Claims for Patent: 7,049,320

Summary for Patent: 7,049,320

Title:	NK1 antagonists
Abstract:	A NK1 antagonist having the formula (I), wherein Ar1 and Ar2 are optionally substituted phenyl or heteroaryl, X1 is an ether, thio or imino linkage, R4 and R5 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.
Inventor(s):	Sunil Paliwal, Gregory A. Reichard, Cheng Wang, Dong Xiao, Hon-Chung Tsui, Neng-Yang Shih, Juan D. Arredondo, Michelle Laci Wrobleski, Anandan Palani
Assignee:	Opko Health Inc
Application Number:	US10/321,687
Patent Claims:	1. A compound having the formula (I): or a pharmaceutically-acceptable salt thereof, wherein Ar1 and Ar2 are each X1 is —O—, R1 and R2 are each independently selected from the group consisting of H, C1–C6 alkyl, hydroxy(C1–C3alkyl), C3–C8cycloalkyl, —CH2F, —CHF2 and —CF3; or R1 and R2, together with the carbon atom to which they are both attached, form a C3 to C6 alkylene ring; or R1 and R2, together with the carbon atom to which they are both attached, form a C═O group; R3 is selected from the group consisting of H, C1–C6 alkyl, hydroxy(C1–C3 alkyl), C3–C8 cycloalkyl, —CH2F, —CHF2 and —CF3; each R6 is independently selected from the group consisting of H, C1–C6 alkyl and —OH; each R7 is independently selected from the group consisting of H and C1–C6 alkyl; n2 is 2; R4 and R5, 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 substituents independently selected from the group consisting of R30 and R31; R8, R9 and R10 are each independently selected from the group consisting of H, C1–C6 alkyl, C3–C8 cycloalkyl, —OR12, halogen, —CN, —NO2, —CF3, —CHF2, —CH2F, —CH2CF3, —OCF3, —OCHF2, —OCH2F, —OCH2CF3, —COOR12, —CONR21R22, —OC(O)NR21R22, —OC(O)R12, —NR21COR12, —NR21CO2R15, —NR21CONR21R22, —NR21SO2R15, —NR21R22, —SO2NR21R22, —S(O)n6R15, and (R19)r-aryl; R12 is H, C1–C6 alkyl or C3–C8 cycloalkyl; R13 and R14 are each independently selected from the group consisting of H, C1–C6 alkyl, C3–C8 cycloalkyl, (C3–C8)cycloalkyl(C1–C6)alkyl, —CH2CF3, and aryl; n6 is 0, 1 or 2; R15 is C1–C6 alkyl, C3–C8 cycloalkyl, —CF3 or —CH2CF3; R18 is H, C1–C6 alkyl, C3–C8 cycloalkyl, (C3–C8)cycloalkyl(C1–C6)alkyl, hydroxy(C2–C6)alkyl or —P(O)(OH)2; each R19 is a substituent on the aryl ring to which it is attached, and is independently selected from the group consisting of H, C1–C6 alkyl, C3–C8 cycloalkyl, C1–C6 alkoxy, —OH, halogen, —CN, —NO2, —CF3, —CHF2, —CH2F, —OCF3, —OCHF2, —OCH2F, —O—(C1–C6 alkyl), —O—(C3–C8 cycloalkyl), —COOR12, —CONR21R22, —OC(O)NR21R22, —OC(O)R12, —NR21R22, —NR21COR12, —NR21CO2R12, —NR21CONR21R22, —NR21SO2R15 and —S(O)n6R15; R21 and R22 are each independently selected from the group consisting of H, C1–C6 alkyl, C3–C8 cycloalkyl and benzyl; R23 and R24 are each independently selected from the group consisting of H and C1–C6 alkyl; or R23 and R24, together with the carbon atom to which they are both attached, form a C═O or cyclopropyl group; R27 is H, —OH or C1–C6 alkyl; R28 and R29 are each independently selected from the group consisting of H and C1–C2 alkyl; or R30 and R31 are each independently selected from the group consisting of H, —OH, C1–C6 alkyl, C3–C8 cycloalkyl, (C3–C8)cycloalkyl(C1–C6)alkyl and —C(O)NR13R14; or R30 and R31, together with the carbon atom to which they are both attached, form ═O, ═S, a cyclopropyl ring or ═NR36; R32 and R33 are each independently selected from the group consisting of H and C1–C6 alkyl; R34 is H, C1–C6 alkyl, C3–C8 cycloalkyl, (C3–C8)cycloalkyl(C1–C6)alkyl or hydroxy(C2–C6)alkyl; R35 is H, C1–C6 alkyl, C3–C8 cycloalkyl, (C3–C8)cycloalkyl(C1–C6)alkyl, —P(O)(OH)2, allyl, hydroxy(C2–C6)alkyl, (C1–C6)alkoxy(C1–C6)alkyl, —SO2R15 or —(CH2)2—N(R12)—SO2—R15; R36 is H, C1–C6 alkyl, C3–C8 cycloalkyl, (C3–C8)cycloalkyl(C1–C6)alkyl, —NO2, —CN or OR12; R37 is 1 to 3 substituents independently selected from the group consisting of H, C1–C6 alkyl, —OH, C1–C6 alkoxy and halogen; r is 1 to 3; X2 is —NR35—, —O—, —S—, —S(O)—, —SO2—, —CH2—, —CF2— or —CR12F—; X3 is —NR34—, —N(CONR13R14)—, —N(CO2R13)—, —N(SO2R15)—, —N(COR12)—, —N(SO2NHR13)—, —O—, —S—, —S(O)—, —SO2—, —CH2—, —CF2— or —CR12F—; n3 is 1 to 5; and n5 is 1 to 3; or a diastereomer, enantiomer, stereoisomer, regiostereomer, rotomer, or tautomer thereof. 2. The compound or salt according to claim 1, wherein for Ar2, at least two of R8, R9 and R10 are each —CF3. 3. The compound or salt according to claim 1, wherein for Ar1, R8, R9 and R10 are each independently selected from the group consisting of H, —OH and halogen. 4. The compound or salt according to claim 1 represented by the formula wherein for Ar2, R8 and R9 are independently selected from the group consisting of —CF3, —CHF2, —CH2F, halogen, C1–C6 alkyl, —OCF3 and —OR12, and for Ar1, R9 and R10 are independently selected from the group consisting of H, —OH and halogen. 5. The compound or salt according to claim 1, where the 5- or 6-membered ring is selected from the group consisting of wherein R35 is H, C1–C6 alkyl, C3–C8 cycloalkyl, or (C3–C8)cycloalkyl(C1–C6)alkyl; n5 is 1 or 2; X2 is —CH2—, or —O—, R+is H, C1–C6 alkyl or C3–C8 cycloalkyl; and R31 is H, —OH or C1–C6 alkyl. 6. The compound or salt according to claim 1, where the 5- to 6-membered ring is: wherein R30 is H, C1–C6 alkyl or C3–C8 cycloalkyl; R31 is H, —OH or C1–C6 alkyl; each R35 is independently selected from the group consisting of H, C1–C6 alkyl, C3–C8 cycloalkyl, and (C3–C8)cycloalkyl(C1–C6)alkyl; n4 is 2 or 3 and n7 is 0. 7. The compound or salt according to claim 5 wherein the 5- to 6-membered ring is selected from the group consisting of 8. The compound according to claim 6, wherein the 5- to 6-membered ring is 9. The compound or salt according to claim 1, wherein the compound is selected from the group consisting of: thereof. 10. The compound or salt according to claim 1, wherein the compound is: 11. The compound or salt according to claim 1, wherein the compound is: 12. The compound or salt according to claim 1, wherein the compound is: 13. The compound or salt according to claim 1, wherein the compound is: 14. The compound or salt according to claim 1, wherein the compound is: 15. A pharmaceutical composition comprising a therapeutically effective amount of at least one compound of claim 1 in a pharmaceutically acceptable carrier. 16. A method of treating emesis comprising administering to a patient an effective amount of at least one compound or salt of claim 1. 17. A method of treating cough comprising administering to a patient an effective amount of at least one compound or salt of claim 1.