Azabicyclo-(3,3,1)-nonylbenzamide derivatives, processes for their preparation, and pharmaceutical compositions containing them

Claim 2

A compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof: wherein X is methoxy or ethoxy, Y is amino or C l - 6 alkanoylamino, Z is hydrogen, chloro or bromo and R l is methyl, chloro or fluoro.

Claim 3

A compound according to claim 1, characterised in that X is methoxy.

Claim 4

A compound according to either of the preceding claims, characterised in that Y is amino.

Claim 5

A compound according to any one of the preceding claims, characterised in that Z is chloro.

Claim 6

4-amino-5-chloro-2-methoxy-N-(3'β-[9'-(4-methylbenzyl)-9'-azabicyclo-[3.3.1]-nonyl])benzamide; 4-amino-5-chloro-2-methoxy-N-(3'p-[9'-(4-chlorobenzyl)-9'-azabicyclo-[3.3.1]-nonyl])benzamide; 4-amino-5-chloro-2-methoxy-N-(3'β-[9'-(4-fluorobenzyl)-9'-azabicyclo-[3.3.1]-nonyl])benzamide; 4-amino-5-bromo-2-methoxy-N-(3'β-[9'-(4-fluorobenzyl)-9'-azabicyclo-[3.3.1]-nonyl])benzamide; 4-acetylamino-5-chloro-2-methoxy-N-(3'β-[9'-(4-fluorobenzyl)-9'-azabicyclo[3.3.1]nonyl]) benzamide; 4-acetylamino-5-chloro-2-methoxy-N-(3'β-[9'-(4-chlorobenzyl)-9'-azabicyclo[3.3.1]-nonyl])benzamide; 4-acetylamino-5-chloro-2-methoxy-N-(3'β-[9'-(4-methylbenzyl)-9'-azabicyclo[3.3.1]nonyl])benzamide; 4-acetylamino-2-methoxy-N-(3'β-[9'-(4-fluorobenzyl)-9'-azabicyclo-[3.3.1]nonylJ)benzamide; 4-amino-2-methoxy-N-(3'β-[9'-(4-fluorobenzyl)-9'-azabicyclo[3.3.1]nonyl])-benzamide; or a pharmaceutically acceptable salt or solvate thereof.

Claim 7

4-amino-5-chloro-2-methoxy-N-(3'β-[9'-(4-methylbenzyl)-9'-azabicyclo-[3.3.1]-nonyl])benzamide; 4-amino-5-chloro-2-methoxy-N-(3'p-[9'-(4-chlorobenzyl)-9'-azabicyclo-[3.3.1]-nonyl])benzamide; 4-amino-5-chloro-2-methoxy-N-(3'β-[9'-(4-fluorobenzyl)-9'-azabicyclo-[3.3.1]-nonyl])benzamide; 4-amino-5-bromo-2-methoxy-N-(3'β-[9'-(4-fluorobenzyl)-9'-azabicyclo-[3.3.1]-nonyl])benzamide; 4-acetylamino-5-chloro-2-methoxy-N-(3'β-[9'-(4-fluorobenzyl)-9'-azabicyclo[3.3.1]nonyl]) benzamide; 4-acetylamino-5-chloro-2-methoxy-N-(3'β-[9'-(4-chlorobenzyl)-9'-azabicyclo[3.3.1]-nonyl])benzamide; 4-acetylamino-5-chloro-2-methoxy-N-(3'β-[9'-(4-methylbenzyl)-9'-azabicyclo[3.3.1]nonyl])benzamide; 4-acetylamino-2-methoxy-N-(3'β-[9'-(4-fluorobenzyl)-9'-azabicyclo-[3.3.1]nonylJ)benzamide; 4-amino-2-methoxy-N-(3'β-[9'-(4-fluorobenzyl)-9'-azabicyclo[3.3.1]nonyl])-benzamide; or a pharmaceutically acceptable salt or solvate thereof.

Claim 8

4-Amino-5-chloro-2-methoxy-N-(3'β-[9'-(4-fluorobenzyl)-9'-azabicyclo[3.3.1]-nonyl])benzamide or a pharmaceutically acceptable salt or solvate thereof.

Claim 9

4-Amino-5-chloro-2-methoxy-N-(3'β-[9'-(4-fluorobenzyl)-9'-azabicyclo[3.3.1]-nonyl])benzamide or a pharmaceutically acceptable salt or solvate thereof.

Claim 10

A pharmaceutical composition characterised by a compound according to any one of claims 1 to 6 and a pharmaceutically acceptable carrier.

Claim 11

A compound according to any one of claims 1 to 6 or a composition according to claim 7 for use in the treatment of disorders of the central nervous system.

Claim 12

A process of preparing a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, characterised by reacting a compound of formula (II): wherein X and Z are as defined in claim 1, R 2 is Y as defined in claim 1 or a protected amino group and Q 1 is a leaving group, with a compound of formula (III): wherein R 3 is a protecting group or p-methylbenzyl, p-chlorobenzyl or p-fluorobenzyl; in the case where R 2 is a protected amino group, removing the protecting group; in the case where R 3 is a protecting group, removing the protecting group and reacting the secondary amine with a compound of formula (IV): wherein Q 2 is a leaving group and R 1 is as defined in claim 1, and when M is CO, reducing the resulting N-benzoyl compound to give the corresponding N-benzyl compound; in the case where R 2 is Y, optionally converting the amino group or the C l - 6 alkanoylamino group into the other; and optionally forming a pharmaceutically acceptable salt or solvate thereof.

Claim 13

A process of preparing a compound of formula (I), wherein Z is chloro or bromo, or a pharmaceutically acceptable salt or solvate thereof, characterised by chlorinating or brominating a compound of formula (XII): wherein X is as defined in claim 1, R 2 is as defined in claim 9 and R 3 ' is hydrogen or R 3 as defined in claim 9; in the case where R 2 is a protected amino group, removing the protecting group; in the case where R 3 - is R 3 and is a protecting group, removing the protecting group to give a compound of formula (XII), wherein R 3 - is hydrogen; in the case where R 3 - is hydrogen, reacting the secondary amine with a compound of formula (IV), as defined in claim 9, and when M is CO, reducing the resulting N-benzoyl compound to give the corresponding N-benzyl compound; in the case where R 2 is Y, optionally converting the amino group or the C l - 6 alkanoylamino group into the other; and optionally forming a pharmaceutically acceptable salt or solvate thereof.

Claim 14

A process of preparing a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, characterised by reducing a compound of formula (XIII): wherein X and Z are as defined in claim 1 and R 3 ' is as defined in claim 10; in the case where R 3 ' is R 3 and is a protecting group, removing the protecting group to give a compound of formula (XIII), wherein R 3 ' is hydrogen; in the case where R 3 ' is hydrogen, reacting the secondary amine with a compound of formula (IV), as defined in claim 9, and when M is CO, reducing the resulting N-benzoyl compound to give the corresponding N-benzyl compound; optionally converting the primary amino group to a C l - 6 alkanoylamino group; and optionally forming a pharmaceutically acceptable salt or solvate thereof.

Claim 15

A process of preparing a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, characterised by carrying out a Hoffman degradation on a compound of formula (XIV): wherein X and Z are as defined in claim 1 and R 3 ' is as defined in claim 10; in the case where R 3 ' is R 3 and is a protecting group, removing the protecting group to give a compound of formula (XIV), wherein R 3 ' is hydrogen; in the case where R 3 ' is hydrogen, reacting the secondary amine with a compound of formula (IV) as defined in claim 9; and when M is CO, reducing the resulting N-benzoyl compound to give the corresponding N-benzyl compound; optionally converting the primary amino group to a C l - 6 alkanoylamino group; and optionally forming a pharmaceutically acceptable salt or solvate thereof.

Claim 16

A process of preparing a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, characterised by methylating or ethylating a compound of formula (XV): wherein Z is as defined in claim 1, R 2 is as defined in claim 9 and R 3 ' is as defined in claim 10; in the case where R 2 is a protected amino group, removing the protecting group; in the case where R 3 - is R 3 and is a protecting group, removing the protecting group to give a compound of formula (XIV), wherein R 3 ' is hydrogen; in the . case where R 3 - is hydrogen, reacting the secondary amine with a compound of formula (IV), as defined in claim 9, and when M is CO, reducing the resulting N-benzoyl compound to give the corresponding N-benzyl compound; in the case where R 2 is Y, optionally converting the amino group or the C 1-6 alkanoylamino group into the other; and optionally forming a pharmaceutically acceptable salt or solvate thereof.

Claim 17

A process according to any one of claims 9 to 13, characterised in that R 3 in claim 9 and R 3 - in claims 10 to 13 is p-methylbenzyl, p-chlorobenzyl or p-fluorobenzyl.

Claim 18

A compound of formula (XVI): wherein: R 7 is methoxy or ethoxy, R 8 is nitro or aminocarbonyl and Rg is hydrogen, chloro or bromo; or R 7 is hydroxy, R 8 is amino or C l - 6 alkanoylamino and Rg is hydrogen, chloro or bromo; and M is CH 2 or CO; and R 1 is as defined in claim 1.

Claim 19

A compound of formula (XVII): wherein V is amino or C l - 6 alkanoylamino and W is hydrogen or V and W together with the carbon atom to which they are attached are an oximino group, and R 1 is as defined in claim 1.

Claim 20

The compound of formula (VI): wherein R3 is p-fluorobenzyl.

Claim 21

The compound of formula (VI): wherein R3 is p-fluorobenzyl.

Claim 22

A process of preparing a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof: wherein X is methoxy or ethoxy, Y is amino or C l - 6 alkanoylamino, Z is hydrogen, chloro or bromo and R 1 is methyl, chloro or fluoro, characterised by reacting a compound of formula (II): wherein X and Z are as defined above, R 2 is Y as defined above or a protected amino group and Q l is a leaving group, with a compound of formula (III): wherein R 3 is a protecting group or p-methylbenzyl, p-chlorobenzyl or p-fluorobenzyl; in the case where R 2 is a protected amino group, removing the protecting group; in the case where R 3 is a protecting group, removing the protecting group and reacting the secondary amine with a compound of formula (IV): wherein Q 2 is a leaving group, M is CO or CH 2 , and R 1 is as defined above, and when M is CO, reducing the resulting N-benzoyl compound to give the corresponding N-benzyl compound; in the case where R 2 is Y, optionally converting the amino group or the C l - 6 alkanoylamino group into the other; and optionally forming a pharmaceutically acceptable salt or solvate thereof.

Claim 23

A process of preparing a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof: wherein X is methoxy or ethoxy, Y is amino or C l - 6 alkanoylamino, Z is hydrogen, chloro or bromo and R 1 is methyl, chloro or fluoro, characterised by reacting a compound of formula (II): wherein X and Z are as defined above, R 2 is Y as defined above or a protected amino group and Q l is a leaving group, with a compound of formula (III): wherein R 3 is a protecting group or p-methylbenzyl, p-chlorobenzyl or p-fluorobenzyl; in the case where R 2 is a protected amino group, removing the protecting group; in the case where R 3 is a protecting group, removing the protecting group and reacting the secondary amine with a compound of formula (IV): wherein Q 2 is a leaving group, M is CO or CH 2 , and R 1 is as defined above, and when M is CO, reducing the resulting N-benzoyl compound to give the corresponding N-benzyl compound; in the case where R 2 is Y, optionally converting the amino group or the C l - 6 alkanoylamino group into the other; and optionally forming a pharmaceutically acceptable salt or solvate thereof.

Claim 24

A process of preparing a compound of formula (I), wherein Z is chloro or bromo, or a pharmaceutically acceptable salt or solvate thereof, characterised by chlorinating or brominating a compound of formula (XII): wherein X and R 2 are as defined in claim 1 and R 3 - is hydrogen or R 3 as defined in claim 1; in the case where R 2 is a protected amino group, removing the protecting group; in the case where R 3 ' is R 3 and is a protecting group, removing the protecting group to give a compound of formula (XII), wherein R 3 - is hydrogen; in the case where R 3 - is hydrogen, reacting the secondary amine with a compound of formula (IV), as defined in claim 1; and when M is CO, reducing the resulting N-benzoyl compound to give the corresponding N-benzyl compound; in the case where R 2 is Y, optionally converting the amino group or the C l - 6 alkanoylamino group into the other; and optionally forming a pharmaceutically acceptable salt or solvate thereof.

Claim 25

A process of preparing a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, characterised by reducing a compound of formula (XIII): wherein X and Z are as defined in claim 1 and R 3 ' is as defined in claim 2; in the case where R 3 ' is R 3 and is a protecting group, removing the protecting group to give a compound of formula (XIII), wherein R 3 - is hydrogen; in the case where R 3 - is hydrogen, reacting the secondary amine with a compound of formula (IV), as defined in claim 1,. and when M is CO, reducing the resulting N-benzoyl compound to give the corresponding N-benzyl compound; optionally converting the primary amino group to a C 1-6 alkanoylamino group; and optionally forming a pharmaceutically acceptable salt or solvate thereof.

Claim 26

A process of preparing a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, characterised by carrying out a Hoffman degradation on a compound of formula (XIV): wherein X and Z are as defined in claim 1 and R 3 - is as defined in claim 2; in the case where R 3 - is R 3 and is a protecting group, removing the protecting group to give a compound of formula (XIV), wherein R 3 - is hydrogen; in the case wherein R 3 - is hydrogen, reacting the secondary amine with a compound of formula (IV) as defined in claim 1, and when M is CO, reducing the resulting N-benzoyl compound to give the corresponding N-benzyl compound; optionally converting the primary amino group to a C l - 6 alkanoylamino group; and optionally forming a pharmaceutically acceptable salt or solvate thereof.

Claim 27

A process of preparing a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, characterised by methylating or ethylating a compound of formula (XIV): wherein Z and R 2 are as defined in claim 1 and R 3 - is as defined in claim 2; in the case where R 2 is a protected amino group, removing the protecting group; in the case where R 3 - is R 3 and is a protecting group, removing the protecting group to give a compound of formula (XIV), wherein R 3 - is hydrogen; in the case where R 3 ' is hydrogen, reacting the secondary amine with a compound of formula (IV), as defined in claim 1, and when M is CO, reducing the resulting N-benzoyl compound to give the corresponding N-benzyl compound; in the case where R 2 is Y, optionally converting the amino group or the C l - 6 alkanoyl- amino group into the other; and optionally forming a pharmaceutically acceptable salt or solvate thereof.

Claim 28

A process according to any one of claims 1 to 5,characterised in that R 3 in claim 1 and R 3 - in claims 2 to 5, is p-methylbenzyl, p-chlorobenzyl or p-fluorobenzyl.

Claim 29

A process according to any one of claims 1 to 6, characterised in that the compound of formula (I) is 4-amino-5-chloro-2-methoxy-N-(3'P-[9'-(4-methylbenzyl)-9'-azabicyclo-[3.3.1]-nonyl])-benzamide; 4-amino-5-chloro-2-methoxy-N-(3'β-[9'-(4-chlorobenzyl)-9'-azabicyclo-[3.3.1]-nonyl])benzamide; 4-amino-5-chloro-2-methoxy-N-(3'P-[9'-(4-fluorobenzyl)-9'-azabicyclo-[3.3.1]-nonyl])benzamide; 4-amino-5-bromo-2-methoxy-N-(3'β-[9'-(4-fluorobenzyl)-9'-azabicyclo-[3.3.1]-nonyl])benzamide; 4-acetylamino-5-chloro-2-methoxy-N-(3'β-[9'-(4-fluorobenzyl)-9'-azabicyclo[3.3.1]nonyl])benzamide; 4-acetylamino-5-chloro-2-methoxy-N-(3'p-[9'-(4-chlorobenzyl)-9'-azabicyclo[3.3.1]-nonyl])benzamide; 4-acetylamino-5-chloro-2-methoxy-N-(3'β-[9'-(4-methylbenzyl)-9'-azabicyclo[3.3.1]nonyl])-benzamide; 4-acetylamino-2-methoxy-N-(3'β-[9'-(4-fluorobenzyl)-9'-azabicyclo-[3.3.1]nonyl])-benzamide; 4-amino-2-methoxy-N-(3'P-[9'-(4-fluorobenzyl)-9'-azabicyclo[3.3.1]nonyl])-benzamide; or a pharmaceutically acceptable salt or solvate thereof.

Claim 30

A process according to any one of claims 1 to 6, characterised in that the compound of formula (I) is 4-amino-5-chloro-2-methoxy-N-(3'β-[9'-(4-fluorobenzyl)-9'-azabicyclo[3.3.1]-nonyl])-benzamide or a pharmaceutically acceptable salt or solvate thereof.

Claim 31

A process of manufacturing a pharmaceutical composition, characterised in that a compound of formula (I) is admixed with a pharmaceutically acceptable carrier.

Claim 32

A process of manufacturing a pharmaceutical composition, characterised in that a compound of formula (I) is admixed with a pharmaceutically acceptable carrier.

Claim 33

A process according to claim 9, characterised in that the compound of formula (I) is 4-amino-5-chloro-2-methoxy-N-(3'β-[9'-(4-methylbenzyl)-9'-azabicyclo-[3.3.1]-nonyl])benzamide; 4-amino-5-chloro-2-methoxy-N-(3'β-[9'-(4-chlorobenzyl)-9'-azabicyclo-[3.3.1]-nonyl])benzamide; 4-amino-5-chloro-2-methoxy-N-(3'β-[9'-(4-fluorobenzyl)-9'-azabicyclo-[3.3.1]-nonyl])benzamide; 4-amino-5-bromo-2-methoxy-N-(3'β-[9'-(4-fluorobenzyl)-9'-azabicyclo-[3.3.1]-nonyl])benzamide; 4-acetylamino-5-chloro-2-methoxy-N-(3'β-[9'-(4-fluorobenzyl)-9'-azabicyclo[3.3.1]nonyl])-benzamide; 4-acetylamino-5-chloro-2-methoxy-N-(3'β-[9'-(4-chlorobenzyl)-9'-azabicyclo[3.3.1]-nonyl])benzamide; 4-acetylamino-5-chloro-2-methoxy-N-(3'β-[9'-(4-methylbenzyl)-9'-azabicyclo[3.3.1]nonyl])benzamide; 4-acetylamino-2-methoxy-N-(3'β-[9'-(4-fluorobenzyl)-9'-azabicyclo-[3.3.1]nonyl])benzamide; 4-amino-2-methoxy-N-(3'P-[9'-(4-fluorobenzyl)-9'-azabicyclo[3.3.1]nonyl])benzamide; or a pharmaceutically acceptable salt or solvate thereof.

Claim 34

A process according to claim 8, characterised in that the compound of formula (I) is 4-amino-5-chloro-2-methoxy-N-(3'β-[9'-(4-fluorobenzyl)-9'-azabicyclo-[3.3.1]-nonyl])benzamide; or a pharmaceutically acceptable salt or solvate thereof.