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Claims for Patent: 7,049,320

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Claims for Patent: 7,049,320

Title:NK.sub.1 antagonists
Abstract: A NK.sub.1 antagonist having the formula (I), ##STR00001## wherein Ar.sup.1 and Ar.sup.2 are optionally substituted phenyl or heteroaryl, X.sup.1 is an ether, thio or imino linkage, R.sup.4 and R.sup.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.
Inventor(s): Paliwal; Sunil (Scotch Plains, NJ), Reichard; Gregory A. (Ann Arbor, MI), Wang; Cheng (Summit, NJ), Xiao; Dong (Warren, NJ), Tsui; Hon-Chung (East Brunswick, NJ), Shih; Neng-Yang (North Caldwell, NJ), Arredondo; Juan D. (Montclair, NJ), Wrobleski; Michelle Laci (Whitehouse Station, NJ), Palani; Anandan (Bridgewater, NJ)
Assignee: Schering Corporation (Kenilworth, NJ)
Application Number:10/321,687
Patent Claims: 1. A compound having the formula (I): ##STR00227## or a pharmaceutically-acceptable salt thereof, wherein Ar.sup.1 and Ar.sup.2 are each ##STR00228## X.sup.1 is --O--, R.sup.1 and R.sup.2 are each independently selected from the group consisting of H, C.sub.1 C.sub.6 alkyl, hydroxy(C.sub.1 C.sub.3alkyl), C.sub.3 C.sub.8cycloalkyl, --CH.sub.2F, --CHF.sub.2 and --CF.sub.3; or R.sup.1 and R.sup.2, together with the carbon atom to which they are both attached, form a C.sub.3 to C.sub.6 alkylene ring; or R.sup.1 and R.sup.2, together with the carbon atom to which they are both attached, form a C.dbd.O group; R.sup.3 is selected from the group consisting of H, C.sub.1 C.sub.6 alkyl, hydroxy(C.sub.1 C.sub.3 alkyl), C.sub.3 C.sub.8 cycloalkyl, --CH.sub.2F, --CHF.sub.2 and --CF.sub.3; each R.sup.6 is independently selected from the group consisting of H, C.sub.1 C.sub.6 alkyl and --OH; each R.sup.7 is independently selected from the group consisting of H and C.sub.1 C.sub.6 alkyl; n.sub.2 is 2; R.sup.4 and R.sup.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: ##STR00229## wherein said 5- or 6-membered heterocycloalkyl ring is optionally substituted with from 1 to 6 substituents independently selected from the group consisting of R.sup.30 and R.sup.31; R.sup.8, R.sup.9 and R.sup.10 are each independently selected from the group consisting of H, C.sub.1 C.sub.6 alkyl, C.sub.3 C.sub.8 cycloalkyl, --OR.sup.12, halogen, --CN, --NO.sub.2, --CF.sub.3, --CHF.sub.2, --CH.sub.2F, --CH.sub.2CF.sub.3, --OCF.sub.3, --OCHF.sub.2, --OCH.sub.2F, --OCH.sub.2CF.sub.3, --COOR.sup.12, --CONR.sup.21R.sup.22, --OC(O)NR.sup.21R.sup.22, --OC(O)R.sup.12, --NR.sup.21COR.sup.12, --NR.sup.21CO.sub.2R.sup.15, --NR.sup.21CONR.sup.21R.sup.22, --NR.sup.21SO.sub.2R.sup.15, --NR.sup.21R.sup.22, --SO.sub.2NR.sup.21R.sup.22, --S(O).sub.n6R.sup.15, and (R.sup.19).sub.r-aryl; R.sup.12 is H, C.sub.1 C.sub.6 alkyl or C.sub.3 C.sub.8 cycloalkyl; R.sup.13 and R.sup.14 are each independently selected from the group consisting of H, C.sub.1 C.sub.6 alkyl, C.sub.3 C.sub.8 cycloalkyl, (C.sub.3 C.sub.8)cycloalkyl(C.sub.1 C.sub.6)alkyl, --CH.sub.2CF.sub.3, and aryl; n.sub.6 is 0, 1 or 2; R.sup.15 is C.sub.1 C.sub.6 alkyl, C.sub.3 C.sub.8 cycloalkyl, --CF.sub.3 or --CH.sub.2CF.sub.3; R.sup.18 is H, C.sub.1 C.sub.6 alkyl, C.sub.3 C.sub.8 cycloalkyl, (C.sub.3 C.sub.8)cycloalkyl(C.sub.1 C.sub.6)alkyl, hydroxy(C.sub.2 C.sub.6)alkyl or --P(O)(OH).sub.2; each R.sup.19 is a substituent on the aryl ring to which it is attached, and is independently selected from the group consisting of H, C.sub.1 C.sub.6 alkyl, C.sub.3 C.sub.8 cycloalkyl, C.sub.1 C.sub.6 alkoxy, --OH, halogen, --CN, --NO.sub.2, --CF.sub.3, --CHF.sub.2, --CH.sub.2F, --OCF.sub.3, --OCHF.sub.2, --OCH.sub.2F, --O--(C.sub.1 C.sub.6 alkyl), --O--(C.sub.3 C.sub.8 cycloalkyl), --COOR.sup.12, --CONR.sup.21R.sup.22, --OC(O)NR.sup.21R.sup.22, --OC(O)R.sup.12, --NR.sup.21R.sup.22, --NR.sup.21COR.sup.12, --NR.sup.21CO.sub.2R.sup.12, --NR.sup.21CONR.sup.21R.sup.22, --NR.sup.21SO.sub.2R.sup.15 and --S(O).sub.n6R.sup.15; R.sup.21 and R.sup.22 are each independently selected from the group consisting of H, C.sub.1 C.sub.6 alkyl, C.sub.3 C.sub.8 cycloalkyl and benzyl; R.sup.23 and R.sup.24 are each independently selected from the group consisting of H and C.sub.1 C.sub.6 alkyl; or R.sup.23 and R.sup.24, together with the carbon atom to which they are both attached, form a C.dbd.O or cyclopropyl group; R.sup.27 is H, --OH or C.sub.1 C.sub.6 alkyl; R.sup.28 and R.sup.29 are each independently selected from the group consisting of H and C.sub.1 C.sub.2 alkyl; or R.sup.30 and R.sup.31 are each independently selected from the group consisting of H, --OH, C.sub.1 C.sub.6 alkyl, C.sub.3 C.sub.8 cycloalkyl, (C.sub.3 C.sub.8)cycloalkyl(C.sub.1 C.sub.6)alkyl and --C(O)NR.sup.13R.sup.14; or R.sup.30 and R.sup.31, together with the carbon atom to which they are both attached, form .dbd.O, .dbd.S, a cyclopropyl ring or .dbd.NR.sup.36; R.sup.32 and R.sup.33 are each independently selected from the group consisting of H and C.sub.1 C.sub.6 alkyl; R.sup.34 is H, C.sub.1 C.sub.6 alkyl, C.sub.3 C.sub.8 cycloalkyl, (C.sub.3 C.sub.8)cycloalkyl(C.sub.1 C.sub.6)alkyl or hydroxy(C.sub.2 C.sub.6)alkyl; R.sup.35 is H, C.sub.1 C.sub.6 alkyl, C.sub.3 C.sub.8 cycloalkyl, (C.sub.3 C.sub.8)cycloalkyl(C.sub.1 C.sub.6)alkyl, --P(O)(OH).sub.2, allyl, hydroxy(C.sub.2 C.sub.6)alkyl, (C.sub.1 C.sub.6)alkoxy(C.sub.1 C.sub.6)alkyl, --SO.sub.2R.sup.15 or --(CH.sub.2).sub.2--N(R.sup.12)--SO.sub.2--R.sup.15; R.sup.36 is H, C.sub.1 C.sub.6 alkyl, C.sub.3 C.sub.8 cycloalkyl, (C.sub.3 C.sub.8)cycloalkyl(C.sub.1 C.sub.6)alkyl, --NO.sub.2, --CN or OR.sup.12; R.sup.37 is 1 to 3 substituents independently selected from the group consisting of H, C.sub.1 C.sub.6 alkyl, --OH, C.sub.1 C.sub.6 alkoxy and halogen; r is 1 to 3; X.sup.2 is --NR.sup.35--, --O--, --S--, --S(O)--, --SO.sub.2--, --CH.sub.2--, --CF.sub.2-- or --CR.sup.12F--; X.sup.3 is --NR.sup.34--, --N(CONR.sup.13R.sup.14)--, --N(CO.sub.2R.sup.13)--, --N(SO.sub.2R.sup.15)--, --N(COR.sup.12)--, --N(SO.sub.2NHR.sup.13)--, --O--, --S--, --S(O)--, --SO.sub.2--, --CH.sub.2--, --CF.sub.2-- or --CR.sup.12F--; n.sub.3 is 1 to 5; and n.sub.5 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 Ar.sup.2, at least two of R.sup.8, R.sup.9 and R.sup.10 are each --CF.sub.3.

3. The compound or salt according to claim 1, wherein for Ar.sup.1, R.sup.8, R.sup.9 and R.sup.10 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 ##STR00230## wherein for Ar.sup.2, R.sup.8 and R.sup.9 are independently selected from the group consisting of --CF.sub.3, --CHF.sub.2, --CH.sub.2F, halogen, C.sub.1 C.sub.6 alkyl, --OCF.sub.3 and --OR.sup.12, and for Ar.sup.1, R.sup.9 and R.sup.10 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 ##STR00231## wherein R.sup.35 is H, C.sub.1 C.sub.6 alkyl, C.sub.3 C.sub.8 cycloalkyl, or (C.sub.3 C.sub.8)cycloalkyl(C.sub.1 C.sub.6)alkyl; n.sub.5 is 1 or 2; X.sup.2 is --CH.sub.2--, or --O--, R.sup.+is H, C.sub.1 C.sub.6 alkyl or C.sub.3 C.sub.8 cycloalkyl; and R.sup.31 is H, --OH or C.sub.1 C.sub.6 alkyl.

6. The compound or salt according to claim 1, where the 5- to 6-membered ring is: ##STR00232## wherein R.sup.30 is H, C.sub.1 C.sub.6 alkyl or C.sub.3 C.sub.8 cycloalkyl; R.sup.31 is H, --OH or C.sub.1 C.sub.6 alkyl; each R.sup.35 is independently selected from the group consisting of H, C.sub.1 C.sub.6 alkyl, C.sub.3 C.sub.8 cycloalkyl, and (C.sub.3 C.sub.8)cycloalkyl(C.sub.1 C.sub.6)alkyl; n.sub.4 is 2 or 3 and n.sub.7 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 ##STR00233##

8. The compound according to claim 6, wherein the 5- to 6-membered ring is ##STR00234##

9. The compound or salt according to claim 1, wherein the compound is selected from the group consisting of: ##STR00235## thereof.

10. The compound or salt according to claim 1, wherein the compound is: ##STR00236##

11. The compound or salt according to claim 1, wherein the compound is: ##STR00237##

12. The compound or salt according to claim 1, wherein the compound is: ##STR00238##

13. The compound or salt according to claim 1, wherein the compound is: ##STR00239##

14. The compound or salt according to claim 1, wherein the compound is: ##STR00240##

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.
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