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 according to structural formula (I):
or a pharmaceutically-acceptable salt thereof, wherein
Ar 1 is phenyl, wherein said phenyl can be unsubstituted or substituted with 1 to 3 fluoro;
Ar 2 is bis(trifluoromethyl)phenyl;
X 1 is —O—;
R 1 and R 2 are each independently selected from the group consisting of H, C 1 -C 6 alkyl and hydroxyl(C 1 -C 3 alkyl), providing that at least one of R 1 and R 2 is H;
R 3 is H;
R 4 and R 5 are each independently selected from the group consisting of —(CR 28 R 29 ) n1 -G, wherein,
n 1 is an integer between 0 to 5;
G is —H, —NR 13 R 14 , —NR 12 C(O)R 14 , —C(O)NR 13 R 14 , —OC(O)NR 13 R 14 , —NR 12 C(O)OR 13 , —NR 12 (C(O)NR 13 R 14 ), —NR 12 SO 2 R 13 , —OH, —O(C 1-6 alkyl), —C(OR 12 )(R 13 )(R 14 ), —OC(O)R 14 , —C(O)R 13 , R 19 -heteroaryl, R 19 -phenyl, or heterocycloalkenyl,
wherein heteroaryl is selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, furanyl, benzofuranyl, thienyl, benzothienyl, thiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazoyl, tetrazolyl, isothiazolyl, benzothiazolyl, benzoxazolyl, oxazolyl, pyrrolyl, isoxazolyl, 1,3,5-triazinyl, and indolyl; and
wherein hetereocycloalkenyl is optionally substituted with 1 substituent independently selected from R 30 and R 31 ;
provided that R 4 and R 5 are not both selected from the group consisting of H, alkyl and cycloalkyl; and when one of R 4 and R 5 is —OH, then the other one of R 4 and R 5 is not alkyl or R 19 -phenyl;
R 6 and R 7 are each H;
n 2 is 2;
R 12 is H, C 1 -C 6 alkyl or C 3 -C 5 cycloalkyl;
R 13 and R 14 are each independently selected from the group consisting of H, C 1 -C 6 alkyl, —CH 2 CF 3 , C 3 -C 6 cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, furanyl, benzofuranyl, thienyl, benzothienyl, thiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazoyl, tetrazolyl, isothiazolyl, benzothiazolyl, benzoxazolyl, oxazolyl, pyrrolyl, isoxazolyl, 1,3,5-triazinyl and indolyl; or
R 13 and R 14 , together with the nitrogen atom to which they are both attached, form a 5- to 6-membered saturated or unsaturated ring that is optionally substituted with —OR 12 , where one of the carbon atoms in the ring is optionally replaced by a heteroatom selected from —O—;
n 6 is 0, 1 or 2;
R 18 is H;
each R 19 is a substituent on the phenyl or heteroaryl ring to which it is attached, and is independently selected from the group consisting of H and C 1 -C 6 alkyl;
R 23 and R 24 are each independently selected from the group consisting of H and C 1 -C 6 alkyl; or
R 23 and R 24 , together with the carbon atom to which they are both attached, form a C═O or cyclopropyl group;
R 27 is H, —OH or C 1 -C 6 alkyl;
R 28 and R 29 are each independently selected from the group consisting of H and C 1 -C 2 alkyl;
R 30 and R 31 are each independently selected from the group consisting of H, —OH, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl and —C(O)NR 13 R 14 ; or
R 30 and R 31 , together with the carbon atom to which they are both attached, form ═O, ═S, a cyclopropyl ring or ═NR 36 ;
R 32 and R 33 are each independently H or C 1 -C 6 alkyl;
R 34 is H, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl or hydroxy(C 2 -C 6 )alkyl;
R 35 is H, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, —P(O)(OH) 2 , allyl, hydroxy(C 2 -C 6 )alkyl, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, —SO 2 R 15 or —(CH 2 ) 2 —N(R 12 )—SO 2 —R 15 ;
R 36 is H, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, —NO 2 , —CN or OR 12 ;
R 37 is 1 to 3 substituents independently selected from the group consisting of H, C 1 -C 6 alkyl, —OH, C 1 -C 6 alkoxy and halogen;
r is 1 to 3;
X 2 is —NR 35 —, —O—, —S—, —S(O)—, —SO 2 —, —CH 2 —, —CF 2 — or —CR 12 F—;
X 3 is —NR 34 —, —N(CONR 13 R 14 )—, —N(CO 2 R 15 )—, —N(COR 12 )—, —N(SO 2 NHR 13 )—, —O—, —S—, —S(O)—, —SO 2 —, —CH 2 —, —CF 2 — or —CR 12 F—;
n 3 is 1 to 5; and
n 5 is 1 to 3;
or a diastereomer, enantiomer, stereoisomer, regiostereomer, rotomer, or tautomer thereof;
wherein the physiological disorder, symptom or disease is emesis and/or nausea.
2. The method of claim 1 , wherein R 4 is —NR 13 R 14 , —NR 12 C(O)R 14 , —NR 12 C(O)OR 13 , —NR 12 (C(O)NR 13 R 14 ), —OH, —O—(C 1 -C 6 )alkyl, —O—(C 3 -C 8 )cycloalky, —OC(O)R 14 , —OC(O)NR 13 R 14 , —NR 12 SO 2 R 13 , —SO 2 NR 13 R 14 , R 19 -heteroaryl,
wherein X 2 is —O—, —S—, —CH 2 — or —NR 35 —; and
R 5 is —C(O)OR 13 or —C(O)NR 13 R 14 .
3. The method of claim 1 , wherein R 12 and R 27 are independently selected from the group consisting of H and —CH 3 ; n 3 is 2 or 3; and n 5 is 1 or 2.
4. The method of claim 1 , wherein the compound is selected from the group consisting of:
5. The method of claim 1 , wherein the compound is represented by the following structural formula:
or a pharmaceutically acceptable salt thereof.
6. The method of claim 1 , wherein the compound is represented by the following structural formula:
or a pharmaceutically acceptable salt thereof.
7. The method of claim 1 , wherein the compound is represented by the following structural formula:
or a pharmaceutically acceptable salt thereof.
8. The method of claim 1 , wherein the compound is represented by the following structural formula:
or a pharmaceutically acceptable salt thereof.