Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-07-01
2004-11-16
Bernhardt, Emily (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S254020, C514S254030, C514S253010, C514S255030, C514S218000, C544S295000, C544S360000, C544S367000, C544S369000, C544S379000, C544S380000, C540S575000
Reexamination Certificate
active
06818644
ABSTRACT:
The present invention relates to substituted piperazine derivatives of general formula
their isomers, their salts, particularly the physiologically acceptable salts thereof which have valuable pharmacological properties.
The compounds of the above general formula I are valuable inhibitors of the microsomal triglyceride-transfer protein (MTP) and are therefore suitable for lowering the plasma level of the atherogenic lipoproteins.
In the above general formula I
n denotes the number 1, 2, 3, 4 or 5,
m denotes the number 2 or 3,
X denotes a carbon-carbon bond, an oxygen atom, a methylene, ethylene, imino or N-(C
1-3
-alkyl)-imino group,
R
a
denotes a phenyl group or heteroaryl group substituted by the groups R
1
and R
2
, wherein
R
1
denotes a hydrogen, fluorine, chlorine or bromine atom, a C
1-3
-alkyl group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, a hydroxy group, a C
1-4
-alkoxy group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, a phenoxy, heteroaryloxy, phenyl-C
1-3
-alkoxy, carboxy, C
1-3
-alkoxycarbonyl, aminocarbonyl, C
1-3
-alkylaminocarbonyl, N,N-di-(C
1-3
-alkyl)-aminocarbonyl, nitro, amino, C
1-3
-alkylamino, di-(C
1-3
-alkyl)-amino, phenyl-C
1-3
-alkyl-amino, N-(C
1-3
-alkyl)-phenyl-C
1-3
-alkylamino, C
1-3
-alkylcarbonylamino, N-(C
1-3
-alkyl)-C
1-3
-alkylcarbonyl-amino, C
1-3
-alkylsulphonyl-amino or N-(C
1-3
-alkyl)-C
1-3
-alkylsulphonylamino group, while the abovementioned phenyl or heteroaryl moieties of the group R
1
may be substituted by one to five fluorine, chlorine or bromine atoms, a C
1-3
-alkyl group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, a hydroxy group, or a C
1-4
-alkoxy group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, and
R
2
denotes a hydrogen, fluorine, chlorine or bromine atom, a C
1-3
-alkyl group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, or a C
1-4
-alkoxy group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, or
R
1
and R
2
together represent a methylenedioxy group, or R
a
denotes a monocyclic heteroaryl or phenyl group which is substituted in each case by a phenyl or monocyclic heteroaryl group, while the abovementioned phenyl groups and heteroaryl groups may in each case be substituted by a fluorine, chlorine or bromine atom, a C
1-3
-alkyl group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, by a hydroxy, C
1-3
-alkoxy, carboxy, C
1-3
-alkoxycarbonyl, amino-carbonyl, C
1-3
-alkylaminocarbonyl or N,N-di-(C
1-3
-alkyl)-aminocarbonyl group,
R
b
and R
c
independently of one another denote a hydrogen atom or a C
1-3
-alkyl group and
R
f
and R
g
, which may be identical or different, denote hydrogen atoms, C
1-6
-alkyl groups wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, C
3-7
-cycloalkyl groups, phenyl, heteroaryl, phenyl-C
1-3
-alkyl or heteroaryl-C
1-3
-alkyl groups, while the abovementioned phenyl groups and heteroaryl groups may in each case be substituted by one to three fluorine, chlorine or bromine atoms, by one to three C
1-3
-alkyl groups wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, by one to three hydroxy groups, one to three C
1-3
-alkoxy groups wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, or by a carboxy, C
1-3
-alkoxycarbonyl, aminocarbonyl, C
1-3
-alkylaminocarbonyl, N,N-di-(C
1-3
-alkyl)-aminocarbonyl, N,N-di-(C
1-3
-alkyl)-amino, nitro or amino group, or
R
f
and R
g
together with the nitrogen atom between them denote a 3- to 7-membered cycloalkyleneimino group, while the methylene group in the 4 position of a 6- or 7-membered cycloalkyleneimino group may additionally be replaced by an oxygen or sulphur atom, by a sulphinyl, sulphonyl, imino or N-(C
1-3
-alkyl)-imino group,
while the tricyclic group in the abovementioned general formula I may be mono- or disubstituted by fluorine or chlorine atoms, by methyl or methoxy groups and the substituents may be identical or different.
By the abovementioned heteroaryl groups are meant 6-membered heteroaryl groups containing one, two or three nitrogen atoms, or 5-membered heteroaryl groups which may contain one to four heteroatoms such as, for example, nitrogen, oxygen and sulphur, while hydrogen atoms bound to nitrogen may optionally be replaced by C
1-3
-alkyl groups.
Preferred compounds of the above general formula I are those wherein
n denotes the number 3, 4 or 5,
m denotes the number 2 or 3,
X denotes a carbon-carbon bond, an oxygen atom, a methylene, ethylene, imino or N-(C
1-3
-alkyl)-imino group,
R
a
denotes a phenyl group or heteroaryl group substituted by the groups R
1
and R
2
, wherein
R
1
denotes a hydrogen, fluorine, chlorine or bromine atom, a C
1-3
-alkyl group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, a hydroxy group, a C
1-4
-alkoxy group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, a phenoxy, heteroaryloxy, phenyl-C
1-3
-alkoxy, carboxy, C
1-3
-alkoxycarbonyl, aminocarbonyl, C
1-3
-alkylaminocarbonyl, N,N-di-(C
1-3
-alkyl)-aminocarbonyl, nitro, amino, C
1-3
-alkylamino, di-(C
1-3
-alkyl)-amino, phenyl-C
1-3
-alkyl-amino, N-(C
1-3
-alkyl)-phenyl-C
1-3
-alkylamino, C
1-3
-alkylcarbonylamino, N-(C
1-3
-alkyl)-C
1-3
-alkyl-carbonylamino, C
1-3
-alkylsulphonylamino or N-(C
1-3
-alkyl)-C
1-3
-alkylsulphonylamino group, while the abovementioned phenyl or heteroaryl moieties of the group R
1
may be substituted by one to five fluorine, chlorine or bromine atoms, a C
1-3
-alkyl group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, a hydroxy group, or a C
1-4
-alkoxy group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, and
R
2
denotes a hydrogen, fluorine, chlorine or bromine atom, a C
1-3
-alkyl group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, or a C
1-4
-alkoxy group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, or
R
1
and R
2
together represent a methylenedioxy group,
or R
a
denotes a monocyclic heteroaryl or phenyl group which is substituted in each case by a phenyl or monocyclic heteroaryl group, while the abovementioned phenyl groups and heteroaryl groups may in each case be substituted by a fluorine, chlorine or bromine atom, a C
1-3
-alkyl group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, by a hydroxy, or C
1-3
-alkoxy group,
R
b
and R
c
independently of one another denote a hydrogen atom or a C
1-3
-alkyl group and
R
f
and R
g
, which may be identical or different, denote hydrogen atoms, C
1-6
-alkyl groups wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, C
3-7
-cycloalkyl groups, phenyl, heteroaryl, phenyl-C
1-3
-alkyl or heteroaryl-C
1-3
-alkyl groups, while the abovementioned phenyl groups and heteroaryl groups may in each case be substituted by one to three fluorine, chlorine or bromine atoms, by one to three C
1-3
-alkyl-groups, wherein the-hydrogen-atoms may be wholly or partly replaced by fluorine atoms, by one to three hydroxy groups, one to three C
1-3
-alkoxy groups wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, or by a carboxy, C
1-3
-alkoxycarbonyl, aminocarbonyl, C
1-3
-alkylaminocarbonyl, N,N-di-(C
1-3
-alkyl)-aminocarbonyl, N,N-di-(C
1-3
-alkyl)-amino, nitro or amino group, or
R
f
and R
g
together with the nitrogen atom between them denote a 3- to 7-membered cycloalkyleneimino group, while the methylene group in the 4 position of a 6- or 7-membered cycloalkyleneimino group may additionally be replaced by an oxygen or sulphur atom, by a sulphinyl, sulphonyl, imino or N-(C
1-3
-alkyl)-imino group,
the isomers and the salts thereof.
Particularly preferred compounds of the above general formula I are those wherein
n denotes the number 3, 4 or 5,
m denotes the number 2 or 3,
X denotes a carbon-carbon b
Heckel Armin
Lehmann-Lintz Thorsten
Mark Michael
Thomas Leo
Bernhardt Emily
Boehringer Ingelheim Pharm GmbH & Co, KG
Bottino Anthony P.
Raymond Robert P.
Witkowski Timothy X.
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