Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1995-04-06
1997-05-27
Grumbling, Matthew V.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
544354, A61K 31495, C07D24144
Patent
active
056332556
DESCRIPTION:
BRIEF SUMMARY
This is a national stage application, filed under 35 USC 371, of PCT/FR93/00991, filed 07 Oct. 1993.
The present invention, produced at the Pierre Fabre Medicament Research Center, relates to novel chemical compounds, a process for their preparation and their application as medicaments.
Syntheses of 1,2-dihydro-2-oxoquinoxalines which are variously functionalized at position 3 are reported in the literature. Among these compounds, there may be noted esters (F. E. King and J. W. Clark-Lewis, J. Chem. Soc. 1953, 172-177), amides (H. Bredereck and W. Pfleiderer, Chem. Ber., 87, 1119-23 (1954) or amines. In this category, E. Schipper and A. R. Day describe the synthesis of 1,2-dihydro-3-amino-2-oxoquinoxaline (J. Am. Chem. Soc., 73, 5672-5675 (1951)) and J. W. Clark-Lewis describes that of 1,2-dihydro-3-aminomethyl-1-methyl-2-oxoquinoxaline (J. Chem. Soc. 1957, 422). Moreover, the presence at position 3 of a carbon chain, which may or may not be functionalized, imparts a bronchodilatory activity to the molecules, which is claimed in the following patents:
The present invention relates to the compounds of general formula I ##STR2## in which R.sub.1 and R.sub.2 represent, independently of each other, hydrogen or a linear or branched C.sub.1 -C.sub.4 alkyl radical, hydroxyalkyl group.
In addition, the invention covers the salts of the compounds of general formula I with pharmaceutically acceptable acids in the case of compounds which are sufficiently basic.
The compounds of general formula I of the invention may be prepared according to the following reaction scheme: ##STR3##
The starting compounds of general formula II in which R represents methyl or ethyl may be obtained according to known methods, for example those described by Abdulla et al., J. Heterocyclic Chem., 13, 427 (1976) or by Sen et al., J. Indian Chem. Soc., Vol. 38, No. 4, 1961, p. 225-228. The hydroxy ester II is treated with a reactant R.sub.3 X in which R.sub.3 has the same meaning as above and X represents a nucleofugal group such as the iodine, chlorine or bromine atom or a mesylate or tosylate group. The reaction may be carried out in the presence of a base such as sodium hydride, in a polar aprotic solvent such as DMF. It may also be performed in a medium such as K.sub.2 CO.sub.3 -acetone. After saponification with sodium hydroxide or with potassium hydroxide in an alcoholic medium, the compound III obtained, for which R represents a hydrogen atom, is treated with diphenylphosphoryl azide in tert-butanol in the presence of a base such as triethylamine. The reaction is preferably carried out at a temperature between 50.degree. C. and the boiling point of tert-butanol to give, via the non-isolated intermediate isocyanate, the compound IV.
Compound IV is treated C.sub.1 -C.sub.4 alkyl group and Y representing a labile group such as halogen (Cl, Br, I), mesylate or tosylate. .noteq.H, R.sub.2 =H).
The alkylation reaction is advantageously carried out under phase transfer conditions using a water-immiscible solvent such as THF and a phase transfer catalyst such as, by way of example, benzyltriethylammonium chloride. The acidic hydrolysis may be performed by treatment with alcoholic hydrochloric acid at a temperature between room temperature and the boiling point of the solvent, or with trifluoroacetic acid at room temperature. The same compound IV is subjected directly to acidic hydrolysis to yield the compound I in which R.sub.1 =R.sub.2 =H.
The compounds of general formula I for which R.sub.1 and/or R.sub.2 represent hydrogen may be alkylated according to the standard methods used to alkylate primary or secondary amines such as, by way of example, treatment with a C.sub.1 -C.sub.4 alkyl halide, to give the compounds I in which R.sub.1 and R.sub.2 .noteq.H.
The examples below illustrate the invention without, however, limiting the scope thereof.
The microanalyses and the infrared and NMR spectra confirm the structure of the compounds obtained.
EXAMPLE 1
To a suspension of 18.25 g (0.084 mol) of 3-ethyl 2-hydroxyquinoxaline carboxylate in 300
REFERENCES:
patent: 3446809 (1969-05-01), Harris
patent: 4181724 (1980-01-01), Hall
F.E. King and J.W. Clark-Lewis, J.Chem. Soc. 1953, 172-177.
H. Bredereck and W. Pfleiderer, Chem. Ber. 87, 1119-23 (1954).
E. Schipper and A.R. Day, J.Am. Chem. Soc. 73, 5672-5675 (1951).
J.W. Clark-Lewis, J.Chem. Soc., 1957, 422.
Abdulla et al., J. Heterocyclic Chem. 13, 427 (1976).
Sen et al., J. Indian Chem. Soc. 38, No. 4, 225-228 (1961).
Clark-Lewis, The Chemical Society, 1951, 422-430.
Tennant, The Chemical Society, 1963, 2428-2433.
J. Clark-Lewis "Quinoxaline Derivatives, Part III", J. Chem. Soc., 78, 1957 pp. 422-430.
Autin Jean-Marie
Bigg Dennis
Patoiseau Jean-Francois
Tarayre Jean-Pierre
Grumbling Matthew V.
Pierre Fabre Medicament
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