-2-ethoxy-N-pyridin-3-yl-benzamide;
N-(6-Butoxy-pyridin-3-yl)-2-diethylamino-N-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-ylmethyl)-acetamide;
N-(6-Butoxy-pyridin-3-yl)-N-(4-tert-butyl-benzyl)-2-diethylamino-acetamide;
′N-Biphenyl-2-ylmethyl-N-(6-butoxy-pyridin-3-yl)-2-diethylamino-acetamide;
N-(2-Methoxy-phenyl)-N-naphthalen-2-ylmethyl-benzamide;
N-(4-Methoxy-benzyl)-N-(2-methoxy-phenyl)-benzamide;
N-(3-Methoxy-benzyl)-N-(2-methoxy-phenyl)-benzamide;
N-Biphenyl-2-ylmethyl-N-(2-methoxy-phenyl)-benzamide; or
N-[4-(3-Diethylamino-propyl)-phenyl]-N-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-ylmethyl)-benzamide.
In a more preferred embodiment of the compounds of Formula I, the present invention provides the compounds:
N-Biphenyl-2-ylmethyl-2-ethoxy-N-(6-methoxy-pyridin-3-yl)-benzamide;
N-Biphenyl-2-ylmethyl-2-methoxy-N-(6-methoxy-pyridin-3-yl)-benzamide;
N-Biphenyl-2-ylmethyl-2-methoxy-N-pyridin-3-ylmethyl-benzamide;
Benzo[b]thiophene-2-carboxylic acid biphenyl-2-ylmethyl-pyridin-4-yl-amide;
N-Biphenyl-2-ylmethyl-N-(6-methoxy-pyridin-3-yl)-2-nitro-benzamide;
N-Biphenyl-2-ylmethyl-4-ethoxy-N-(6-methoxy-pyridin-3-yl)-benzamide;
N-Biphenyl-2-ylmethyl-2-ethoxy-N-pyridin-3-ylmethyl-benzamide;
Benzo [1,3]dioxole-4-carboxylic acid biphenyl-2-ylmethyl-pyridin-3-ylmethyl-amide;
N-Biphenyl-2-ylmethyl-2-bromo-N-pyridin-3-ylmethyl-benzamide; or
3-Chloro-benzo [b]thiophene-2-carboxylic acid biphenyl-2-ylmethyl-pyridin-3-ylmethyl-amide.
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