Quaternary ammonium compounds

Details Quaternary ammonium compounds Quaternary ammonium compounds

2002-03-25

2004-07-06

Kifle, Bruck (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C544S049000

Reexamination Certificate

active

06759406

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to new quaternary ammonium compounds and to pharmaceutical compositions containing them.
DESCRIPTION OF THE INVENTION
The new quaternary ammonium compounds enable the vectorisation of active ingredients in cartilaginous tissue and hence the treatment of pathologies caused by attack on the cartilage whether they are articular or cancerous pathologies. They may also be used as diagnostic reagents, capable, for example, of revealing a pathology of the cartilage or a metabolism (radioactive marker, stained marker, . . . ).
The therapeutic agents currently available commercially for the treatment of articular pathologies, such as arthritis or osteoarthritis, generally exhibit a low affinity for the target tissues and require the administration of high doses to achieve the desired therapeutic effect.
The administration of such strong doses of active ingredients gives rise to an increase in the frequency of side effects. For example, the administration of non-steroidal anti-inflammatories is known to cause significant digestive toxicity.
In the field of bone cancerology, the therapeutic agents currently used for the treatment of chondrosarcomas are likewise known, for example, to produce undesirable side effects, especially toxicities, for example haematological or non-haematological toxicities.
Finally, in the field of diagnostic products for cartilaginous pathologies, the products currently used have the disadvantage of lacking specificity for the targets at which they are aimed.
There has thus been particular interest in functionalising those different kinds of compound in order specifically to target cartilaginous tissue and thus limit, or even suppress, the undesirable effects observed when such compounds are administered directly.
The new compounds forming the subject of the present invention make it possible, both by increasing the tropism and by decreasing the doses administered, for the side effects to be significantly attenuated and for the therapeutic index of the active molecules to be strengthened.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates more specifically to compounds of a formula corresponding to formula (Ia) or (Ib):
wherein:
M represents a molecule that can be used for the treatment or diagnosis of pathologies caused by attack on the cartilage,
R
1
, R
2
and R
3
, which may be identical or different, represent a linear or branched (C
1
-C
6
)alkyl group, or R
1
, R
2
and R
3
, together with the nitrogen atom carrying them, form a saturated or unsaturated nitrogen-containing heterocycle,
X represents a linear or branched (C
1
-C
6
)alkylene chain in which one or more —CH
2
-groups are optionally replaced by a sulphur atom, an oxygen atom, an —NR— group (wherein R represents a linear or branched (C
1
-C
6
)alkyl group), a —CO— group, a —CO—NH— group, a —CO
2
— group, an —SO— group or an —SO
2
— group,
n represents 0 or 1, and
Hal represents a halogen atom,
or,
R
4
represents a linear or branched (C
1
-C
6
)alkyl group,
Hal represents a halogen atom, and
represents a molecule that can be used for the treatment or diagnosis of pathologies caused by attack on the cartilage, wherein the nitrogen atom may optionally be included in a saturated or unsaturated nitrogen-containing heterocyclic system, or included in a double bond.
Preferably, the compounds of formula (Ia) are compounds wherein:
n is 1,
X represents a linear or branched (C
1
-C
6
)alkylene chain, a group —NR—(CH
2
)
m
— (wherein R is as defined hereinbefore), a group —CO—(CH
2
)
m
—, or a group —CO—NH—(CH
2
)
m
, in which groups m represents an integer from 1 to 5 inclusive.
R
1
, R
2
and R
3
in the compounds of formula (Ia) are preferably identical or different, linear or branched (C
1
-C
6
)alkyl groups or, together with the nitrogen atom carrying them, form a pyridine or piperidine ring (in which case one of those groups is a linear or branched (C
1
-C
6
)alkyl group).
The molecules M or
that can be used for the treatment or the diagnosis of pathologies caused by attack on the cartilage are more especially: antiinflammatories, antiarthritics, antiosteoarthritics, analgesics or specific anti-tumour agents.
Preferred compounds of formula (Ia) used as active ingredient are:
molecules derived from tenidap of formula (Ia
1
):
wherein:
X
1
represents a linear or branched (C
1
-C
6
)alkylene group,
R′
1
, R′
2
and R′
3
, which may be identical or different, represent a linear or branched (C
1
-C
6
)alkyl group, and
Hal represents a halogen atom,
molecules derived from melphalan of formula (Ia
2
):
wherein:
X
2
represents a group —NH—(CH
2
)
m
— wherein m is as defined hereinbefore,
R′
1
, R′
2
and R′
3
are as defined hereinbefore, and
Hal represents a halogen atom,
molecules derived from chlorambucil of formula (Ia
3
);
wherein:
X
2
, R′
1
, R′
2
and R′
3
are as defined hereinbefore, and
Hal represents a halogen atom,
molecules derived from glucosamine of formula (Ia
4
):
wherein:
X
4
represents a group —CO—(CH
2
)
m
— wherein m is as defined hereinbefore,
R
1
, R
2
and R
3
are as defined hereinbefore, and
Hal represents a halogen atom.
Preferred compounds of formula (Ib) used as active ingredient are:
molecules derived from piroxicam of formula (Ib
1
):
wherein R
4
and Hal are as defined hereinbefore,
molecules of formula (Ib
2
):
wherein R
4
and Hal are as defined hereinbefore.
Preferred compounds of formula (Ia) used as diagnostic reagents are compounds of formula (Ia
5
):
wherein X
1
, R
1
, R
2
, R
3
and Hal are as defined hereinbefore.
The invention relates also to a process for the preparation of the compounds of formula (Ia) or (Ib).
The compounds of formula (Ia) are obtained according to conventional processes of organic chemistry by functionalisation in one or more steps, according to the nature of the X group required, of a compound of formula M—P (wherein M is as defined for formula (Ia) and P represents a hydrogen atom or a hydroxy group) or of a precursor of the compound of formula M—P followed by the reactions necessary for the formation of the final compound of formula (Ia).
The compounds of formula (Ib) are obtained by reaction of an alkyl halide with a compound of formula
as defined hereinbefore.
The molecules derived from tenidap of formula (Ia
1
) defined hereinbefore are obtained starting from 4-nitrophenyl 5-chloro-2,3-dihydro-2-oxo-1H-indole-1-carboxylate, which is reacted with an amine of formula (II):
wherein X
1
, R′
1
and R′
2
are as defined hereinbefore,
to yield a compound of formula (III):
wherein X
1
, R′
1
and R′
2
are as defined hereinbefore,
which is subjected to the action of 2-thenoyl chloride in basic medium, under an inert atmosphere, and then to treatment with an acid,
to yield a compound of formula (IV):
which is converted into the corresponding sodium salt,
which is then subjected to the action of a linear or branched (C
1
-C
6
)alkyl halide (R′
3
Hal) to yield a compound of formula (V):
which, in hydrochloric medium, yields a compound of formula (Ia
1
), which if necessary is purified.
The molecules derived from melphalan of formula (Ia
2
) defined hereinbefore are obtained starting from melphalan, the amine function of which has been protected beforehand by a tert-butoxycarbonyl group (Boc), using an amine of formula (VI) in the presence of a peptide coupling reagent:
wherein R′
1
, R′
2
and m are as defined hereinbefore,
to yield a compound of (VII):
wherein m, R′
1
and R′
2
are as defined hereinbefore,
which is subjected to the action of a linear or branched (C
1
-C
6
)alkyl halide, then to treatment with HCl,
to yield a compound of formula (Ia
2
), which if necessary is purified.
The molecules derived from chlorambucil of formula (Ia
3
) defined hereinbefore are obtained starting from chlorambucil, the acid function of which is converted into the corresponding acid chloride,
which is then reacted with an amine of formula (VI), in the presence

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