Catechol O-methyltransferase activity inhibiting compounds

Patent metadata

Field	Value
Publication number	US-9458128-B2
Application number	US-201314403023-A
Country	US
Kind code	B2
Filing date	May 23, 2013
Priority date	May 24, 2012
Publication date	Oct 4, 2016
Grant date	Oct 4, 2016

Abstract

Compounds of formula (I), wherein R 1 is as defined in the claims, exhibit COMT enzyme inhibiting activity and are thus useful as COMT inhibitors. Methods of treatment and pharmaceutical dosage forms are also disclosed.

First claim

The invention claimed is:

1. A compound of formula I,

wherein
R 1 is (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 7 )cycloalkyl, (C 4 -C 10 )cycloalkenyl, aryl, (R 2 ) 2 C═C—, halogen, hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkyl-S—, (C 4 -C 10 )cycloalkenyloxy, (C 4 -C 10 )cycloalkenyl-S—, aryloxy, aryl-S—, heteroaryloxy, heteroaryl-S—, (R 3 ) 2 N—, (R 4 ) 2 C═N—, heterocyclyl, heteroaryl, aryl(C 1 -C 6 )alkyl, (1-amino-1-carboxymethyl)-(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-S—(C 1 -C 6 )alkyl, (R 3 ) 2 N—(C 1 -C 6 )alkyl, carboxy(C 2 -C 6 )alkenyl, (C 3 -C 7 )cycloalkyl(C 2 -C 6 )alkenyl, aryl(C 2 -C 6 )alkenyl, (C 1 -C 6 )alkoxy(C 2 -C 6 )alkenyl, heterocyclyl(C 2 -C 6 )alkenyl, heteroaryl(C 2 -C 6 )alkenyl, carboxy(C 2 -C 6 )alkynyl, (C 3 -C 7 )cycloalkyl(C 2 -C 6 )alkynyl, aryl(C 2 -C 6 )alkynyl, (C 1 -C 6 )alkoxy(C 2 -C 6 )alkynyl, heterocyclyl(C 2 -C 6 )alkynyl, heteroaryl(C 2 -C 6 )alkynyl, halo(C 1 -C 6 )alkoxy, hydroxy(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkyl-(C═O)—O—, R 5 —(S═O)—, R 5 —(O═S═O)—, hydroxy(C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy-(C═O)—(C 2 -C 6 )alkenyl or (C 1 -C 6 )alkyl-(C═O)—O—(C 1 -C 6 )alkyl, wherein said (C 4 -C 10 )cycloalkenyl, aryl, heterocyclyl, heteroaryl or (C 3 -C 7 )cycloalkyl as such or as part of another group is unsubstituted or substituted with 1, 2 or 3 substituent(s) R 6 ;
R 2 is, independently at each occurrence, carboxy or aryl, wherein said aryl is, independently at each occurrence, unsubstituted or substituted with 1, 2 or 3 substituent(s) R 6 ;
R 3 is, independently at each occurrence, H, (C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, aryl, (C 3 -C 7 )cycloalkyl(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl or (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, wherein said (C 3 -C 7 )cycloalkyl or aryl as such or as part of another group is, independently at each occurrence, unsubstituted or substituted with 1 substituent being (C 1 -C 6 )alkyl, halogen, hydroxy, (C 1 -C 6 )alkoxy or hydroxy(C 1 -C 6 )alkyl;
R 4 is, independently at each occurrence, H or aryl, wherein said aryl is, independently at each occurrence, unsubstituted or substituted with 1 substituent being (C 1 -C 6 )alkyl, halogen or (C 1 -C 6 )alkoxy;
R 5 is (C 1 -C 6 )alkyl, aryl, hydroxy or (C 1 -C 6 )alkoxy, wherein said aryl is unsubstituted or substituted with 1, 2 or 3 substituent(s) R 6 ;
R 6 is, independently at each occurrence, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, cyano, aryl, halogen, hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkyl-S—, (C 4 -C 10 )cycloalkenyloxy, (C 4 -C 10 )cycloalkenyl-S—, aryloxy, aryl-S—, heteroaryloxy, heteroaryl-S—, (R 7 ) 2 N—, carboxy(C 1 -C 6 )alkyl, aryl(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, heterocyclyl(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-(C═O)—, (C 1 -C 6 )alkoxy-(C═O)—, heterocyclyl-(C═O)—, (R 7 ) 2 N—(C═O)—, halo(C 1 -C 6 )alkoxy, R 8 —(S═O)—, R 8 —(O═S═O)—, (C 1 -C 6 )alkoxy-(C═O)—(C 1 -C 6 )alkyl, (R 7 ) 2 N—(C═O)—(C 1 -C 6 )alkyl or (C 1 -C 6 )alkoxy(C 1 -C 6 )alkoxy-(C═O)—, wherein said aryl, heteroaryl or heterocyclyl as such or as part of another group is, independently at each occurrence, unsubstituted or substituted with 1 substituent being (C 1 -C 6 )alkyl;
or R 6 and R 6 both attached to the same carbon ring atom form, together with the carbon ring atom to which they are attached, a —(C═O)— group;
R 7 is, independently at each occurrence, H, (C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl or carboxy(C 1 -C 6 )alkyl, wherein said (C 3 -C 7 )cycloalkyl is, independently at each occurrence, unsubstituted or substituted with 1 substituent being (C 1 -C 6 )alkyl;
R 8 is, independently at each occurrence, (C 1 -C 6 )alkyl, hydroxy, (C 1 -C 6 )alkoxy or (R 9 ) 2 N—;
R 9 is, independently at each occurrence, (C 1 -C 6 )alkyl;
or a pharmaceutically acceptable salt or ester thereof.

2. The compound according to claim 1 , wherein
R 1 is (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 4 -C 10 )cycloalkenyl, aryl, halogen, hydroxy, (C 4 -C 10 )cycloalkenyloxy, aryloxy, aryl-S—, heteroaryl-S—, (R 3 ) 2 N—, (R 4 ) 2 C═N—, heterocyclyl, heteroaryl, aryl(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (R 3 ) 2 N—(C 1 -C 6 )alkyl, carboxy(C 2 -C 6 )alkenyl, (C 3 -C 7 )cycloalkyl(C 2 -C 6 )alkenyl, aryl(C 2 -C 6 )alkenyl, (C 1 -C 6 )alkoxy(C 2 -C 6 )alkenyl, heteroaryl(C 2 -C 6 )alkenyl, aryl(C 2 -C 6 )alkynyl, (C 1 -C 6 )alkoxy(C 2 -C 6 )alkynyl, R 5 —(S═O)—, R 5 —(O═S═O)— or (C 1 -C 6 )alkoxy-(C═O)—(C 2 -C 6 )alkenyl, wherein said (C 4 -C 10 )cycloalkenyl, aryl, heterocyclyl, heteroaryl or (C 3 -C 7 )cycloalkyl as such or as part of another group is unsubstituted or substituted with 1, 2 or 3 substituent(s) R 6 ;
R 3 is, independently at each occurrence, H, (C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, aryl, (C 3 -C 7 )cycloalkyl(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl or (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, wherein said (C 3 -C 7 )cycloalkyl or aryl as such or as part of another group is unsubstituted or substituted with 1 substituent being (C 1 -C 6 )alkyl;
R 4 is, independently at each occurrence, H or aryl, wherein said aryl is, independently at each occurrence, substituted with 1 substituent being (C 1 -C 6 )alkyl, halogen or (C 1 -C 6 )alkoxy;
R 5 is aryl, wherein said aryl is substituted with 1 substituent R 6 ;
R 6 is, independently at each occurrence, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, carboxy, cyano, aryl, halogen, hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkyl-S—, aryloxy, heteroaryl, carboxy(C 1 -C 6 )alkyl, aryl(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, heterocyclyl(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-(C═O)—, (C 1 -C 6 )alkoxy-(C═O)—, heterocyclyl-(C═O)—, (R 7 ) 2 N—(C═O)—, halo(C 1 -C 6 )alkoxy, R 8 —(O═S═O)—, (C 1 -C 6 )alkoxy-(C═O)—(C 1 -C 6 )alkyl, (R 7 ) 2 N—(C═O)—(C 1 -C 6 )alkyl or (C 1 -C 6 )alkoxy(C 1 -C 6 )alkoxy-(C═O)—, wherein said aryl, heteroaryl or heterocyclyl as such or as part of another group is, independently at each occurrence, unsubstituted or substituted with 1 substituent being (C 1 -C 6 )alkyl;
or R 6 and R 6 both attached to the same carbon ring atom form, together with the carbon ring atom to which they are attached, a —(C═O)— group;
R 7 is, independently at each occurrence, H, (C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl or carboxy(C 1 -C 6 )alkyl, wherein said (C 3 -C 7 )cycloalkyl is unsubstituted;
R 8 is, independently at each occurrence, (C 1 -C 6 )alkyl or (R 9 ) 2 N—;
R 9 is, independently at each occurrence, (C 1 -C 6 )alkyl.

3. The compound according to claim 2 , wherein
R 1 is (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 4 -C 10 )cycloalkenyl, aryl, halogen, (C 4 -C 10 )cycloalkenyloxy, aryloxy, aryl-S—, heteroaryl-S—, (R 3 ) 2 N—, (R 4 ) 2 C═N—, heterocyclyl, heteroaryl, aryl(C 1 -C 6 )alkyl, (R 3 ) 2 N—(C 1 -C 6 )alkyl, carboxy(C 2 -C 6 )alkenyl, (C 3 -C 7 )cycloalkyl(C 2 -C 6 )alkenyl or aryl(C 2 -C 6 )alkenyl, wherein said (C 4 -C 10 )cycloalkenyl, aryl, heterocyclyl, heteroaryl or (C 3 -C 7 )cycloalkyl as such or as part of another group is unsubstituted or substituted with 1, 2 or 3 substituent(s) R 6 ;
R 3 is, independently at each occurrence, H, (C 1 -C 6 )alkyl or (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl;
R 4 is, independently at each occurrence, H or aryl, wherein said aryl is, independently at each occurrence, substituted with 1 substituent being (C 1 -C 6 )alkyl, halogen or (C 1 -C 6 )alkoxy;
R 6 is, independently at each occurrence, (C 1 -C 6 )alkyl, cyano, aryl, halogen, hydroxy, (C 1 -C 6 )al

Assignees

• Orion Corp

Inventors

• Ahlmark Marko
• Din Belle David
• Kauppala Mika
• Luiro Anne
• Pajunen Taina
• Pystynen Jarmo
• Tiainen Eija
• Vaismaa Matti
• Messinger Josef

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P25/16

  Anti-Parkinson drugs · CPC title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• C07D309/22

  Radicals substituted by oxygen atoms · CPC title

• C07C255/53

  containing cyano groups and hydroxy groups bound to the carbon skeleton · CPC title