Tri-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 —XR a group where X is —O—, —S(O) m —[where m is zero or an integer of value 1 or 2], or —N(R b )—[where R b is a hydrogen atom or an optionally substituted alkyl group] and R a is a hydrogen atom or an optionally substituted alkyl group or, (2) ═N—; L is (1) a —C(R)═C(R 1 )(R 2 ) or [—CH(R)] n CH(R 1 )(R 2 ) group; is (2) a —(X a ) n Alk′Ar′, or Alk′X a Ar′ group; or is (3) X a R 1 ; Z is a group (A), (B), (C) or (D): wherein Ar is a monocyclic or bicyclic aryl group optionally containing one or more heteroatoms selected from oxygen, sulphur or nitrogen atoms; Z 1 is a group —NR 12 C(O)—[where R 12 is a hydrogen atom or an optionally substituted alkyl or (Alk) t Ar group], —C(O)NR 12 —, —NR 12 C(S)—, —C(S)NR 12 —, —C≡C—, —NR 12 SO 2 —, or —SO 2 NR 12 —; Alk is an optionally substituted straight or branched alkyl chain optionally interrupted by an atom or group X; t is zero or an integer of value 1, 2 or 3; R 3 is a hydrogen or a fluorine atom or an optionally substituted straight or branched alkyl group or an OR 11 group [where R 11 is a hydrogen atom or an optionally substituted alkyl, alkenyl, alkoxyalkyl, alkanoyl, formyl, carboxamido or thiocarboxamido group]; R 4 is a hydrogen atom or an optionally substituted alkyl, —CO 2 R 8 , —CSNR 9 R 10 , —CN, —CH 2 CN, or —(CH 2 ) t Ar group where t is zero or an integer of value 1, 2 or 3 and Ar is a monocyclic or bicyclic aryl group optionally containing one or more heteroatoms selected from oxygen, sulphur or nitrogen atoms; provided that when L is a group of type (2) or (3) above then Z is a group of type (A) or type (B) in which R 4 is a —(CH 2 ) t Ar group; R 5 is a group —(CH 2 ) t Ar; R 6 is a hydrogen or a fluorine atom, or an optionally substituted alkyl or —CO 2 R 8 , —CONR 9 R 10 , —CSNR 9 R 10 , —CN or —CH 2 CN group; R 7 is a hydrogen or a fluorine atom, an optionally substituted straight or branched alkyl group, or an OR c group where R c is a hydrogen atom or an optionally substituted alkyl or alkenyl group, alkoxyalkyl, alkanoyl, formyl, carboxamido or thiocarboxamido group; and the salts, solvates, hydrates, prodrugs 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 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 —XR a  group where X is —O—, —S(O) m —[where m is zero or an integer of value 1 or 2], or —N(R b )— where R b  is a hydrogen atom or an optionally substituted alkyl group] and R a  is a hydrogen atom or an optionally substituted alkyl group or, (2) ═N—;  
 L is (1) a —C(R)═C(R 1 )(R 2 ) or [—CH(R)] n CH(Rl)(R 2 ) group where R is a hydrogen or a fluorine atom or a methyl group, and R 1  and R 2 , which may be the same or different, is each a hydrogen or fluorine atom or an optionally substituted alkyl, alkenyl, alkynyl, alkoxy, alkylthio, —CO 2 R 8  [where R 8  is a hydrogen atom or an optionally substituted alkyl, aralkyl or aryl group], —CONR 9 R 10  [where R 9  and R 10 , which may be the same or different are defined for R 8 ], —CSNR 9 R 10 ,—CN or —NO 2  group, or R 1  and R 2 , together with the C atom to which they are attached are linked to form an optionally substituted cycloalkyl, cycloalkenyl or heterocycloaliphatic group and n is zero or the integer 1; or is (2)—(X a ) n Alk′Ar′, or -Alk′X a Ar′ where X a  is a group X, Ar′ is an optionally substituted heterocycloaliphatic, or an optionally substituted monocylic or bicyclic aryl group optionally containing one or more heteroatoms selected from oxygen, sulphur or nitrogen atoms, Alk′ is an optionally substituted straight or branched alkylene, alkenylene or alkynylene chain optionally interrupted by one or more L 1  atoms or groups [where L 1  is a linker atom or group] and n is zero or the integer 1; or is (3) X a R′ where R′ Ar′ or is an optionally substituted polycycloalkyl or polycycloalkenyl group optionally containing one or more —O—, or —S— atoms or —N(R b )— groups;  
 Z is a group (A), (B), (C) or (D):  
                     
 wherein  
 Ar is a monocyclic or bicyclic aryl group optionally containing one or more heteroatoms selected from oxygen, sulphur or nitrogen atoms;  
 Z′ is a group —NR 12 C(O)—[where R 12  is a hydrogen atom or an optionally substituted alkyl or (Alk) t Ar group], —C(O)NR 12 —, —NR 12 C(S)—, —C(S)NR 12 —, —C≡C—, —NR 12 SO 2 —, or —SO 2 NR 12 —;  
 Alk is an optionally substituted straight or branched alkyl chain optionally interrupted by an atom or group X;  
 t is zero or an integer of value 1, 2 or 3;  
 R 3  is a hydrogen or a fluorine atom or an optionally substituted straight or branched alkyl group or an OR 11  group (where R 11  is a hydrogen atom or an optionally substituted alkyl, alkenyl, alkoxyalkyl, alkanoyl, formyl, carboxamido or thiocarboxamido group];  
 R 4  is a hydrogen atom or an optionally substituted alkyl, —CO 2 R8, —CSNR 9 R 10 , —CN, —CH 2 CN, or —(CH 2 ) t Ar group where t is zero or an integer of value 1, 2 or 3 and Ar is a monocyclic or bicyclic aryl group optionally containing one or more heteroatoms selected from oxygen, sulphur or nitrogen atoms, provided that when L is a group of type (2) or (3) above then Z is a group of type (A) or type (B) in which R 4  is a —(CH 2 ) t Ar group;  
 R 5  is a group —(CH 2 ) t Ar;  
 R 6  is a hydrogen or a fluorine atom, or an optionally substituted alkyl or —CO 2 R8, —CONR 9 R 10 , —CSNR 9 R 10 , —CN or —CH 2 CN group;  
 R 7  is a hydrogen or a fluorine atom, an optionally substituted straight or branched alkyl group, or an OR c  group where R c  is a hydrogen atom or an optionally substituted alkyl or alkenyl group, alkoxyalkyl, alkanoyl, formyl, carboxamido or thiocarboxamido group; and the salts, solvates, hydrates, prodrugs and N-oxides thereof.  
 
     
     
         2 . A compound according to  claim 1  wherein W is a ═C(XRa)— group.  
     
     
         3 . A compound according to  claim 2  wherein L is a —C(R)═C(R 1 )(R 2 ) group in which R 1  and R 2 , together with the C atom to which they are attached are linked to form a cycloalkyl group.  
     
     
         4 . A compound according to  claim 1  wherein Z is a group (A) or (B), in which R 3 , R 6  and R 7  is each a hydrogen atom, R 4  is an aryl group and R 5  is a heteroaryl group.  
     
     
         5 . A compound according to  claim 4  wherein R 4  is an optionally substituted phenyl group and R 5  is an optionally substituted pyridyl group.  
     
     
         6 . A compound which is: 
 4-{2-[4-Methoxy-3-(phenylpentyloxy)phenyl]-2-phenylethyl}pyridine;    4-[2-(4-Methoxy-3-(3-thienyloxy)phenyl)-2-phenylethyl]pyridine;    4-{2-[3-(4-Biphenyloxy)-4-methoxyphenyl)-2-phenyl]ethyl}pyridine;    4-[2-(3-((2RS)-exo-Bicyclo[2.2.1 ]hept-2-yloxy)-4-methoxyphenyl)-2-phenylethyl]pyridine;    3-(3-Cyclopentylidenyl-4-methoxyphenyl)pyridine;    the resolved enantiomer; and the salts, solvates, hydrates, prodrugs and n-oxides thereof    
     
     
         7 . 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 —XR a  group where X is —O—, —S(O) m —[where m is zero or an integer of value 1 or 2], or —N(R b )—[where R b  is a hydrogen atom or an optionally substituted alkyl group] and R a  is a hydrogen atom or an optionally substituted alkyl group or, (2) ═N—;  
 L is (1) a —C(R)═C(R 1 )(R 2 ) or [—CH(R)] n CH(R 1 )(R 2 ) group where R is a hydrogen or a fluorine atom or a methyl group, and R 1  and R 2 , which may be the same or different, is each a hydrogen or fluorine atom or an optionally substituted alkyl, alkenyl, alkynyl, alkoxy, alkylthio, —CO 2 R 8  [where R 8  is a hydrogen atom or an optionally substituted alkyl, aralkyl or aryl group], —CONR 9 R 10  [where R 9  and R 10 , which may be the same or different are defined for R 8 ], —CSNR 9 R 10 ,—CN or —NO 2  group, or R 1  and R 2 , together with the C atom to which they are attached are linked to form an optionally substituted cycloalkyl, cycloalkenyl or heterocycloaliphatic group and n is zero or the integer 1; or is (2)—(X a ) n Alk′Ar′, or -Alk′X a Ar′ where X a  is a group X, Ar′ is an optionally substituted heterocycloaliphatic, or an optionally substituted monocylic or bicyclic aryl group optionally containing one or more heteroatoms selected from oxygen, sulphur or nitrogen atoms, Alk′ is an optionally substituted straight or branched alkylene, alkenylene or alkynylene chain optionally interrupted by one or more L 1  atoms or groups [where L 1  is a linker atom or group] and n is zero or the integer 1; or is (3) X a R′ where R′ is Ar′ or is an optionally substituted polycycloalkyl or polycycloalkenyl group optionally containing one or more —O—, or —S— atoms or —N(R b )— groups;  
 Z is a group (A), (B), (C) or (D):  
                     
 wherein  
 Ar is a monocyclic or bicyclic aryl group optionally containing one or more heteroatoms selected from oxygen, sulphur or nitrogen atoms;  
 Z 1  is a group —NR 12 C(O)—[where R 12  is a hydrogen atom or an optionally substituted alkyl or (Alk) t Ar group], —C(O)NR 12 —, —NR 12 C(S)—, —C(S)NR 12 —, —C≡C—, —NR 12 SO 2 —, or —SO 2 NR 12 —;  
 Alk is an optionally substituted straight or branched alkyl chain optionally interrupted by an atom or group X;  
 t is zero or an integer of value 1, 2 or 3;  
 R 3  is a hydrogen or a fluorine atom or an optionally substituted straight or branched alkyl group or an OR 11  group [where R 11  is a hydrogen atom or an optionally substituted alkyl, alkenyl, alkoxyalkyl, alkanoyl, formyl, carboxamido or thiocarboxamido group];  
 R 4  is a hydrogen atom or an optionally substituted alkyl, —CO 2 R 8 , —CSNR 9 R 10 , —CN, —CH 2 CN, or —(CH 2 ) t Ar group where t is zero or an integer of value 1, 2 or 3 and Ar is a monocyclic or bicyclic aryl group optionally containing one or more heteroatoms selected from oxygen, sulphur or nitrogen atoms, provided that when L is a group of type (2) or (3) above then Z is a group of type (A) or type (B) in which R 4  is a —(CH 2 ) t Ar group;  
 R 5  is a group —(CH 2 ) t Ar;  
 R 6  is a hydrogen or a fluorine atom, or an optionally substituted alkyl or —CO 2 R 8 , —CONR 9 R 10 , —CSNR 9 R 10 , —CN or —CH 2 CN group;  
 R 7  is a hydrogen or a fluorine atom, an optionally substituted straight or branched alkyl group, or an OR c  group where R c  is a hydrogen atom or an optionally substituted alkyl or alkenyl group, alkoxyalkyl, alkanoyl, formyl, carboxamido or thiocarboxamido group; and the salts, solvates, hydrates, prodrugs and N-oxides thereof; together with one or more pharmaceutically acceptable carriers, excipients or diluents.  
 
     
     
         8 . 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 —XR a  group where X is —O—, —S(O) m —[where m is zero or an integer of value 1 or 2], or —N(R b )—[where R b  is a hydrogen atom or an optionally substituted alkyl group] and R a  is a hydrogen atom or an optionally substituted alkyl group or, (2) ═N—;  
 L is (1) a —C(R)═C(R 1 )(R 2 ) or [—CH(R)] n CH(R 1 )(R 2 ) group where R is a hydrogen or a fluorine atom or a methyl group, and R 1  and R 2 , which may be the same or different, is each a hydrogen or fluorine atom or an optionally substituted alkyl, alkenyl, alkynyl, alkoxy, alkylthio, —C02R8 [where R8 is a hydrogen atom or an optionally substituted alkyl, aralkyl or aryl group], —CONR 9 R 10  [where R 9  and R 10 , which may be the same or different are defined for R 8 ], —CSNR 9 R 10 ,—CN or —NO 2  group, or R 1  and R 2 , together with the C atom to which they are attached are linked to form an optionally substituted cycloalkyl, cycloalkenyl or heterocycloaliphatic group and n is zero or the integer 1; or is (2)—(X a ) n Alk′Ar′, or -Alk′X a Ar′ where X a  is a group X, Ar′ is an optionally substituted heterocycloaliphatic, or an optionally substituted monocylic or bicyclic aryl group optionally containing one or more heteroatoms selected from oxygen, sulphur or nitrogen atoms, Alk′ is an optionally substituted straight or branched alkylene, alkenylene or alkynylene chain optionally interrupted by one or more L 1  atoms or groups [where L 1  is a linker atom or group] and n is zero or the integer 1; or is (3) X a R′ where R′ is Ar′ or is an optionally substituted polycycloalkyl or polycycloalkenyl group optionally containing one or more —O—, or —S— atoms or —N(R b )— groups;  
 Z is a group (A), (B), (C) or (D):  
                     
 wherein  
 Ar is a monocyclic or bicyclic aryl group optionally containing one or more heteroatoms selected from oxygen, sulphur or nitrogen atoms;  
 Z 1  is a group —NR 12 C(O)—[where R 12  is a hydrogen atom or an optionally substituted alkyl or (Alk) t Ar group], —C(O)NR 12 —, —NR 12 C(S)—, —C(S)NR 12 —, —C≡C—, —NR 12 SO 2 —, or —SO 2 NR 12 —;  
 Alk is an optionally substituted straight or branched alkyl chain optionally interrupted by an atom or group X; t is zero or an integer of value 1, 2 or 3;  
 R 3  is a hydrogen or a fluorine atom or an optionally substituted straight or branched alkyl group or an OR 11  group [where R 11  is a hydrogen atom or an optionally substituted alkyl, alkenyl, alkoxyalkyl, alkanoyl, formyl, carboxamido or thiocarboxamido group];  
 R 4  is a hydrogen atom or an optionally substituted alkyl, —CO 2 R 8 , —CSNR 9 R 10 , —CN, —CH 2 CN, or —(CH 2 ) t Ar group where t is zero or an integer of value 1, 2 or 3 and Ar is a monocyclic or bicyclic aryl group optionally containing one or more heteroatoms selected from oxygen, sulphur or nitrogen atoms, provided that when L is a group of type (2) or (3) above then Z is a group of type (A) or type (B) in which R 4  is a —(CH 2 ) t Ar group;  
 R 5  is a group —(CH 2 ) t Ar;  
 R 6  is a hydrogen or a fluorine atom, or an optionally substituted alkyl or —CO 2 R 8 , —CONR 9 R 10 , —CSNR 9 R 1 , —CN or —CH 2 CN group; R 7  is a hydrogen or a fluorine atom, an optionally substituted straight or branched alkyl group, or an OR c  group where R c  is a hydrogen atom or an optionally substituted alkyl or alkenyl group, alkoxyalkyl, alkanoyl, formyl, carboxamido or thiocarboxamido group; and the salts, solvates, hydrates, prodrugs and N-oxides thereof;  
 which comprises in a final step: 
 a) coupling a compound of formula (3)  
                     i) where L 2  is a group X a H with a reagent L 3 Alk′Ar′, or L 3 R′ in which L 3  is a leaving group; or    ii) where L 2  is a group -Alk′L 3  with a reagent Ar′X a H;    
 b) reacting a compound of formula (12)  
                     
  where R 4  is a hydrogen atom, or an alkyl or —(CH 2 ) t Ar group with a phosphonate ester to give a compound of formula (1) wherein Z is a group (B);  
 c) coupling a compound of formula (18)  
                     
  with an organopalladium compound to give a compound of formula (1) wherein Z is a group (B);  
 d) reacting a compound of formula (19)  
                     
  with an organometallic reagent followed by dehydration of the corresponding alcohol to give a compound of formula (1) wherein L is a group —C(R)═CH(R 1 );  
 e) decarboxylating an acid of formula (21)  
                     
  to give a compound of formula (1) wherein R 3 , R 6  and R 7  is each a hydrogen atom;  
 f) cyclisation of a compound of formula (23)  
                     
  where R 16  is a carboxylic acid (CO 2 H) or a reactive derivative thereof; or a nitrile (-CN) or an imine salt with a bifunctional reagent W 1 R 5a W 2  and, where necessary, a compound R 5b W 3  [where W 1 , W 2  and W 3 , which may be the same or different, is each a reactive functional group or a protected derivative thereof; and R 5a  and R 5b are components of the heteroaryl group R 5  such that when added together with WI, W 2  and W 3  to the group R 16  in compounds of formula (19) the resulting group —RW 1 R 5a W 2  or —RW 1 R 5a W 2 R 5b W 3  constitutes the heteroaryl group R 5 ]; to give a compound of formula (1) wherein R 3 , R 6  and R 7  is each a hydrogen atom and R 5  is a heteroaryl group to give a compound of formula (1) wherein R 3 , R 6  and R 7  is each a hydrogen atom and R 5  is a heteroaryl group;  
 g) coupling a compound of formula (25)  
                     
  where E is a boronic acid —B(OH) 2  or a tin reagent Sn(R) 3 , in which R is an alkyl group with a reagent Z-L 4 , where L 4  is a leaving group, in the presence of a complex metal catalyst; to give a compound of formula (1) wherein Z is a group (C);  
 h) coupling a compound of formula (26)  
                     
  where A is a —CO 2 H or —NHR 12  group, or an active derivative thereof with a compound R 12 NH(Alk t (Xn)Ar or Ar(X) n Alk) t CO 2 H or an active derivative thereof to give a compound of formula (1) wherein Z is a group (D) in which —Z 1  is —NR 12 C(O)— or —C(O)NR 12 —;  
 i) reacting a compound of formula (29)  
                     
  with a reagent Ar(X) n (Alk) t L 5  in which L 5  is a leaving group to give a compound of formula (1) wherein Z 1  is a —C═C-chain;  
 j) reacting a compound of formula (30)  
                     
  where (i) W b  is a —NHR 12  group with a compound Ar(X) n (Alk) t SO 2 Hal (where Hal is a halogen atom); or  
  (ii) W b  is a —SO 2 Hal group with a compound Ar(X) n (Alk) t NHR 12  to give a compound of formula (1) wherein Z 1  is a —NR 12 SO 2 — or —SO 2 NR 12 — group;  
 k) reacting a compound of formula (31)  
                     
  where Hall is a halogen atom  
  where a diazoalkane to give a compound of formula (1) where L is a —CH(R 1 )(R 2 )group in which R 2  is a —CO 2 H group; or  
 l) interconverting a compound of formula (1) to another compound of formula (1).