Arylquinoziline derivatives as alpha2-adrenoceptor subtype c (alpha-2c) antagonists for the treatment of sleep apnea

Patent metadata

Field	Value
Publication number	US-2022218677-A1
Application number	US-202017595116-A
Country	US
Kind code	A1
Filing date	May 4, 2020
Priority date	May 9, 2019
Publication date	Jul 14, 2022
Grant date	—

Abstract

The present invention relates to α2-Adrenoceptor subtype C (alpha-2C) antagonists, in particular arylquinolizine derivatives of formula (I) for the use in a method for the treatment and/or prophylaxis of sleep-related breathing disorders, preferably obstructive and central sleep apneas and snoring.

First claim

1 . A method for treatment or prophylaxis of a sleep-related breathing disorder, comprising administering a compound of formula (I)

wherein
X is CR 2 R 2 ′, O, S or NR 2 ;
Z is —CHR 8 —(CH 2 )n- or a single bond;
R 1 is hydroxy, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halogen, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy-(C═O)—, CO—, CN, NO 2 , NH 2 , mono- or di(C 1 -C 6 )alkylamino or carboxyl;
R 2 and R 2 ′ are independently H, hydroxy or (C 1 -C 6 )alkyl or R 2 and R 2 ′ form, together with the carbon ring atoms to which they are attached, a carbonyl group;
R 3 is H, hydroxy, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, (C 3 -C 7 )cycloalkyl(C 1 -C 6 )alkyl, aryl, aryl(C 1 -C 6 )alkyl, aryloxy, aryl(C 1 -C 6 )alkoxy, aryloxy(C 1 -C 6 )alkyl, aryl(C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, NH 2 , amino(C 1 -C 6 )alkyl, mono- or di(C 1 -C 6 )alkylamino, mono- or di(C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-CO—, (C 1 -C 6 )alkyl-CO—O—, (C 1 -C 6 )alkyl-CO—O—(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy-CO—, (C 1 -C 6 )alkoxy-CO—(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy-CO—(C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, carbamoyl, mono- or di(C 1 -C 6 )alkylcarbamoyl, carboxyl or (C 1 -C 6 )alkyl-S-(C 1 -C 6 )alkyl, wherein the said (C 3 -C 7 )cycloalkyl or aryl is unsubstituted or substituted with 1 or 2 substituents each independently being hydroxy, (C 1 -C 6 )alkyl, halogen, (C 1 -C 6 )alkoxy, NH 2 , CN or NO 2 , or one of R 3 or R 4 and R 6 together form a bond between the ring atoms to which they are attached;
R 4 is H, hydroxy, (C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy or (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl;
R 5 is H, hydroxy, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, (C 3 -C 7 )cycloalkyl(C 1 -C 6 )alkyl, aryl, aryl(C 1 -C 6 )alkyl, aryloxy, aryl(C 1 -C 6 )alkoxy, aryloxy(C 1 -C 6 )alkyl, aryl(C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-CO—, (C 1 -C 6 )alkyl-CO—O—, (C 1 -C 6 )alkyl-CO—O—-(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy-CO—, (C 1 -C 6 )alkoxy-CO—(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy-CO—(C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, carbamoyl, mono- or di(C 1 -C 6 )alkylcarbamoyl, carboxyl or (C 1 -C 6 )alkyl-S-(C 1 -C 6 )alkyl, wherein the said (C 3 -C 7 )cycloalkyl or aryl is unsubstituted or substituted with 1 or 2 substituents each independently being hydroxy, (C 1 -C 6 )alkyl, halogen, (C 1 -C 6 )alkoxy, NH 2 , CN or NO 2 , or R 4 and R 5 form, together with the carbon ring atoms to which they are attached, a condensed five to seven membered saturated carbocyclic ring unsubstituted or substituted with 1 to 3 substituent(s) R 9 each independently being hydroxy, (C 1 -C 6 )alkyl, halogen, NH 2 , NO 2 , (C 3 -C 7 )cycloalkyl, hydroxy(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, amino(C 1 -C 6 )alkyl, mono- or di(C 1 -C 6 )alkylamino, mono- or di(C 1 C 6 )alkylamino (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, carboxyl, (C 1 -C 6 )alkyl-CO—, (C 1 -C 6 )alkyl-CO—O—, (C 1 -C 6 )alkoxy-CO—, (C 1 -C 6 )alkoxy-CO—(C 1 -C 6 )alkyl, carbamoyl mono- or di(C 1 -C 6 )alkylcarbamoyl or oxo;
R 6 is H, hydroxy, (C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy or (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl or R 6 forms a bond between the ring atom to which it is attached and the ring atom to which R 7 is attached;
R 7 is H, hydroxy, (C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy or (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl;
R 8 is H, hydroxy, (C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy or (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl or, only when n is 0, R 7 and R 8 form, together with the carbon ring atoms to which they are attached, a condensed five to seven membered saturated carbocyclic ring unsubstituted or substituted with 1 to 3 substituent(s) R 10 each independently being hydroxy, (C 1 -C 6 )alkyl, halogen, NH 2 , NO 2 , (C 3 -C 7 )cycloalkyl, hydroxy(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, amino(C 1 -C 6 )alkyl, mono- or di(C 1 -C 6 )alkylamino, mono- or di(C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, carboxyl, (C 1 -C 6 )alkyl-CO—, (C 1 -C 6 )alkyl-CO—O—, (C 1 -C 6 )alkoxy-CO—, (C 1 -C 6 )alkoxy-CO—(C 1 -C 6 )alkyl, carbamoyl, mono- or di(C 1 -C 6 )alkylcarbamoyl or oxo;
R 15 is H, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, amino(C 1 -C 6 )alkyl, mono- or di(C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-CO—, (C 1 -C 6 )alkyl-CO—O—(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy-CO—, (C 1 -C 6 )alkoxy-CO—(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy-CO—(C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, carbamoyl, mono- or di(C 1 -C 6 )alkylcarbamoyl or carboxyl;
R 16 is H or (C 1 -C 6 )alkyl;
R 7 and R 8 are attached to the carbon ring atoms, which are adjacent;
m is 0 to 2; and
n is 0 or 1,
or a pharmaceutically acceptable salt or ester thereof.

2 . The method according to claim 1 , wherein the compound of formula (I) is 1α-ethyl-1,2,3,4,6,7,12,12bβ-octahydro-indolo[2,3-a] quinolizin-l-ol, (1β-ethyl-1,2,3,4,6,7,12,12bα-octahydro-indolo[2,3 -a]quinolizin-1-y1)-methanol, 1α-Methyl-1,2,3,4,6,7,12,12bβ-octahydroindolo[2,3 -a] quinolizin-l-ol, (1α-Methyl-1,2,3,4,6,7, 12,12bβ-octahydroindolo[2,3 -a] quinolizin-1-yl)-methanol, 1,2,3,4,4aβ,5,6,7,8, 13,13bβ, 13cα-dodecahydro-6a,13-diaza-indeno-[1,2-c]phenanthrene, 1,2,3,4,4aβ,5,6,7,8,13,13bβ,13cβ-dodecahydro-6a,13-diaza-indeno[1,2-c]phenanthrene or 3,4,443,5,6,7,8,13,130,13ca-decahydro-2H-6a,13-diaza-indeno[1,2-c]phenanthren-1-one.

3 . The method according to claim 1 , wherein the compound of formula (I) is 1α-Methyl-1,3,4,5,6,11b-hexahydro-2H-11-oxa-4a-aza-benzo[a]fluoren-1-ol, (1α-Methyl-1,3,4,5,6,11bβ-hexahydro-2H-11-oxa-4a-aza-benzo[a]fluoren-1-yl)-methanol, (−)-(1α-Methyl-1,3,4,5,6,11bβ-hexahydro-2H-11-oxa-4a-aza-benzo[a]fluoren-1-yl)-methanol, (+)-(1α-Methyl-1,3,4,5,6,11-bβhexahydro-2H-11-oxa-4a-aza-benzo[a]fluoren-1-yl)-methanol, 1α-Isopropyl-1,3,4,5,6,11b-Hexahydro-2H-11-oxa-4a-aza-benzo[a]fluoren-1-ol, 1α-Ethyl-1,3,4,5,6,11bβ-hexahydro-2H-11-oxa-4a-aza-benzo[a]fluoren-1-ol, (1α-Ethyl-1,3,4,5,6,11bβ-hexahydro-2H-11-oxa-4a-aza-benzo[a]fluoren-1-yl)-methanol, 5,6,7,7aβ,8,9,10,11,11aβ,11bα-Decahydro-12-oxa-6a-aza-indeno[1,2-a]fluorene, 1-Methyl-1α,3,4,6,11bβ-hexahydro-2H-11-oxa-4a-aza-benzo[a]fluorene, (1-Hydroxymethyl-1,3,4,5,6,11b-hexahydro-2H-11-oxa-4a-aza-benzo[a]fluoren-1-yl]-methanol, 1-Methoxymethyl-1α-methyl-1,3,4,5,6,11bβ-hexahydro-2H-11-oxa-4a-aza-benzo[a]fluorene, (−)-1-Methoxymethyl-1a-methyl-1,3,4,5,6,11bβ-hexahydro-2H-11-oxa-4a-aza-benzo[a]fluorene, (+)-1-Methoxymethyl-1β-methyl-1,3,4,5,6,11bβ-hexahydro-2H-11-oxa-4a-aza-benzo[a]fluorene, 2,3 ,4,4aβ,5,6,7,8,13bβ,13cβ-Decahydro-1H-13-oxa-6a-aza-indeno[1,2-c]phenanthrene, 2,3,4,4aβ,5,6,7,8,13bα, 13cβ-Decahydro-1H-13-oxa-6a-aza-indeno[1,2-c]phenanthrene, 1α-Methyl-1,3,4,5,6,11bα-hexahydro-2H-11-oxa-4a-aza-benzo[a]fluorene-1-carboxylic acid ethyl ester, 1-Ethoxymethyl-1α-methyl-1,3,4,5,6,11bβ-hexahydro-2H-11-oxa-4a-aza-benzo[a]fluorene, (1α-Methyl-1,3,4,5,6,11bα-hexahydro-2H-11-oxa-4a-aza-benzo[a]fluoren-1-yl)-methanol, (−)-(1α-Methyl-1,3,4,5,6,11bα-hexahydro-2H-11-oxa-4a-aza-benzo[a]fluoren-1-yl)-methanol, (+)-(1α-Methyl-1 ,3,4,5,6,11bα-hexahydro-2H-11-oxa-4a-aza-benzo[a]fluoren-1-yl)-methanol, 1α-Ethyl-1,3,4,5,6,11b α-hexahydro-2H-11-oxa-4

Assignees

• Bayer Ag

Inventors

• Delbeck Martina
• Hahn Michael

Classifications

• A61P43/00

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

• A61K45/06 Primary

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61K31/4375 Primary

  the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine · CPC title