Triazepinones, process for their preparation and their...

Details Triazepinones, process for their preparation and their... Triazepinones, process for their preparation and their...

2000-07-14

2001-07-10

Kifle, Bruce (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C540S492000

Reexamination Certificate

active

06258804

ABSTRACT:

The present invention relates to novel triazepine derivatives, to a process for their preparation and to pharmaceutical compositions containing them.
The invention relates more specifically to novel triazepine derivatives which are useful in therapy for inhibiting the reaction of glucose or of its oxidation products (&agr;-dicarbonyl derivatives such as glyoxal or methylglyoxal) with the amine groups of proteins, and which consequently find an application in the treatment of diabetes and its complications.
The subject of the present invention is thus compounds of general formula:
in which:
R is chosen from a hydrogen atom, a methyl group and a group of formula:
 and
R
1
, R
2
, R
3
and R
4
are chosen, independently of each other, from:
a) a hydrogen atom,
b) a C
1
-C
8
alkyl, cyclo(C
3
-C
8
)alkyl, cyclo(C
3
-C
8
)alkyl(C
1
-C
8
)alkyl, cyclo(C
3
-C
8
)alkyloxy(C
1
-C
8
)alkyl, cyclo(C
3
-C
8
)alkyl(C
1
-C
8
)alkoxy(C
1
-C
8
)alkyl, (C
1
-C
8
)alkoxy(C
1
-C
8
)alkyl, (C
1
-C
8
) hydroxyalkyl, (C
6
-C
14
) aryl, (C
6
-C
14
) heteroaryl, hetero(C
6
-C
14
)aryl(C
1
-C
8
)alkyl, (C
6
-C
14
)aryl(C
1
-C
8
)alkyl, (C
6
-C
14
)aryl(C
1
-C
8
)alkyl(C
6
-C
14
)aryl, (C
6
-C
14
)aryloxy(C
1
-C
8
)alkyl or (C
6
-C
14
)aryl (C
1
-C
8
)alkyloxy(C
1
-C
8
)alkyl group,
it being possible for the various aryl, cycloalkyl and heteroaryl groups to be substituted themselves with 1 to 3 substituents chosen from a (C
1
-C
8
) alkyl group, a C
1
-C
8
alkoxy group, a halogen chosen from fluorine, chlorine, bromine and iodine, and a trifluoromethoxy, hydroxyl, cyano, nitro, amino, carbamoyl, C
1
-C
8
alkylamino, (C
1
-C
8
) alkylthio(C
1
-C
8
)alkylsulphinyl, C
1
-C
8
alkylsulphonyl, sulphonylamino or sulphamoyl (C
1
-C
8
)alkylcarbonylamino group, it being possible for two of these groups to form a methylenedioxy group;
it being possible for R
1
and R
2
as well as R
3
and R
4
to form, with the nitrogen which bears them, a group of general formula:
in which n represents a number from 1 to 4 and X is chosen from —CH
2
—, —O—, —S—, —NH— and —NR′—, R′having the meaning given for R
1
in b);
c) a group of formula:
in which Q represents a linear or branched C
2
-C
14
alkylene group;
R
5
and R
6
are chosen, independently of each other, from a hydrogen atom and a group mentioned above in b);
it being possible for R
5
and R
6
also to form, with the nitrogen which bears them, a group of general formula (1);
d) a bicyclic amine residue of fused or bridged type, and their salts with pharmaceutically acceptable acids.
The C
1
-C
8
alkyl groups can be linear or branched. As examples, mention may be made of methyl, ethyl, isopropyl, butyl, isobutyl, tert-butyl and pentyl groups.
The C
1
-C
8
alkoxy groups can similarly be linear or branched. As examples, mention may be made of methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy and pentoxy groups.
The term aryl group is understood to refer to a monocyclic, bicyclic or tricyclic group containing from 6 to 14 carbon atoms. As examples of an aryl group mention may be made of phenyl, &agr;-naphthyl, &bgr;-naphthyl and fluorenyl groups.
The heteroaryl groups can be chosen in particular from pyridyl, pyrimidyl, pyrrolyl, furyl, thienyl, quinolyl, indolyl, benzothienyl, benzofuryl, benzopyranyl, benzothiopyranyl, dibenzofuryl, carbazolyl and benzothiazinyl groups.
The expression bicyclic amine residue of fused or bridged type is understood to denote residues of the type:
The compounds of general formula (I) contain basic nitrogen atoms and can be salified with inorganic or organic acids. Examples of salts, with acids, of the compounds of general formula (I) include pharmaceutically acceptable salts such as, in a non-exhaustive manner, hydrochloride, hydrobromide, sulphate, succinate, maleate, fumarate, malate, tartrate and sulphonates such as methanesulphonate, benzenesulphonate and toluenesulphonate.
The compounds of formula I can be prepared by reaction of &agr;-keto aldehydes of general formula:
with biguanides of general formula:
Biguanides of formula (III) are described in particular in U.S. Pat. No. 2,455,896, FR-A-2,085,665, FR-A-1,518,398, FR-A-2,230,347 and U.S. Pat. No. 2,961,377.
This reaction can be carried out in an alcohol of low molecular weight (for example methanol) or, more advantageously, in water.
The structure of the compounds obtained was confirmed by analysis of the
1
H,
15
N and
13
C spectra.
The example which follows illustrates the preparation of the compounds of formula (I).


REFERENCES:
patent: 2961377 (1960-11-01), Shapiro et al.
Uyeda et al. (Biocontrol Sci. (1997), 2(1), 35-38) Abstract.*
Chemical Abstracts, vol. 127, No. 3, Jul. 21, 1997 Columbus, Ohio, US; abstract No. 28696w, Masaru Uyeda et al: “Formartion of chlorhexidine degradation intermediate through pyryvate incorporation by Pseudomonas sp. No. A-3” p. 28; XP002078367 & Biocontrol Sci., vol. 2, No. 1, 1997, pp. 35-38.
F. E. King et al: “Benzimidazole analogues of paludrine” Journal of the Chemical Society, 1948, pp. 1366-1371, XP002078366.
B. Agai et al: “Condensed 1,3,5-triazepines. III. Derivatives of 4,5-dihydro-(1,3,5)triazepino(1,2-a)benzim idazoles” Tetrahedron, vol. 32, No. 7, 1976, pp. 839-842, XP002078365.

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