OMEGA-CARBOXY ARYL SUBSTITUTED DIPHENYL UREAS AS p38 KINASE INHIBITORS

Abstract

This invention relates to the use of a group of aryl ureas in treating p38 mediated diseases, and pharmaceutical compositions for use in such therapy.

1 - 38 . (canceled) 
   
   
       39 . A method of treating a condition mediated by p38 within a host, said method comprising administering to said host a compound of Formula I:
   A-D-B  (I)   
     or a pharmaceutically acceptable salt thereof, wherein
 D is —NH—C(O)—NH—, 
 A is a substituted moiety of up to 40 carbon atoms of the formula: -L-(M-L 1 ) q , where L is a 5 or 6 membered cyclic structure bound directly to D, L 1  comprises a substituted cyclic moiety having at least 5 members, M is a bridging group having at least one atom, q is an integer of from 1-3; and each cyclic structure of L and L 1  contains 0-4 members of the group consisting of nitrogen, oxygen and sulfur, and 
 B is a substituted or unsubstituted, up to tricyclic aryl or heteroaryl moiety of up to 30 carbon atoms with at least one 6-member cyclic structure bound directly to D containing 0-4 members of the group consisting of nitrogen, oxygen and sulfur other than phenyl, 
 wherein L 1  is substituted by at least one substituent selected from the group consisting of —SO 2 R x , —C(O)R x  and —C(NR y )R z , 
 R y  is hydrogen or a carbon based moiety of up to 24 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally halosubstituted, up to per halo; 
 R z  is hydrogen or a carbon based moiety of up to 30 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen; 
 R x  is R z  or NR a R b  where R a  and R b  are 
 a) independently hydrogen,
 a carbon based moiety of up to 30 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen, or 
 —OSi(R f ) 3  where R f  is hydrogen or a carbon based moiety of up to 24 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen; or 
 
 b) R a  and R b  together form a 5-7 member heterocyclic structure of 1-3 heteroatoms selected from N, S and O, or a substituted 5-7 member heterocyclic structure of 1-3 heteroatoms selected from N, S and O substituted by halogen, hydroxy or carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen; or 
 c) one of R a  or R b  is —C(O)—, a C 1 -C 5  divalent alkylene group or a substituted C 1 -C 5  divalent alkylene group bound to the moiety L to form a cyclic structure with at least 5 members, wherein the substituents of the substituted C 1 -C 5  divalent alkylene group are selected from the group consisting of halogen, hydroxy, and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen; 
 where B is substituted, L is substituted or L 1  is additionally substituted, the substituents are selected from the group consisting of halogen, up to per-halo, and Wn, where n is 0-3; 
 wherein each W is independently selected from the group consisting of —CN, —CO 2 R 7 , —C(O)NR 7 R 7 , —C(O)—R 7 , —NO 2 , —OR 7 , —SR 7 , —NR 7 R 7 , —NR 7 C(O)OR 7 , —NR 7 C(O)R 7 , -Q-Ar, and carbon based moieties of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O and optionally substituted by one or more substituents independently selected from the group consisting of —CN, —CO 2 R 7 , —C(O)R 7 , —C(O)NR 7 R 7 , —OR 7 , —SR 7 , —NR 7 R 7 , —NO 2 , —NR 7 C(O)R 7 , —NR 7 C(O)OR 7  and halogen up to per-halo; with each R 7  independently selected from H or a carbon based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen, 
 wherein Q is —O—, —S—, —N(R 7 )—, —(CH 2 ) m —, —C(O)—, —CH(OH)—, —(CH 2 ) m O—, —(CH 2 ) m S—, —(CH 2 ) m N(R 7 )—, —O(CH 2 ) m —CHX a —, —CX a   2 —, —S—(CH 2 ) m — and —N(R 7 )(CH 2 ) m —, where m=1-3, and X a  is halogen; and 
 Ar is a 5- or 6-member aromatic structure containing 0-2 members selected from the group consisting of nitrogen, oxygen and sulfur, which is optionally substituted by halogen, up to per-halo, and optionally substituted by Z n1 , wherein n1 is 0 to 3 and each Z is independently selected from the group consisting of —CN, —CO 2 R 7 , —C(O)R 7 , —C(O)NR 7 R 7 , —NO 2 , —OR 1 , —SR 7 —NR 7 R 7 , —NR 7 C(O)OR 7 , —NR 7 C(O)R 7 , and a carbon based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O and optionally substituted by one or more substituents selected from the group consisting of —CN, —CO 2 R 7 , —COR 7 , —C(O)NR 7 R 7 , —OR 7 , —SR 7 , —NO 2 , —NR 7 R 7 , —NR 7 C(O)R 7 , and —NR 7 C(O)OR 7 , with R 7  as defined above. 
 
   
   
       40 . A method as in  claim 39  for the treatment of a disease other than cancer. 
   
   
       41 . A method as in  claim 39  wherein the condition within a host treated by administering a compound of formula I is rheumatoid arthritis, osteoarthritis, septic arthritis, tumor metastasis, periodontal disease, corneal ulceration, proteinuria, coronary thrombosis from atherosclerotic plaque, aneurysmal aortic, birth control, dystrophobic epidermolysis bullosa, degenerative cartilage loss following traumatic joint injury, osteopenias mediated by MMP activity, tempero mandibular joint disease or demyelating disease of the nervous system. 
   
   
       42 . A method as in  claim 39  wherein M is a bridging group which is one or more groups selected from the group consisting of —O—, —S—, —N(R 7 )—, —(CH 2 ) m —, —C(O)—, —CH(OH)—, —(CH 2 ) m O—, —(CH 2 ) m S—, —(CH 2 ) m N(R 7 )—, —O(CH 2 ) m —CHX a —, —CX a   2 —, —S—(CH 2 ) m — or —N(R 7 )(CH 2 ) m —, where m=1-3, X a  is halogen and R 7  is as defined in claim  1 . 
   
   
       43 . A method as in  claim 42 , wherein said substituted cyclic moiety L 1  is phenyl, pyridyl or pyrimidinyl. 
   
   
       44 . A method of  claim 39  wherein L 1  is substituted by —C(O)R x  or —SO 2 R x , wherein R x  is NR a R b . 
   
   
       45 . A method of  claim 39  wherein the cyclic structures of B and L bound directly to D are substituted in the ortho position by hydrogen. 
   
   
       46 . A method of  claim 39  wherein B is substituted with 1-3 substituents which are chlorine, C 1 -C 6  alkoxy or C 1 -C 6  alkyl, substituted by one or more halogen substituents up to per halo substituted C 1 -C 6  alkyl. 
   
   
       47 . A method of  claim 39  wherein B is substituted by trifluoromethyl or tert-butyl, and optionally halogen up to per halo. 
   
   
       48 . A method of  claim 39  wherein the pharmaceutically acceptable salt of a compound of formula I is a basic salt of hydrochloric acid or p-toluene sulfonic acid (tosylate salt). 
   
   
       49 . A method of  claim 39  wherein the pharmaceutically acceptable salt of a compound of formula I is a pharmaceutically acceptable salt of N-(4-chloro-3-(trifluoromethyl)phenyl)-N′-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea that is a basic salt of hydrochloric acid or p-toluene sulfonic acid (tosylate salt). 
   
   
       50 . A method as in  claim 39  wherein the condition within a host treated by administering a compound of formula I is rheumatic fever, bone resorption, postmenopausal osteoperosis, sepsis, gram negative sepsis, septic shock, endotoxic shock, toxic shock syndrome, systemic inflammatory response syndrome, inflammatory bowel disease (Crohn's disease and ulcerative colitis), Jarisch-Herxheimer reaction, asthma, adult respiratory distress syndrome, acute pulmonary fibrotic disease, pulmonary sarcoidosis, allergic respiratory disease, silicosis, coal worker's pneumoconiosis, alveolar injury, hepatic failure, liver disease during acute inflammation, severe alcoholic hepatitis, malaria ( Plasmodium falciparum  malaria and cerebral malaria), non-insulin-dependent diabetes mellitus (NIDDM), congestive heart failure, damage following heart disease, atherosclerosis, Alzheimer's disease, acute encephalitis, brain injury, multiple sclerosis (demyelation and oligiodendrocyte loss in multiple sclerosis), advanced cancer, lymphoid malignancy, pancreatitis, impaired wound healing in infection, inflammation and cancer, myelodysplastic syndromes, systemic lupus erythematosus, biliary cirrhosis, bowel necrosis, psoriasis, radiation injury/toxicity following administration of monoclonal antibodies, host-versus-graft reaction (ischemia reperfusion injury and allograft rejections of kidney, liver, heart, and skin), lung allograft rejection (obliterative bronchitis) or complications due to total hip replacement. 
   
   
       51 . A method as in  claim 39  wherein the condition within a host treated by administering a compound of formula I is an infectious disease selected from the group consisting of tuberculosis,  Helicobacter pylori  infection during peptic ulcer disease, Chaga's disease resulting from  Trypanosoma cruzi  infection, effects of Shiga-like toxin resulting from  E. coli  infection, effects of enterotoxin A resulting from  Staphylococcus  infection, meningococcal infection, and infections from  Borrelia burgdorferi, Treponema pallidum , cytomegalovirus, influenza virus, Theiler's encephalomyelitis virus, and the human immunodeficiency virus (HIV). 
   
   
       52 . A method of inhibiting p38 within a host, said method comprising administering to said host a pharmacologically effective amount of a compound of one of the formulae B1, B2 or B3: 
     
       
         
         
             
             
         
       
       wherein A is of the formula: -L-(M-L 1 ) q , where L is phenyl, optionally substituted by halogen, q is 1, m is oxygen and L 1  is of the formula: 
     
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       53 . A method as in  claim 52  wherein the host has one of the following conditions: rheumatoid arthritis, osteoarthritis, septic arthritis, tumor metastasis, periodontal disease, corneal ulceration, proteinuria, coronary thrombosis from atherosclerotic plaque, aneurysmal aortic, birth control, dystrophobic epidermolysis bullosa, degenerative cartilage loss following traumatic joint injury, osteopenias mediated by MMP activity, tempero mandibular joint disease or demyelating disease of the nervous system. 
   
   
       54 . A method as in  claim 52  where the compound administered is a tosylate salt. 
   
   
       55 . A method as in  claim 52  wherein the host has one of the following conditions: rheumatic fever, bone resorption, postmenopausal osteoperosis, sepsis, gram negative sepsis, septic shock, endotoxic shock, toxic shock syndrome, systemic inflammatory response syndrome, inflammatory bowel disease (Crohn's disease and ulcerative colitis), Jarisch-Herxheimer reaction, asthma, adult respiratory distress syndrome, acute pulmonary fibrotic disease, pulmonary sarcoidosis, allergic respiratory disease, silicosis, coal worker's pneumoconiosis, alveolar injury, hepatic failure, liver disease during acute inflammation, severe alcoholic hepatitis, malaria ( Plasmodium falciparum  malaria and cerebral malaria), non-insulin-dependent diabetes mellitus (NIDDM), congestive heart failure, damage following heart disease, atherosclerosis, Alzheimer's disease, acute encephalitis, brain injury, multiple sclerosis (demyelation and oligiodendrocyte loss in multiple sclerosis), advanced cancer, lymphoid malignancy, pancreatitis, impaired wound healing in infection, inflammation and cancer, myelodysplastic syndromes, systemic lupus erythematosus, biliary cirrhosis, bowel necrosis, psoriasis, radiation injury/toxicity following administration of monoclonal antibodies, host-versus-graft reaction (ischemia reperfusion injury and allograft rejections of kidney, liver, heart, and skin), lung allograft rejection (obliterative bronchitis) or complications due to total hip replacement. 
   
   
       56 . A method for a treatment of the disease within a host selected from the group consisting of rheumatoid arthritis, osteoarthritis, septic arthritis, tumor metastasis, periodontal disease, corneal ulceration, proteinuria, coronary thrombosis from atherosclerotic plaque, aneurysmal aortic, birth control, dystrophobic epidermolysis bullosa, degenerative cartilage loss following traumatic joint injury, osteopenias mediated by MMP activity, tempero mandibular joint disease or demyelating disease of the nervous system said method comprising administering to a host a compound selected from the group consisting of: 
     N-(4-chloro-3-(trifluoromethyl)phenyl)-N′-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea; 
     N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N′-(3-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea and their pharmaceutically acceptable salts. 
   
   
       57 . A method for a treatment of the condition within a host selected from the group consisting of rheumatic fever, bone resorption, postmenopausal osteoperosis, sepsis, gram negative sepsis, septic shock, endotoxic shock, toxic shock syndrome, systemic inflammatory response syndrome, inflammatory bowel disease (Crohn's disease and ulcerative colitis), Jarisch-Herxheimer reaction, asthma, adult respiratory distress syndrome, acute pulmonary fibrotic disease, pulmonary sarcoidosis, allergic respiratory disease, silicosis, coal worker's pneumoconiosis, alveolar injury, hepatic failure, liver disease during acute inflammation, severe alcoholic hepatitis, malaria ( Plasmodium falciparum  malaria and cerebral malaria), non-insulin-dependent diabetes mellitus (NIDDM), congestive heart failure, damage following heart disease, atherosclerosis, Alzheimer's disease, acute encephalitis, brain injury, multiple sclerosis (demyelation and oligiodendrocyte loss in multiple sclerosis), lymphoid malignancy, pancreatitis, impaired wound healing in infection, myelodysplastic syndromes, systemic lupus erythematosus, biliary cirrhosis, bowel necrosis, psoriasis, radiation injury/toxicity following administration of monoclonal antibodies, host-versus-graft reaction (ischemia reperfusion injury and allograft rejections of kidney, liver, heart, and skin), lung allograft rejection (obliterative bronchitis) or complications due to total hip replacement said method comprising administering to a host a compound selected from the group consisting of: 
     N-(4-chloro-3-(trifluoromethyl)phenyl)-N′-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea; 
     N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N′-(3-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea and their pharmaceutically acceptable salts. 
   
   
       58 . A method for treating an infectious disease within a host selected from the group consisting of tuberculosis,  Helicobacter pylori  infection during peptic ulcer disease, Chaga's disease resulting from  Trypanosoma cruzi  infection, effects of Shiga-like toxin resulting from  E. coli  infection, effects of enterotoxin A resulting from  Staphylococcus  infection, meningococcal infection, and infections from  Borrelia burgdorferi, Treponema pallidum , cytomegalovirus, influenza virus, Theiler's encephalomyelitis virus, and the human immunodeficiency virus (HIV) said method comprising administering to a host a compound selected from the group consisting of: 
     N-(4-chloro-3-(trifluoromethyl)phenyl)-N′-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea; 
     N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N′-(3-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea and their pharmaceutically acceptable salts.