NK1 antagonists
View Patent ↗A NK 1 antagonist having the formula (I), wherein Ar 1 and Ar 2 are optionally substituted phenyl or heteroaryl, X 1 is an ether, thio or imino linkage, R 4 and R 5 are not both H or alkyl, and the remaining variables are as defined in the specification, useful for treating a number of disorders, including emesis, depression, anxiety and cough. Pharmaceutical compositions. Methods of treatment and combinations with other agents are also disclosed.
1. A method for treating a physiological disorder, symptom or disease in a patient, comprising administering to the patient an effective amount of at least one compound of Formula I:
or a pharmaceutically-acceptable salt thereof, wherein
Ar 1 is phenyl;
X 2 is —O—;
R 1 and R 2 are each independently selected from the group consisting of H, C 1 -C 6 alkyl, hydroxy(C 1 -C 3 alkyl), C 3 -C 8 cycloalkyl, —CH 2 F, —CHF 2 and —CF 3 ; or R 1 and R 2 , together with the carbon atom to which they are both attached, form a C 3 to C 6 alkylene ring; or R 1 and R 2 , together with the carbon atom to which they are both attached, form a C═O group;
R 3 is selected from the group consisting of H, C 1 -C 6 alkyl, hydroxy(C 1 -C 3 alkyl), C 3 -C 8 cycloalkyl, —CH 2 F, —CHF 2 and —CF 3 ;
each R 6 is independently selected from the group consisting of H, C 1 -C 6 alkyl and —OH;
each R 7 is independently selected from the group consisting of H and C 1 -C 6 alkyl;
n 2 is 2;
R 4 and R 5 , together with the carbon atom to which they are both attached, form a 5- or 6-membered heterocycloalkyl ring selected from the group consisting of:
wherein said 5- or 6-membered heterocycloalkyl ring is optionally substituted with from 1 to 6 substitutents independently selected from the group consisting of R 30 and R 31 ;
R 18 is H, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, hydroxy(C 2 -C 6 )alkyl or —P(O)(OH) 2 ;
R 30 and R 31 are each independently selected from the group consisting of H and C 1 -C 2 alkyl, or
R 30 and R 31 , together with the carbon atom to which they are both attached, form ═O;
R 32 and R 33 are each independently selected from the group consisting of H and C 1 -C 6 alkyl;
or a,
where the physiological disorder, symptom or disease is asthma, emesis, nausea, depression, anxiety, cough or migraine.
2. The method according to claim 1 , wherein the compound is selected from:
or a pharmaceutically acceptable salt thereof.
3. The method according to claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
4. The method according to claim 1 , wherein the physiological disorder, symptom or disease is emesis and nausea.
5. The method according to claim 1 , wherein the physiological disorder, symptom or disease is cough.
6. The method according to claim 1 , wherein R 1 and R 2 are each independently selected from the group consisting of H and C 1 -C 6 alkyl.
7. The method according to claim 6 , wherein R 1 and R 2 are each independently selected from the group consisting of H and CH 3 .
8. The method according to claim 1 , wherein R 3 is H or C 1 -C 6 alkyl.
9. The method according to claim 8 , wherein R 3 is H.
10. The method according to claim 1 , wherein each R 6 is independently H or C 1 -C 6 alkyl.
11. The method according to claim 10 , wherein each R 6 is H.
12. The method according to claim 1 , wherein each R 7 is H.
13. The method according to claim 1 , wherein R 18 is H or C 1 -C 6 alkyl.
14. The method according to claim 13 , wherein R 18 is H.
15. The method according to claim 1 , wherein R 32 and R 33 are each H.