Substituted piperidines

1. A compound of the formula

in which

A is an oxygen atom or —NR 4 —,

where

R 4 is hydrogen or C 1 -C 3 -alkyl,

or

R 2 and R 4 together with the nitrogen atom to which they are bonded form a 4- to 6-membered heterocycle, in which the heterocycle may be substituted by 1 to 3 substituents selected independently from the group consisting of halogen, cyano, hydroxyl, amino, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy and C 1 -C 4 -alkylamino,

R 1 is phenyl, where phenyl may be substituted by 1 to 3 substituents selected independently from the group consisting of halogen, monofluoromethyl, difluoromethyl, trifluoromethyl, 1,1-difluoroethyl, 2,2,2-trifluoroethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoromethylsulphanyl, difluoromethylsulphanyl, trifluoromethylsulphanyl, methylsulphonyl, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy and C 1 -C 4 -alkoxycarbonyl,

R 2 is C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, 4- to 6-membered heterocyclyl, phenyl or 5- or 6-membered heteroaryl, where cycloalkyl, heterocyclyl, phenyl and heteroaryl may be substituted by 1 to 3 substituents selected independently from the group consisting of halogen, cyano, hydroxyl, amino, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoromethylsulphanyl, difluoromethylsulphanyl, trifluoromethylsulphanyl, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, C 1 -C 6 -alkylamino and phenyl, in which phenyl may be substituted by 1 to 3 substituents selected independently from the group consisting of halogen and trifluoromethyl, and where C 1 -C 6 -alkyl may be substituted by one substituent selected from the group consisting of hydroxyl, trifluoromethyl, C 1 -C 4 -alkoxy, C 1 -C 4 -alkylsulphonyl, C 3 -C 6 -cycloalkyl and phenyl, in which cycloalkyl and phenyl may be substituted by 1 to 3 substituents selected independently from the group consisting of halogen, cyano, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, C 1 -C 4 -alkyl and C 1 -C 4 -alkoxy,

R 3 is C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkylamino, C 3 -C 7 -cycloalkyl, 4- to 7-membered heterocyclyl, phenyl, 5- or 6-membered heteroaryl, C 3 -C 7 -cycloalkyloxy, C 3 -C 7 -cycloalkylamino, 4- to 7-membered heterocyclylamino, phenylamino or 5- or 6-membered heteroarylamino, where alkyl, C 2 -C 6 -alkoxy and alkylamino may be substituted by one substituent selected from the group consisting of halogen, hydroxyl, amino, cyano, C 1 -C 4 -alkoxy, C 1 -C 4 -alkoxycarbonyl, C 3 -C 7 -cycloalkyl, 4- to 6-membered heterocyclyl, phenyl and 5- or 6-membered heteroaryl, and where cycloalkyl, heterocyclyl, phenyl, heteroaryl, cycloalkyloxy, cycloalkylamino, heterocyclylamino, phenylamino and heteroarylamino may be substituted by 1 to 3 substituents selected independently from the group consisting of halogen, cyano, oxo, hydroxyl, amino, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoromethylsulphanyl, difluoromethylsulphanyl, trifluoromethylsulphanyl, hydroxycarbonyl, aminocarbonyl, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, C 1 -C 6 -alkylamino, C 1 -C 4 -alkoxycarbonyl, C 1 -C 4 -alkylaminocarbonyl and cyclopropyl, in which alkyl may be substituted by one hydroxyl substituent,

or a salt thereof.

2. A compound according to claim 1 , characterized in that

A is an oxygen atom,

R 1 is phenyl, where phenyl is substituted by 1 to 2 substituents selected independently from the group consisting of fluorine, trifluoromethyl, 1,1-difluoroethyl, 2,2,2-trifluoroethyl, trifluoromethoxy and ethyl,

R 2 is methyl, ethyl or isopropyl, where ethyl may be substituted by one substituent selected from the group consisting of hydroxyl, methoxy and ethoxy, and

R 3 is 1-oxidothiomorpholin-4-yl, 1,1-dioxidothiomorpholin-4-yl, 3-hydroxyazetidin-1-yl, 3-hydroxypyrrolidin-1-yl or 4-hydroxypiperidin-1-yl.

3. A compound according to claim 1 , characterized in that

A is an oxygen atom,

R 1 is phenyl, where phenyl is substituted by one substituent in the para position to the site of attachment to the piperidine ring, selected from the group consisting of trifluoromethyl, 1,1-difluoroethyl, 2,2,2-trifluoroethyl and trifluoromethoxy,

R 2 is ethyl, where ethyl may be substituted by one methoxy substituent, and

R 3 is 1-oxidothiomorpholin-4-yl or 1,1-dioxidothiomorpholin-4-yl.

4. A compound according to claim 1 , characterized in that the —R 1 and 1,2,4-oxadiazol-5-yl substituents are in cis-positions to one another.

5. A process for preparing a compound of the formula (I) according to claim 1 or a salt thereof, characterized in that either

[A] a compound of the formula

in which

R 1 and R 3 are each as defined in claim 1

is reacted with a compound of the formula

in which

A and R 2 are each as defined in claim 1

or

[B] a compound of the formula

in which

R 1 and R 3 are each as defined in claim 1 ,

is reacted with a compound of the formula

in which

A and R 2 are each as defined in claim 1

or

[C] a compound of the formula

in which

A, R 1 and R 2 are each as defined in claim 1

is reacted with 0.8 to 1.1 equivalents of meta-chloroperbenzoic acid to give a compound of the formula

in which

A, R 1 and R 2 are each as defined in claim 1

or

[D] a compound of the formula (Ia) is reacted with 2.0 to 3.0 equivalents of meta-chloroperbenzoic acid to give a compound of the formula

in which

A, R 1 and R 2 are each as defined in claim 1

or

[E] a compound of the formula

in which

A, R 1 and R 2 are each as defined in claim 1

is reacted with a compound of the formula

in which

R 3 is as defined in claim 1 and

X 1 is halogen or hydroxyl or 4-nitrophenoxy,

or

[F] a compound of the formula (XV) is reacted in the first stage with 4-nitrophenyl chloroformate and in the second stage with a compound of the formula

R 3 —H  (XVI)

in which

R 3 is as defined in claim 1 .

6. A pharmaceutical composition comprising a compound according to claim 1 and an inert, non-toxic, pharmaceutically acceptable excipient.

7. A method for treating thromboembolic disorders in a human or animal comprising the step of administering an anticoagulatory amount of a compound according to claim 1 to a human or animal in need thereof.

8. A compound according to claim 1 , characterized in that

A is an oxygen atom,

R 1 is phenyl,

where phenyl is substituted by one substituent in the para position to the site of attachment to the piperidine ring, selected from the group consisting of trifluoromethyl, 2,2,2-trifluoroethyl, trifluoromethoxy and ethyl,

R 2 is ethyl,

where ethyl may be substituted by one methoxy substituent,

R 3 is 1-oxidothiomorpholin-4-yl or 1,1-dioxidothiomorpholin-4-yl.

9. A compound according to claim 1 , characterized in that

A is an oxygen atom,

R 1 is phenyl,

where phenyl is substituted by one 2,2,2-trifluoroethyl substituent in the para position to the site of attachment to the piperidine ring,

R 2 is ethyl,

where ethyl may be substituted by one methoxy substituent,

R 3 is 1-oxidothiomorpholin-4-yl or 1,1-dioxidothiomorpholin-4-yl.

10. A compound according to claim 1 , characterized in that

A is an oxygen atom,

R 1 is phenyl,

where phenyl is substituted by one substituent in the para position to the site of attachment to the piperidine ring, selected from the group consisting of trifluoromethyl, 1,1-difluoroethyl, 2,2,2-trifluoroethyl and trifluoromethoxy,

R 2 is ethyl,

where ethyl may be substituted by one methoxy substituent,

R 3 is 1,1-dioxidothiomorpholin-4-yl.

11. A compound according to claim 1 , characterized in that the carbon atom to which R 1 is bonded has S configuration and the carbon atom to which the 1,2,4-oxadiazol-5-yl is bonded likewise has S configuration.

12. A compound which is [3-(3-ethoxy-1,2,4-oxadiazol-5-yl)-5-(4-ethylphenyl)piperidin-1-yl](1-oxidothiomorpholin-4-yl)methanone [enantiomerically pure cis isomer],

or

{3-(4-ethylphenyl)-5-[3-(2-methoxyethoxy)-1,2,4-oxadiazol-5-yl]piperidin-1-yl}(1-oxidothio-morpholin-4-yl)methanone [enantiomerically pure cis isomer],

or

(1,1-Dioxidothiomorpholin-4-yl){3-(4-ethylphenyl)-5-[3-(2-methoxyethoxy)-1,2,4-oxadiazol-5-yl]-piperidin-1-yl}methanone [enantiomerically pure cis isomer],

or

{3-(3-Ethoxy-1,2,4-oxadiazol-5-yl)-5-[4-(2,2,2-trifluoroethyl)phenyl]piperidin-1-yl}(1-oxidothio-morpholin-4-yl)methanone [enantiomerically pure cis isomer],

or

(1,1-Dioxidothiomorpholin-4-yl){3-(3-ethoxy-1,2,4-oxadiazol-5-yl)-5-[4-(2,2,2-trifluoroethyl)-phenyl]piperidin-1-yl}methanone [enantiomerically pure cis isomer],

or a salt thereof.

13. A compound which is [3-(3-ethoxy-1,2,4-oxadiazol-5-yl)-5-(4-ethylphenyl)piperidin-1-yl](1-oxidothiomorpholin-4-yl)methanone [enantiomerically pure cis isomer],

or

{3-(4-ethylphenyl)-5-[3-(2-methoxyethoxy)-1,2,4-oxadiazol-5-yl]piperidin-1-yl}(1-oxidothio-morpholin-4-yl)methanone [enantiomerically pure cis isomer],

or

(1,1-Dioxidothiomorpholin-4-yl){3-(4-ethylphenyl)-5-[3-(2-methoxyethoxy)-1,2,4-oxadiazol-5-yl]-piperidin-1-yl}methanone [enantiomerically pure cis isomer],

or

{3-(3-Ethoxy-1,2,4-oxadiazol-5-yl)-5-[4-(2,2,2-trifluoroethyl)phenyl]piperidin-1-yl}(1-oxidothio-morpholin-4-yl)methanone [enantiomerically pure cis isomer],

or

(1,1-Dioxidothiomorpholin-4-yl){3-(3-ethoxy-1,2,4-oxadiazol-5-yl)-5-[4-(2,2,2-trifluoroethyl)-phenyl]piperidin-1-yl}methanone [enantiomerically pure cis isomer].

14. The compound of claim 1 , wherein the compound is a compound having the formula

or a salt thereof.

15. The compound of claim 14 , wherein the compound is a compound having the formula

16. The compound of claim 14 , wherein the compound is an enantiomerically pure cis isomer.

17. The compound of claim 15 , wherein the compound is an enantiomerically pure cis isomer.