2,5,-diazabicyclo[2.2.1]heptane derivatives, their...

Details 2,5,-diazabicyclo[2.2.1]heptane derivatives, their... 2,5,-diazabicyclo[2.2.1]heptane derivatives, their...

2001-08-16

2003-10-21

Shah, Mukund J. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S252040, C514S252110, C514S256000, C514S269000, C546S238000, C546S330000, C546S349000, C546S350000, C546S350000, C546S325000

Reexamination Certificate

active

06635645

ABSTRACT:

The compounds of the present invention correspond to the general formula (I)
in which
one of the symbols X, Y and Z represents a nitrogen atom, another represents a group of formula C—R
3
and the third represents a nitrogen atom or a group of formula C—R
4
,
R
3
and R
4
represent, independently of each other, a hydrogen or halogen atom or a trifluoromethyl, cyano, hydroxyl, (C
1
-C
6
)alkyl or (C
1
-C
6
)alkoxy group,
R
1
and R
2
represent, independently of each other, a hydrogen or halogen atom or a trifluoromethyl, cyano, hydroxyl, (C
1
-C
6
)alkyl or (C
1
-C
6
)alkoxy group, or a phenyl group optionally substituted with one or two halogen atoms, with one or two trifluoromethyl groups, with a cyano group, with a nitro group, with a hydroxyl group, with a (C
1
-C
6
)alkyl group, with one or two
 (C
1
-C
6
)alkoxy groups, with a methylenedioxy group, with an acetyl group, with a trifluoromethoxy group or with a methylthio group,
R represents a hydrogen atom or a (C
1
-C
6
)alkyl group, with the exclusion, however, of the compounds of general formula (I) in which X represents a group of formula CH, Y and Z each represent a nitrogen atom, and R
1
or R
2
does not represent an optionally substituted phenyl group.
The compounds thus excluded are described in U.S. Pat. No. 5,478,939 as muscarine agonists.
The compounds of the invention can exist in the form of bases or of addition salts with acids. They can also exist in the form of (S,S) or (R,R) isomers.
The preferred compounds are those in the formula of which the heterocycle containing X, Y and Z is a 3-pyridyl or 3-pyridazinyl group.
In accordance with the invention, and according to the preceding scheme, the compounds of general formula (I) can be prepared by reacting 1,1-dimethylethyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate of formula (II) with a heterocyclic compound of general formula (III), in which X, Y, Z, R
1
and R
2
are as defined above and W represents a halogen atom.
Thus, it is possible to carry out a Buchwald coupling (
J. Org. Chem
. (1997) 62 6066-6068) in the presence of a palladium catalyst such as palladium acetate, tris(dibenzylideneacetone)dipalladium(0), etc., of a complexation ligand such as triphenylphosphine, tributylphosphine or 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, and of a base, for example an organic base such as sodium t-butoxide, or an inorganic base such as caesium carbonate.
When X or Z represents a nitrogen atom, it is also possible to carry out a standard nucleophilic substitution reaction in the presence of a strong base such as caesium carbonate or triethylamine.
A compound of general formula (IV) is obtained, in which, if so desired, it is possible to modify the substituents R
1
or R
2
; for example, when R
1
or R
2
represents a halogen atom, it can be substituted with an alkyl or phenyl group by a Suzuki reaction, using an alkylboronic or phenylboronic acid, in the presence of tetrakis(triphenylphosphine)palladium.
The compound of general formula (IV) is then deprotected in a known manner, for example using trifluoroacetic acid or hydrochloric acid, to give a compound of general formula (Ia), which corresponds to the general formula (I) when R represents a hydrogen atom.
It is then possible, if so desired, to carry out an alkylation of this compound, either by a reductive amination (formaldehyde and sodium cyanoborohydride) or by an Eschweiler-Clarke reaction (formaldehyde and formic acid).
1,1-Dimethylethyl (1S)-diazabicyclo[2.2.1]heptane-2-carboxylate of formula (II) is described in
J. Org. Chem
. (1988) 53 1580-1582 and 1,1-dimethylethyl (1R)-diazabicyclo[2.2.1]heptane-2-carboxylate of formula (II) is described in patent application EP-400,661.
The compounds of general formula (III) are commercially available or are accessible by methods described in the literature.
The examples which follow illustrate the preparation of a number of compounds of the invention. The elemental microanalyses and the IR and NMR spectra confirm the structures of the compounds obtained.
The numbers indicated in parentheses in the example titles correspond to those in the first column of Table 1 given later.
In the compound names, the hyphen “-” forms part of the name, and the underscore line “_” serves merely to indicate the line break; it should be removed if a line break does not occur at that point, and should not be replaced either with a normal hyphen or with a space.


REFERENCES:
patent: 4954502 (1990-09-01), Smith et al.
patent: 4994460 (1991-02-01), Dextraze et al.
patent: 5478939 (1995-12-01), Trybulski et al.
Clementi et al.European Journal of Pharmacology, 393, Mar. 10, 2000.

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