Novel compounds

Abstract

The invention provides compounds of general formula (I) wherein m, n, Z 1 , Z 2 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are as defined in the specification, process for their preparation, pharmaceutical compositions containing them and their use in therapy.

1 . A compound of general formula  
       
         
           
           
               
               
           
         
       
       wherein: 
 m is 0, 1, 2 or 3;  
 each R 1  independently represents halogen, cyano, nitro, carboxyl, hydroxyl, C 3 -C 6  cycloalkyl, C 1 -C 6  alkoxy, C 1 -C 6  alkoxycarbonyl, C 1 -C 6  haloalkyl, C 1 -C 6  haloalkoxy, —NR 9 R 10 , C 3 -C 6  cycloalkylamino, C 1 -C 6  alkylthio, C 1 -C 6  alkylcarbonyl, C 1 -C 6  alkylcarbonylamino, sulphonamido, C 1 -C 6  alkylsulphonyl, —C(O)NR 11 R 12 , —NR 13 C(O)—(NH) P R 14 , phenyl, or C 1 -C 6  alkyl optionally substituted by carboxyl or C 1 -C 6  alkoxycarbonyl;  
 p is 0 or 1;  
 X represents an oxygen atom or a CH 2 , OCH 2 , CH 2 O, CH 2 NH, NH, carbonyl or sulphonyl group and Y represents a nitrogen atom or a CH or C(OH) group, provided that when X represents an oxygen atom or a CH 2 O, CH 2 NH or NH group, then Y represents a CH group;  
 Z 1  represents a group (CH 2 ) q  where q is 1 or 2;  
 Z 2  represents a bond or a group CH 2 , with the proviso that when Z 1  is CH 2 , Z 2  is CH 2 , and when Z 1  is (CH 2 ) 2 . Z 2  is a bond;  
 Q represents an oxygen or sulphur atom or a group CH 2  or NH;  
 R represents a group  
                     
 n is 0, 1 or 2;  
 each R 3  independently represents a C 1 -C 6  alkyl, C 1 -C 6  alkoxycarbonyl, —CH 2 OH or carboxyl group;  
 R 4 , R 5 , R 6  and R 7  each independently represent a hydrogen atom or a C 1 -C 6  alkyl group, or R 4 , R 5 , R 6  and R 7  together represent a C 1 -C 4  alkylene chain linking the two carbon atoms to which they are attached to form a 4- to 7-membered saturated carbocycle, or R 5 , R 6  and R 7  each represent a hydrogen atom and R 4  and R 8  together with the carbon atoms to which they are attached form a 5- to 6-membered saturated carbocycle;  
 R 8  represents a hydrogen atom, a C 1 -C 6  alkyl group or is linked to R 4  as defined above;  
 R 9  and R 10  each independently represent a hydrogen atom or a C 1 -C 6  alkyl group, or R 9  and R 10  together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocycle;  
 R 11  and R 12  each independently represent a hydrogen atom or a C 1 -C 6  alkyl group optionally substituted by C 1 -C 6  alkoxycarbonyl;  
 R 13  represents a hydrogen atom or a C 1 -C 6  alkyl group;  
 R 14  represents a hydrogen atom, or a C 1 -C 6  alkyl group optionally substituted by carboxyl, C 1 -C 6  alkoxy or C 1 -C 6  alkoxycarbonyl;  
 R 15  represents a group C 2 -C 6  alkyl, C 2 -C 6  alkenyl, C 3 -C 6  cycloalkyl, C 5 -C 6  cycloalkenyl, adamantyl, phenyl or a saturated or unsaturated 5- to 10-membered heterocyclic ring system comprising at least one heteroatom selected from nitrogen, oxygen and sulphur, wherein each group may be optionally substituted by one or more substituents independently selected from nitro, hydroxyl, oxo, halogen, carboxyl, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, C 1 -C 6  alkylthio, C 1 -C 6  alkylcarbonyl, C 1 -C 6  alkoxycarbonyl, phenyl and —NHC(O)—R 17 , with the proviso that R 15  does not represent an unsubstituted 1-pyrrolidinyl, an unsubstituted 1-piperidinyl or an unsubstituted 1-hexamethyleneiminyl group;  
 t is 0, 1, 2 or 3;  
 each R 16  independently represents halogen, cyano, nitro, carboxyl, hydroxyl, C 3 -C 6  cycloalkyl, C 1 -C 6  alkoxy, C 1 -C 6  alkoxycarbonyl, C 1 -C 6  haloalkyl, C 1 -C 6  haloalkoxy, —NR 18 R 19 , C 3 -C 6  cycloalkylamino, C 1 -C 6  alkylthio, C 1 -C 6  alkylcarbonyl, C 1 -C 6  alkylcarbonylamino, sulphonamido (—SO 2 NH 2 ), C 1 -C 6  alkylsulphonyl, —C(O)NR 20 R 21 , —NR 22 C(O)(NH) v R 23 , phenyl, or C 1 -C 6  alkyl optionally substituted by carboxyl or C 1 -C 6  alkoxycarbonyl;  
 R 17  represents a C 1 -C 6  alkyl, amino or phenyl group;  
 R 18  and R 19  each independently represent a hydrogen atom or a C 1 -C 6  alkyl group, or R 18  and R 19  together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocycle;  
 R 20  and R 21  each independently represent a hydrogen atom or a C 1 -C 6  alkyl group optionally substituted by C 1 -C 6  alkoxycarbonyl;  
 v is 0 or 1;  
 R 22  represents a hydrogen atom or a C 1 -C 6  alkyl group; and  
 R 23  represents a hydrogen atom, or a C 1 -C 6  alkyl group optionally substituted by carboxyl, C 1 -C 6  alkoxy or C 1 -C 6  alkoxycarbonyl;  
 or a pharmaceutically acceptable salt or solvate thereof.  
 
     
     
         2 . A compound according to  claim 1 , wherein X represents an oxygen atom or a CH 2  or NH group.  
     
     
         3 . A compound according to  claim 1 , wherein Y represents a CH group.  
     
     
         4 . A compound according to  claim 1 , wherein Q represents an oxygen atom.  
     
     
         5 . A compound according to  claim 1 , wherein R 15  represents a group C 2 -C 5  alkyl, C 2 -C 4  alkenyl, C 3 -C 6  cycloalkyl, C 5 -C 6  cycloalkenyl, adamantyl, phenyl or a saturated or unsaturated 5- to 10-membered heterocyclic ring system comprising at least one heteroatom selected from nitrogen, oxygen and sulphur, wherein each group may be optionally substituted by one, two or three substituents independently selected from hydroxyl, oxo, halogen, carboxyl, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, C 1 -C 6  alkylthio, C 1 -C 6  alkylcarbonyl, Cl-C 6  alkoxycarbonyl, phenyl and —NHC(O)—R 17 .  
     
     
         6 . A compound according to  claim 5 , wherein the saturated or unsaturated 5- to 10-membered heterocyclic ring system comprising at least one heteroatom selected from nitrogen, oxygen and sulphur, is pyrrolidinyl, piperidinyl, pyrazolyl, thiazolidinyl, thienyl, thiadiazolyl, isoxazolyl, pyrrolyl, furanyl, thiazolyl, indolyl, quinolinyl, benzimidazolyl, triazolyl, tetrazolyl or pyridinyl.  
     
     
         7 . A compound according to  claim 1 , wherein each R 16  independently represents halogen, cyano, C 1 -C 4  alkoxy, C 1 -C 4  alkoxycarbonyl, C 1 -C 4 haloalkyl, C 1 -C 4  alkylcarbonyl, phenyl or C 1 -C 4  alkyl.  
     
     
         8 . A compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as defined in  claim 1  being selected from: 
 Thiophene-2-carboxylic acid (2-{3-[4-(3,4-dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,    N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-benzamide,    N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-nicotinamide,    Pyridine-2-carboxylic acid (2-{3-[4-(3,4-dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,    N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-isonicotinamide,    Cyclohexanecarboxylic acid (2-{3-[4-(3,4-dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,    N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-3-hydroxy-butyramide,    5-Methyl-thiophene-2-carboxylic acid (2-{3-[4-(3,4-dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,    Cyclobutanecarboxylic acid (2-{3-[4-(3,4-dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,    N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-propionamide,    Pentanoic acid (2-{3-[4-(3,4-dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,    Pent-4-enoic acid (2-{3-[4-(3,4-dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,    Cyclopentanecarboxylic acid (2-{3-[4-(3,4-dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,    N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-3-methyl-butyramide,    4-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenylcarbamoyl)-3-methyl-butyric acid,    N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-succinamic acid,    N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-2-methyl-propoxy}-phenyl)-benzamide,    N-(2-{3-[4-(3,4-Dichloro-phenylamino)-piperidin-1-yl]-2-hydroxy-2-methyl-propoxy}-phenyl)-benzamide.    
     
     
         9 . A process for the preparation of a compound of formula (I) as defined in  claim 1  which comprises reacting a compound of general formula  
       
         
           
           
               
               
           
         
         or a salt thereof, wherein m, n, t, R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 16 , Q, Z 1  and Z 2  are as defined in formula (I), with a compound of general formula  
           R 15 —CO 2 H  (III)  
         or chemically equivalent derivative thereof, wherein R 15  is as defined in formula (I);  
         and optionally thereafter forming a pharmaceutically acceptable salt or solvate of the compound of formula (I) obtained.  
       
     
     
         10 . A pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as claimed in any one of  claim 1  in association with a pharmaceutically acceptable adjuvant, diluent or carrier.  
     
     
         11 . A process for the preparation of a pharmaceutical composition as claimed in  claim 10  which comprises mixing a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as claimed in  claim 1  with a pharmaceutically acceptable adjuvant, diluent or carrier.  
     
     
         12 - 18 . (canceled)  
     
     
         19 . A method of treating an inflammatory disease in a patient suffering from, or at risk of, said disease, which comprises administering to the patient a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as claimed in  claim 1 .  
     
     
         20 . A method of treating an airways disease in a patient suffering from, or at risk of, said disease, which comprises administering to the patient a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as claimed in  claim 1 .  
     
     
         21 . A method of treating a human disease or condition in which modulation of chemokine receptor activity is beneficial, in a patient suffering from, or at risk of, said disease or condition, which comprises administering to the patient a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as claimed in  claim 1 .  
     
     
         22 . A method of treating rheumatoid arthritis in a patient suffering from, or at risk of, rheumatoid arthritis, which comprises administering to the patient a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as claimed in  claim 1 .  
     
     
         23 . A method of treating chronic obstructive pulmonary disease in a patient suffering from, or at risk of, said disease, which comprises administering to the patient a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as claimed in  claim 1 .  
     
     
         24 . A method of treating asthma, in a patient suffering from, or at risk of, asthma, which comprises administering to the patient a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as claimed in  claim 1 .  
     
     
         25 . A method of treating multiple sclerosis in a patient suffering from, or at risk of, multiple sclerosis, which comprises administering to the patient a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as claimed in  claim 1.