Patent EA-004762-B1 (EA)
Title: New substituted (dihydro)benzoxazime and (dihydro)benzothiazine compounds, a process for their preparation and pharmaceutical compositions containing them
Inventor: VIAUD MARIE-CLAUDE
IPC: C07D265/36
Filed: 2000-12-05
Abstract: 1. Compounds of formula (I): wherein: R<1> represents a hydroxy group or (C1-C6)alkoxy group, G represents -CH2-CH2 group, A represents a -NHC(Z)R, wherein Z represents an oxygen or sulphur atom, and R represents linear or branched (C1-C6)alkyl group, (C3-C8)cycloalkyl group, (C2-C6)alkynyl group, phenyl or furyl, R<2> represents a hydrogen atom or phenyl, X represents an oxygen atom, their enantiomers and diastereoisomers, and also addition salts thereof with a pharmaceutically acceptable acid or base. 2. Compounds of formula (I) according to claim 1, wherein R<1> represents a hydroxy group, their enantiomers and diastereoisomers, and also addition salts thereof with a pharmaceutically acceptable acid or base. 3. Compounds of formula (I) according to claim 1, wherein R<1> represents (C1-C6)alkoxy group, their enantiomers and diastereoisomers, and also addition salts thereof with a pharmaceutically acceptable acid or base. 4. Compounds of formula (I) according to claim 1, wherein R<2> represents a hydrogen atom, their enantiomers and diastereoisomers, and also addition salts thereof with a pharmaceutically acceptable acid or base. 5. Compounds of formula (I) according to claim 1, wherein R<2> represents phenyl, their enantiomers and diastereoisomers, and also addition salts thereof with a pharmaceutically acceptable acid or base. 6. Compounds of formula (I) according to claim 1, wherein A represents NHCOR group, their enantiomers and diastereoisomers, and also addition salts thereof with a pharmaceutically acceptable acid or base. 7. Compounds of formula (I) according to claim 1 that are -N-[2-(6-hydroxy-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]-acetamide, -N-[2-(6-methoxy-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]-acetamide, -N-[2-(6-methoxy-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]-butanamide, -N-[2-(6-methoxy-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]-3-butenamide, -N-[2-(6-methoxy-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]-cyclopropanecarboxamide, -N-[2-(6-methoxy-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]-2-furamide, -N-[2-(6-methoxy-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]-benzamide, -N-[2-(6-hydroxy-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]-2-furamide, their enantiomers and diastereoisomers, and also addition salts thereof with a pharmaceutically acceptable acid or base. 8. Compounds of formula (I) according to claim 1 that are -N-[2-(6-hydroxy-3-phenyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]-acetamide, -N-[2-(6-methoxy-3-phenyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]-benzamide, -N-[2-(6-methoxy-3-phenyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]-2-furamide, -N-[2-(6-methoxy-3-phenyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]-butanamide, -N-[2-(6-methoxy-2-phenyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]-acetamide, -N-[2-(6-methoxy-2-phenyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]-2-furamide, -N-[2-(6-methoxy-2-phenyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]-benzamide, -N-[2-(6-methoxy-2-phenyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]-butanamide, -N-[2-(6-methoxy-2-phenyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]-cyclopropanecarboxamide, their enantiomers and diastereoisomers, and also addition salts thereof with a pharmaceutically acceptable acid or base. 9. Process for the preparation of the compounds of formula (I) according to claim 1, characterised in that there is used as starting material a compound of formula (II): wherein R<1>, R<2>, X are as defined in claim 1, with which there is reacted, in basic medium, a compound of formula (III): Br-G-CN (III) wherein G is as defined in claim 1, to yield a compound of formula (IV): wherein R', R<2>, X, G are as defined hereinbefore, which is subjected to hydrolysis, under acid or basic conditions, to yield a compound of formula (V): wherein R<1>, R<2>, X, G have the same definitions as hereinbefore, which is acted upon, in the presence of a coupling agent or after conversion into the corresponding acid chloride, by an amine NH3, to yield a compound of formula (I/a): wherein R<1>, R<2>, X and G are as defined hereinbefore, which compound of formula (I/a) is subjected to the action of NaOBr to yield, after hydrolysis, a compound of formula (VI): wherein R<1>, R<2>, X, G are as defined hereinbefore, which compounds of formula (VI) (which furthermore can be obtained by reduction of the compound of formula (IV)) are subjected to the action: - of an acyl chloride of formula (VII): wherein R is as defined hereinbefore, or to a corresponding (mixed or symmetrical) acid anhydride, to obtain a compound of formula (I/b), a particular case of the compounds of formula (I): wherein R<1>, R<2>, R, X, G have the same definitions as hereinbefore, and/or formulae (I/b) and (I/c) may be subjected to the action of a thionisation agent, such as Lawesson's reagent, to yield a compound of formula (I/c), a particular case of the compounds of formula (I): wherein R<1>, R<2>, X and are as defined hereinbefore, and Y represents -NHC(S)R, wherein R is as defined hereinbefore, wherein the compounds of formulae (I/b) and (I/c) constituting the totality of the compounds of formula (I) and wherein those compounds may be purified according to a conventional separation technique, may be converted, if desired, into their addition salts with a pharmaceutically acceptable acid or base, and may optionally be separated into their isomers according to a conventional separation technique. 10. A pharmaceutical composition comprising the compound of formula (I) according to any one of claims 1 to 8, or an addition salt thereof with a pharmaceutically acceptable acid or base, in combination with one or more pharmaceutically acceptable excipients. 11. Pharmaceutical compositions according to claim 10, for use in the preparation of medicaments for the treatment of disorders of the melatoninergic system.