5-aryl-3-(8-azabicyclo[3.2.1]oct-3-yl)-1,3,4-oxadi...

Details 5-aryl-3-(8-azabicyclo[3.2.1]oct-3-yl)-1,3,4-oxadi... 5-aryl-3-(8-azabicyclo[3.2.1]oct-3-yl)-1,3,4-oxadi...

1999-10-15

2001-07-03

Raymond, Richard L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

Reexamination Certificate

active

06255319

ABSTRACT:

The present invention relates to compounds corresponding to the general formula (I)
in which
R
1
represents a (C
1
-C
4
)alkyl or (C
3
-C
7
)cycloalkylmethyl group,
X
1
represents a hydrogen or halogen atom or a (C
1
-C
4
)alkoxy group,
or alternatively
OR
1
and X
1
together represent a group of formula —OCH
2
O—, —O(CH
2
)
2
—, —O(CH
2
)
3
—, —O(CH
2
)
2
O— or —(CH
2
)
3
O—,
X
2
represents a hydrogen atom or an amino group,
X
3
represents a hydrogen or halogen atom, and
R
2
represents a hydrogen atom, (C
1
-C
6
)alkyl group, a phenyl(C
1
-C
4
)alkyl group, or a group of general formula —(CH
2
)
n
CO—Z in which n represents a number from 1 to 6 and Z represents a 1-piperidyl or 4-(dimethylamino)-1-piperidyl group.
When R
2
represents an alkyl group, such a group is preferably a butyl group.
When R
2
represents a phenyl(C
1
-C
3
)alkyl group such a group is preferably a 2-phenylethyl group.
When R
2
represents a group of general formula —(CH
2
)
n
CO—Z, such a group is preferably a 4-[4-(dimethylamino)-1-piperidyl]-4-oxobutyl group, a 5-[4-(dimethylamino)-1-piperidyl]-5-oxopentyl group or a 6-[4-(dimethylamino)-1-piperidyl]-6-oxohexyl group.
The compounds of the invention can exist in the form of free bases or of pharmaceutically acceptable addition salts with acids. On account of the tropane ring, they can also be in the form of endo or exo isomers. Moreover, certain substituents R
2
can contain an asymmetric carbon atom; the compounds can thus exist in various pure or mixed geometrical and/or optical isomer forms.
N-(8-azabicyclo[3.2.1]oct-3-yl) benzamides having a structure nearly similar to that of the compounds of the invention and having affinities for the 5-HT
3
and 5-HT
4
receptors, are disclosed in patent application EP-0554794.
In accordance with the invention, the compounds of general formula (I) can be prepared by a process illustrated by the scheme which follows.
An ester of general formula (II), in which R
1
, X
1
, X
2
and X
3
are as defined above and R
3
represents a methyl or ethyl group, is reacted with hydrazine hydrate, in the absence of solvent or in a polar protic solvent, for example ethanol, in order to obtain a hydrazide of general formula (III) which is cyclized into the oxadiazole of general formula (IV) either by means of phosgene, in an aprotic solvent, for example dioxane, or by means of phenyl chloroformate, in an aprotic solvent, for example toluene.
The oxadiazole of general formula (IV) is then reacted with a tropanol of general formula (V), in which R
2
is as defined with respect to the general formula (I), but is other than a hydrogen atom, or alternatively represents a (1,1-dimethylethoxy)carbonyl protecting group, in the presence of triphenylphosphine and ethyl azodicarboxylate, in an aprotic solvent, for example tetrahydrofuran, after which, if necessary, the nitrogen of the tropane ring is deprotected by means of trifluoroacetic acid in order to obtain a compound of general formula (I) in which R
2
represents a hydrogen atom and, if so desired, the compound obtained is reacted with a derivative of general formula R
2
—X, in which X represents a leaving group, for example a halogen atom or a methanesulphonate or para-toluenesulphonate group, and R
2
is as defined with respect to the general formula (I), but is other than a hydrogen atom, in the presence of triethylamine, in an aprotic solvent, for example acetonitrile. The starting esters of general formula (II) and/or the corresponding acids are described in particular in patent applications EP-0,231,139, EP-0,234,872, WO-84/03281, WO-93/16072 and WO-94/19344.
The tropanols of general formula (V) are known or can be prepared according to any known methods. 8-[(1,1-Dimethylethoxy)carbonyl]-8-azabicyclo[3.2.]octan-3-ol can be prepared by the method described in
Drug Metabolism and Disposition
(1992) 20(4) 596-602.


REFERENCES:
patent: WO 97/17345 (1997-05-01), None

Affiliated with

Also associated with

Rating

5-aryl-3-(8-azabicyclo[3.2.1]oct-3-yl)-1,3,4-oxadi... does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with 5-aryl-3-(8-azabicyclo[3.2.1]oct-3-yl)-1,3,4-oxadi..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and 5-aryl-3-(8-azabicyclo[3.2.1]oct-3-yl)-1,3,4-oxadi... will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2540555