Quinoline derivatives(2)

Abstract

NK 3 receptor antagonists of formula (I): are useful in treating inter alia pulmonary disorders, CNS disorders and neurodegenerative disorders.

1 . A compound, or solvate or salt thereof, of formula (I):  
       
         
           
           
               
               
           
         
       
       in which: 
 Ar is an optionally substituted phenyl, naphthyl or C 5-7  cycloalkdienyl group, or an optionally substituted single or fused ring heterocyclic group, having aromatic character, containing from 5 to 12 ring atoms and comprising up to four hetero-atoms in the or each ring selected from S, O, N;  
 R is linear or branched C 1-8  alkyl, C 3-7  cycloalkyl, C 4-7  cycloalkylalkyl, optionally substituted phenyl or phenyl C 1-6  alkyl, an optionally substituted five-membered heteroaromatic ring comprising up to four heteroatoms selected from O and N, hydroxy C 1-6  alkyl, amino C 1-6  alkyl, C 1-6  alkylaminoalkyl, di C 1-6  alkylaminoalkyl, C 1-6  acylaminoalkyl, C 1-6  alkoxyalkyl, C 1-6  alkylcarbonyl, carboxy, C 1-6  alkoxyxcarbonyl, C 1-6  alkoxycarbonyl C 1-6  alkyl, aminocarbonyl, C 1-6  alkylaminocarbonyl, di C 1-6  alkylaminocarbonyl, halogeno C 1-6  alkyl; or is a group —(CH 2 ) p — when cyclized onto Ar, where p is 2 or 3.  
 R 1  and R 2 , which may be the same or different, are independently hydrogen or C 1-6  linear or branched alkyl, or together form a —(CH 2 )n— group in which n represents 3, 4, or 5; or R 1  together with R forms a group —(CH 2 ) q —, in which q is 2, 3, 4 or 5.  
 R 3  and R 4 , which may be the same or different are independently hydrogen, C 1-6  linear or branched alkyl, C 1-6  alkenyl, aryl, C 1-6  alkoxy, hydroxy, halogen, nitro, cyano, carboxy, carboxamido, sulphonamido, C 1-6  alkoxycarbonyl, trifluoromethyl, acyloxy, phthalimido, amino, mono- and di-C 1-6  alkylamino,  
  —O(CH 2 ) r —NT 2 , in which r is 2, 3, or 4 and T is hydrogen or C 1-6  alkyl or it forms with the adjacent nitrogen a group  
                     
  in which V and V 1  are independently hydrogen or oxygen and u is 0, 1 or  2; —O(CH   2 ) s —OW 2  in which s is 2, 3, or 4 and W is hydrogen or C 1-6  alkyl; hydroxyalkyl, aminoalkyl, mono-or di-alkylaminoalkyl, acylamino, alkylsulphonylamino, aminoacylamino, mono- or di-alkylaminoacylamino; with up to four R 3  substituents being present in the quinoline nucleus; or R 4  is a group —(CH 2 ) t — when cyclized onto R 5  as aryl, in which t is 1, 2, or 3;  
 R 5  is branched or linear C 1-6  alkyl, C 3-7  cycloalkyl, C 4-7  cycloalkylalkyl, optionally substituted aryl, or an optionally substituted single or fused ring heterocyclic group, having aromatic character, containing from 5 to 12 ring atoms and comprising up to four hetero-atoms in the or each ring selected from S, O, N;  
 X is O, S, or N—C≡N.  
 
     
     
         2 . A compound according to  claim 1  in which: 
 Ar is phenyl, optionally substituted by C 1-6  alkyl or halogen; thienyl or aC 5-7  cycloalkdienyl group;  
 
     
     
         3 . A compound according to  claim 1  in which: 
 R is C 1-6  alkyl, C 1-6  alkoxycarbonyl, C 1-6  alkylcarbonyl or hydroxy C 1-6  alkyl.  
 
     
     
         4 . A compound according to  claim 1  in which: 
 R 1  and R 2  are each hydrogen or C 1-6  alkyl.  
 
     
     
         5 . A compound according to  claim 1  in which: 
 R 3  is hydrogen, hydroxy, halogen, C 1-6  alkoxy or C 1-6  alkyl.  
 
     
     
         6 . A compound according to  claim 1  in which: 
 R 4  is hydrogen, C 1-6  alkyl, C 1-6  alkoxy, hydroxy, amino, halogen, aminoalkoxy, mono- or di-alkylaminoalkoxy, mono- or di-alkylaminoalkyl, phthaloylalkoxy, mono- or di-alkylaminoacylamino or acylamino;  
 
     
     
         7 . A compound according to  claim 1  in which: 
 R 5  is phenyl, thienyl, furyl, pyrryl or thiazolyl.  
 
     
     
         8 . A compound of formula (I) according to  claim 1 , or a salt or solvate thereof, in which: 
 Ar is phenyl, 2-chlorophenyl, 2-thienyl or cyclohexadienyl;    R is methyl, ethyl, n-propyl, —COOMe, or —COMe;    R 1  and R 2  are each hydrogen or methyl;    R 3  is hydrogen, methoxy, or hydroxy;    R 4  is hydrogen, methyl, ethyl, methoxy, hydroxy, amino, chlorine, bromine, dimethylaminoethoxy, 2-(1-phthaloyl)ethoxy, aminoethoxy, 2-(1-pyrrolidinyl)ethoxy, dimethylaminopropoxy, dimethylaminoacetylamino, acetylamino, or dimethylaminomethyl;    R 5  is phenyl, 2-thienyl, 2-furyl, 2-pyrryl, 2-thiazolyl or 3-thienyl;    and X is oxygen.    
     
     
         9 . A compound according to  claim 1 , or a salt or solvate thereof, of formula (Ia)  
       
         
           
           
               
               
           
         
         in which 
 R, R 2 , R 3  and R 4  are as defined for formula (I), in  claim 1  and Y and Z, which may be the same or different, are each Ar as defined for formula (I) in  claim 1 .  
 
       
     
     
         10 . A compound according to  claim 9 , of formula (Ib):  
       
         
           
           
               
               
           
         
         in which R, R 2 , R 3  and R 4 , Y and Z are as defined in  claim 9 .  
       
     
     
         11 . A compound according to  claim 1  selected from the group consisting of: 
 (R,S)-N-(α-methylbenzyl)-2-phenylquinoline-4-carboxamide;  
 (+)-(S)-N-(α-methylbenzyl)-2-phenylquinoline-4-carboxamide;  
 (−)-(R)-N-(α-methylbenzyl)-2-phenylquinoline-4-carboxamide;  
 (R,S)-N-[α-(methoxycarbonyl)benzyl]-2-phenylquinoline-4-carboxamide;  
 (+)-(S)-N-[α-(methoxycarbonyl)benzyl]-2-phenylquinoline-4-carboxamide;  
 (−)-(R)-N-[α-(methoxycarbonyl)benzyl]-2-phenylquinoline-4-carboxamide;  
 (R,S)-N-[α-(methoxycarbonyl)benzyl]-7-methoxy-2-phenylquinoline-4-carboxamide;  
 (R,S)-N-[α-(methoxycarbonyl)benzyl]-7-hydroxy-2-phenylquinoline-4-carboxamide;  
 (R,S)-N-[α-(carboxy)benzyl]-7-methoxy-2-phenylquinoline-4-carboxamide hydrochloride;  
 (R,S)-N-[α-(methylaminocarbonyl)benzyl]-2-phenylquinoline-4-carboxamide;  
 (R,S)-N-[α-(methoxycarbonyl)benzyl]-2-(2-thienyl)quinoline-4-carboxamide;  
 (R,S)-N-[α-(methoxycarbonyl)benzyl]-2-(2-furyl)quinoline-4-carboxamide;  
 (R,S)-N-[α-(methoxycarbonyl)benzyl]-2-(4-pyridyl)quinoline-4-carboxamide;  
 (R,S)-N-[α-(methoxycarbonyl)-2-thienylmethyl]-2-phenylquinoline-4-carboxamide;  
 (R,S)-N-[α-(methoxycarbonylmethyl)benzyl]-2-phenylquinoline-4-carboxamide;  
 (−)-(R)-N-[α-(methoxycarbonyl)-1,4-cyclohexadienylmethyl]-2-phenylquinoline-4-carboxamide;  
 (R,S)-N-[α-(1-hydroxyethyl)benzyl]-2-phenylquinoline-4-carboxamide single diast;  
 (R,S)-N-(α-ethylbenzyl)-3-methoxy-2-phenylquinoline-4-carboxamide;  
 (R,S)-N-(α-ethylbenzyl)-3-n-butyl-2-phenylquinoline-4-carboxamide;  
 (R,S)-N-[α-(methoxycarbonyl)benzyl]benzo-1,3-cycloheptadieno[1,2-b]quinoline-8-carboxamide;  
 (R,S)-N-(α-ethylbenzyl)-3-hexyl-2-phenylquinoline-4-carboxamide;  
 (−)-(S)-N-(α-ethylbenzyl)-3-methyl-2-phenylquinoline-4-carboxamide;  
 (+)-(R)-N-(α-ethylbenzyl)-3-methyl-2-phenylquinoline-4-carboxamide;  
 (R,S)-N-[α-(methoxycarbonyl)benzyl]-2-(2-methoxyphenyl)quinoline-4-carboxamide;  
 (R,S)-N-(α-ethylbenzyl)-3-phenyl-2-phenylquinoline-4-carboxamide;  
 (R,S)-N-[α-(methoxycarbonyl)benzyl]-2-(2-fluorophenyl)quinoline-4-carboxamide;  
 (R,S)-N-[α-(ethyl)-3,4-dichlorobenzyl]-2-phenylquinoline-4-carboxamide;  
 (R,S)-N-[α-(hydroxymethyl)benzyl]-2-phenylquinoline-4-carboxamide;  
 (R,S)-N-(α-ethylbenzyl)-2-phenylquinoline-4-carboxamide;  
 (R,S)-N-[α-(methoxycarbonyl)benzyl]-3-methyl-2-phenylquinoline-4-carboxamide;  
 (R,S)-N-(α-ethylbenzyl)-3-methyl-2-phenylquinoline-4-carboxamide;  
 (R,S)-N-[α-(methoxycarbonyl)benzyl]-7-chloro-2-phenylquinoline-4-carboxamide;  
 (R,S)-N-[α-(methoxycarbonyl)benzyl]-6-methyl-2-phenylquinoline-4-carboxamide;  
 (R,S)-N-[α-(methoxymethyl)benzyl]-2-phenylquinoline-4-carboxamide;  
 (R,S)-N-[α-(methoxycarbonyl)benzyl]-6-chloro-2-phenylquinoline-4-carboxamide;  
 (R,S)-N-[α-(methoxycarbonyl)benzyl]-3-ethyl-2-phenylquinoline-4-carboxamide;  
 (R,S)-N-(α-n-propylbenzyl)-2-phenylquinoline-4-carboxamide;  
 (R,S)-N-(α-ethylbenzyl)-3-ethyl-2-phenylquinoline-4-carboxamide;  
 (R,S)-N-α-ethylbenzyl)-3-phthalimido-2-phenylquinoline-4-carboxamide;  
 (R,S)-N-(α-ethylbenzyl)-3-n-propyl-2-phenylquinoline-4-carboxamide;  
 (−)-(S)-N-(α-ethylbenzyl)-6-bromo-3-methyl-2-(4-bromophenyl)quinoline-4-carboxamide;  
 (−)-(S)-N-(α-ethylbenzyl)-6-bromo-3-methyl-2-phenylquinoline-4-carboxamide;  
 (R,S)-N-[α-(methoxycarbonyl)benzyl]-6-methoxy-2-phenylquinoline-4-carboxamide;  
 (R,S)-N-[α-(methoxycarbonyl)benzyl]-2-(2-benzofuryl)quinoline-4-carboxamide;  
 (R,S)-N-[(1,2-diphenyl)ethyl]-2-phenylquinoline-4-carboxamide;  
 (R,S)-N-(α-trifluoromethylbenzyl)-2-phenylquinoline-4-carboxamide;  
 (−)-(S)-N-(α-ethylbenzyl)-3-methoxy-2-phenylquinoline-4-carboxamide;  
 (−)-(S)-N-(α-ethylbenzyl)-3-ethyl-2-phenylquinoline-4-carboxamide;  
 (R,S)-N-[α-(ethyl)-4-chlorobenzyl]-2-phenylquinoline-4-carboxamide;  
 (R,S)-N-[α-(methoxycarbonyl)benzyl]-N-methyl-2-phenylquinoline-4-carboxamide;  
 (R,S)-N-[α-(methoxycarbonyl)benzyl]-2-(3-thienyl)quinoline-4-carboxamide;  
 (R,S)-N-[α-(methoxycarbonyl)benzyl]-5,6-dihydrobenzo[a]acridine-7-carboxamide;  
 (R,S)-N-[α-(methoxycarbonyl)benzyl]-2-(2-pyrryl)quinoline-4-carboxamide;  
 (R,S)-N-[α-(methoxycarbonyl)benzyl]-2-(2-thiazolyl)quinoline-4-carboxamide;  
 (R,S)-N-(1-indanyl)-2-phenylquinoline-4-carboxamide;  
 (R,S)-N-(α-n-butylbenzyl)-2-phenylquinoline-4-carboxamide;  
 (R,S)-N-[α-(methoxycarbonyl)benzyl]-2-(4-methylphenyl)quinoline-4-carboxamide;  
 (R,S)-N-α-heptylbenzyl)-2-phenylquinoline-4-carboxamide;  
 (R,S)-N-[α-(methoxycarbonyl)benzyl]-2-(2-methylphenyl)quinoline-4-carboxamide;  
 (R,S)-N-[α-(methoxycarbonyl)benzyl]-2-(4-methoxyphenyl)quinoline-4-carboxamide;  
 N-(1-phenylcyclopentyl)-2-phenylquinoline-4-carboxamide;  
 (R,S)-N-[α-(methoxycarbonyl)benzyl]-2-(4-hydroxyphenyl)quinoline-4-carboxamide;  
 (R,S)-N-[α-(methoxycarbonyl)benzyl]-2-(3,4-methylendioxyphenyl)quinoline-4-carboxamide;  
 N-(α,α-dimethylbenzyl)-2-phenylquinoline-4-carboxamide;  
 (R,S)-N-[α-(ethyl)4-methylbenzyl]-2-phenylquinoline-4-carboxamide;  
 (R,S)-N-[α-(methoxycarbonyl)benzyl]-2-(3-pyrryl)quinoline-4-carboxamide;  
 (R,S)-N-[α-(methoxycarbonyl)benzyl]-2-(3,4-dichlorophenyl)quinoline-4-carboxamide;  
 (−)-(R)-N-[α-(aminomethyl)benzyl]-2-phenylquinoline-4-carboxamide;  
 (−)-(S)-N-(α-ethylbenzyl)-3-amino-2-phenylquinoline-4-carboxamide;  
 (−)-(S)-N-(α-ethylbenzyl)-3-chloro-2-phenylquinoline-4-carboxamide;  
 (−)-(S)-N-(α-ethylbenzyl)-3-bromo-2-phenylquinoline-4-carboxamide;  
 (R,S)-N-(α-iso-propylbenzyl)-2-phenylquinoline-4-carboxamide;  
 (−)-(S)-N-(α-ethylbenzyl)-2-phenylquinoline-4-carboxamide;  
 (+)-(R)-N-(α-ethylbenzyl)-2-phenylquinoline-4-carboxamide;  
 (R,S)-N-[α-(methoxycarbonyl)benzyl]-6-fluoro-2-phenylquinoline-4-carboxamide;  
 (R,S)-N-[α-(methoxycarbonyl)benzyl]-2-cyclohexylquinoline-4-carboxamide;  
 (R,S)-N-[α-(methoxycarbonyl)benzyl]-2-(3-chlorophenyl)quinoline-4-carboxamide;  
 (R,S)-N-[α-(methoxycarbonyl)benzyl]-2-(2-chlorophenyl)quinoline-4-carboxamide;  
 (R,S)-N-(α-ethylbenzyl)-3-hydroxy-2-phenylquinoline-4-carboxamide;  
 (R,S)-N-[(α-(methoxycarbonyl)benzyl]-8-acetyloxy-2-phenylquinoline-4-carboxamide;  
 (R,S)-N-[α-(methoxycarbonyl)benzyl]-8-hydroxy-2-phenylquinoline-4-carboxamide;  
 (R,S)-N-[α-(methoxycarbonyl)benzyl]-2-(2,4-dichlorophenyl)quinoline-4-carboxamide;  
 (−)-(R)-N-[α-(methoxycarbonyl)-4-hydroxybenzyl]-2-phenylquinoline-4-carboxamide hydrochloride;  
 N-diphenylmethyl-2-phenylquinoline-4-carboxamide;  
 (−)-(S)-N-(α-ethylbenzyl)-3-hydroxy-2-phenylquinoline-4-carboxamide;  
 (+)-(R)-N-(α-ethylbenzyl)-3-hydroxy-2-phenylquinoline-4-carboxamide;  
 (−)-(R)-N-[α-(methoxycarbonyl)benzyl]-3-hydroxy-2-phenylquinoline-4-carboxamide:  
 (−)-(R)-N-[α-(dimethylaminomethyl)benzyl]2-phenylquinoline-4-carboxamide;  
 (R,S)-N-[α-(dimethylaminocarbonyl)benzyl]-2-phenylquinoline-4-carboxamide;  
 (R,S)-N-[α-(aminocarbonyl)benzyl]-2-phenylquinoline-4-carboxamide;  
 (R,S)-N-[α-(1-pyrrolidinylcarbonyl)benzyl]-2-phenylquinoline-4-carboxamide;  
 (−)-(R)-N-[α-(carboxy)benzyl]-2-phenylquinoline-4-carboxamide hydrochloride;  
 (R,S)-N-[α-(methoxycarbonyl)benzyl]-2-(4-chlorophenyl)quinoline-4-carboxamide;  
 (R)-N-[α-(methoxycarbonyl)-4-methoxybenzyl]-2-phenylquinoline-4-carboxamide;  
 (R,S)-N-[α-(methoxycarbonyl)-α-(methyl)benzyl]-N-methyl-2-phenylquinoline-4-carboxamide hydrochloride;  
 (R,S)-N-[α-(methylcarbonyl)benzyl]-2-phenylquinoline-4-carboxamide;  
 (R,S)-N-[α-(2-hydroxyethyl)benzyl]-2-phenylquinoline-4-carboxamide;  
 (−)-(S)-N-(α-ethylbenzyl)-3-(2-dimethylamioethoxy)-2-phenylquinoline-4-carboxamide hydrochloride;  
 (−)-(S)-N-(α-ethylbenzyl)-3-acetylamino-2-phenylquinoline-4-carboxamide;  
 (−)-(S)-N-(α-ethylbenzyl)-3-(3-dimethylaminopropoxy)-2-phenylquinoline-4-carboxamide hydrochloride;  
 (−)-(S)-N-(α-ethylbenzyl)-3-[2-(1-phthaloyl)ethoxy]-2-phenylquinoline-4-carboxamide hydrochloride;  
 (−)-(S)-N-(α-ethylbenzyl)-3-(2-aminoethoxy)-2-phenylquinoline-4-carboxamide hydrochloride;  
 (+)-(S)-N-(α-ethylbenzyl)-3-[2-(1-pyrrolidinyl)ethoxy]-2-phenylquinoline-4-carboxamide hydrochloride;  
 (−)-(S)-N-(α-ethylbenzyl)-3-(dimethylaminoacetylamino)-2-phenylquinoline-4-carboxamide;  
 N-(α,α-dimethylbenzyl)-3-hydroxy-2-phenylquinoline-4-carboxamide;  
 N-(α,α-dimethylbenzyl)-3-amino-2-phenylquinoline-4-carboxamide;  
 (−)-(S)-N-(α-ethylbenzyl)-5-methyl-2-phenylquinoline-4-carboxamide;  
 (R,S)-N-[α-(1-hydroxyethyl)benzyl]-3-methyl-2-phenylquinoline-4-carboxamide;  
 (R,S)-N-[α-(methylcarbonyl)benzyl]-3-methyl-2-phenylquinoline-4-carboxamide;  
 (R,S)-N-[α-(ethyl)-4-pyridylmethyl]-2-phenylquinoline-4-carboxamide;  
 (R,S)-N-[α-(ethyl)-2-thienylmethyl]-2-phenylquinoline-4-carboxamide;  
 (+)-(S)-N-(α-ethylbenzyl)-3-dimethylaminomethyl-2-phenylquinoline-4-carboxamide hydrochloride;  
 (S)-N-(α-ethylbenzyl)-3-methyl-7-methoxy-2-phenylquinoline-4-carboxamide;  
 (S)-N-(α-ethylbenzyl)-3-amino-5-methyl-2-phenylquinoline-4-carboxamide;  
 (S)-N-(α-ethylbenzyl)-3-methoxy-5-methyl-2-phenylquinoline-4-carboxamide;  
 
     
     
         12 . A process for preparing a compound of formula (I) as defined in  claim 1 , or a solvate or salt thereof which comprises reacting a compound of formula (III)  
       
         
           
           
               
               
           
         
         in which R′, R′ 1 , R′ 2  and Ar′ are R, R 1 , R 2  and Ar as defined for formula (I) or a group or atom convertible to R, R 1 , R 2  and Ar, with a compound of formula (II)  
         
           
             
             
                 
                 
             
           
         
         or an active derivative thereof, in which R′ 3 , R′ 4 , R′ 5  and X′ are R 3 , R 4 , R 5  and X as defined for formula (I) or a group convertible to R 3 , R 4 , R 5  and X, to form a compound of formula (Ic)