Patent EA-003666-B1 (EA)
Title: New polycyclic azaindole compounds, a process for their preparation and pharmaceutical compositions containing them
Inventor: GUILLAUMET GERARD
IPC: A61K31/4355
Filed: 2000-10-13
Abstract: 1. Compounds of formula (I): wherein: - the symbol represents the grouping - R<1> represents a (C1-C6) alkyl group, (C1-C6) alkoxy or hydroxyalkyl - R represents a (C1-C6) alkyl, aryl or heteroaryl group, - B forms with the nitrogen atom and the carbon atom to which it is attached a ring having from 5 to 8 ring members, which may contain one or more unsaturated bonds and may contain, in addition to the nitrogen atom, an additional an oxygen atom, - R<2> and R<3> represent a hydrogen atom or together form an oxo group, - R<4> and R<5> represent a hydrogen atom or form together with two adjacent atoms of the B ring carrying them a group selected from aryl and heteroaryl, it being understood that: - "aryl" is understood to mean a phenyl, naphthyl or biphenyl group, those groups being unsubstituted or substituted by one or more identical or different groups selected from hydroxy, alkoxy, alkyl, ammo, alkylamino, dialkylamino, nitro, cyano, polyhaloalkyl, formyl, carboxy, alkoxycarbonyl, amido, and halogen atoms, - "heteroaryl" is understood to mean a furyl, pyrrolyl, imidazolyl, pyridyl, thienyl, pyrazinyl, benzothienyl, benzofuranyl, indolyl, benzimidazolyl, quinolyl or quinazolinyl group, those groups being unsubstituted or substituted by one or more identical or different groups selected from hydroxy, alkoxy, alkyl, amino, alkylamino, dialkylamino, nitro, cyano, polyhaloalkyl, formyl, carboxy, amido, and halogen atoms, their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acids. 2. Compounds of formula (I) according to claim 1 wherein B forms with the nitrogen atom and the carbon atom to which it is attached a pyrrolidine, piperidine, (perhydro)asepine or (perhydro)azocine ring, their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acids or bases. 3. Compounds of formula (I) according to claim 1 wherein B forms with the nitrogen atom and the carbon atom to which it is attached a 1,3-(perhydro)oxazine ring, their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acids or bases. 4. Compounds of formula (I) according to claim 1 wherein R<2>, R<3>, R<4> and R<5> simultaneously represent a hydrogen atom, their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acids or bases. 5. Compounds of formula (I) according to claim 1 wherein R<2> and R<3> represent a hydrogen atom and R<4> and R<5> form together with the adjacent carbon atoms carrying them a phenyl group, their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acids or bases. 6. Compounds of formula (I) according to claim 1 wherein R<1> represents a group or, their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acids or bases. 7. Compounds of formula (I) according to claim 1 that are N-[2-(2-meihoxy-6H-pyrido[2',3':4,5]pyrrolo[2,1-a]isoindol-11-yl)ethyl]acetamide, N-[2-(2-methoxy-6H-pyrido[2',3':4,5]pyrrolo[2,1-a]isoindol-11-yl)ethyl]-2-furamide, N-[2-(2-methoxy-6H-pyrido[2',3':4,5]pyrrolo[2,1-a]isoindol-11-yl)ethyl]benzamide, 2-iodo-H-[2-(2-methoxy-6H-pyrido[2',3':4,5]pyrrolo[2,1-a]isoindol-11-yl)ethyl]benzamide and addition salts thereof with a pharmaceutically acceptable acids or bases. 8. Compounds of formula (I) according to claim 1 that are N-[2-(3-methoxy-6,7,8,9-tetrahydropyrido[3,2-b]indolizin-5-yl)ethyl]acetamide, N-[2-(2-methoxy-6,7,8,9-tetrahydropyrido[2,3-b]indolizin-10-yl)ethyl]-2-furamide, N-[2-(2-methoxy-6,7,8,9-tetrahydropyrido[2,3-b]indolizin-10-yl)ethyl]acetamide, N-[2-(2-hydroxy-6,7,8,9-tetrahydropyrido[2,3-b]indolizin-10-yl)ethyl]-2-furamide and addition salts thereof with a pharmaceutically acceptable acids or bases. 9. Compounds of formula (I) according to claim 1 that are N-[2-(8-methoxy-3,4-dihydro-2H-pyrido[2',3':4,5]pyrrolo[2,1-b][1,3]oxazin-10-yl)ethyl]acetamide, H-[2-(8-methoxy-3,4-dihydro-2H-pyrido[2',3':4,5]pyrrolo[2,1-b][1,3]oxazin-10-yl)ethyl]-2-furamide and addition salts thereof with a pharmaceutically acceptable acids or bases. 10. Compound of formula (I) according to claim 1 that is H-[2-(10-methoxy-5,6-dihydropyrido[2',3':4,5]pyrrolo[2,1-a]isoquinolin-12-yl)ethyl]-2-furamide and addition salts thereof with a pharmaceutically acceptable acids or bases. 11. Compounds of formula (I) according to claim 1 that are H-[2-(11-methoxy-6,7-dihydro-5H-pyrido[2',3':4,5]pyrrolo[2,1-a][2]benzazepin-13-yl)ethyl]acetamide, N-[2-(11-methoxy-6,7-dihydro-5H-pyrido[2',3':4,5]pyrrolo[2,1-a][2]benzazepin-13-yl)-ethyl]-2-furamide, H-[2-(11-hydroxy-6,7-dihydro-5H-pyrido[2',3':4,5]pyrrolo[2,1-a]- [2]benzazepin-13-yl)ethyl]-2-furamide and addition salts thereof with a pharmaceutically acceptable acids or bases. 12. Compound of formula (I) according to claim 1 that is H-[2-(2-methoxy-6-oxo-6H-pyrido[2',3':4,5]pyrrolo[2,1-a]isoindol-11-yl)ethyl]-2-furamide and addition salts thereof with a pharmaceutically acceptable acids or bases. 13. Process for the preparation of compounds of formula (I) according to claim 1, characterised in that amidating reaction is carried out between acid anhydride and an amine, wherein a molecule comprising a heterocyclic radical W may stand for either anhydride or amine. 14. Process according to claim 13, characterized in that the compound of formula (I/a) : wherein W, G1, R and R' are as defined hereinbefore are used as starting material a compound of formula (II): wherein W represents a radical of formula (III) : wherein R<1>, R<2>, R<3>, R<4>, R<5>, B, the symbol are as defined hereinbefore, which is subjected to the action of a reducing agent to obtain a compound of formula (IV): wherein W is as defined hereinbefore, which, after conversion to the corresponding halogen compound, is subjected to the action of a cyanide salt to yield a compound of formula (V): wherein W is as defined hereinbefore, - or, in succession, a Wittig reaction and then reduction to obtain a compound of formula (VI): wherein W is as defined hereinbefore , X represents a group CN or COOalk (wherein alk represents an alkyl group) and G'1 represents a chain as defined hereinbefore for G1 having from 2 to 4 carbon atoms, which compounds of formula (V) and (VI) are hydrolysed in an acidic or basic medium to obtain a compound of formula (VII) : wherein W and G1 are as defined hereinbefore, which is subjected, in the presence of a coupling agent or after conversion to the corresponding acid chloride, to the action of an amine HNRR'. 15. Process according to claim 13, characterized in that the compound of formula (I/b): wherein W, G1 and R are as defined hereinbefore, is obtained from the compound of formula (1/a), wherein R and R<1> simultaneously represent a hydrogen atom, is subjected to the action of NaOBr to yield, after hydrolysis, a compound of formula (VIII): W-G1-NH2 (VIII) wherein W and G1 are as defined hereinbefore, which is subjected to the action of: - an acyl chloride of formula (IX): wherein R is as defined hereinbefore, or the corresponding acid anhydride (mixed or symmetric). 16. Process according to claim 13, characterized in that the compound of formula (I/b'): wherein W and R are as defined hereinbefore, which compound of formula (1/b) may also be obtained when G1 represents a chain (CH2)2,starting from a compound of formula (II) by the action of nitromethane to yield a compound of formula (III'): wherein W is as defined hereinbefore, which is subjected to the action of a reducing agent, such as NaBH4, for example, to obtain a compound of formula (IV'): wherein W is as defined hereinbefore, which is subjected to catalytic hydrogenation to obtain a compound of formula (V'): wherein W is as defined hereinbefore, which is subjected to the action of an acid chloride of formula (IX) or the corresponding acid anhydride (mixed or symmetric). 17. Process according to claim 13, characterized in that the compound of formula (I/c): wherein W, G1 and R are as defined hereinbefore, - or which compound of formula (VIII) is subjected to the action of a compound of formula (X): wherein R is as defined hereinbefore. 18. Process according to claim 13, characterized in that the compound of formula (I/d): wherein W, G1 and Ra are as defined hereinbefore and Y represents a group R or -NRR' wherein R and R' are as defined hereinbefore, which compounds of formula (I/b) and (I/c) may be subjected to the action of formula (XI): Ra-J (XI) wherein Ra can have any of the meanings of R with the exception of the hydrogen atom and J represents a leaving group, such as a halogen atom or a tosyl group. 19. Compounds of formula (XVII): wherein R<1>, R<2>, R<3>, R<4>, R<5>, B and the symbol are as defined in claim 1, for use as intermediates in the synthesis of compounds of formula (I). 20. Pharmaceutical compositions comprising as active ingredient at least one compound of formula (I) according to any one of claims 1 to 15 or an addition salt thereof with a pharmaceutically acceptable acid or base, in combination with one or more pharmaceutically acceptable excipients. 21. Pharmaceutical compositions according to claim 20 for use in the manufacture of a medicament for the treatment of disorders of the melatoninergic system.