Long acting betamimetics for the treatment of respiratory diseases
View Patent ↗The present invention relates to the compounds of general formula 1 wherein the groups R, R1, R2, R3 and A may have the meanings given in the claims and specification, processes for preparing them and their use as medicaments, particularly for the treatment of inflammatory and obstructive respiratory complaints.
1. A compound of formula 1
wherein
n denotes 1 or 2;
A denotes oxygen or a single bond;
R denotes —C 1 -C 6 -alkyl, which is mono- or polysubstituted by one or more halogen atoms;
R 1 , R 2 and R 3 which may be identical or different denote hydrogen, C 1 -C 6 -alkyl, halogen-C 1 -C 6 -alkylene, OH, HO—C 1-6 -alkylene, —O—C 1 -C 6 -alkyl, C 6 -C 10 -aryl, C 6 -C 10 -aryl-C 1 -C 4 -alkylene, C 6 -C 10 -aryl-C 1 -C 6 -alkylene-O, —COOH, —COOC 1 -C 6 -alkyl, —O—C 1 -C 6 -alkylene-COOH, —O—C 1 -C 6 -alkylene-COOC 1 -C 6 -alkyl, —NHSO 3 H, —NHSO 2 —C 1 -C 6 -alkyl, CN, NH 2 , —NH—C 1 -C 6 -alkyl, —N(C 1 -C 6 -alkyl) 2 , NO 2 , —S—C 1 -C 6 -alkyl, —SO 2 —C 1 -C 6 -alkyl, —SO—C 1 -C 6 -alkyl, —O(CO)C 1 -C 6 -alkyl, —COC 1 -C 6 -alkyl, —NHCOC 1 -C 6 -alkyl or halogen;
or an acid addition salt thereof with a pharmacologically acceptable acid.
2. The compound of formula 1 according to claim 1 , wherein
n denotes 1 or 2;
A denotes oxygen or a single bond;
R denotes C 1 -C 4 -alkyl, which is mono- to trisubstituted, by one or more halogen atoms;
R 1 , R 2 and R 3 which may be identical or different denote hydrogen, C 1 -C 4 -alkyl, halogen-C 1 -C 4 -alkylene, OH, HO—C 1 -C 4 -alkylene, —O—C 1 -C 4 -alkyl, phenyl, phenyl-C 1 -C 4 -alkylene, phenyl-C 1 -C 4 -alkylene-O, —COOH, —COOC 1 -C 4 -alkyl, —O—C 1 -C 4 -alkylene-COOH, —O—C 1 -C 4 -alkylene-COOC 1 -C 4 -alkyl, —NHSO 2 —C 1 -C 4 -alkyl, CN, NH 2 , —NH—C 1 -C 4 -alkyl, —N(C 1 -C 4 -alkyl) 2 , NO 2 , —S—C 1 -C 4 -alkyl, —SO 2 —C 1 -C 4 -alkyl, —SO—C 1 -C 4 -alkyl, —O(CO)C 1 -C 4 -alkyl, —COC 1 -C 4 -alkyl, —NHCOC 1 -C 4 -alkyl or halogen.
3. The compound of formula 1 according to claim 1 , wherein
n denotes 1 or 2,
A denotes oxygen or a single bond;
R denotes a methyl or ethyl group which is mono-, di- or trisubstituted by one or more halogen atoms selected from fluorine or chlorine;
R 1 and R 2 which may be identical or different denote hydrogen, halogen, C 1 -C 4 -alkyl or —O—C 1 -C 4 -alkyl; and
R 3 denotes hydrogen, C 1 -C 4 -alkyl, OH, halogen, —O—C 1 -C 4 -alkyl, halogen-C 1 -C 4 -alkylene, —O—C 1 -C 4 -alkylene-COOH, or —O—C 1 -C 4 -alkylene-CO—O—C 1 -C 4 -alkyl.
4. The compound of formula 1 according to claim 1 , wherein
n denotes 1;
A denotes oxygen or a single bond;
R denotes —CH 2 -CH 2 Cl, —CH 2 CCl 3 , —CHCl—CCl 3 , —CCL 3 , —CH 2 Cl, —CHCl 2 , —CH 2 CF 3 , —CHF—CF 3 , —CF 3 , —CH 2 F, —CH 2 -CH 2 F or —CHF 2 ;
R 1 and R 2 which may be identical or different denote hydrogen, fluorine, chlorine, methyl or methoxy; and
R 3 denotes hydrogen, C 1 -C 4 -alkyl, OH, fluorine, chlorine, bromine, —O—C 1 -C 4 -alkyl, —CF 3 , —O—C 1 -C 4 -alkylene-COOH or —O—C 1 -C 4 -alkylene-CO—O—C 1 -C 4 -alkyl.
5. The compound of formula 1 according to claim 1 , wherein
n denotes 1;
A denotes oxygen or a single bond;
R denotes —CH 2 CF 3 , —CHF—CF 3 , —CF 3 , —CH 2 F, —CH 2 —CH 2 F or —CHF 2 ;
R 1 and R 2 which may be identical or different denote hydrogen, fluorine, chlorine, methyl or ethyl; and
R 3 denotes hydrogen, fluorine, chlorine, methyl, ethyl, OH, methoxy, ethoxy, —CF 3 , —O—CH 2 —COOH, —O—CH 2 —COOmethyl or —O—CH 2 —COOethyl.
6. The compound of formula 1 according to claim 1 , wherein the compound of formula 1 is in the form of an individual optical isomer, mixtures of the individual enantiomers or racemates thereof.
7. The compound of formula 1 according to claim 1 , wherein the compound of formula 1 is in the form of an acid addition salt thereof with a pharmacologically acceptable acid.
8. A pharmaceutical composition comprising the compound of formula 1 according to claim 1 or a pharmaceutically acceptable acid addition salt therof and a pharmaceutically acceptable excipient.
9. The pharmaceutical composition according to claim 8 , which is in a form suitable for inhalation.
10. The pharmaceutical composition according to claim 9 , wherein the form suitable for inhalation is selected from the group consisting of inhalable powders, propellant-driven metering aerosols and propellant-free inhalable solutions.
11. The compound of formula 1 according to claim 1 , wherein:
R 1 and R 2 denote hydrogen.
12. The compound of formula 1 according to claim 1 , wherein:
A denotes a single bond.
13. The compound of formula 1 according to claim 1 , wherein:
R 3 denotes hydrogen, fluorine, chlorine, methyl, ethyl, OH, ruethoxy or ethoxy.
14. The compound of formula 1 according to claim 1 , wherein:
R denotes —CF 3 , —CH 2 F or —CHF 2 .
15. The compound of formula 1 according to claim 1 , wherein the compound is:
8-{2-[2-(4-fluoro-3-trifluoromethyl-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo [1,4]oxazin-3-one;
8-{2-[1,1-dimethyl-2-(4-trifluoromethyl-phenyl)-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;
8-{2-[1,1-dimethyl-2-(3-trifluomethyl-phenyl)-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;
8-{2-[1,1-dimethyl-2-(4-trifluoromethoxy-phenyl)-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;
8-{2-[2-(4-chloro-3-trifluoroethyl-phenyl)-1,1-dimethyl-ethylamine]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;
8-{2-[1,1-dimethyl-2-(2-trifluoromethyl-phenyl)-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one; or
8-{2-[2-(3,5-bis-trifluoromethyl-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one.
16. The compound of formula 1 according to claim 1 , wherein the compound is in the form of an enantiomerically pure R-enantiomer of the compound.