Aryl-substituted propanolamine derivatives, their...

Details Aryl-substituted propanolamine derivatives, their... Aryl-substituted propanolamine derivatives, their...

1999-10-01

2001-06-12

Fonda, Kathleen K. (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C514S053000, C514S054000, C514S061000, C536S004100, C536S017400, C536S018700

Reexamination Certificate

active

06245744

ABSTRACT:

The invention relates to substituted propanolamine derivatives and to their acid addition salts.
Several classes of active substances for the treatment of obesity and disorders of lipid metabolism have already been described:
polymeric adsorbers such as, for example, cholestyramine,
benzothiazepines (WO 93/16055),
bile acid dimers and conjugates (EP 0 489 423) and
4-amino-2-ureidopyrimidine-5-carboxamides (EP 0 557 879).
The invention was based on the object of providing further compounds which have a therapeutically exploitable hypolipidemic effect.
The invention therefore relates to propanolamine derivatives of formula I
in which
R
1
is phenyl, or heteroaryl, which is unsubstituted or optionally substituted by one to three independent radicals, it being possible for the aromatic or heteroaromatic ring to be mono- to trisubstituted by fluorine, chlorine, bromine, iodine, —OH, —CF
3
, —NO
2
, —CN, —(C
1
-C
8
)-alkoxy, —(C
1
-C
8
)-alkyl, —NH
2
, —NH—R
9
, —N(R
9
)R
10
, —CHO, —COOH, —COOR
11
, —(C═O)—R
12
, —(C
1
-C
6
)-alkyl—OH, —(C
1
-C
6
)-alkyl(—OH)-phenyl, —(C
1
-C
6
)-alkyl-CF
3
, —(C
1
-C
6
)-alkyl-NO
2
, —(C
1
-C
6
)-alkyl-CN, —(C
1
-C
6
)-alkyl-NH
2
, —(C
1
-C
6
)-alkyl-NH—R
9
, —(C
1
-C
6
)-alkyl-N(R
9
)R
10
, —(C
1
-C
6
)-alkyl-CHO, —(C
1
-C
6
)-alkyl-COOH, —(C
1
-C
6
)-alkyl-COOR
11
, —(C
1
-C
6
)-alkyl-(C═O)—R
12
, —O—(C
1
-C
6
)-alkyl-OH, —O—(C
1
-C
6
)-alkyl-CF
3
, —O—(C
1
-C
6
)-alkyl-N
2
, —O—(C
1
-C
6
)-alkyl-CN, —O—(C
1
-C
6
)-alkyl-NH
2
, —O—(C
1
-C
6
)-alkyl-NH—R
9
, —O—(C
1
-C
6
)-alkyl-N(R
9
)R
10
, —O—(C
1
-C
6
)-alkyl-CHO, —O—(C
1
-C
6
)-alkyl-COOH, —O—(C
1
-C
6
)-alkyl-COOR
11
, —O—(C
1
-C
6
)-alkyl-(C═O)—R
12
, —N—S
3
H, —S
2
—CH
3
, —O—(C
1
-C
6
)-alkyl-O—(C
1
C
6
)-alkyl-phenyl, (C
1
C
6
) -alkylthio, or pyridyl, it being possible for one or more hydrogen(s) in the alkyl radicals to be replaced by fluorine and it being possible for phenyl and pyridyl, in turn, to be monosubstituted by methyl, methoxy or halogen;
R
2
is H, —OH, —CH
2
OH, —OMe, —CHO, or —NH
2
;
R
3
is a sugar residue, disugar residue, trisugar residue, tetrasugar residue, it being possible for the sugar residue, disugar residue, trisugar residue or tetrasugar residue to be optionally mono- or polysubstituted by one of the sugar protective groups, HO—SO
2
—, or (HO)
2
—PO—;
R
4
is H, methyl, F, or —OMe;
R
9
to R
12
each independently of one another is H or —(C
1
-C
8
)-alkyl;
Z is —NH—(C
0
-C
16
)-alkyl-C═O—, —O—(C
0
-C
16
)-alkyl-C═O—, —(C═O)
m
—(C
11
-C
16
)-alkyl-(C═O)
n
, amino acid residue, diamino acid residue, it being possible for the amino acid residue or diamino acid residue optionally to be mono- or polysubstituted by an amino acid protective group, or a covalent bond;
n is 0 or 1;
m is 0 or 1;
and their pharmaceutically tolerated salts and physiologically functional derivatives.
Preferred compounds of formula I are those in which one or more radical(s) has, or have, the following meaning:
R
1
is phenyl, pyridyl, thienyl, furyl, pyrimidyl, indolyl, thiazolyl, imidazolyl, coumarinyl, phthaliminyl, quinoyl, piperazinyl, tetrazolyl, triazolyl, oxazolyl isoxazolyl, isothiazolyl or their benzo-fused derivatives, it being possible for the aromatic or heteroaromatic ring to be mono- to trisubstituted by fluorine, chlorine, bromine, iodine, —OH, —CF
3
, —NO
2
, —CN, —(C
1
-C
8
)-alkoxy, —(C
1
-C
8
)-alkyl, —NH
2
, —NH—R
9
, —N(R
9
)R
10
, —CHO, —COOH, —COOR
11
, —(C═O)—R
12
, —(C
1
-C
6
)-alkyl-OH, —(C
1
-C
6
)-alkyl(—OH)-phenyl, —(C
1
-C
6
)-alkyl-CF
3
, —(C
1
-C
6
)-alkyl-NO
2
, (C
1
-C
6
)-alkyl-CN, —(C
1
-C
6
)-alkyl-NH
2
, —(C
1
-C
6
)-alkyl-NH—R
9
, —(C
1
-C
6
)-alkyl-N(R
9
)R
10
, —(C
1
-C
6
)-alkyl-CHO, —(C
1
-C
6
)-alkyl-COOH, —(C
1
-C
6
)-alkyl-COOR
11
, —(C
1
-C
6
)-alkyl-(C═O)—R
12
, —O—(C
1
-C
6
)-alkyl-OH, —O—(C
1
-C
6
)-alkyl-CF
3
, —O—(C
1
-C
6
)-alkyl-NO
2
, —O—(C
1
-C
6
)-alkyl-CN, —O—(C
1
-C
6
)-alkyl-NH
2
, —O—(C
1
-C
6
)-alkyl-NH—R
9
, —O—(C
1
-C
6
)-alkyl-N(R
9
)R
10
, —O—(C
1
-C
6
)-alkyl-CHO, —O—(C
1
-C
6
)-alkyl-COOH, —O—(C
1
-C
6
)-alkyl-COOR
11
, —O—(C
1
-C
6
)-alkyl-(C═O)—R
12
, —N—SO
3
H, —SO
2
—CH
3
, —O—(C
1
-C
6
)-alkyl-O—(C
1
-C
6
)alkyl-phenyl, —(C
1
-C
6
)-alkylthio, pyridyl, it being possible for one or more hydrogen(s) in the alkyl radicals to be replaced by fluorine and it being possible for phenyl and pyridyl, in turn, to be monosubstituted by methyl, methoxy or halogen;
R
2
is H, —OH, —CH
2
OH, —OMe, —CHO, or —NH
2
;
R
3
is a sugar residue, disugar residue, trisugar residue, tetrasugar residue, it being possible for the sugar residue, disugar residue, trisugar residue or tetrasugar residue to be optionally mono- or polysubstituted by a sugar protective group, HO—SO
2
—, or (HO)
2
—PO—;
R
4
is H, methyl, F, or —OMe;
R
9
to R
12
each independently of one another is H, or —(C
1
-C
8
)-alkyl;
Z is —NH—(C
0
-C
16
)-alkyl-C═O—, —O—(C
0
-C
16
)-alkyl-C═O—, —(C═O)
m
—(C
1
-C
16
)-alkyl-(C═O)
n
, an amino acid residue, a diamino acid residue, it being possible for the amino acid residue or the diamino acid residue optionally to be mono- or polysubstituted by an amino acid protective group, or a covalent bond;
n is 0 or 1;
m is 0 or 1;
and their pharmaceutically tolerated salts and physiologically functional derivatives.
Especially preferred compounds of formula I are those in which one or more radical(s) has, or have, the following meaning:
R
1
is phenyl, pyridyl, thienyl, furyl, pyrimidyl, indolyl, thiazolyl, imidazolyl, coumarinyl, phthaliminyl, quinoyl, piperazinyl, tetrazolyl, triazolyl, oxazolyl, isoxazolyl, isthiazolyl, it being possible for the aromatic or heteroaromatic ring to be mono- or disubstituted by fluorine, chlorine, bromine, iodine, —OH, —CF
3
, —NO
2
, —CN, —(C
1
-C
8
)-alkoxy, —(C
1
-C
8
)-alkyl, —(C
3
-C
6
)-cycloalkyl, —NH
2
, —CHO, —COOH, or OCF
3
;
R
2
is H, —OH, —CH
2
OH, —OMe, CHO, or —NH
2
;
R
3
is a sugar residue, a disugar residue, the sugar residue or disugar residue optionally being mono- or polysubstituted by one of the sugar protective groups, HO—SO
2
—, or (HO)
2
—PO—;
R
4
is H, methyl, F, or —OMe;
Z is —NH—(C
0
-C
16
)-alkyl-C═O—, —O—(C
1
-C
16
)-alkyl-C═O—, —(C═O)
m
—(C
1
-C
16
)-alkyl-(C═O)
n
, or a covalent bond;
n is 0 or 1;
m is 0 or 1;
and their physiologically tolerated acid addition salts.
Very especially preferred compounds of formula I are those in which one or more radical(s) has, or have, the following meaning:
R
1
is phenyl, thiazolyl, oxazolyl, isoxazolyl, it being possible for the aromatic or heteroaromatic ring to be mono- to disubstituted by fluorine, chlorine, bromine, or —(C
1
-C
8
)-alkyl;
R
2
is H, —OH, —CH
2
OH, —OMe, —CHO, or —NH
2
;
R
3
is
the sugar residue optionally being mono- or polysubstituted by one of the sugar protective groups, or HO—SO
2
—;
R
4
is H, methyl, F, or —OMe;
Z is —NH—(C
6
-C
12
)-alkyl-C═O—, —O—(C
6
-C
12
)-alkyl-C═O—, or —(C═O)
m
—(C
6
-C
12
)-alkyl-(C═O)
n
;
n is 0 or 1;
m is 0 or 1;
and their physiologically tolerated acid addition salts.
In the abovementioned heteroaryl groups, examples of suitable heteroatoms are O, S, and N.
Unless otherwise defined, heteroaromatic rings have 1-15 carbon atoms and 1-6 heteroatoms, preferably 1-5 carbon atoms and 1-2 heteroatoms.
Examples of the heteroaryl groups mentioned in the above definitions are thiophene, furan, pyridine, pyrimidine, indole, quinoline, oxazole, isoxazole, thiazole, or isothiazole.
The term alkyl is to be understood to mean straight-chain or branched hydrocarbon chains.
Sugar residues are Be understood to mean compounds derived from aldoses and ketoses having 3 to 7 carbon atoms, which can belong to the D- or L-series; they also include amino sugars, sugar alcohols or sugar acids. Examples which may be mentioned are glucose, mannose, fructose, galactose, ribose, erythrose, glycerinaldehyde, sedoheptulose, glucosamine, galactosamine, glucuronic acid, galacturonic acid, gluconic acid, galactonic acid, mannonic acid, glucamine, 3-amino-1,2-propanediol, glucaric acid and galactaric a

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