Substituted...

Details Substituted... Substituted...

1999-10-01

2003-07-22

Low, Christopher S. F. (Department: 1653)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S274000, C514S336000, C514S357000, C514S340000, C514S341000, C514S342000, C544S310000, C544S316000, C546S256000, C546S264000

Reexamination Certificate

active

06596728

ABSTRACT:

RELATED APPLICATIONS
Under the provisions of Section 119 of 35 U.S.C., Applicants hereby claim the benefit of the filing date of Federal Republic of Germany Patent Application Number 19845406.6, filed Oct. 2, 1998, which Application is hereby incorporated by reference.
The present invention relates to substituted 1,3-diaryl-2-pyridin-2-yl-3-(pyridin-2-ylamino)propanol derivatives and pharmaceutically tolerated salts and physiologically functional derivatives thereof.
BACKGROUND OF THE INVENTION
Several classes of active compounds for treatment of adiposity and disturbances in lipid metabolism have already been described, e.g.,
polymeric adsorbers, such as cholestyramine,
benzothiazepines (WO 93/16055),
bile acid dimers and conjugates (EP 0 489 423), and
4-amino-2-ureido-pyrimidine-5-carboxamides (EP 0 557 879).
SUMMARY OF THE INVENTION
The object of the present invention is to provide further compounds displaying a therapeutically valuable hypolipidemic action.
The present invention therefore relates to 1,3-diaryl-2-pyridin-2-yl-3-(pyridin-2-ylamino)propanol derivatives of formula (I) or salts thereof,
wherein:
Z is
—NH—(C
1
-C
16
-alkyl)-(C═O)—,
—(C═O)—(C
1
-C
16
-alkyl)-(C═O)—, or
—(C═O)-phenyl-(C═O)—;
A
1
, A
2
, A
3
, A
4
, each independently of one another is an amino acid radical, or an amino acid radical which is mono- or polysubstituted by amino acid-protective groups;
E is —SO
2
—R
4
or —CO—R
4
;
R
1
is phenyl, thiazolyl, oxazolyl, thienyl, thiophenyl, furanyl, pyridyl, or pyrimidyl, wherein the rings are unsubstituted, or substituted up to 3 times by F, Cl, Br, —OH, —CF
3
, —NO
2
, —CN, —OCF
3
, —(C
1
-C
6
)-alkyl, —O—(C
1
-C
6
)-alkyl, —S—(C
1
-C
6
)-alkyl, —SO—(C
1
-C
6
)-alkyl, —SO
2
—(C
1
-C
6
)-alkyl, —(C
1
-C
6
)-alkyl, —(C
3
-C
6
)-cycloalkyl, —COOH, —COO—(C
1
-C
6
)-alkyl, —COO—(C
3
-C
6
)cycloalkyl, —CONH
2
, —CONH—(C
1
-C
6
)-alkyl, —CON[(C
1
-C
6
)-alkyl]
2
, —CONH—(C
3
-C
6
)-cycloalkyl, —NH
2
, —NH—CO—(C
1
-C
6
)-alkyl, or —NH—CO-phenyl;
R
2
is H, —OH, —CH
2
OH, or —OMe;
R
3
is H, F, methyl, or —OMe;
R
4
is —(C
1
-C
16
-alkyl), —(C
0
-C
16
-alkylene)-R
5
, —(C═O)—(C
0
-C
16
-alkylene)-R
5
, —(C═O)—(C
0
-C
16
-alkylene)-NH—R
5
, —(C
1
-C
8
-alkenylene)-R
5
, —(C
1
-C
8
-alkynyl), —(C
1
-C
4
-alkylene)-S(O)
r
—R
5
, —(C
1
-C
4
-alkylene)-O—R
5
, or —(C
1
-C
4
-alkylene)-NH—R
5
;
R
5
is —COO—R
6
, —(C═O)—R
6
, —(C
1
-C
6
-alkylene)-R
7
, —(C
1
-C
6
-alkenylene)-R
7
, —(C
1
-C
7
)-cycloalkyl, phenyl, naphthyl, thienyl, thiophenyl, furanyl, pyridyl, pyrimidyl, dihydropyrimidine-2,4-dion-6-yl, chromanyl, phthalimidoyl, or thiazolyl, wherein the rings are unsubstituted, or substituted up to 3 times by F, Cl, Br, —OH, —CF
3
, —NO
2
, —CN, —OCF
3
, —(C
1
-C
6
)-alkyl, —O—(C
1
-C
6
)-alkyl, —S—(C
1
-C
6
)-alkyl, —SO—(C
1
-C
6
)-alkyl, —SO
2
—(C
1
-C
6
)-alkyl, —(C
1
-C
6
)-alkyl, —(C
3
-C
6
)-cycloalkyl, —COOH, —COO—(C
1
-C
6
)-alkyl, —COO—(C
3
-C
6
)-cycloalkyl, —CONH
2
, —CONH—(C
1
-C
6
)-alkyl, —CON[(C
1
-C
6
)-alkyl]
2
, —CONH—(C
3
-C
6
)-cycloalkyl, —NH
2
, —NH—CO—(C
1
C
6
)-alkyl, —NH—CO-phenyl, or pyridyl;
R
6
is H or —(C
1
-C
6
)-alkyl;
R
7
is H, —(C
1
-C
7
)-cycloalkyl, phenyl, naphthyl, thienyl, thiophenyl, furanyl, pyridyl, pyrimidyl, dihydropyrimidine-2,4-dion-6-yl, chromanyl, phthalimidoyl, or thiazolyl, wherein the rings are unsubstituted, or substituted up to 3 times by F, Cl, Br, —OH, —CF
3
, —NO
2
, —CN, —OCF
3
, —(C
1
C
6
)-alkyl, —O—(C
1
-C
6
)-alkyl, —S—(C
1
-C
6
)-alkyl, —SO—(C
1
-C
6
)-alkyl, —SO
2
—(C
1
-C
6
)-alkyl, —(C
1
-C
6
)-alkyl, —(C
3
-C
6
)-cycloalkyl, —COOH, —COO—(C
1
-C
6
)-alkyl, —COO—(C
3
-C
6
)-cycloalkyl, —CONH
2
, —CONH—(C
1
-C
6
)-alkyl, —CON[(C
1
-C
6
)-alkyl]
2
, —CONH—(C
3
-C
6
)-cycloalkyl, —NH
2
, —NH—CO—(C
1
-C
6
)-alkyl, or —NH—CO-phenyl;
l, q, m, n, o, p each independently of one another is 0 or 1, where the sum of l+q+m+n+o+p is greater than or equal to 1; and
r is 0, 1, or 2;
with the proviso that in formula (I), when R
1
is unsubstituted phenyl, R
2
is H, R
3
is H, and l, m, n, o, and p are all zero, then R
4
is other than —CH
3
or —C(CH
3
)
3
.
Preferred compounds of formula (I) or salts thereof are those in which one or more radical(s) has or have the following meaning:
Z is
—NH—(C
1
-C
16
-alkyl)-(C═O)—,
—(C═O)—(C
1
-C
16
-alkyl)-(C═O)—, or
—(C═O)-phenyl-(C═O)—;
A
1
, A
2
, A
3
, A
4
, each independently of one another is an amino acid radical, or an amino acid radical which is mono- or polysubstituted by amino acid-protective groups;
E is —SO
2
—R
4
or —CO—R
4
;
R
1
is phenyl, thiazolyl, oxazolyl, thienyl, thiophenyl, furanyl, pyridyl, or pyrimidyl, wherein the rings are unsubstituted or substituted up to 3 times by F, Cl, Br, —OH, —CF
3
, —NO
2
, —CN, —OCF
3
, —(C
1
-C
6
)-alkyl, —O—(C
1
-C
6
)-alkyl, —S—(C
1
-C
6
)-alkyl, —SO—(C
1
-C
6
)-alkyl, —SO
2
—(C
1
-C
6
)-alkyl, —(C
1
-C
6
)-alkyl, —(C
3
-C
6
)-cycloalkyl, —COOH, —COO—(C
1
-C
6
)-alkyl, —COO—(C
3
-C
6
)-cycloalkyl, —CONH
2
, —CONH—(C
1
-C
6
)-alkyl, —CON[(C
1
-C
6
)-alkyl]
2
, —CONH—(C
3
-C
6
)-cycloalkyl, —NH
2
, —NH—CO—(C
1
-C
6
)-alkyl, or —NH—CO-phenyl;
R
2
is H, —OH, —CH
2
OH, or —OMe;
R
3
is H, F, methyl, or —OMe;
R
4
is —(C
1
-C
16
-alkyl), —(C
0
-C
16
-alkylene)-R
5
, —(C═O)—(C
0
-C
16
-alkylene)-R
5
, —(C═O)—(C
0
-C
16
alkylene)-NH—R
5
, —(C
1
-C
8
-alkenylene)-R
5
, —(C
1
-C
8
-alkynyl), —(C
1
-C
4
-alkylene)-S(O)
r
R
5
, —(C
1
-C
4
-alkylene)-O—R
5
or —(C
1
-C
4
-alkylene)-NH—R
5
;
R
5
is —COO—R
6
, —(C═O)—R
6
, —(C
1
-C
6
-alkylene)-R
7
, —(C
1
-C
6
-alkenylene)-R
7
, —C
1
-C
7
)-cycloalkyl, phenyl, naphthyl, thienyl, thiophenyl, furanyl, pyridyl, pyrimidyl, dihydropyrimidine-2,4-dion-6-yl, chromanyl, phthalimidoyl, or thiazolyl, wherein the rings are unsubstituted or substituted up to 3 times by F, Cl, Br, —OH, —CF
3
, —NO
2
, —CN, —OCF
3
, —(C
1
-C
6
)-alkyl, O—(C
1
-C
6
)-alkyl, —S—(C
1
-C
6
)-alkyl, —SO—(C
1
-C
6
)-alkyl, —SO
2
—(C
1
-C
6
)-alkyl, (C
1
-C
6
)-alkyl, —(C
3
-C
6
)-cycloalkyl, —COOH, —COO—(C
1
-C
6
)-alkyl, —COO—(C
3
-C
6
)-cycloalkyl, —CONH
2
, —CONH—(C
1
-C
6
)-alkyl, —CON[(C
1
-C
6
)alkyl]
2
, —CONH—(C
3
-C
6
)-cycloalkyl, —NH
2
, —NH—CO—(C
1
-C
6
)-alkyl, —NH—CO-phenyl, or pyridyl;
R
6
is H or —(C
1
-C
6
)-alkyl;
R
7
is H, —(C
1
-C
7
)-cycloalkyl, phenyl, naphthyl, thienyl, thiophenyl, furanyl, pyridyl, pyrimidyl, dihydropyrimidine-2,4-dion-6-yl, chromanyl, phthalimidoyl, or thiazolyl, wherein the rings are unsubstituted or substituted up to 3 times by F, Cl, Br, —OH, —CF
3
, —NO
2
, —CN, —OCF
3
, —(C
1
-C
6
)-alkyl, —O—(C
1
-C
6
)-alkyl, —S—(C
1
-C
6
)-alkyl, —SO—(C
1
-C
6
)-alkyl, —SO
2
—(C
1
-C
6
)-alkyl, —(C
1
-C
6
)-alkyl, —(C
3
-C
6
)-cycloalkyl, —COOH, —COO—(C
1
-C
6
)-alkyl, —COO—(C
3
-C
6
)-cycloalkyl, —CONH
2
, —CONH—(C
1
-C
6
)-alkyl, —CON[(C
1
-C
6
)alkyl]
2
, —CONH—(C
3
-C
6
)-cycloalkyl, —NH
2
, —NH—CO—(C
1
-C
6
)-alkyl, or —NH—CO-phenyl;
l is 0 or 1;
m, n are 0;
o is 1;
p is 0 or 1;
q is 0 or 1; and
r is 0, 1, or 2.
Particularly preferred compounds of formula (I) or salts thereof are those in which one or more radical(s) has or have the following meaning:
Z is
—NH—(C
1
-C
12
-alkyl)-(C═O)—,
—(C═O)—(C
1
-C
12
-alkyl)-(C═O)—, or
—(C═O)-phenyl-(C═O)—;
A
1
, A
2
, A
3
, A
4
each independently of one another is an amino acid radical, or an amino acid radical which is mono- or polysubstituted by amino acid-protective groups;
E is —SO
2
—R
4
or —CO—R
4
;
R
1
is phenyl, thiazolyl, or oxazolyl, wherein the rings are unsubstituted or substituted up to 3 times by —(C
1
-C
6
)-alkyl;
R
2
is H, —OH, —CH
2
OH, or —OMe;
R
3
is H, F, methyl, or —OMe;
R
4
is —(C
1
-C
16
-alkyl), —(C
0
-C
16
-alkylene)-R
5
, —(C═O)—(C
0
-C
16
-alkylene)-R
5
, —(C═O)—(C
0
-C
16
-alkylene)-NH—R
5
, —(C
1
-C
8
-alkenylene)-R
5
, —(C
1
-C
8
-alkynyl), —(C
1
-C
4
-alkylene)-S(O)
r
—R
5
, —(C
1
-C
4
-alkylene)-O—R
5
, or —(C
1
-C
4
-alkylene)-NH—R
5
;
R
5
is —COO—R
6
, —(C═O)—R
6
, —(C
1
-C
7
)-cycloalkyl, phen

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