Nk1 antagonists

Abstract

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.

What is claimed is: 
     
         1 . A compound having the formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically-acceptable salt thereof, wherein 
         Ar 1  and Ar 2  are each independently selected from the group consisting of R 17 -heteroaryl and 
       
       
         
           
           
               
               
           
         
         X 1  is —O—, —S—, —SO—, —SO 2 —, —NR 34 —, —N(COR 12 )— or —N(SO 2 R 15 )—; 
         when X 1  is —SO—, —SO 2 —, —N(COR 12 )— or —N(SO 2 R 15 )—, then:
 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 
 
         when X 1  is —O—, —S— or —NR 34 —, then:
 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 1 to 4; 
         R 4  and R 5  are each independently selected from the group consisting of —(CR 28 R 29 ) n1 -G, 
         where,
 n 1  is 0 to 5; and 
 G is H, —CF 3 , —CHF 2 , —CH 2 F, —OH, —O—(C 1 -C 6  alkyl), —OCH 2 F, —OCHF 2 , —OCF 3 , —OCH 2 CF 3 , —O—(C 3 -C 8  cycloalkyl), —O—(C 1 -C 6 )alkyl(C 3 -C 8  cycloalkyl), —NR 13 R 14 , —SO 2 NR 13 R 14 , —NR 12 SO 2 R 13 , —NR 12 C(O)R 14 , —NR 12 C(O)OR 13 , —NR 12 (C(O)NR 13 R 14 ), —C(O)NR 13 R 14 , —C(O)OR 13 , —C 3 -C 8  cycloalkyl, (R 19 ) r -aryl, (R 19 ) r -heteroaryl, —OC(O)R 14 , —OC(O)NR 13 R 14 , —C(═NOR 14 )(R 13 ), —C(O)R 13 , —C(OR 12 )(R 13 )(R 14 ), heterocycloalkenyl optionally substituted by 1 to 4 substituents independently selected from the group consisting of R 30  and R 31 , 
 
       
       
         
           
           
               
               
           
         
         R 4  and R 5  together are ═O, ═NOR 12 ; or 
         R 4  and R 5 , together with the carbon atom to which they are both attached, form a 4- to 8-membered heterocycloalkyl or heterocycloalkenyl ring containing 1 to 3 groups Independently selected from X 2 , provided that at least one X 2  is —NR 35 —, —O—, —S—, —S(O)— or —SO 2 —, the ring being optionally substituted with from 1 to 6 substituents independently selected from the group consisting of 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; 
         further provided that, 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 ) r -aryl; 
         R 8 , R 9  and R 10  are each independently selected from the group consisting of H, C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, —OR 12 , halogen, —CN, —NO 2 , —CF 3 , —CHF 2 , —CH 2 F, —CH 2 CF 3 , —OCF 3 , —OCHF 2 , —OCH 2 F, —OCH 2 CF 3 , —COOR 12 , —CONR 21 R 22 , —OC(O)NR 21 R 22 , —OC(O)R 12 , —NR 21 COR 12 , —NR 21 CO 2 R 15 , —NR 21 CONR 21 R 22 , —NR 21 SO 2 R 15 , —NR 21 R 22 , —SO 2 NR 21 R 22 , —S(O) n6 R 15 , (R 19 ) r -aryl and (R 19 ) r -heteroaryl; 
         R 12  is H, C 1 -C 6  alkyl or C 3 -C 8  cycloalkyl; 
         R 13  and R 14  are each independently selected from the group consisting of H, C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, —CH 2 CF, aryl and heteroaryl; or 
         R 13  and R 14 , together with the nitrogen atom to which they are both attached, form a 4- to 7-membered saturated or unsaturated ring that is optionally substituted with —OR 17 , where one of the carbon atoms In the ring is optionally replaced by a heteroatom selected from the group consisting of —O—, —S— and —NR 34 —; 
         n 6  is 0, 1 or 2; 
         R 15  is C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl, —CF 3  or —CH 2 CF 3 ; 
         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 8 )alkyl or —P(O)(OH) 2 ; 
         each R 19  is a substituent on the aryl or heteroaryl ring to which it is attached, and is independently selected from the group consisting of H, C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl, C 1 -C 6  alkoxy, —OH, halogen, —CN, —NO 2 , —CF 3 —CHF 2 , —CH 2 F, —OCF 3 , —OCHF 2 , —OCH 2 F, —O—(C 1 -C 6  alkyl), —O—(C 3 -C 8  cycloalkyl), —COOR 12 , —CONR 21 R 22 , —OC(O)NR 21 R 22 , —OC(O)R 12 , —NR 21 R 22 , —NR 21 COR 12 , —NR 21 CO 2 R 12 , —NR 21 CONR 21 R 22 , —NR 21 SO 2 R 15  and —S(O) n6 R 15 ; 
         R 21  and R 22  are each independently selected from the group consisting of H, C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl and benzyl; or 
         R 21  and R 22 , together with the nitrogen atom to which they are both attached, form a 4- to 7-membered saturated or unsaturated ring, where one of the carbon atoms in the ring is optionally replaced by a heteroatom selected from the group consisting of —O—, —S— and —NR 34 —; 
         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 selected from the group consisting of H and 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 13 )—, —N(SO 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, tautomer or prodrug thereof. 
       
     
     
         2 . The compound or salt according to  claim 1 , where X 1  is —O—. 
     
     
         3 . The compound or salt according to  claim 1 , where Ar 1  and Ar 2  are each 
       
         
           
           
               
               
           
         
       
     
     
         4 . The compound or salt according to  claim 3 , where for Ar 2 , at least two of R 8 , R 9  and R 10  are each —CF 3 . 
     
     
         5 . The compound or salt according to  claim 3 , where for Ar 1 , R 8 , R 9  and R 10  are each independently selected from the group consisting of H, —OH and halogen. 
     
     
         6 . The compound or salt according to  claim 1  represented by the formula 
       
         
           
           
               
               
           
         
         wherein X 1  is —O— or —NR 34 —; for Ar 2 , R 8  and R 9  are independently selected from the group consisting of —CF 3 , —CHF 2 , —CH 2 F, halogen, C 1 -C 6  alkyl, —OCF 3  and —OR 12 ; for Ar 1 , R 9  and R 10  are independently selected from the group consisting of H, —OH and halogen; and n 2  is 1 or 2. 
       
     
     
         7 . The compound according to  claim 6  wherein one of R 4  and R 5  is H and the other is —C(R 28 R 29 ) n1 -G, wherein n 1  is 0, 1 or 2. 
     
     
         8 . The compound according to  claim 7  wherein one of R 4  and R 5  is H and the other is selected from the group consisting of —NR 13 R 14 , —NR 12 C(O)R 14 , —C(O) NR 13 R 14 , —OC(O)R 14 , —OC(O)NR 13 R 14 , NR 12 C(O)OR 13 , —C(O)OR 13 , —NR 12 (C(O)NR 13 R 14 ), —NR 12 SO 2 R 13 , —SO 2 NR 13 R 14 , R 19 -heteroaryl, 
       
         
           
           
               
               
           
         
       
     
     
         9 . The compound or salt according to  claim 6  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 )cycloalkyl, —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 . 
       
     
     
         10 . The compound or salt according to  claim 8 , where 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. 
     
     
         11 . The compound or salt according to  claim 9 , wherein R 12  and R 27  are H; n 3  is 2 or 3; and n 5  is 1 or 2. 
     
     
         12 . The compound or salt according to  claim 6 , wherein R 4  and R 5 , together with the carbon atom to which they are both attached, form a 4- to 8-membered heterocycloalkyl or heterocycloalkenyl ring containing 1 to 3 groups independently selected from X 2 , provided that at least one X 2  is —NR 35 —, —O—, —S—, —S(O)— or —SO 2 —, the ring being optionally substituted with from 1 to 6 substituents independently selected from the group consisting of R 30  and R 31 . 
     
     
         13 . The compound or salt according to  claim 12 , where the 4- to 8-membered ring is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         wherein R 35  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 1 -C 6 )alkyl; n 5  is 1, 2 or 3; X 2  is —NR 35 —, —CH 2 —, —O— or —S—; R 30  is H, C 1 -C 6  alkyl or C 3 -C 8  cycloalkyl; and R 31  is H, —OH or C 1 -C 6  alkyl. 
       
     
     
         14 . The compound or salt according to  claim 12 , where the 4- to 8-membered ring is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         wherein R 30  is H, C 1 -C 6  alkyl or C 3 -C 8  cycloalkyl; R 3  is H, —OH or C 1 -C 6  alkyl; each R 35  is independently selected from the group consisting of H, C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl and hydroxy(C 1 -C 6 )alkyl; n 4  and n 7  are independently 0-5, provided that the sum of n 4  and n 7  is 1-5. 
       
     
     
         15 . The compound or salt according to  claim 13  wherein the 4- to 8-membered ring is selected from the group consisting of 
       
         
           
           
               
               
           
         
       
     
     
         16 . The compound according to  claim 14 , wherein the 4- to 8-membered ring is selected from the group consisting of 
       
         
           
           
               
               
           
         
       
     
     
         17 . The compound or salt according to  claim 1 , wherein the compound is selected from the group consisting of Examples 3, 9, 12a, 13, 14, 15, 20, 23, 29, 36, 40, 43b, 44b, 45, 50, 53, 56b, 57, 60a, 61, 62, 63, 72a, 73b, 74a, 75b, 76a, 82a, 82b, 90, 96, 105, 106b, 109, 110a, 111a, 112 and 113, and the stereoisomers thereof. 
     
     
         18 . The compound or salt according to  claim 17 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
     
     
         19 . The compound or salt according to  claim 17 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
     
     
         20 . The compound or salt according to  claim 17 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
     
     
         21 . The compound or salt according to  claim 17 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
     
     
         22 . The compound or salt according to  claim 17 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
     
     
         23 . The compound or salt according to  claim 17 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
     
     
         24 . The compound or salt according to  claim 17 , herein the compound is: 
       
         
           
           
               
               
           
         
       
     
     
         25 . The compound or salt according to  claim 17 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
     
     
         26 . The compound or salt according to  claim 17 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
     
     
         27 . A pharmaceutical composition comprising a therapeutically effective amount of at least one compound of  claim 1  in a pharmaceutically acceptable carrier. 
     
     
         28 . The pharmaceutical composition according to  claim 27 , further comprising at least one selective serotonin reuptake inhibitor. 
     
     
         29 . The pharmaceutical composition according to  claim 27 , further comprising at least one serotonin 5-HT 3  receptor antagonist, or at least one corticosteroid or at least one substituted benzamide. 
     
     
         30 . The pharmaceutical composition according to  claim 27 , further comprising at least one serotonin 5-HT 3  receptor antagonist and at least one corticosteroid. 
     
     
         31 . The pharmaceutical composition according to  claim 27 , further comprising at least one substituted benzamide and at least one corticosteroid. 
     
     
         32 . 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 or salt according to  claim 1 , or a pharmaceutical composition thereof, where the physiological disorder, symptom or disease is a respiratory disease, cough, inflammatory disease, skin disorder, ophthalmalogical disorder, depression, anxiety, phobia, bipolar disorder, alcohol dependence, psychoactive substance abuse, epilepsy, nociception, psychosis, schizophrenia, Alzheimer's disease, AIDs related dementia, Towne's disease, stress related disorder, obsessive/compulsive disorder, bulemia, anorexia nervosa, binge eating, mania, premenstrual syndrome, gastrointestinal disorder, atherosclerosis, fibrosing disorder, obesity, Type II diabetes, headache, neuropathic pain, post-operative pain, chronic pain syndrome, bladder disorder, genitourinary disorder, emesis or nausea. 
     
     
         33 . The method according to  claim 32  for treating asthma, emesis, nausea, depression, anxiety, cough or migraine. 
     
     
         34 . The method of  claim 33  for treating depression or anxiety further comprising administering to the patient an effective amount of at least one selective serotonin reuptake inhibitor. 
     
     
         35 . The method according to  claim 34 , where the selective serotonin reuptake inhibitor is fluoxetine, fluvoxamine, paroxetine, sertaline, or a pharmaceutically-acceptable salt thereof. 
     
     
         36 . The method of  claim 33  for treating emesis further comprising administering to the patient an effective amount of at least one serotonin 5-HT 3  receptor antagonist or at least one corticosteroid or at least one substituted benzamide. 
     
     
         37 . The method of  claim 33  for treating emesis further comprising administering to the patient an effective amount of at least one serotonin 5-HT 3  receptor antagonist and at least one corticosteroid. 
     
     
         38 . The method of  claim 33  for treating emesis further comprising administering to the patient an effective amount of at least one corticosteroid and at least one substituted benzamide. 
     
     
         39 . The method according to  claim 36 , where the serotonin 5-HT 3  receptor antagonist is ondansetron, dolasetron, palonsetron or granisetron, the corticosteroid is dexamethasone, and the substituted benzamide is metoclopramide. 
     
     
         40 . A method for antagonizing an effect of a Substance P at a neurokinin-1 receptor site or for blocking at least one neurokinin-1 receptor, in a mammal in need of such treatment, comprising administering to the mammal an effective amount of at least the compound or salt according to  claim 1 , or a pharmaceutical composition thereof.