Tetra-substituted phenyl derivatives and processes for their preparation

Abstract

Compounds of general formula (1): are described wherein ═W— is (1) ═C(Y)— where Y is a halogen atom, or an alkyl, or -X a R 1 group where X a is —O—, —S(O) m — [where m is zero or an integer of value 1 or 2], or N(R a )- [where R a is a hydrogen atom or an optionally substituted alkyl group] and R 1 is a hydrogen atom or an optionally substituted alkyl group or, (2) ═N—; X is as described above for X a or is a chain —CR═C(R b )— or [—CH(R)] q —CH(R b )- where R is a hydrogen or a fluorine atom or a methyl group, R b is as described below for R 2 and q is zero or the integer 1; R 2 is (1) an optionally substituted alkyl, alkenyl, cycloalkyl or cycloalkenyl group when X is —O—, —S(O) m — or —N(R a )-; or is (2) when X is other than —O—, —S(O) m — or —N(R a )-, a hydrogen atom, or an optionally substituted straight or branched alkyl, alkenyl or alkynyl, alkoxy, alkylthio, —CO 2 R 9 (where R 9 is a hydrogen atom or an optionally substituted alkyl, aryl or aralkyl group), —CONR 10 R 11 (where R 10 and R 11 which may be the same or different is as described for R 9 ), —CSNR 10 R 11 , —CN or NO 2 group; or R 2 and R b , together with the carbon atom to which they are both attached, are linked to form an optionally substituted cycloalkyl or cycloalkenyl group optionally containing one or more X a atoms or groups; R 3 is an atom or group R 13 or -L 1 R 13 where L 1 is a linker group and R 13 is various substituents; R 4 is a hydrogen atom or is as defined for R 6 ; R 5 is a hydrogen or a fluorine atom, or an OR c group where R c is a hydrogen atom or an optionally substituted straight or branched alkyl, alkenyl, alkoxyalkyl, alkanoyl, formyl, carboxamido, thiocarboxamido, cycloalkyl, or cycloalkenyl group; R 6 is a group —(CH 2 ) n Ar where Ar is an optionally substituted monocyclic or bicyclic aryl ring optionally interrupted by one or more heteroatoms —O—, —S— or —N— and n is zero or the integer 1, 2 or 3; R 7 and R 8 , which may be the same or different, is a hydrogen or a fluorine atom, or an optionally substituted straight or branched alkyl group; and the salts, solvates, prodrugs, hydrates and N-oxides thereof. Compounds according to the invention are phosphodiesterase type IV inhibitors and are useful in the prophylaxis and treatment of disease such as asthma where an unwanted inflammatory response or muscular spasm is present.

1 . A compound of formula (1)  
       
         
           
           
               
               
           
         
       
       wherein 
 ═W— is (1) ═C(Y)— where Y is a halogen atom, or an alkyl, or -X a R 1  group where X a  is —O—, —S(O) m — [where m is zero or an integer of value 1 or 2], or —N(R a )- [where R a  is a hydrogen atom or an optionally substituted alkyl group] and R 1  is an optionally substituted alkyl group or, (2) ═N—;  
 X is as described above for X a  or is a chain —CR═C(R b )- or —[—CH(R)] q —CH(R b )- where R is a hydrogen or a fluorine atom or a methyl group, R b  is as described below for R 2  and q is zero or the integer 1;  
 R 2  is (1) an optionally substituted alkyl, alkenyl, cycloalkyl or cycloalkenyl group when X is —O—, —S(O) m — or —N(R a )-; or when X is —CR═C(R b )- or —[—CH(R)] q CH(R b )- is (2) a hydrogen atom, or an optionally substituted straight or branched alkyl, alkenyl or alkynyl, alkoxy, alkylthio, —CO 2 R 9  (where R 9  is a hydrogen atom or an optionally substituted alkyl, aryl or aralkyl group), —CONR 10 R 11  (where R 10  and R 11  which may be the same or different is as described for R 9 ), —CSNR 10 R 11 , —CN or NO 2  group; or R 2  and R b , together with the carbon atom to which they are both attached, are linked to form an optionally substituted cycloalkyl or cycloalkenyl group optionally containing one or more X a  atoms or groups;  
 R 3  is an atom or group R 13  or -L 1 R 13  where L 1  is a linker group and R 13  is a halogen atom or an Alk 1  [where Alk 1  is an optionally substituted straight or branched C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl group optionally interrupted by one, two, or three —O—, or —S— atoms or —S(O) p —, [where p is an integer 1 or 2], or —N(R a )- groups], or an amino (—NH 2 ), substituted amino, nitro, cyano, hydroxyl (—OH), substituted hydroxyl, cycloalkyl, cycloalkoxy, formyl [HC(O)—], carboxyl (—CO 2 H), esterified carboxyl, thiol (—SH), substituted thiol, —C(O)Alk 1 , —SO 3 H, —SO 2 Alk 1 , —SO 2 NH 2 , —SO 2 NHAlk 1 , —SO 2 N[Alk 1 ] 2 , —SO 2 NHAr [where Ar is as defined below for R 6 ], —SO 2 N(Alk 1 )Ar, —CONH 2 , —CONHAlk 1 , —CON[Alk 1 ] 2 , —CONHAr, —CON(Alk 1 )Ar, —NHSO 2 H, —NAlk 1 SO 2 H, —NHSO 2  Alk 1 , —NAlk 1 SO 2 Alk 1 , —N[SO 2 Alk 1 ] 2 , —N(Alk 1 )SO 2 N(Alk 1 )Ar, —NHSO 2 NH 2 , —N(Alk 1 )SO 2 NH 2 , —NHSO 2 NHAlk 1 , —N(Alk 1 )SO 2 NHAlk 1 , —NHSO 2 N[Alk 1 ] 2 , —NAlk 1  SO 2 N[Alk 1 ] 2 , —NHSO 2  NHAr, —N(Alk 1 )SO 2 N HAr, —NHSO 2 N(Alk 1 )Ar, —N(Alk 1 )SO 2 N(Alk 1 )Ar, —NHC(O)Alk 1 , —N(Alk 1 )C(O)Alk 1 , —N[C(O)Alk 1 ] 2 , —NHC(O)OAlk 1 , —N(Alk 1 )C(O)OAlk 1 , —Ar, -Het [where Het is a C 5-7  heterocycloalkyl group], —CONHet 1  [where —NHet 1  is a C 5-7  cycloamino group optionally containing one or more —O— or —S— atoms or —N(R a )— groups], —SO 2 NHet 1 , —NHSO 2 NHet 1 , —CSAlk 1 , —CSNH 2 , —CSNHAlk 1 , —CSN[Alk 1 ] 2 , —CSNHAr, —CSN(Alk 1  )Ar, —NHC(S)Alk 1 , —N(Alk 1 )C(S)Alk 1 , —CSNHet 1  group, —N[C(S)Alk 1 ] 2 , —N[C(O)Alk 1 ]SO 2 Alk 1 , —N[C(S)Alk 1 ]SO 2 Alk 1 , —NHC(O)NH 2 , —NHC(O)NHAlk 1 , —NHC(O)N[Alk 1 ] 2 , —N(Alk 1 )CONH 2 , —N(Alk 1 )C(O)NHAlk 1 , —N(Alk 1 )C(O)N[Alk 1 ] 2 , —NHC(S)NH 2 , —NHC(S)NHAlk 1 , —NHC(S)N[Alk 1 ] 2 , —N (Alk 1 )CSNH 2 , —N(Alk 1  )C(S)NHAlk 1 , or —N(Alk 1 )C(S)N[Alk 1 ] 2 , group;  
 R 4  is a hydrogen atom or is as defined for R 6 ;  
 R 5  is a hydrogen or a fluorine atom, or an OR c  group where R c  is a hydrogen atom or an optionally substituted straight or branched alkyl, alkenyl, alkoxyalkyl, alkanoyl, formyl, carboxamido, thiocarboxamido, cycloalkyl, or cycloalkenyl group;  
 R 6  is a group —(CH 2 ) n Ar where Ar is an optionally substituted monocyclic or bicyclic aryl ring optionally interrupted by one or more heteroatoms —O—, —S— or —N— and n is zero or the integer 1, 2 or 3;  
 R 7  and R 8 , which may be the same or different, is a hydrogen or a fluorine atom, or an optionally substituted straight or branched alkyl group;  
 and the salts, solvates, prodrugs, hydrates and N-oxides thereof.  
 
     
     
         2 . A compound according to    claim 1    wherein ═W— is ═C(X a R 1 )- and X is —O—, —S(O) m — or —N(R a )-.  
     
     
         3 . A compound according to    claim 2    wherein R 2  is an optionally substituted cyclopentyl group.  
     
     
         4 . A compound according to    claim 2    wherein R 5 , R 7  and R 8  is each a hydrogen atom.  
     
     
         5 . A compound according to    claim 4    wherein R 4  is a hydrogen atom or a phenyl or substituted phenyl group.  
     
     
         6 . A compound according to    claim 5    wherein R 6  is an optionally substituted pyridyl group.  
     
     
         7 . A compound according to    claim 6    wherein R 3  is a halogen atom, or an alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, heteroaryl or heteroaralkyl group.  
     
     
         8 . A compound which is: 
 4-[2-(5-Cyclopentyloxy-2-iodo-4-methoxyphenyl)ethyl]pyridine;    4-[2-(5-Cyclopentyloxy-4-methoxy-2-phenyl)ethyl]pyridine;    4-{2-[5-Cyclopentyloxy-4-methoxy-2-(2-phenylethenyl)phenyl]ethyl}pyridine;    4-{2-[5-Cyclopentyloxy-4-methoxy-2-(2-phenylethyl)phenyl]ethyl}pyridine;    4-{2-[5-Cyclopentyloxy-4-methoxy-2-(1 -naphthyl)phenyl]ethyl}pyridine;    4-{2-[5-Cyclopentyloxy-4-methoxy-2-(2-naphthyl)phenyl]ethyl}pyridine;    4-{2-[5-Cyclopentyloxy-4-methoxy-2-(3-pyridyl)phenyl]ethyl}pyridine;    or each isomer or enantiomer, and/or the salts, hydrates, solvates, prodrugs and N-oxides thereof.    
     
     
         9 . A pharmaceutical composition comprising a compound of formula (1)  
       
         
           
           
               
               
           
         
       
       wherein 
 ═W— is (1) ═C(Y)— where Y is a halogen atom, or an alkyl, or -X a R 1  group where X a  is —O—, —S(O) m — [where m is zero or an integer of value 1 or 2], or —N(R a )- [where R a  is a hydrogen atom or an optionally substituted alkyl group] and R 1  is an optionally substituted alkyl group or, (2) ═N—;  
 X is as described above for X a  or is a chain CR═C(R b )- or —[—CH(R)] q —CH(R b )- where R is a hydrogen or a fluorine atom or a methyl group, R b  is as described below for R 2  and q is zero or the integer 1;  
 R 2  is (1) an optionally substituted alkyl, alkenyl, cycloalkyl or cycloalkenyl group when X is —O—, —S(O) m — or —N(R a )-; or when X is —CR═C(R b )- or —[—CH(R)] q CH(R b )- is (2) a hydrogen atom, or an optionally substituted straight or branched alkyl, alkenyl or alkynyl, alkoxy, alkylthio, —CO 2 R 9  (where R 9  is a hydrogen atom or an optionally substituted alkyl, aryl or aralkyl group), —CONR 10 R 11  (where R 10  and R 11  which may be the same or different is as described for R 9 ), —CSNR 10 R 11 , —CN or NO 2  group; or R 2  and R b , together with the carbon atom to which they are both attached, are linked to form an optionally substituted cycloalkyl or cycloalkenyl group optionally containing one or more X a  atoms or groups;  
 R 3  is an atom or group R 13  or -L 1 R 13  where L 1  is a linker group and R 13  is a halogen atom or an Alk 1  [where Alk 1  is an optionally substituted straight or branched C 1-6  alkyl, C 2-6 alkenyl or C 2-6 alkynyl group optionally interrupted by one, two, or three —O—, or —S— atoms or —S(O) p —, [where p is an integer 1 or 2], or —N(R a )- groups], or an amino (—NH 2 ), substituted amino, nitro, cyano, hydroxyl (—OH), substituted hydroxyl, cycloalkyl, cycloalkoxy, formyl [HC(O)—], carboxyl (—CO 2 H), esterified carboxyl, thiol (—SH), substituted thiol, —C(O)Alk 1 , —SO 3 H, —SO 2 Alk 1 , —SO 2 NH 2 , —SO 2 NHAlk 1 , —SO 2 N[Alk 1 ] 2 , —SO 2 NHAr [where Ar is as defined below for R 6 ], —SO 2 N(Alk 1 )Ar, —CONH 2 , —CONHAlk 1 , —CON[Alk 1 ] 2 , —CONHAr, —CON(Alk 1 )Ar, —NHSO 2 H, —NAlk 1 SO 2 H, —NHSO 2 Alk 1 , —NAlk 1 SO 2 Alk 1 , —N[SO 2 Alk 1 ] 2 , —N(Alk 1 )SO 2 N(Alk 1 )Ar, —NHSO 2 NH 2 , —N(Alk 1 )SO 2 NH 2 , —NHSO 2 NHAlk 1 , —N(Alk 1 )SO 2 NHAlk 1 , —NHSO 2 N[Alk 1 ] 2 , —NAlk 1 SO 2 N[Alk 1 ] 2 , —NHSO 2 NHAr, —N(Alk 1 )SO 2 NHAr, —NHSO 2 N(Alk 1 )Ar, —N(Alk 1 )SO 2 N(Alk 1 )Ar, —NHC(O)Alk 1 , —N(Alk 1 )C(O)Alk 1 , —N[C(O)Alk 1 ] 2 , —NHC(O)OAlk 1 , —N(Alk 1 )C(O)OAlk 1 , —Ar, —Het [where Het is a C 5-7  heterocycloalkyl group], —CONHet 1  [where —NHet 1  is a C 5-7  cycloamino group optionally containing one or more —O— or —S— atoms or —N(R a )— groups], —SO 2 NHet 1 , —NHSO 2 NHet 1 , —CSAlk 1 , —CSNH 2 , —CSNHAlk 1 , —CSN[Alk 1 ] 2 , —CSNHAr, —CSN(Alk 1 )Ar, —NHC(S)Alk 1 , —N(Alk 1 )C(S)Alk 1 , —CSNHet 1  group, —N[C(S)Alk 1 ] 2 , —N[C(O)Alk 1 ]SO 2 Alk 1 , —N[C (S)Alk 1 ]SO 2 Alk 1 , —NHC(O)NH 2 , —NHC(O)NHAlk 1 , —NHC(O)N[Alk 1 ] 2 , —N(Alk)CONH 2 , —N(Alk 1 )C(O)NHAlk 1 , —N(Alk 1 )C(O)N[Alk 1 ] 2 , —NHC(S)NH 2 , —NHC(S)NHAlk 1 , —NHC(S)N[Alk 1 ] 2 , —N(Alk 1 )CSNH 2 , —N(Alk 1 )C(S)NHAlk 1 , or —N(Alk 1 )C(S)N[Alk 1 ] 2 , group;  
 R 4  is a hydrogen atom or is as defined for R 6 ;  
 R 5  is a hydrogen or a fluorine atom, or an OR c  group where R c  is a hydrogen atom or an optionally substituted straight or branched alkyl, alkenyl, alkoxyalkyl, alkanoyl, formyl, carboxamido, thiocarboxamido, cycloalkyl, or cycloalkenyl group;  
 R 6  is a group —(CH 2 ) n Ar where Ar is an optionally substituted monocyclic or bicyclic aryl ring optionally interrupted by one or more heteroatoms —O—, —S— or —N— and n is zero or the integer 1, 2 or 3;  
 R 7  and R 8 , which may be the same or different, is a hydrogen or a fluorine atom, or an optionally substituted straight or branched alkyl group;  
 and the salts, solvates, prodrugs, hydrates and N-oxides thereof.  
 
     
     
         10 . A process for the preparation of a compound of formula (1)  
       
         
           
           
               
               
           
         
       
       wherein 
 ═W— is (1) ═C(Y)— where Y is a halogen atom, or an alkyl, or -X a R 1  group where X a  is —O—, —S(O) m — [where m is zero or an integer of value 1 or 2], or —N(R a )- [where R a  is a hydrogen atom or an optionally substituted alkyl group] and R 1  is an optionally substituted alkyl group or, (2) ═N—;  
 X is as described above for X a  or is a chain —CR═C(R b )- or —[—CH(R)] q CH(R b )- where R is a hydrogen or a fluorine atom or a methyl group, R b  is as described below for R 2  and q is zero or the integer 1;  
 R 2  is (1) an optionally substituted alkyl, alkenyl, cycloalkyl or cycloalkenyl group when X is —O—, S(O) m — or —N(R a )—; or when X is —CR═C(R b )- or —[—CH(R)] q CH(R b )- is (2) a hydrogen atom, or an optionally substituted straight or branched alkyl, alkenyl or alkynyl, alkoxy, alkylthio, —CO 2 R 9  (where R 9  is a hydrogen atom or an optionally substituted alkyl, aryl or aralkyl group), —CONR 10 R 11  (where R 10  and R 11  which may be the same or different is as described for R 9 ), —CSNR 10 R 11 , —CN or NO 2  group; or R 2  and R b , together with the carbon atom to which they are both attached, are linked to form an optionally substituted cycloalkyl or cycloalkenyl group optionally containing one or more X a  atoms or groups;  
 R 3  is an atom or group R 13  or -L 1 R 13  where L 1  is a linker group and R 13  is a halogen atom or an Alk 1  [where Alk 1  is an optionally substituted straight or branched C 1-6  alkyl, C 2-6 alkenyl or C 2-6 alkynyl group optionally interrupted by one, two, or three —O—, or —S— atoms or —S(O) p —, [where p is an integer 1 or 2], or —N(R a )- groups], or an amino (—NH 2 ), substituted amino, nitro, cyano, hydroxyl (—OH), substituted hydroxyl, cycloalkyl, cycloalkoxy, formyl [HC(O)—], carboxyl (—CO 2 H), esterified carboxyl, thiol (—SH), substituted thiol, —C(O)Alk 1 , —SO 3 H, —SO 2 Alk 1 , —SO 2 NH 2 , —SO 2 NHAlk 1 , —SO 2 N[Alk 1 ] 2 , —SO 2 NHAr [where Ar is as defined below for R 6 ], —SO 2 N(Alk 1 )Ar, —CONH 2 , —CONHAlk 1 , —CON[Alk 1 ] 2 , —CONHAr, -CON(Alk 1 )Ar, —NHSO 2 H, —NAlk 1 SO 2 H, —NH SO 2  Alk 1 , —NAlk 1 SO 2 Alk 1 , —N[SO 2 Alk 1 ] 2 , —N(Alk 1 )SO 2 N(Alk 1 )Ar, —NHSO 2 NH 2 , —N(Alk 1 )SO 2 NH 2 , —NHSO 2 NHAlk 1 , —N(Alk 1 )SO 2 NHAlk 1 , —NHSO 2 N[Alk 1 ] 2 , —NAlk 1 SO 2 N[Alk 1 ] 2 , —NHSO 2 NHAr, —N(Alk 1 )SO 2 N HAr, —NHSO 2 N(Alk 1 )Ar, —N(Alk 1 )SO 2 N(Alk 1 )Ar, —NHC(O)Alk 1 , —N(Alk 1 )C(O)Alk 1 , —N[C(O)Alk 1 ] 2 , —NHC(O)OAlk 1 , —N(Alk 1 )C(O)OAlk 1 , —Ar, -Het [where Het is a C 5-7  heterocycloalkyl group], —CONHet 1  [where —NHet 1  is a C 5-7  cycloamino group optionally containing one or more —O— or —S— atoms or —N(R a )- groups], —SO 2 NHet 1 , —NHSO 2 NHet 1 , —CSAlk 1 , —CSNH 2 , —CSNHAlk 1 , —CSN[Alk 1 ] 2 , —CSNHAr, —CSN(Alk 1 )Ar, —NHC(S)Alk 1 , —N(Alk 1 )C(S)Alk 1 , —CSNHet 1  group, —N[C(S)Alk 1 ] 2 , —N[C(O)Alk 1 SO 2 Alk 1 , —N[C(S)Alk 1 ]SO 2 Alk 1 , —NHC(O)NH 2 , —NHC(O)NHAlk 1 , —NHC(O)N(Alk 1 ] 2 , —N(Alk 1 )CONH 2 , —N(Alk 1 )C(O)NHAlk 1 , —N(Alk 1 )C(O)N[Alk 1 ] 2 , —NHC(S)NH 2 , —NHC(S)NHAlk 1 , —NHC(S)N[Alk 1 ] 2 , —N(Alk 1 )CSNH 2 , —N(Alk 1 )C(S)NHAlk 1 , or —N(Alk 1 )C(S)N[Alk 1 ] 2 , group;  
 R 4  is a hydrogen atom or is as defined for R 6 ;  
 R 5  is a hydrogen or a fluorine atom, or an OR c  group where R c  is a hydrogen atom or an optionally substituted straight or branched alkyl, alkenyl, alkoxyalkyl, alkanoyl, formyl, carboxamido, thiocarboxamido, cycloalkyl, or cycloalkenyl group;  
 R 6  is a group —(CH 2 ) n Ar where Ar is an optionally substituted monocyclic or bicyclic aryl ring optionally interrupted by one or more heteroatoms —O—, —S— or —N— and n is zero or the integer 1, 2 or 3;  
 R 7  and R 8 , which may be the same or different, is a hydrogen or a fluorine atom, or an optionally substituted straight or branched alkyl group;  
 and the salts, solvates, prodrugs, hydrates and N-oxides thereof.  
 which comprises in a final step  
 a) cross-coupling an intermediate of formula (3)  
                     
  where Hal is an iodine or bromine atom with a coupling reagent to give a compound of formula (1) where R 3  is a group L 1 R 13 ;  
 b) hydrogenation of a compound of formula (16)  
                     
  to give a compound of formula (1) wherein R 8  and R 5  is each a hydrogen atom;  
 c) alkylation of a compound of formula (17)  
                     
  where X is —O—, —S— or —N(R a )- with a reagent R 2 L where L is a leaving group;  
 d) coupling an intermediate of formula (19)  
                     
  wherein R is a hydrogen atom or a methyl group;  
 with an olefination agent to give a compound of formula (1) wherein X is a chain —C(R)═C(R b )- in which R is a hydrogen atom or a methyl group.  
 e) alkylation of a compound of formula (25)  
                     
  with a reagent R 1 L where L is a leaving group to give a compound of formula (1) in which ═W— is ═C(OR 1 )—;  
 f) halogenation of a compound of formula (4)  
                     
  to give a compound of formula (1) where R 3  is a halogen atom; or  
 g) interconverting a compound of formula (1) to another compound of formula (1).