Biphenyl derivatives, production thereof and uses as medicines

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

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C514S243000, C514S248000, C514S252030, C514S252140, C514S258100, C514S266220, C514S318000, C514S319000, C514S330000, C544S180000, C544S183000, C544S215000, C544S235000, C544S238000, C544S284000, C546S194000, C546S196000, C546S198000, C546S199000, C546S200000, C546S201000, C546S202000, C546S207000, C546S208000, C546S209000, C546S210000, C546S213000, C546S214000, C546S224000

Reexamination Certificate

active

06617325

ABSTRACT:

The present invention relates to biphenyl 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,
R
a
and R
b
, which may be identical or different, each denote a hydrogen, fluorine, chlorine or bromine atom, a C
1-3
-alkyl group wherein the hydrogen atoms may be wholly or partially replaced by fluorine atoms, a hydroxy, C
1-3
-alkoxy, amino, C
1-3
-alkylamino or di-(C
1-3
-alkyl)-amino group,
R
c
denotes a hydrogen atom,
a C
1-10
-alkyl, C
3-7
-cycloalkyl or C
3-7
-cycloalkyl-C
1-3
-alkyl group, wherein in each case the hydrogen atoms may be wholly or partially replaced by fluorine atoms,
a phenyl, naphthyl or monocyclic 5 or 6-membered heteroaryl group optionally substituted by a fluorine, chlorine or bromine atom, by a C
1-3
-alkyl group wherein the hydrogen atoms may be wholly or partially replaced by fluorine atoms, by a 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, by 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, by a nitro, amino, C
1-3
-alkylamino, di-(C
1-3
-alkyl)-amino, C
1-3
-alkylcarbonylamino, N-(C
1-3
-alkyl)-C
1-3
-alkylcarbonylamino, C
1-3
-alkylsulphonylamino or N-(C
1-3
-alkyl)-C
1-3
-alkylsulphonylamino group, wherein the 6-membered heteroaryl group contains one, two or three nitrogen atoms and the 5-membered heteroaryl group contains an imino group optionally substituted by a C
1-3
-alkyl group, an oxygen or sulphur atom, or an imino group optionally substituted by a C
1-3
-alkyl group and an oxygen or sulphur atom or one or two nitrogen atoms, and moreover a phenyl ring may be fused to the abovementioned monocyclic heterocyclic groups via two adjacent carbon atoms,
R
d
denotes a phenyl, naphthyl or monocyclic 5 or 6-membered heteroaryl group optionally substituted by a fluorine, chlorine or bromine atom, by a C
1-3
-alkyl group wherein the hydrogen atoms may be wholly or partially replaced by fluorine atoms, by a 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, by a 3- to 7-membered cycloalkyleneimino group, wherein the methylene group may additionally be replaced in the 4 position in a 6-or 7-membered cycloalkyleneimino group by an oxygen or sulphur atom, by a sulphinyl, sulphonyl, imino or N-(C
1-3
-alkyl)-imino group, by a nitro, amino, C
1-3
-alkylamino, di-(C
1-3
-alkyl)-amino, C
1-3
-alkylcarbonylamino, N-(C
1-3
-alkyl)-C
1-3
-alkylcarbonylamino, C
1-3
-alkylsulphonylamino or N-(C
1-3
-alkyl)-C
1-3
-alkylsulphonylamino group, wherein the 6-membered heteroaryl group contains one, two or three nitrogen atoms and the 5-membered heteroaryl group contains an imino group optionally substituted by a C
1-3
-alkyl group, an oxygen or sulphur atom, or an imino group optionally substituted by a C
1-3
-alkyl group and an oxygen or sulphur atom or one or two nitrogen atoms, and moreover a phenyl ring may be fused to the abovementioned monocyclic heterocyclic groups via two adjacent carbon atoms,
R
e
denotes a carboxy group, a C
1-6
-alkoxycarbonyl or C
3-7
-cycloalkoxycarbonyl group wherein the alkyl or cycloalkyl moiety may be substituted in each case from the 2 position, relative to the oxygen atom, by a C
1-3
-alkoxy, amino, C
1-3
-alkylamino or di-(C
1-3
-alkyl)-amino group, a phenyl-C
1-3
-alkoxycarbonyl or heteroaryl-C
1-3
-alkoxycarbonyl group, while the heteroaryl moiety is as hereinbefore defined,
R
f
denotes a hydrogen atom, a C
1-3
-alkyl or phenyl-C
1-3
-alkyl group and
R
g
denotes a hydrogen atom or a C
1-3
-alkyl group.
However, preferred compounds of the above general formula I are those wherein
R
b
to R
g
are as hereinbefore defined and
R
a
is in the 3′ or 4′ position and has the meanings given hereinbefore with the exception of the hydrogen atom,
the isomers and salts thereof.
However, particularly preferred compounds of the above general formula I are those wherein
n denotes the number 3, 4 or 5,
R
a
denotes a hydrogen, fluorine, chlorine or bromine atom, a C
1-3
-alkyl, trifluoromethyl or C
1-3
-alkoxy group,
R
b
denotes a hydrogen, fluorine, chlorine or bromine atom,
R
c
denotes a C
1-5
-alkyl, C
3-7
-cycloalkyl or C
3-7
-cycloalkyl-C
1-3
-alkyl group or
a phenyl group optionally substituted by a fluorine, chlorine or bromine atom or by a C
1-3
-alkyl group,
R
d
denotes a phenyl group optionally substituted by a fluorine, chlorine or bromine atom or by a C
1-3
-alkyl group,
R
e
denotes a carboxy group, a C
1-6
-alkoxycarbonyl or C
3-7
-cycloalkoxycarbonyl group wherein the alkyl or cycloalkyl moiety may be substituted in each case from the 2 position, relative to the oxygen atom, by a C
1-3
-alkoxy, amino, C
1-3
-alkylamino or di-(C
1-3
-alkyl)-amino group, a phenyl-C
1-3
-alkoxycarbonyl, pyridyl-C
1-3
-alkoxycarbonyl or pyrimidyl-C
1-3
-alkoxycarbonyl group,
R
f
denotes a hydrogen atom or a C
1-3
-alkyl group and
R
g
denotes a hydrogen atom or a C
1-3
-alkyl group,
the isomers and salts thereof.
The following are mentioned as examples of particularly valuable compounds:
(a) methyl 2-methyl-2-phenyl-5-{4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-piperidin-1-yl}-pentanecarboxylate,
(b) methyl 2-ethyl-2-phenyl-5-{4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-piperidin-1-yl}-pentanecarboxylate and
(c) methyl 2-methyl-2-phenyl-6-{4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-piperidin-1-yl}-hexanecarboxylate.
According to the invention, the new compounds are obtained by methods known from the literature, for example by the following methods:
a. reacting a compound of general formula
wherein
R
a
, R
b
, R
f
and R
g
are as hereinbefore defined, with a compound of general formula
wherein
n and R
c
to R
e
are as hereinbefore defined and
Z
1
denotes a nucleofugic leaving group such as a halogen atom, e.g. a chlorine, bromine or iodine atom, or a p-nitrophenyl group.
The reaction is preferably carried out in a solvent such as methylene chloride, acetonitrile, tetrahydrofuran, toluene, acetone/water, dimethylformamide or dimethylsulphoxide optionally in the presence of a base such as sodium hydride, potassium carbonate, potassium tert-butoxide or N-ethyl-diisopropylamine at temperatures between 0 and 100° C., preferably at temperatures between 10 and 60° C.
b. In order to prepare a compound of general formula I, wherein R
e
has the meanings given hereinbefore for R
e
with the exception of the carboxy group:
esterifying a compound of general formula
wherein
n, R
a
to R
d
, R
f
and R
g
are as hereinbefore defined, or the reactive derivatives thereof with an alcohol of general formula
H—R
e
′,   (V)
wherein
R
e
′ denotes a C
1-6
-alkoxy or C
3-7
-cycloalkoxy group wherein the alkyl or cycloalkyl moiety may be substituted in each case from the 2 position, relative to the oxygen atom, by a C
1-3
-alkoxy, amino, C
1-3
-alkylamino or di-(C
1-3
-alkyl)-amino group, a phenyl-C
1-3
-alkoxy or heteroaryl-C
1-3
-alkoxy group, while the heteroaryl moiety is as hereinbefore defined, or, in order to prepare a tert-butyl ester, 2,2-dimethyl-ethene, in the presence of an acid.
The reaction is optionally carried out in the presence of a solvent or mixture of solvents such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran or dioxane, but preferably in an excess of th

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