3-(Pyrrolidin-3-yl)-1,3,4-oxadiazol-2(3H)-one derivatives...

Details 3-(Pyrrolidin-3-yl)-1,3,4-oxadiazol-2(3H)-one derivatives... 3-(Pyrrolidin-3-yl)-1,3,4-oxadiazol-2(3H)-one derivatives...

1999-11-04

2001-06-19

Higel, Floyd D. (Department: 1609)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S364000, C546S209000, C548S144000

Reexamination Certificate

active

06248757

ABSTRACT:

The present invention relates to compounds of the general formula (I)
in which
R
1
represents a hydrogen atom or a (C
1
-C
4
)alkyl or cyclo(C
3
-C
7
)alkylmethyl group,
X
1
represents a hydrogen 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 —O(CH
2
)
3
O—,
X
2
represents a hydrogen atom, an amino group or a group of general formula —NHCO
2
R in which R represents a (C
1
-C
4
)alkyl or phenyl(C
1
-C
2
)alkyl group,
X
3
represents a hydrogen or halogen atom, and
R
2
represents a hydrogen atom or a (C
1
-C
6
)alkyl group, or a phenyl(C
1
-C
4
)alkyl or [(4-dimethylamino)piperid-1-ylcarbonyl] (C
2
-C
4
)alkyl group.
Since the carbon atom via which the pyrrolidine ring is attached to the rest of the molecule is asymmetric, the compounds of the invention can exist in the form of pure enantiomers or mixtures of enantiomers.
They can also exist in the form of bases or addition salts with acids.
The compounds of general formula (I) can be prepared according to 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 an oxadiazole of general formula (IV) either using phosgene, in an aprotic solvent, for example dioxane, or using phenyl chloroformate, in an aprotic solvent, for example toluene.
When, in the general formula (II), X
2
represents an amino group, the latter reacts with the phosgene and the product obtained is esterified with an alcohol of general formula ROH, in which R is defined as above, the amino group thus being protected by a group —CO
2
R. The oxadiazole of general formula (IV) is then reacted with an alcohol of general formula (V), in which Boc represents a (1,1-dimethylethoxy)carbonyl group, in the presence of triphenylphosphine and ethyl azodicarboxylate, in an aprotic solvent, for example tetrahydrofuran, after which the (1,1-dimethylethoxy)_carbonyl protecting group is removed using trifluoroacetic acid. A compound of general formula (I) in which R
2
represents a hydrogen atom is thus obtained.
If so desired, the latter compound can then be subjected to an alkylation using a derivative of general formula R
2
-X, in which X represents a leaving group, for example a halogen atom or a methane-sulphonate or para-toluenesulphonate group, and R
2
is as defined above, but other than a hydrogen atom, in the presence of triethylamine, in an aprotic solvent, for example acetonitrile. Finally, when X
2
is a group —NHCO
2
R, the protecting group can, if so desired, be removed in acidic medium.
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 alcohols of general formula (V) are known or can be prepared according to any known method; (R/S)-1-[(1,1-dimethylethoxy)carbonyl]pyrrolidin-3-ol is described in
J. Am. Chem. Soc
. (1982) 104 5852-5853, and the (R) enantiomer is described in
Tetrahedron
(1988) 44 (17) 5479-5486.
The examples which follow illustrate in detail the preparation of a number of compounds according to the invention. The elemental microanalyses and the IR and NMR spectra confirm the structures of the compounds obtained. The compound numbers indicated in parentheses in the titles correspond to those in the table given later. In the compound names, the hyphen “-” forms part of the name, and the line “_” serves merely to indicate the line break; it should be removed in the absence of a line break and should not be replaced either by a normal hyphen or by a space.


REFERENCES:
patent: 5525619 (1996-06-01), Koenig et al.
patent: WO93/16072 (1993-08-01), None
patent: WO95/32965 (1995-12-01), None
patent: WO97/17345 (1997-05-01), None

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