Pyridopyranoazepine derivatives, their preparation and their...

Details Pyridopyranoazepine derivatives, their preparation and their... Pyridopyranoazepine derivatives, their preparation and their...

2001-08-17

2003-03-25

Huang, Evelyn Mei (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S214030, C546S063000, C544S171000

Reexamination Certificate

active

06538003

ABSTRACT:

This application is the 371 of PCT/FR00/00502, filed on Mar. 1, 2000.
The present invention relates to compounds of general formula (I)
in which
R
1
is a hydrogen atom, a (C
1
-C
4
)alkyl group, a phenyl(C
1
-C
4
)alkyl group, a phenylhydroxy(C
1
-C
4
)alkyl group, a furanyl(C
1
-C
4
)alkyl group, or a furanyl-hydroxy(C
1
-C
4
)alkyl group,
R
2
is either a hydrogen or halogen atom or a trifluoromethyl, cyano, hydroxyl, nitro, acetyl, (C
1
-C
6
)alkyl or (C
1
-C
6
)alkoxy group or a group of general formula NR
4
R
5
in which R
4
is a hydrogen atom or a (C
1
-C
4
)alkyl or (C
1
-C
4
)alkanoyl group and R
5
is a hydrogen atom or a (C
1
-C
4
)alkyl group, or else R
4
and R
5
; form, with the nitrogen atom which carries them, a C
4
-C
7
ring, or a phenyl or naphthyl group optionally substituted by a halogen atom or a trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, nitro, acetyl, (C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxy or methylenedioxy group linked in the 2 and 3 positions of the phenyl ring, and
R
3
is a hydrogen or halogen atom or a (C
1
-C
4
)alkyl group.
The compounds of general formula (I) can exist in the state of bases or of addition salts to acids. In addition, the atoms in positions 5a and 10a being asymmetric, a compound can exist in the form of pure geometric and optical isomers or of mixtures of the latter.
According to the invention, it is possible to prepare the compounds of general formula (I) by a process illustrated by the scheme which follows.
A 2-methylpyridin-3-ol of general formula (II), in which R
2
and R
3
are as defined above, is reacted with an alkyllithium, then the intermediate thus obtained is condensed with 1-azabicyclo[2.2.2]octan-3-one of formula (III), at low temperature and in an aprotic solvent such as tetrahydrofuran.
A compound of general formula (IV) is obtained, in which it is possible, if desired, to introduce or modify the substituents R
2
and R
3
according to any method known by the person skilled in the art.
The compound of general formula (IV) is then subjected to a dehydration, which is accompanied by a rearrangement, in acid medium, for example methanesulphonic acid or sulphuric acid at high temperature.
A compound of general formula (Ia) is obtained, in which it is possible to modify the R
2
and R
3
substituents and/or to introduce the R
1
substituent according to any method known to the person skilled in the art.
The starting compounds of formulae (II) and (III) are commercially available (R
2
═R
3
═H) or can be prepared according to known methods.
The examples which follow illustrate the preparation of some compounds of the invention. The elemental microanalyses, and the I.R. and N.M.R. spectra, as well as the X-ray diffraction spectra, in certain cases, confirm the structures of the compounds obtained.
The numbers indicated in brackets in the titles of the examples correspond to those of the 1st column of the table given further on.
In the names of the compounds, the dash “−” is part of the word, and the dash “_” only serves for the splitting at the end of the line; it is to be suppressed in the absence of splitting, and must not be replaced either by a normal dash or by a space.


REFERENCES:
patent: 6143761 (2000-11-01), Lochead
patent: 2761072 (1998-09-01), None
patent: WO-9711072 (1997-03-01), None
Gopalakrishnan M et al. European Journal of Pharmacology. 290 (1995) 237-246.*
Levin ED, Simon BB. Psychopharmacology (Berl) Aug. 1998; 138(3-4), 217-230.*
Nordvall et al., J. Medicinal Chemistry, vol. 39, No. 17, pp. 3269-3277, (1996).
Derwent Patent Abstract No. 199844 (2001).

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