Pharmacologically active quinazolinedione derivatives

Patent metadata

Field	Value
Publication number	US-2017137387-A1
Application number	US-201515309679-A
Country	US
Kind code	A1
Filing date	May 8, 2015
Priority date	May 9, 2014
Publication date	May 18, 2017
Grant date	—

Abstract

Compounds of formula (I),

wherein R 1 through R 8 are as defined in the claims, exhibit a positive allosteric GABA B modulator effect and are thus useful as positive allosteric modulators of the GABA B receptor.

First claim

1 . A compound of formula I,

wherein
R 1 is (C 1 -C 5 )alkyl, (C 2 -C 5 )alkenyl, (C 2 -C 5 )alkynyl, (C 4 -C 7 )cycloalkyl, oxetan-2-yl, oxetan-3-yl, carboxy(C 2 -C 5 )alkyl, cyano(C 2 -C 5 )alkyl, aryl(C 2 -C 5 )alkyl, halohydroxy(C 1 -C 5 )alkyl, hydroxy(C 1 -C 9 )alkyl, (C 1 -C 3 )alkoxy(C 1 -C 5 )alkyl, methylthio(C 1 -C 5 )alkyl, methylsulfinyl(C 1 -C 5 )alkyl, methylsulfonyl(C 1 -C 5 )alkyl, amino(C 1 -C 5 )alkyl, ((C 1 -C 3 )alkylamino)(C 1 -C 5 )alkyl, (di(C 1 -C 3 )alkylamino)(C 1 -C 5 )alkyl, heterocyclyl(C 1 -C 5 )alkyl, heteroaryl(C 1 -C 5 )alkyl, (C 1 -C 5 )alkylcarbonyl(C 1 -C 5 )alkyl, (C 3 -C 6 )cycloalkylcarbonyl(C 1 -C 5 )alkyl, arylcarbonyl(C 1 -C 5 )alkyl, (C 1 -C 3 )alkoxycarbonyl(C 2 -C 5 )alkyl, aminocarbonyl(C 2 -C 5 )alkyl, ((C 1 -C 3 )alkylamino)carbonyl(C 2 -C 5 )alkyl, (di(C 1 -C 3 )alkylamino)carbonyl(C 2 -C 5 )alkyl, (N—(C 1 -C 3 )alkyl-N-methoxyamino)carbonyl(C 2 -C 5 )alkyl, heterocyclylcarbonyl(C 2 -C 5 )alkyl, halo(C 1 -C 3 )alkoxy(C 1 -C 5 )alkyl, hydroxy(C 1 -C 3 )alkoxy(C 1 -C 5 )alkyl, methoxy(C 1 -C 3 )alkoxy(C 1 -C 5 )alkyl, or (C 1 -C 5 )alkylcarbonylhydroxy(C 1 -C 5 )alkyl, wherein the (C 4 -C 7 )cycloalkyl, aryl, heterocyclyl, or heteroaryl as such or as part of another group is unsubstituted or substituted with 1 substituent being methyl or hydroxy;
R 2 is phenyl, phenylmethyl, or 2-phenylethyl, wherein the phenyl as such or as part of another group is substituted with 1, 2, or 3 substituent(s) R 9 ;
R 3 is H, (C 1 -C 3 )alkyl, phenyl, phenylmethyl, or methoxy(C 1 -C 3 )alkyl, wherein the phenyl as such or as part of another group is unsubstituted;
or R 2 and R 3 form, together with the carbon atom to which they are attached, cyclopentyl or cyclohexyl, wherein the cyclopentyl or cyclohexyl is substituted with 2 substituents R 10 ;
R 4 is H;
or R 3 and R 4 form, together with the carbon atom to which they are attached, (C 3 -C 6 )cycloalkyl, wherein the (C 3 -C 6 )cycloalkyl is unsubstituted;
R 5 is H, halogen, or (C 1 -C 5 )alkoxy;
R 6 is H, methyl, halogen, hydroxy, (C 1 -C 3 )alkoxy, halo(C 1 -C 3 )alkyl, methoxy(C 1 -C 3 )alkyl, or halo(C 1 -C 3 )alkoxy;
R 7 is H, (C 1 -C 5 )alkyl, (C 4 -C 7 )cycloalkyl, halogen, (C 1 -C 3 )alkoxy, heterocyclyl, nitro, halo(C 1 -C 3 )alkyl, methoxy(C 1 -C 3 )akyl, halo(C 1 -C 3 )alkoxy, or dimethylamino, wherein the (C 4 -C 7 )cycloalkyl or heterocyclyl is unsubstituted;
or R 6 and R 7 form, together with the carbon ring atoms to which they are attached, a 5- or 6-membered non-aromatic heterocyclic ring containing 2 ring heteroatoms being O, wherein the heterocyclic ring is unsubstituted;
R 8 is H, halogen, (C 1 -C 3 )alkoxy, or methoxy(C 1 -C 3 )alkoxy;
or R 1 and R 8 form together *—CHR 11 —C(R 12 ) 2 —O—*′, wherein * and *′ indicate respective points of attachment;
R 9 is, independently at each occurrence, methyl, cyano, halogen, methoxy, phenyloxy, nitro, phenylmethyl, halomethyl, halomethoxy, or dimethylamino, wherein the phenyl as part of another group is unsubstituted;
or R 9 and R 9 attached to adjacent carbon ring atoms form, together with the carbon ring atoms to which they are attached, a 5- or 6-membered non-aromatic heterocyclic ring containing 1 or 2 ring heteroatom(s) being 0 or a 6-membered aromatic carbocyclic ring, wherein the heterocyclic ring or carbocyclic ring is unsubstituted;
R 10 and R 10 attached to adjacent carbon ring atoms form, together with the carbon ring atoms to which they are attached, phenyl, wherein the phenyl is unsubstituted or substituted with 1, 2, 3, or 4 substituent(s) being, independently at each occurrence, halogen or methoxy;
R 11 is H, (C 1 -C 5 )alkyl, carboxy, hydroxy(C 1 -C 5 )alkyl, or (C 1 -C 5 )alkylcarbonyl; and
R 12 is, independently at each occurrence, (C 1 -C 5 )alkyl, carboxy, hydroxy(C 1 -C 5 )alkyl, or (C 1 -C 5 )alkylcarbonyl;
or a pharmaceutically acceptable ester or salt thereof;
with the provisos that
a) when R 1 is (C 2 -C 5 )alkenyl, R 5 , R 6 , R 7 , and R 8 are not simultaneously H;
b) when R 1 is (di(C 1 -C 3 )alkylamino)(C 1 -C 5 )alkyl, R 9 is not methoxy;
c) when R 2 is phenylmethyl, R 9 is not methoxy;
d) the compound is not 3-(4-methoxybenzyl)-1-methylquinazoline-2,4(1H,3H)-dione, 1-methyl-3-(3-methyl-4-nitrobenzyl)-6-(perfluoropropan-2-yl)quinazoline-2,4(1H,3H)-dione, 1-methyl-3-(4-methylbenzyl)quinazoline-2,4(1H,3H)-dione, 3-(4-fluorophenethyl)-1-methyl-7-nitroquinazoline-2,4(1H,3H)-dione, 3-(4-methoxybenzyl)-1-(2-(4-methylpiperazin-1-yl)ethyl)quinazoline-2,4(1H,3H)-dione, 3-(4-methoxybenzyl)-1-(3-(4-methylpiperazin-1-yl)propyl)quinazoline-2,4(1H,3H)-dione, 3-(benzo[d][1,3]dioxol-5-ylmethyl)-1-(2-oxo-2-phenylethyl)quinazoline-2,4(1H,3H)-dione, 1-(3,3-dimethyl-2-oxobutyl)-3-(3-methylphenethyl)quinazoline-2,4(1H,3H)-dione, 3-(4-chlorophenethyl)-1-(furan-2-ylmethyl)quinazoline-2,4(1H,3H)-dione, 3-(4-chlorophenethyl)-1-methylquinazoline-2,4(1H,3H)-dione, 3-(4-fluorobenzyl)-6-iodo-1-methylquinazoline-2,4(1H,3H)-dione, 3-(4-chlorobenzyl)-6-iodo-1-methylquinazoline-2,4(1H,3H)-dione, 3-(3-fluorobenzyl)-6-iodo-1-methylquinazoline-2,4(1H,3H)-dione, 3-(3-chlorobenzyl)-6-iodo-1-methylquinazoline-2,4(1H,3H)-dione, 3-(4-bromobenzyl)-6-iodo-1-methylquinazoline-2,4(1H,3H)-dione, 3-(3,4-difluorobenzyl)-6-iodo-1-methylquinazoline-2,4(1H,3H)-dione, 2-(3-(3,4-dichlorobenzyl)-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl)propanoic acid, ethyl 2-(3-(3,4-dichlorobenzyl)-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl)propanoate, or 4-((7-nitro-2,4-dioxo-1-propyl-1,2-dihydroquinazolin-3(4H)-yl)methyl)benzonitrile.

2 . The compound according to claim 1 , wherein R 11 is H or (C 1 -C 5 )alkyl.

3 . The compound according to claim 2 , wherein R 11 is H.

4 . The compound according to claim 1 , wherein
R 2 is phenyl, wherein the phenyl is substituted with 1 or 2 substituent(s) R 9 ; or R 2 and R 3 form, together with the carbon atom to which they are attached, cyclopentyl or cyclohexyl, wherein the cyclopentyl or cyclohexyl is substituted with 2 substituents R 10 .

5 . The compound according to claim 1 , wherein R 4 is H.

6 . The compound according to claim 1 , wherein
R 9 is, independently at each occurrence, cyano, halogen, methoxy, phenyloxy, nitro, halomethyl, halomethoxy, or di ethylamino, wherein the phenyl as part of another group is unsubstituted; or R 9 and R 9 attached to adjacent carbon ring atoms form, together with the carbon ring atoms to which they are attached, a 5-membered non-aromatic heterocyclic ring containing 1 ring heteroatom being O, wherein the heterocyclic ring is unsubstituted.

7 . The compound according to claim 6 , wherein R 9 is, independently at each occurrence, halogen, methoxy, or halomethoxy.

8 . The compound according to claim 1 , wherein
R 7 is H, halogen, (C 1 -C 3 )alkoxy, or halo(C 1 -C 3 )alkyl; or R 6 and R 7 form, together with the carbon ring atoms to which they are attached, a 5- or 6-membered non-aromatic heterocyclic ring containing 2 ring heteroatoms being O, wherein the heterocyclic ring is unsubstituted.

9 . The compound according to claim 8 , wherein R 7 is halogen or halo(C 1 -C 3 )alkyl.

10 . The compound according to claim 1 , wherein
R 1 is (C 1 -C 5 )alkyl, (C 2 -C 5 )alkenyl, (C 2 -C 5 )alkynyl, oxetan-3-yl, carboxy(C 2 -C 5 )alkyl, cyano(C 2 -C 5 )alkyl, hydroxy(C 1 -C 9 )alkyl, (C 1 -C 3 )alkoxy(C 1 -C 5 )alkyl, heterocyclyl(C 1 -C 5 )alkyl, (C 1 -C 5 )alkylcarbonyl(C 1 -C 5 )al

Assignees

• Orion Corp

Inventors

• Prusis Peteris
• Höglund Iisa
• Törmakangas Olli
• Hietanen Ari
• Arvela Riina
• Vesalainen Anniina
• Heikkinen Terhi

Classifications

• A61P43/00

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

• A61P25/18

  Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia · CPC title

• A61P25/22

  Anxiolytics · CPC title

• A61P25/24

  Antidepressants · CPC title

• A61P25/20

  Hypnotics; Sedatives · CPC title