4-(1-piperazinyl) benzoic acid derivatives, process for...

Details 4-(1-piperazinyl) benzoic acid derivatives, process for... 4-(1-piperazinyl) benzoic acid derivatives, process for...

1999-10-20

2001-08-28

Raymond, Richard L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S254100, C514S255030, C544S363000, C544S379000, C544S393000

Reexamination Certificate

active

06281215

ABSTRACT:

The present invention relates to new 4-(1-pipera-zinyl)benzoic acid derivatives which are useful in the treatment of diabetes.
The subject of the present invention is thus compounds of general formula (I):
in which:
Ar is selected from
a mono-, bi- or tricyclic aryl group having from 6 to 14 carbon atoms,
a heteroaromatic group selected from the pyridyl, pyrimidyl, pyrrolyl, furyl, thienyl, quinolyl, indolyl, benzothienyl, benzofuryl, benzopyrranyl, benzothiopyrannyl, dibenzofuryl, carbazolyl and benzothiazinyl groups,
it being possible for the Ar group to carry 1 to 3 substituents selected from a C
1
-C
8
alkyl, (C
3
-C
8
)cycloalkyl (C
1
-C
6
)alkyl, C
1
-C
8
alkoxy, (C
3
-C
8
)cycloalkyloxy (C
1
-C
6
)alkyl, (C
3
-C
8
)cycloalkyl (C
1
-C
6
)alkoxy (C
1
-C
6
)alkyl, (C
3
-C
8
)cycloalkyloxy (C
3
-C
8
)cycloalkyl (C
1
-C
6
)alkoxy, (C
1
-C
6
)alkoxy (C
1
-C
6
)alkyl, C
6
-C
14
aryl, C
6
-C
14
heteroaryl, (C
6
-C
14
)heteroaryl (C
1
-C
6
)alkyl, (C
6
-C
14
)aryl (C
1
-C
6
)alkyl, (C
6
-C
14
)aryl (C
1
-C
6
)alkyl (C
6
-C
14
)aryl, (C
6
-C
14
)aryloxy, (C
6
-C
14
)aryloxy (C
1
-C
6
)alkyl, (C
6
-C
14
)aryl (C
1
-C
6
)alkyloxy or (C
6
-C
14
)aryl (C
1
-C
6
)alkyloxy (C
1
-C
6
)alkyl group, a halogen, a trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, nitro, amino, carboxyl, (C
1
-C
6
)alkoxycarbonyl, carbamoyl, (C
1
-C
8
)alkylthio, (C
1
-C
8
)alkylsulphinyl, (C
1
-C
8
) alkylsulphonyl, sulphoamino, (C
1
-C
8
)alkylsulphonylamino, sulphamoyl or (C
1
-C
8
)alkylcarbonylamino group, or two of these substituents forming a methylenedioxy group.
R
1
, R
2
and R
3
are selected, independently of each other, from:
a hydrogen atom,
a C
1
-C
8
alkyl or (C
1
-C
6
)alkoxy (C
1
-C
6
)alkyl group,
a cycloalkyl group containing from 3 to 8 carbon atoms, a (C
3
-C
8
)cycloalkyl (C
1
-C
6
)alkyl group, a (C
3
-C
8
)cycloalkyloxy (C
1
-C
6
)alkyl or (C
3
-C
8
)cycloalkyl (C
1
-C
6
)-alkoxy (C
1
-C
6
)alkyl group,
a C
6
-C
14
aryl, C
6
-C
14
heteroaryl, (C
6
-C
14
)heteroaryl (C
1
-C
6
)alkyl, (C
6
-C
14
)aryl (C
1
-C
6
)alkyl (C
6
-C
14
)aryl, (C
6
-C
14
)aryl (C
1
-C
6
)alkoxy (C
6
-C3
4
)aryl, (C
6
-C
14
)aryl (C
1
-C
6
)alkoxy (C
1
-C
6
)alkyl or (C
6
-C
14
)aryloxy (C
1
-C
6
)alkyl group,
or alternatively R
1
forms with the nitrogen atom to which R
1
is attached and the Ar group a ring selected from indolinyl, quinolyl, indolyl and tetrahydroquinolyl,
R
4
, R
5
, R
6
are selected, independently of each other, from:
a hydrogen atom,
a C
1
-C
8
alkyl, (C
3
-C
8
)cycloalkyl (C
1
-C
6
)alkyl, C
1
-C
8
alkoxy, (C
3
-C
8
)cycloalkyloxy (C
1
-C
6
)alkyl, (C
3
-C
8
)cycloalkyloxy, (C
3
-C
8
)cycloalkyl (C
1
-C
6
)alkoxy, (C
3
-C
8
)cycloalkyl (C
1
-C
6
)alkoxy (C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxy (C
1
-C
6
)alkyl, C
6
-C
14
aryl, (C
6
-C
14
)aryl (C
1
-C
6
)alkyl, (C
6
-C
14
)aryl (C
1
-C
6
)alkyl (C
6
-C
14
)aryl, (C
6
-C
14
)aryloxy, (C
6
-C
14
)aryloxy (C
1
-C
6
)alkyl, (C
1
-C
14
)aryl (C
1
-C
6
)alkoxy or (C
6
-C
14
)aryl (C
1
-C
6
)alkyloxy (C
1
-C
6
)alkyl group, a halogen, a trifluoromethyl, trifluoromethoxy, cyano, carboxyl, hydroxyl, nitro, amino, (C
1
-C
6
)alkoxycarbonyl, carbamoyl, (C
1
-C
8
)alkylthio, (C
1
-C
8
)alkylsulphinyl, (C
1
-C
8
)alkylsulphonyl, sulphoamino, (C
1
-C
8
)alkylsulphonylamino, sulphamoyl or (C
1
-C
8
)alkylcarbonylamino group, it being possible for two of these groups to form a methylenedioxy group, it being possible for the various aryl groups themselves to be substituted with 1 to 3 substituents selected from a C
1
-C
8
alkyl or C
1
-C
8
alkoxy group, a halogen, a trifluoromethyl, trifluoromethoxy, hydroxyl, nitro and amino group,
their solvates and their pharmaceutically acceptable salts.
As an example of an aryl group, there may be mentioned the phenyl, &agr;-naphthyl, &bgr;-naphthyl and fluorenyl groups.
The C
1
-C
8
alkyl groups may be linear or branched. As examples, there may be mentioned the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl and pentyl groups.
The C
1
-C
8
alkoxy groups may likewise be linear or branched. As examples, there may be mentioned the methoxy, ethoxy, propoxy, isopropoxy, butoxy and isobutoxy groups.
The halogens may be selected from fluorine, chlorine, bromine and iodine.
The invention also relates to the tautomeric, enantiomeric, diasterecisomeric and epimeric forms of the compounds of general formula (I).
The compounds of general formula (I) have a carboxylic acid functional group and may be salified, they then being in the form of salts with bases.
Examples of salts with bases of the compounds of general formula (I) include the pharmaceutically acceptable salts such as the sodium salts, potassium salts, calcium salts and other salts of the same type.
The compounds of general formula (I) can also be salified with amines in order to form pharmaceutically acceptable salts. By way of example, it will be possible for the compounds of general formula (I) to be salified with glucanine, N-methylglucamine, N,N-dimethylglucamine, ethanolamine, morpholine, N-methylmorpholine or lysine.
The compounds of general formula (I) possess basic nitrogen atoms and can be monosalified or disalified with inorganic or organic acids. Examples of salts with acids of the compounds of general formula (I) include the pharmaceutically acceptable salts such as, and non-exhaustively, hydrochloride, hydrobromide, sulphate, succinate, maleate, fumarate, malate, tartrate and sulphonates such as methanesulphonate, benzenesulphonate and toluenesulphonate.
Among the compounds of general formula (I) according to the invention, there may be mentioned more particularly, as preferred compound, 4-{4-[2(N-isopropyl-N-phenylamino)-2-oxoethyl]-1-piperazinyl}benzoic acid, 4-{4-[2-(N-[2,6-dimethylphenyl]amino)-2-oxoethyl]-1-piperazinyl }benzoic acid and 4-{4-2-(N-[2,6-diisopropyl-phenyl]amino-2 -oxoethyl]-1-piperazinyl}benzoic acid.
The invention also relates to a process for the preparation of the compounds of general formula (I). A process of preparation according to the invention comprises reactimg an aromatic amine of general formula (II):
in which Ar and R
1
are as defined above, with a haloacyl halide of general formula (III):
in which Hal represents a chlorine or bromine atom,
R
2
and R
3
are defined above, in order to form a compound of general formula (IV):
in which Ar, R
1
, R
2
, R
3
and Hal are as defined above, and reacting the compound of general formula (IV) with a compound of general formula (V):
in which R
4
, R
5
and R
6
are as defined above and R
7
is a hydrogen atom or a C
1
-C
6
alkyl group, in the presence of a basic agent such as triethylamine in order to form the compound of general formula (VI):
in which Ar, R
1
, R
2
, R
3
, R
4
, R
5
, R
6
and R
7
are as defined above.
In the case where R
7
is an alkyl group, the compound of general formula (VI) can be hydrolyzed by conventional acidic or basic means in order to give the compound of general formula (I):
in which Ar, R
1
, R
2
, R
3
, R
4
, R
5
and R
6
are as defined above.
The compounds of formula (V) are known compounds. They can be synthesized according to the procedure described by V. Prelog and Z. Blazek in Collection Czechloslov. Chem. Communications 6, 211-24 (1934) for ethyl 4-(1-piperazinyl)benzote.
By way of example, the compound (VI), in which R is an alkyl group, can be hydrolyzed in the presence of a basic agent such as dilute sodium hydroxide.
The enantiomers of the compounds of formula (I) can be separated by successive recrystallization of the salt of the acid (I) with an optically active base from solvents such as acetone, ethyl acetate or isopropanol, followed by displacement from the salt into an optically active acid by an inorganic or organic acid, according to a conventional method.
The compounds according to the present invention can be used in the treatment of diabetes, in particular of non-insulin-dependent diabetes because of their hypoglycaemic effect and of their lack of toxicity at the active doses.
The subject of the present invention is the

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