Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-07-20
2001-03-06
Lambkin, Deborah C. (Department: 1613)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S378000, C514S445000, C514S596000, C514S602000, C514S617000, C546S323000, C548S248000, C549S065000, C560S027000, C564S048000, C564S092000, C564S155000
Reexamination Certificate
active
06197798
ABSTRACT:
SUMMARY OF THE INVENTION
The present invention relates to the benzocycloalkane substituted amide derivatives described herein which are particularly useful as inhibitors of microsomal triglyceride transfer protein (MTP) and of apolipoprotein B (Apo B) secretion, methods for preparation thereof, pharmaceutical compositions comprising said compounds, a method of inhibiting MTP and Apo B secretion and of treating conditions in mammals which are responsive to MTP inhibition or inhibition of Apo B secretion using said compounds or pharmaceutical compositions comprising said compounds of the invention.
DETAILED DESCRIPTION OF THE INVENTION
The invention relates to the compounds of formula I
wherein
R
2
—C, R
3
—C, R
4
—C or R
5
—C may be replaced by N;
and wherein n is 1, 2 or 3;
R
1
is aryl, cycloalkyl or heterocyclyl;
R
2
, R
3
, R
4
and R
5
are independently hydrogen, optionally substituted alkyl, halo, amino, substituted amino, trifluoromethyl, cyano, carboxyl, alkoxycarbonyl, aralkoxycarbonyl, (alkyl, aryl or aralkyl)-thio, (alkyl, aryl or aralkyl)-oxy, acyloxy, (alkyl, aryl or aralkyl)-aminocarbonyloxy; or any two of R
2
, R
3
, R
4
and R
5
at adjacent positions are alkylenedioxy;
R
6
is hydrogen, optionally substituted alkyl, amino, substituted amino, acylamino,
wherein
R
a
is hydrogen or optionally substituted alkyl,
R
b
and R
c
are independently hydrogen, optionally substituted alkyl, cycloalkyl, aryl or heterocyclyl; or R
b
and R
c
together represent lower alkylene or lower alkylene interrupted by O, S, or N—(H, alkyl or aralkyl);
R
d
is optionally substituted alkyl, cycloalkyl, aryl or heterocyclyl; and
R
e
is optionally substituted alkyl, aryl, heterocyclyl, cycloalkyl, amino or substituted amino;
and pharmaceutically acceptable salts thereof; and enantiomers thereof.
Compounds of formula I are useful as inhibitors of microsomal triglyceride transfer protein (MTP) and of apolipoprotein B (ApoB) secretion and accordingly for the prevention and treatment of MTP and Apo B dependent conditions.
A particular embodiment of the invention relates to the compounds of formula I′
wherein
R
2
—C, R
3
—C, R
4
—C or R
5
—C may be replaced by N; and wherein n, and R
1
-R
6
have meaning as defined above; pharmaceutically acceptable salts thereof; and enantiomers thereof.
A specific embodiment of the invention relates to the compounds of formula Ia
wherein
X is R
2
—C or N; and n, and R
1
-R
6
have meaning as defined above.
Particular embodiments of the invention relate to the compounds of formula Ia wherein:
(a) R
1
represents aryl;
(b) R
1
represents heterocyclyl, in particular aromatic heterocyclyl (heteroaryl);
(c) n is one;
(d) X is R
2
—C;
(e) X is N;
(f) R
6
is amino, substituted amino or acylamino;
(g) R
6
is
(h) R
6
is
(i) R
6
is
Preferred are the compounds of formula Ia wherein n is 1; R
1
is monocyclic aryl or heteroaryl; X is R
2
—C or N; R
2
, R
3
, R
4
and R
5
are independently hydrogen, lower alkyl halo, trifluoromethyl, lower alkoxy or amino; and R
6
is amino, substituted amino, acylamino,
wherein R
a
is hydrogen; R
b
and R
c
are independently hydrogen, lower alkyl, aralkyl, aryl, heteroaryl or heteroaralkyl; or R
b
and R
c
together with the nitrogen represent piperidino, morpholino, pyrrolidino, or N-lower alkylpiperazino; R
d
and R
e
are lower alkyl, aralkyl, aryl, heteroaryl or heteroaralkyl; and pharmaceutically acceptable salts thereof.
Preferred are the compounds of formula I, I′ or Ia wherein R
6
is located on the 5-, 6- or 7-membered saturated ring (n=1, 2, or 3) at a position not directly adjacent to the ring junction (non-benzylic position).
A particular aspect of the invention relates to the compounds of formula I
wherein R
2
—C, R
3
—C, R
4
—C or R
5
—C may be replaced by N;
wherein n is 1, 2 or 3;
R
1
is phenyl or thienyl which in each case is unsubstituted or substituted by a substituent selected from the group consisting of lower alkyl, lower alkoxy, halo, trifluoromethyl, cyano, and trifluoromethoxy;
R
2
, R
3
, R
4
and R
5
are independently hydrogen, lower alkyl, lower alkoxy, halo, trifluoromethyl, amino, lower alkylamino, di-lower alkyl amino, or lower alkanoyl-amino;
R
6
is amino, phenyl-lower alkyl-amino, lower alkanoyl-amino, lower alkanoyl-amino in which the alkyl group of the alkanoyl group is substituted by phenyl, by lower alkoxy, by phenoxy, by lower alkylthio, by phenylthio, by di-lower alkylamino, by morpholino, by thiomorpholino, by piperazino, or by 4-lower alkyl-piperazino, or is N-methyl-N′-lower alkanoyl-amino, benzoyl-amino, or isoxazolylcarbonyl-amino in which isoxazoyl is unsubstituted or substituted by lower alkyl, or is
wherein
R
a
is hydrogen or alkyl,
R
b
and R
c
are independently hydrogen, lower alkyl, 5- to 7-membered cycloalkyl, or phenyl; or R
b
and R
c
together are morpholino, thiomorpholino or lower alkylene;
R
d
is lower alkyl, lower alkyl substituted by lower alkoxy, by lower alkoxy-lower alkoxy, by morpholino, by thiomorpholino, by 2-oxo-1-pyrrolidino, by pyridyl, by phenyl, or by phenyl which is substituted by a substituent selected from halo, trifluoromethyl, lower alkyl, and lower alkoxy, or is phenyl, phenyl substituted by substituent selected from halo, trifluoromethyl, lower alkyl, and lower alkoxy, or is 5- to 7-membered cycloalkyl, or pyranyl; and
R
e
is lower alkyl, phenyl-lower alkyl, phenyl which is unsubstituted or substituted by a group selected from lower alkyl, lower alkoxy, halo, trifluoromethyl, and lower alkane-sulphonyl, or is naphthyl, thienyl, furyl, isoxazolyl, imidazolyl or quinolinyl each of which is unsubstituted or substituted by a group selected from lower alkyl, halo and trifluoromethyl, or is lower alkyl-amino, di-lower alkyl-amino or 5- to 7-membered cycloalkyl-amino;
and pharmaceutically acceptable salts thereof; and enantiomers thereof.
A particular aspect of the invention relates to the indane derivatives of formula Ib
wherein
Ar is monocyclic aryl or heteroaryl;
X is R
2
—C or N;
R
2
, R
3
, R
4
and R
5
are independently hydrogen, lower alkyl, halo, trifluoromethyl, cyano, or lower alkoxy;
and R
6
has meaning as defined above in each case.
Preferred are the said compounds of formula Ib wherein Ar is phenyl or phenyl substituted by fluoro, chloro, trifluoromethyl, cyano or lower alkyl; X is N or R
2
—C; R
2
, R
3
, R
4
and R
5
are independently hydrogen, lower alkyl, lower alkoxy, halo or trifluoromethyl; and R
6
has meaning as defined above in each case.
Further preferred are the compounds of formula Ic
wherein R
2
, R
3
and R
4
are independently hydrogen, C
1
-C
4
-alkyl, C
1
-C
4
alkoxy, trifluoromethyl, chloro or fluoro; R
7
is trifluoromethyl, chloro or cyano; and R
6
is
wherein R
d
is C
1
-C
4
-alkyl; and R
e
is C
1
-C
4
-alkyl, monocyclic carbocyclic aryl or heterocyclic aryl.
Further preferred are the compounds of formula Ic wherein R
2
is methyl; R
3
is hydrogen; R
4
is hydrogen or methyl; R
7
is trifluoromethyl or chloro; R
d
is C
1
-C
4
-alkyl; and R
e
is C
1
-C
4
-alkyl or thienyl.
A particular embodiment relates to the compounds of formula Ic wherein R
2
is methyl; R
3
is hydrogen; R
4
is hydrogen or methyl; R
6
is —NHSO
2
R
e
wherein R
e
is methyl or thienyl; and R
7
is trifluoromethyl.
Another embodiment relates to the compounds of formula Ic wherein R
2
is methyl; R
3
is hydrogen; R
4
is hydrogen or methyl; R
6
is
wherein R
d
is methyl; and R
7
is trifluoromethyl.
Also preferred in all of the above, is the more active enantiomer in which the carbon atom bearing the substituent R
6
(if R
6
is not hydrogen) has either the (R) or the (S)-configuration.
Listed below are definitions of various terms used to describe the compounds of the instant invention. These definitions apply to the terms as they are used throughout the specification (unless they are otherwise limited in specific instances either individually or as part of a larger group).
The term “lower” referred to herein in connection with organic radicals or compounds respectively generally defines, if not de
Fink Cynthia A.
Ksander Gary M.
Kukkola Paivi J.
Prashad Mahavir
Wallace Eli M.
Gruenfeld Norbert
Lambkin Deborah C.
Novartis AG
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