1,4-diazabicyclo [2.2.2] oct-2-ylmethyl derivatives, their prepa

Details 1,4-diazabicyclo [2.2.2] oct-2-ylmethyl derivatives, their prepa 1,4-diazabicyclo [2.2.2] oct-2-ylmethyl derivatives, their prepa

1999-06-04

2000-05-02

Ambrose, Michael G.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

544351, 544352, A61K 31529, C07D48708

Patent

active

06057321&

DESCRIPTION:

BRIEF SUMMARY
The subject-matter of the present invention is 1,4-diazabicyclo[2.2.2]oct-2-ylmethyl benzoate derivatives, their preparation and their application in therapeutics.
The compounds of the invention correspond to the general formula (I) ##STR2## in which R.sub.1 represents a methyl croup, --, --O(CH.sub.2).sub.3 --, --O(CH.sub.2).sub.2 O-- or --O(CH.sub.2).sub.3 O--,
They can exist in the form of free bases or of addition salts with acids. Furthermore, they comprise an asymmetric carbon atom in the diazabicyclooctane ring and can therefore exist in the form of pure enantiomers or of mixtures of enantiomers.
According to the invention, the compounds of general formula (I) are prepared by a process illustrated by the following scheme. ##STR3##
Ethyl 1,4-diazabicyclo[2.2.2]octane-2-carboxylate of formula (III) (described in Helv. Chimica Acta (1962), Vol. XLV, Part VII, No. 273 2383) is first prepared by reaction between piperazine and ethyl 2,3-dibromopropanoate in an inert solvent, for example toluene or benzene, and optionally in the presence of an organic base, for example triethylamine, then the ester obtained is reduced to 1,4-diazabicyclo[2.2.2]octane-2-methanol of formula (IV) (described in Khim. Farm. Zh. (1989), 23, 30-35 and in Khim. Geterosikl. Soedin. (1980), 10, 1404-1407), for example by means of lithium aluminium hydride, and, finally, the alcohol obtained is treated with a benzoic acid derivative of general formula (V), in which R.sub.1, X.sub.1, X.sub.2 and X3 are as defined above, according to any known esterification method, for example by activation of the acid by means of an imidazolide and by coupling of the latter with the alcohol, converted beforehand to alkoxide, for example by means of butyllithium.
Piperazine and ethyl 2,3-dibromopropanoate are commercially available. Some benzoic acid derivatives of general formula (V) are commercially available; the others can be prepared by methods such as those disclosed in J. Med. Chem. (1993), 36, 4121-4123 and in Patent Applications EP-0234872, WO-9305038 and ES-2019042 or by saponification of corresponding esters, such as those disclosed in Patents DE-3001328 and DE-36433103.
The following example illustrates in detail the preparation of a compound according to the invention. The elemental microanalyses and the IR and NMR spectra confirm the structures of the compounds obtained.


EXAMPLE



(1,4-Diazabicyclo[2.2.2]oct-2-yl)methyl
8-amino-7-chloro-2,3-dihydro-1,4-benzodioxine-5-carboxylate.
16.9 ml (116 mmol) of ethyl 2,3-dibromopropanoate, in solution in 250 ml of toluene, 10. g (116 mmol) of piperazine and 49.ml (348 mmol) of triethylamine, in solution in 150 ml of toluene, are successively introduced into a round-bottomed flask and the mixture is heated at 80.degree. C. with magnetic stirring overnight. The mixture is cooled, the triethylamine hydrobromide is separated off by filtration, they being rinsed with ethyl acetate, the solvents are evaporated from the filtrate under reduced pressure and the residue is distilled at ambient pressure. 6.91 g of compound are obtained, which compound is used as is in the following stage.
0.21 g (5.43 mmol) of lithium aluminium hydride, in suspension in diethyl ether, is introduced into a round-bottomed flask, the suspension is cooled to 0.degree. C. using an ice-cold bath, 1 g (5.43 mmol) of ethyl 1,4-diazabicyclo[2.2.2]octane-2-carboxy-ate, in solution in 10 ml of diethyl ether, is slowly added with magnetic stirring and the mixture is stirred at room temperature for 1 h.
The excess hydride is hydrolysed by slow addition of 0.2 ml of water, 0.2 ml of 15% aqueous sodium hydroxide solution and then a further 0.6 ml of water, the solid is separated off by filtration, it being rinsed with chloroform, and the filtrate is evaporated under reduced pressure.
After distillation, 0.43 g of oily product is obtained. 8-amino-7-chloro-2,3-dihydro-1,4-benzodioxine-5-carboxylate.
0.69 g (3.03 mmol) of 8-amino-7-chloro-2,3-dihydro-1,4-benzodioxine-5-carboxylic acid, in suspension in 5 ml of anhydrous tetrahydrofuran,

REFERENCES:
patent: 4772459 (1988-09-01), Sun et al.
patent: 5663173 (1997-09-01), Jegham et al.

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