Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-01-29
2002-04-23
Bernhardt, Emily (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S253010, C514S254020, C514S254060, C514S255030, C544S295000, C544S360000, C544S368000, C544S370000, C544S394000
Reexamination Certificate
active
06376495
ABSTRACT:
The present invention relates to novel piperazine derivatives which are of use in the treatment of pathologies associated with insulin-resistance syndrome.
The compounds of the invention have the formula:
in which:
n represents 2, 3, 4, 5 or 6;
X represents O or S;
Ar represents an aromatic nucleus chosen from phenyl, pyridyl, pyrimidinyl, benzoxazolyl, benzothiazolyl and benzimidazolyl, the said aromatic nucleus optionally being substituted by one or more radicals chosen from a halogen atom; a (C
1
-C
6
) alkoxy group; a (C
6
-C
10
) aryloxy group; a (C
6
-C
10
)aryl(C
1
-C
6
)alkoxy group in which the aryl part is optionally substituted by halogen, (C
1
-C
6
)alkyl or (C
1
-C
6
)alkoxy; and a (C
1
-C
6
)alkyl group substituted by one or more halogen atoms;
i represents 0, 1, 2, 3 or 4; and
each Z group independently represents a halogen atom; as well as their addition salts with pharmaceutically acceptable bases or acids.
The invention also relates to the solvates of the compounds of formula I.
The term “alkyl” is understood to mean, according to the invention, a linear or branched hydrocarbon-comprising group. Mention may be made, as example of alkyl groups, of the methyl, ethyl, propyl, n-butyl, isobutyl, sec-butyl, tert-butyl, isoamyl, tert-amyl, sec-amyl, pentyl and hexyl groups.
The alkyl parts of the alkoxy and arylalkoxy groups have the same definition as given above for the alkyl group.
Mention may be made, as example of alkyl groups substituted by one or more halogen atoms, of the perfluoroalkyl groups, such as trifluoromethyl or pentafluoroethyl.
The aryl group is a mono- or polycyclic aromatic group, preferably mono- or bicyclic, such as phenyl or naphthyl. The same definition is valid for the aryl parts of the aryloxy and arylalkoxy groups.
The halogen atoms are chosen from bromine, fluorine, iodine and chlorine.
When Ar represents substituted phenyl, the phenyl nucleus can carry one, two, three, four or five substituents. However, when Ar represents substituted phenyl, the phenyl nucleus is preferably mono-, di- or trisubstituted. In this case, the substituents are preferably in the meta or para position.
Examples of preferred aryloxy groups are phenoxy and naphthyloxy.
An example of a preferred arylalkoxy group is the benzyloxy group.
The —CH
2
—COOH group of the compounds of the invention is situated either in the ortho position or in the meta position or in the para position with regard to the chain
However, preference is given to the compounds in which the —CH
2
—COOH group is in the para or ortho position, the para position being especially preferred.
The compounds of formula I have a carboxyl functional group and can be salified. They are then provided in the form of addition salts with organic or inorganic bases.
The addition salts with bases are, for example, pharmaceutically acceptable salts, such as the sodium salts, the potassium salts or the calcium salts, which are obtained by using the corresponding alkali metal or alkaline earth metal hydroxides as bases.
Mention may be made, as other types of addition salts with pharmaceutically acceptable bases, of the salts with amines and in particular glucamine, N-methylglucamine, N,N-dimethylglucamine, ethanolamine, morpholine, N-methylmorpholine or lysine.
The compounds of formula I can also be salified with inorganic or organic acids and preferably pharmaceutically acceptable acids, such as hydrochloric acid, phosphoric acid, fumaric acid, citric acid, oxalic acid, sulphuric acid, ascorbic acid, tartaric acid, maleic acid, mandelic acid, methanesulphonic acid, lactobionic acid, gluconic acid, glucaric acid, succinic acid, sulphonic acid or hydroxypropane-sulphonic acid.
The salts of the compounds of formula I with acids and bases which are not pharmaceutically acceptable form another aspect of the invention. These salts are intermediate compounds of use in the preparation of the compounds of the invention. This is because the compounds of the invention can be isolated as intermediates in the form of one of their non-pharmaceutically acceptable salts, before conversion to a pharmaceutically acceptable compound.
A first group of preferred compounds is composed of the compounds of formula I in which X represents an oxygen atom.
Preference is more particularly given, among the compounds of the invention, to those in which n represents 2 or 3 and better still those in which n is 2.
Another group of preferred compounds is composed of the compounds in which Ar represents unsubstituted pyridyl, unsubstituted pyrimidinyl or optionally substituted phenyl. When Ar represents substituted phenyl, the phenyl group preferably carries one or two substituents chosen from (C
1
-C
6
)alkoxy, halogen, phenoxy, trifluoromethyl and benzyloxy. Better still, when Ar represents substituted phenyl, the phenyl group is substituted in the meta position by a (C
1
-C
6
)alkoxy group, a phenoxy group, a trifluoromethyl group or a halogen atom, such as a fluorine or chlorine atom.
Another group of preferred compounds is composed of the compounds of formula I in which i represents 1 or 0, preferably 0.
According to a preferred alternative form of the invention, when i is 1, the —CH
2
—COOH group is situated in the ortho position with regard to the chain
and the Z substituent is in the para position with respect to this same chain.
A final group of preferred compounds is composed of the compounds of formula I in which the —CH
2
—COOH group is situated in the para position on the phenyl group with respect to the chain
The invention also relates to two processes for the preparation of the compounds of formula I.
According to a first process, an aromatic compound of formula II:
in which Z, X and i are as defined above for the formula I and P
1
is a protective group for a carboxyl functional group, is reacted with a piperazine of formula III:
in which n and Ar are as defined above for the formula I and Grp
1
is a leaving group.
Among the protective groups for carboxyl functional groups, those generally described in Protective Groups in Organic Synthesis, Greene T. W. and Wuts P. G. M., published by John Wiley and Sons, 1991, and in Protective Groups, Kocienski P. J., 1994, Georg Thieme Verlag, may be suitable. It is possible, by way of example, to envisage the protection of the carboxyl functional group in the ester form: in this case, P
1
represents (C
1
-C
6
)alkyl.
A halogen atom (for example chlorine or bromine), a (C
6
-C
10
)arylsulphonyloxy group, in which the aryl group is optionally substituted by one or more (C
1
-C
6
)alkyl groups, or a (C
1
-C
6
)alkylsulphonyloxy group, in which the alkyl group is optionally substituted by one or more halogen atoms, may be selected as example of a Grp
1
group.
The operating conditions for the reaction of the compound II with the piperazine III will be easily determined by a person skilled in the art, this reaction being a nucleophilic substitution.
The reaction of the compound II with the piperazine III is advantageously carried out in a polar aprotic solvent in the presence of a base.
Examples of appropriate solvents are acetonitrile, dimethylformamide, acetone, dimethyl sulphoxide and halogenated hydrocarbons, such as dichloromethane or dichloroethane.
Use may be made, as particularly preferred base, of potassium carbonate.
According to a preferred embodiment, the reaction of II with III is carried out at a temperature of 50 to 120° C., for example at reflux of acetonitrile, when the latter is chosen as solvent, in the presence of an alkali metal iodide, such as potassium iodide.
The amount of potassium iodide which has to be used is variable and depends essentially on the nature of the reactants, on the nature of the solvent and on the reaction temperature.
A catalytic amount of potassium iodide (less than 1 molar equivalent with respect to the compound II) is generally sufficient.
The reaction of the compound II with the compound III is stoichiometric. However, it may be possible to carry out the reaction in the presence of a slight excess of the piperazine III, in such a way that t
Doare Liliane
Kergoat Micheline
Marais Dominique
Mesangeau Didier
Moinet Gerard
Bernhardt Emily
Merck Patent Gesellschaft
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