Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-10-09
2004-11-23
Bernhardt, Emily (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S249000, C514S252170, C514S253050, C514S253060, C514S254020, C514S254060, C514S254110, C514S255030, C540S575000, C544S292000, C544S363000, C544S356000, C544S368000, C544S370000, C544S375000, C544S380000
Reexamination Certificate
active
06821967
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
m denotes the number 2 or 3,
n denotes the number 1, 2, 3, 4 or 5,
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 bi- or tri-nuclear aromatic hydrocarbon wherein an angular methyne group may be replaced by a nitrogen atom,
a bi- or tri-nuclear heteroaromatic hydrocarbon linked to the piperazino group via a carbon atom, consisting of
a 5-membered heteroaryl ring containing one or two nitrogen atoms and a cyclopentadienyl ring fused on via a vinylene group, wherein additionally a methyne group may be replaced by a nitrogen atom and/or an angular methyne group may be replaced by a nitrogen atom,
a 5-membered heteroaryl ring which contains an imino group optionally substituted by a C
1-3
-alkyl, phenyl-C
1-3
-alkyl, phenyl, pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl group, or an oxygen or sulphur atom, and a phenyl or 6-membered heteroaryl ring fused on via one or two of the available vinylene groups, containing one, two or three nitrogen atoms, wherein the fused-on rings may be identical or different, or a naphthyl ring fused on via one of the two available vinylene groups, wherein additionally in a bicyclic or tricyclic group thus formed an angular carbon atom may be replaced by a nitrogen atom, or
a 5-membered heteroaryl ring which contains an imino group optionally substituted by a C
1-3
-alkyl, phenyl-C
1-3
-alkyl, phenyl, pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl group, or an oxygen or sulphur atom, and one or two nitrogen atoms, and a phenyl, naphthyl, pyridine, pyridazine, pyrimidine or pyrazine ring fused on via the available vinylene group, wherein an angular carbon atom may be replaced by a nitrogen atom,
a naphthyl or 6-membered heteroaryl ring containing one, two or three nitrogen atoms, and a pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl ring fused on via a vinylene group,
wherein an angular carbon atom may be replaced by a nitrogen atom, or
a phenyl ring and a 6-membered heteroaryl ring fused on via one or two of the available vinylene groups, containing one, two or three nitrogen atoms, wherein the fused-on rings may be identical or different and additionally in a bicyclic or tricyclic group thus formed an angular carbon atom may be replaced by a nitrogen atom,
a pyridine, pyrazine or pyridazine ring and a phenyl or 6-membered heteroaryl ring fused on via the two available vinylene groups, containing one, two or three nitrogen atoms, wherein the fused-on rings may be identical or different and additionally in a tricyclic group thus formed an angular carbon atom may be replaced by a nitrogen atom,
wherein the bi- and tricyclic groups mentioned above under R
a
may additionally be mono- or disubstituted in the carbon skeleton by a fluorine, chlorine, bromine or iodine atom, by a C
1-3
-alkyl, hydroxy, C
1-3
-alkoxy, carboxy, C
1-3
-alkoxycarbonyl, aminocarbonyl, C
1-3
-alkylaminocarbonyl or N,N-di-(C
1-3
-alkyl)-aminocarbonyl group, wherein the substituents may be identical or different and additionally the hydrogen atoms in the abovementioned alkyl and alkoxy moieties may be wholly or partly replaced by fluorine atoms,
R
b
and R
c
independently of one another in each case denote a hydrogen atom or a C
1-3
-alkyl group,
R
f
and R
g
, which may be identical or different, denote hydrogen atoms or C
1-6
-alkyl groups wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, C
3-7
-cycloalkyl, phenyl, C
1-3
-alkoxy-carbonyl-C
1-2
-alkyl, carboxy-C
1-2
-alkyl, methoxy-C
2-3
-alkyl, heteroaryl, phenyl-C
1-3
-alkyl or heteroaryl-C
1-3
-alkyl groups,
wherein the abovementioned phenyl and heteroaryl groups may be mono-, di- or tri-substituted in the carbon skeleton by fluorine, chlorine or bromine atoms, by C
1-3
-alkyl or C
1-3
-alkoxy groups wherein the hydrogen atoms may be wholly or partially replaced by fluorine atoms, by hydroxy, carboxy, C
1-3
-alkoxycarbonyl, aminocarbonyl, C
1-3
-alkyl-aminocarbonyl, N,N-di-(C
3
-alkyl)-aminocarbonyl, N,N-di-(C
1-3
-alkyl)-amino, nitro or amino groups, wherein the substituents may be identical or different, and/or a hydrogen atom bound to a nitrogen atom of the abovementioned heteroaryl groups may be replaced by a C
1-3
-alkyl group wherein the hydrogen atoms may be wholly or partially replaced by fluorine atoms, by a C
1-3
-alkyl-carbonyl or C
1-4
-alkoxy-carbonyl group, or
R
f
and R
g
together with the nitrogen atom between them denote a 3- to 7-membered cycloalkyleneimino group, wherein the methylene group in the 4 position in 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,
wherein 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 rings mentioned above in the definition of the group R
a
are meant the aromatic and heteroaromatic bi- and tricycles known from the literature, such as, for example, those described in “The Ring Index, Second Edition, A. M. Patterson, L. T. Capell, D. F. Walker, American Chemical Society 1960”; by a bi-nuclear ring, for example, is meant in particular the naphthyl, pyrrolo-pyrrole, benzofuran, pyrido-furan, pyridazino-furan, pyrimido-furan, pyrazino-furan, benzothiophene, pyrido-thiophene, pyridazino-thiophene, pyrimido-thiophene, pyrazino-thiophene, indole, pyrido-pyrrole, pyridazino-pyrrole, pyrimido-pyrrole, pyrazino-pyrrole, benzo-pyrazole, pyrido-pyrazole, pyridazino-pyrazole, pyrimido-pyrazole, pyrazino-pyrazole, benzotriazole, pyridino-triazole, pyridazino-triazole, pyrimido-triazole, pyrazino-triazole, quinoline, isoquinoline, cinnoline, benzo-pyridazine, quinazoline, benzo-pyrimidine, quinoxaline, benzo-pyrazine, phthalazine, pyrido-pyridine, pyridazino-pyridine, pyrimido-pyridine, pyrazino-pyridine, benzoxazole, pyrido-oxazole, pyridazino-oxazole, pyrimidino-oxazole, pyrazino-oxazole, benzothiazole, pyrido-thiazole, pyridazino-thiazole, pyrimidino-thiazole, pyrazino-thiazole, benzimidazole, pyrido-imidazole, pyridazino-imidazole, pyrimidino-imidazole, pyrazino-imidazole, pteridine, triazolo-pyridine, triazolo-pyridazine, triazolo-pyrimidine, triazolo-pyrazine, pyridazino-pyrimidine, pyrimido-pyrimidine or pteridine ring and
by a tri-nuclear ring is meant the phenanthene, anthracene, dibenzofuran, dibenzothiophene, acridine, phenanthridine, phenanthroline, phenanzine, naphtho-pyrrole, naphtho-pyrazole, naphtho-imidazole, naphtho-pyridine, naphtho-pyridazine, naphtho-pyrimidine or naphtho-pyrazine ring.
Moreover, the saturated alkyl and alkoxy moieties mentioned above in the definition which contain more than 2 carbon atoms also include the branched isomers thereof such as, for example, the isopropyl, tert.butyl, isobutyl group, etc.
Preferred compounds of the above general formula I are those wherein
n denotes the number 3, 4 or 5 and m, X, R
a
, R
b
, R
c
, R
f
and R
g
are as hereinbefore defined,
the isomers and salts thereof.
Particularly preferred compounds of the above general formula I are those wherein
m denotes the number 2 or 3,
n denotes the number 3, 4 or 5,
X denotes a carbon-carbon bond or an oxygen atom,
R
a
denotes a bi- or tri-nuclear aromatic hydrocarbon wherein an angular methyne group may be replaced by a nitrogen atom,
a bi- or tri-nuclear heteroaromatic hydrocarbon linked to the piperazino group via a carbon atom, consisting of
a 5-membered heteroaryl ring which contains an imino group optionally substituted by a C
1-3
-a
Heckel Armin
Lehmann-Lintz Thorsten
Mark Michael
Thomas Leo
Bernhardt Emily
Boehringer Ingelheim Pharma KG
Dow David A.
Morris Michael
Raymond Robert P.
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