A2-adrenoceptor subtype c antagonists for the treatment of sleep apnea

Patent metadata

Field	Value
Publication number	US-2025074899-A1
Application number	US-202318726361-A
Country	US
Kind code	A1
Filing date	Jan 5, 2023
Priority date	Jan 7, 2022
Publication date	Mar 6, 2025
Grant date	—

Abstract

The present invention relates to α2-Adrenoceptor subtype C (alpha-2C) antagonists, in particular 3-substituted 1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)azacycles 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 . Compounds of formula (I)

wherein
X is C(R 5 )(R 6 ) or C(R 7 )(R 8 );
Z is —[C(R 4 ) 2 ]n- or a single bond;
R 1 is, independently at each occurrence, hydroxy, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halogen, halo(C 1 -C 6 )alkyl, phenyl(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxy-(C═O)—, CN, NO 2 , NH 2 , mono- or di(C 1 -C 6 )alkylamino or carboxy;
R 2 is, independently at each occurrence, H or (C 1 -C 6 )alkyl;
R 3 is, independently at each occurrence, H or (C 1 -C 6 )alkyl;
R 4 is, independently at each occurrence, H, hydroxy, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, hydroxy(C 1 -C 6 )alkyl, hydroxy(C 2 -C 6 )alkenyl, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyloxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-(C═O)—, (C 1 -C 6 )alkoxy-(C═O)—, hydroxy(C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl or (C 1 -C 6 )alkoxy(C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl;
or
R 4 and R 4 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 5 is H or hydroxy;
or
R 4 and R 5 attached to adjacent carbon ring atoms form a bond between the carbon ring atoms to which they are attached;
R 6 is phenyl unsubstituted or substituted with 1 or 2 substituent(s) R 9 ;
R 7 is (C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl or (C 1 -C 6 )alkoxy-(C═O)—;
R 8 is hydroxy, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 1 -C 6 )alkoxy, halogen, hydroxy(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 2 -C 6 )alkenyl, hydroxy(C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkoxy, phenyl(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyloxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-(C═O)—, (C 1 ,—C 6 )alkoxy-(C═O)—, (C 1 -C 6 )alkoxy-(C═O)—(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-S—, (C 1 -C 6 )alkyl-(C═O)—O—, (C 1 -C 6 )alkyl-(C═O)—O—(C 1 -C 6 )alkyl, hydroxy-(C═O)—(C 1 -C 6 )alkoxy, hydroxy-(C═O)—(C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy-(C═O)—(C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-S—(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl-S—(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl-S—(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-(C═O)—S—(C 1 -C 6 )alkyl (C 1 -C 6 )alkoxy-(C═O)—(C 1 -C 6 )alkyl-S—(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-S—(C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl-S—(C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl-S—(C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-(O═S═O)—(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl-(O═S═O)—(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl-(O═S═O)—(C 1 -C 6 )alky, (C 1 -C 6 )alkyl-(O═S═O)—(C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl-(O═S═O)—(C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl-(O═S═O)—(C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-O—(O═S═O)—(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl-O—(O═S═O)—(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-(O═S═O)—O—(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl-(O═S═O)—O—(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-(O═S═O)—N(R 10 )—(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, CN, NO 2 , (R 10 ) 2 N—, (R 10 ) 2 N—(C 1 -C 6 )alkyl, (R 10 ) 2 N—(C═O)—, (R 10 ) 2 N—(C═O)—(C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, (R 10 ) 2 N—(C═O)—(C 1 -C 6 )alkyl-S—(C 1 -C 6 )alkyl, (R 10 ) 2 N—(C═O)—(C 1 -C 6 )alkyl-(O═S═O)—(C 1 -C 6 )alkyl, carboxy, R 11 —(O═S═O)—, R 11 —(O═S═O)—O— or (C 1 -C 6 )alkoxy-(C 1 -C 6 )alkoxy;
or
R 4 and R 8 attached to adjacent carbon ring atoms form, together with the carbon ring atoms to which they are attached, a condensed phenyl ring, wherein said phenyl ring is unsubstituted or substituted with 1 or 2 substituent(s) each independently being hydroxy, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, hydroxy(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-(C═O)— or (C 1 -C 6 )alkoxy-(C═O)—;
or
R 4 and R 8 attached to adjacent carbon ring atoms form, together with the carbon ring atoms to which they are attached, a condensed 5 or 6 membered saturated or unsaturated carbocyclic ring or a condensed 5 or 6 membered saturated or unsaturated heterocyclic ring containing 1 or 2 heteroatom(s) selected from N, O, and S,
wherein said
carbocyclic or heterocyclic ring is unsubstituted or substituted with 1 or 2 substituent(s) each independently being hydroxy, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, hydroxy(C 1 -C 6 )alkyl, halo(C-C 6 )alkyl, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-(C═O)—, (C 1 -C 6 )alkoxy-(C═O)— or oxo;

or
R 7 and R 8 form, together with the carbon ring atom to which they are attached, a 5 or 6 membered saturated carbocyclic ring or a 5 or 6 membered saturated heterocyclic ring containing 1 or 2 heteroatom(s) selected from N, O, and S, wherein said carbocyclic or heterocyclic ring is unsubstituted or substituted with 1 or 2 substituent(s) each independently being hydroxy, (C 1 -C 6 )alkyl or oxo;
R 9 is, independently at each occurrence, hydroxy, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 1 -C 6 )alkoxy, halogen, hydroxy(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 2 -C 6 )alkenyl, hydroxy(C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkoxy, phenyl(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyloxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-(C═O)—, (C 1 -C 6 )alkoxy-(C═O)—, (C 1 -C 6 )alkoxy-(C═O)—(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-S—, (C 1 -C 6 )alkyl-(C═O)—O—, (C 1 -C 6 )alkyl-(C═O)—O—(C 1 -C 6 )alkyl, hydroxy-(C═O)—(C 1 -C 6 )alkoxy, hydroxy-(C═O)—(C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy-(C═O)—(C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-S—(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl-S—(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl-S—(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-(C═O)—S—(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy-(C═O)—(C 1 -C 6 )alkyl-S—(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-S—(C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl-S—(C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl-S—(C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-(O═S═O)—(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl-(O═S═O)—(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl-(O═S═O)—(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-(O═S═O)—(C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl-(O═S═O)—(C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl-(O═S═O)—(C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-O—(O═S═O)—(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl-O—(O═S═O)—(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-(O═S═O)—O—(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl-(O═S═O)—O—(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-(O═S═O)—N(R 10 )—(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, CN, NO 2 , (R 10 ) 2 N—, (R 10 ) 2 N—(C 1 -C 6 )alkyl, (R 10 ) 2 N—(C═O)—, (R 10 ) 2 N—(C═O)—(C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, (R 10 ) 2 N—(C═O)—(C 1 -C 6 )alkyl-S—(C 1 -C 6 )alkyl, (R 10 ) 2 N—(C═O)—(C 1 -C 6 )alkyl-(O═S═O)—(C 1 -C 6 )alkyl, carboxy, R 11 —(O═S═O)— or R 11 —(O═S═O)—O—;
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 condensed phenyl ring, a condensed 5 or 6 membered unsaturated carbocyclic ring or a condensed 5 or 6 membered unsaturated heterocyclic ring containing 1 or 2 heteroatom(s) selected from O and S, wherein said phenyl, carbocyclic or heterocyclic ring is unsubstituted or substituted with 1 or 2 substituent(s) each independently being hydroxy, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, hydroxy(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-(C═O)

Assignees

• Bayer Ag

Inventors

• Delbeck Martina
• Hahn Michael

Classifications

• A61K45/06

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

• A61K31/453 Primary

  containing a six-membered ring with oxygen as a ring hetero atom · CPC title

• A61K31/4433

  containing a six-membered ring with oxygen as a ring hetero atom · CPC title

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title

• A61K2300/00

  Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00 · CPC title