Bradykinin B2 receptor antagonists
The invention relates to a compound according to general formula (I), which acts as a bradykinin (BK) B2 receptor antagonist; to a pharmaceutical composition containing one or more of the compound(s) of the invention; to a combination preparation containing at least one compound of the invention and at least one further active pharmaceutical ingredient; and to uses of said compound(s), including the use as a medicament.
1. A compound of the general formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
A represents a group:
A 1 is N or CH;
A 2 is N or C—R A2 ;
A 3 is N or C—R A3 ;
A 4 is NH, O, or S;
A 5 is N—R A5 ;
R A1 represents a hydrogen atom or a methyl group;
R A2 and R A3 each, independently of one another, represents a hydrogen atom, halogen atom, OH, CN, NH 2 ; (C 1 -C 3 )alkyl, which may be substituted by one or more, identical or different, group(s) selected from a halogen atom, OH, ═O, and NH 2 ; (C 1 -C 3 )alkoxy, which may be substituted by one or more, identical or different, groups selected from a halogen atom, OH, ═O, and NH 2 ; (C 2 -C 5 )alkoxyalkyl, which may be substituted by one or more, identical or different, groups selected from a halogen atom, OH, ═O, and NH 2 ; C(O)NR B1 R B2 ; or NR B1 R B2 ;
R B1 , R B2 and RAS each, independently of one another, represents a hydrogen atom or a (C 1 -C 3 )alkyl group, which may be substituted by one or more, identical or different, groups selected from a halogen atom, OH, ═O, and NH 2 ;
R 1 represents a (C 1 -C 3 )alkyl or (C 2 -C 5 )alkoxyalkyl group, which alkyl group or alkoxyalkyl group may be substituted by one or more, identical or different, groups selected from a deuterium atom, halogen atom, OH, ═O, and NH 2 ;
R 2 represents a hydrogen atom or a deuterium atom;
R 3 represents a hydrogen atom, (C 1 -C 3 )alkyl, or (C 1 -C 3 )haloalkyl group;
E represents CR E1 R E2 R E3 or Hce;
Hce represents a mono- or bicyclic, partially unsaturated or aromatic heterocycle having 3 to 10 C atoms and 1 to 4 heteroatoms each, independently of one another, selected from N, O or S, which heterocycle is unsubstituted or may be mono-, di- or trisubstituted, at each occasion independently, by halogen, OH, G, NR C1 R C2 or ═O;
R C1 and R C2 each, independently of one another, represents a hydrogen atom or a (C 1 -C 3 )alkyl group;
G represents a (C 1 -C 6 )alkyl group, in which: 1 to 7 H atoms may, at each occasion independently, be replaced by a halogen atom, OR G1 , CN, NR G2 R G3 or (C 3 -C 6 )cycloalkyl; or in which one CH 2 group, or two non-adjacent CH 2 groups, may be replaced by O, C(O), OC(O), C(O)O, C(O)NH, NH, S, SO, SO 2 or a CH═CH group; or both;
R G1 , R G2 , and R G3 each, independently of one another, represents a hydrogen atom, (C 1 -C 4 )alkyl, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) hydroxyalkyl, (C 1 -C 4 ) heteroalkyl, or (C 3 -C 6 ) cycloalkyl group;
R E1 and R E2 each, independently of one another, represents a hydrogen atom, halogen atom, or G; or R E1 and R E2 taken together form ═O or Cyc;
R E3 represents a hydrogen atom, halogen atom, G, OG or OH; and
Cyc represents a mono- or bicyclic, saturated or partially unsaturated 3- to 10-membered cycloalkyl group or 4- to 10-membered heterocycloalkyl group having 1 to 3 heteroatoms each, independently of one another, selected from N, O or S, which cycloalkyl or heterocycloalkyl group is unsubstituted or may be mono-, di-, tri-, or tetrasubstituted, at each occasion independently, by a halogen atom, OH, G, NR C1 R C2 or ═O.
2. The compound, or pharmaceutically acceptable salt thereof, according to claim 1 , wherein:
R 1 represents a (C 1 -C 2 )alkyl or (C 2 -C 4 )alkoxyalkyl group, which alkyl group or alkoxyalkyl group may be substituted by one or more, identical or different, groups selected from a deuterium atom, halogen atom, and OH.
3. The compound, or pharmaceutically acceptable salt thereof, according to claim 2 , wherein:
R 3 represents a hydrogen atom or a methyl group.
4. The compound, or pharmaceutically acceptable salt thereof, according to claim 1 , wherein:
E is CR E1 R E2 R E3 ; and R E1 represents a hydrogen atom, fluorine atom, methyl or ethyl.
5. The compound, or pharmaceutically acceptable salt thereof, according to claim 4 , wherein:
R E2 represents a hydrogen atom, fluorine atom, (C 1 -C 3 )alkyl group in which 1 to 4 H atoms may, at each occasion independently, be replaced by a fluorine atom, OH, ═O, or NR C1 R C2 ; (C 1 -C 3 )alkoxy group in which 1 to 4 H atoms may, at each occasion independently, be replaced by a fluorine atom, OH, ═O, NR C1 R C2 or cyclopropyl; or a (C 2 -C 5 )alkoxyalkyl group in which 1 to 5 H atoms may, at each occasion independently, be replaced by a fluorine atom, OH, ═O, NR C1 R C2 or cyclopropyl.
6. The compound, or pharmaceutically acceptable salt thereof, according to claim 5 , wherein:
R E3 represents a hydrogen atom, fluorine atom, OH, (C 1 -C 3 )alkyl group in which 1 to 5 H atoms may, at each occasion independently, be replaced by a fluorine atom, OH, ═O, or NR C1 R C2 ; (C 1 -C 6 )alkoxy group in which 1 to 5 H atoms may, at each occasion independently, be replaced by a fluorine atom, OH, ═O, NR C1 R C2 or cyclopropyl; or a (C 2 -C 5 )alkoxyalkyl group, in which 1 to 5 H atoms may, at each occasion independently, be replaced by a fluorine atom, OH, ═O, NR C1 R C2 or cyclopropyl.
7. The compound, or pharmaceutically acceptable salt thereof, according to claim 1 , wherein:
E is CR E1 R E2 R E3 ; and R E1 and R E2 are taken together to form ═O or Cyc, wherein Cyc is selected from cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, 1,3-dioxolanyl, morpholinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, (imidazolidin-2-on)yl and (oxazolidin-2-on)yl, and is unsubstituted or may be mono-, di- or trisubstituted, at each occasion independently, by a halogen atom, OH, G, NR C1 R C2 or ═O.
8. The compound, or pharmaceutically acceptable salt thereof, according to claim 7 , wherein:
R E3 represents a hydrogen atom, fluorine atom, OH or a (C 1 -C 3 )alkyl group.
9. The compound, or pharmaceutically acceptable salt thereof, according to claim 1 , wherein:
E is Hce, and Hce represents a monocyclic, partially unsaturated or aromatic heterocycle having 3 to 5 C atoms and 1 to 3 N atom(s); 3 to 5 C atoms, 1-2 N atom(s) and 1 O atom; or 3 to 5 C atoms, 1-2 N atom(s) and 1 S atom; which heterocycle is unsubstituted or is mono-, di- or trisubstituted, at each occasion independently, by a halogen atom, OH, (C 1 -C 3 )alkyl, (C 1 -C 3 )haloalkyl, (C 1 -C 3 )alkoxy, (C 1 -C 3 )haloalkoxy or ═O.
10. The compound, or pharmaceutically acceptable salt thereof, according to claim 3 , wherein E represents a group:
11. The compound, or pharmaceutically acceptable salt thereof, according to claim 1 , wherein:
A represents:
A 1 is N or CH;
A 2 is N;
A 5 is N—R A5 ;
R A5 represents a hydrogen atom or a (C 1 -C 3 )alkyl group, which may be substituted by one or more, identical or different, groups selected from a halogen atom, OH, ═O, and NH 2 ;
R 1 represents a (C 1 -C 3 )alkyl;
R 2 represents a hydrogen atom or a deuterium atom;
R 3 represents a hydrogen atom or (C 1 -C 3 )alkyl;
E represents a group:
12. The compound, or pharmaceutically acceptable salt thereof, according to claim 11 , wherein: A represents:
13. The compound, or pharmaceutically acceptable salt thereof, according to claim 1 , wherein:
A represents:
A 1 is N;
A 2 is N or C—R A2 ;
A 3 is C—R A3 ;
R 1 represents a (C 1 -C 3 )alkyl;
R 2 represents a hydrogen atom or a deuterium atom;
R 3 represents a hydrogen atom or (C 1 -C 3 )alkyl;
E represents a group:
14. The compound, or pharmaceutically acceptable salt thereof, according to claim 13 , wherein:
A represents:
15. The compound, or pharmaceutically acceptable salt thereof, according to claim 1 , wherein
A represents a group:
A 2 is N or C—R A2 ;
A 3 is N or C—R A3 ;
A 4 is NH, O, or S;
R 1 represents a (C 1 -C 3 )alkyl;
R 2 represents a hydrogen atom or a deuterium atom;
R 3 represents a hydrogen atom or (C 1 -C 3 )alkyl;
E represents a group:
16. The compound, or pharmaceutically acceptable salt thereof, according to claim 1 , wherein the compound is:
17. A pharmaceutical composition comprising a compound, or pharmaceutically acceptable salt thereof, according to claim 1 , and at least one carrier substance, excipient and/or adjuvant.
18. The pharmaceutical composition according to claim 17 , wherein the pharmaceutical composition is formulated as an aerosol, a cream, a gel, a pill, a capsule, a syrup, a solution, a transdermal patch or a pharmaceutical delivery device.
19. A method of treating angioedema in a subject comprising administering to the subject with angioedema a compound, or pharmaceutically acceptable salt thereof, according to claim 1 .
20. The method of claim 19 , wherein the angioedema is hereditary angioedema or drug induced angioedema.