Details for Patent: 9,688,693

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 (Monroe Township, NJ), Reichard; Gregory A. (Ann Arbor, MI), Wang; Cheng (Summit, NJ), Xiao; Dong (Warren, NJ), Tsui; Hon-Chung (East Brunswick, NJ), Shih; Neng-Yang (Warren, NJ), Arredondo; Juan D. (Montclair, NJ), Wrobleski; Michelle Laci (Whitehouse Station, NJ), Palani; Anandan (Bridgewater, NJ)
Assignee:	OPKO Health, Inc. (Miami, FL)
Filing Date:	Jul 25, 2014
Application Number:	14/341,097
Claims:	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): ##STR00253## or a pharmaceutically-acceptable salt thereof, wherein Ar.sup.1 is phenyl, wherein said phenyl can be unsubstituted or substituted with 1 to 3 fluoro; Ar.sup.2 is bis(trifluoromethyl)phenyl; 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 and hydroxyl(C.sub.1-C.sub.3alkyl), providing that at least one of R.sup.1 and R.sup.2 is H; R.sup.3 is H; R.sup.4 and R.sup.5 are each independently selected from the group consisting of --(CR.sup.28R.sup.29).sub.n1-G, wherein, n.sub.1 is an integer between 0 to 5; G is --H, --NR.sup.13R.sup.14, --NR.sup.12C(O)R.sup.14, --C(O)NR.sup.13R.sup.14, --OC(O)NR.sup.13R.sup.14, --NR.sup.12C(O)OR.sup.13, --NR.sup.12(C(O)NR.sup.13R.sup.14), --NR.sup.12SO.sub.2R.sup.13, --OH, --O(C.sub.1-6 alkyl), --C(OR.sup.12)(R.sup.13)(R.sup.14), --OC(O)R.sup.14, --C(O)R.sup.13, R.sup.19-heteroaryl, R.sup.19-phenyl, or heterocycloalkenyl, ##STR00254## 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.sup.30 and R.sup.31; provided that R.sup.4 and R.sup.5 are not both selected from the group consisting of H, alkyl and cycloalkyl; and when one of R.sup.4 and R.sup.5 is --OH, then the other one of R.sup.4 and R.sup.5 is not alkyl or R.sup.19-phenyl; R.sup.6 and R.sup.7 are each H; n.sub.2 is 2; R.sup.12 is H, C.sub.1-C.sub.6 alkyl or C.sub.3-C.sub.5 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, --CH.sub.2CF.sub.3, C.sub.3-C.sub.6 cycloalkyl, (C.sub.3-C.sub.8)cycloalkyl(C.sub.1-C.sub.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.sup.13 and R.sup.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.sup.12, where one of the carbon atoms in the ring is optionally replaced by a heteroatom selected from --O--; n.sub.6 is 0, 1 or 2; R.sup.18 is H; each R.sup.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.sub.1-C.sub.6 alkyl; 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; 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 H or 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.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; wherein the physiological disorder, symptom or disease is emesis and/or nausea. 2. The method of claim 1, wherein R.sup.4 is --NR.sup.13R.sup.14, --NR.sup.12C(O)R.sup.14, --NR.sup.12C(O)OR.sup.13, --NR.sup.12(C(O)NR.sup.13R.sup.14), --OH, --O--(C.sub.1-C.sub.6)alkyl, --O--(C.sub.3-C.sub.8)cycloalky, --OC(O)R.sup.14, --OC(O)NR.sup.13R.sup.14, --NR.sup.12SO.sub.2R.sup.13, --SO.sub.2NR.sup.13R.sup.14, R.sup.19-heteroaryl, ##STR00255## wherein X.sup.2 is --O--, --S--, --CH.sub.2-- or --NR.sup.35--; and R.sup.5 is --C(O)OR.sup.13 or --C(O)NR.sup.13R.sup.14. 3. The method of claim 1, wherein R.sup.12 and R.sup.27 are independently selected from the group consisting of H and --CH.sub.3; n.sub.3 is 2 or 3; and n.sub.5 is 1 or 2. 4. The method of claim 1, wherein the compound is selected from the group consisting of: ##STR00256## ##STR00257## ##STR00258## ##STR00259## ##STR00260## ##STR00261## ##STR00262## ##STR00263## ##STR00264## ##STR00265## ##STR00266## ##STR00267## ##STR00268## ##STR00269## ##STR00270## ##STR00271## 5. The method of claim 1, wherein the compound is represented by the following structural formula: ##STR00272## or a pharmaceutically acceptable salt thereof. 6. The method of claim 1, wherein the compound is represented by the following structural formula: ##STR00273## or a pharmaceutically acceptable salt thereof. 7. The method of claim 1, wherein the compound is represented by the following structural formula: ##STR00274## or a pharmaceutically acceptable salt thereof. 8. The method of claim 1, wherein the compound is represented by the following structural formula: ##STR00275## or a pharmaceutically acceptable salt thereof.