Macrolides with Anti-Inflammatory Activity

Abstract

The present invention relates to novel semi-synthetic macrolides having anti-inflammatory activity. More particularly, the invention relates to 14- and 15-membered macrolides substituted at the 4″ position, to their pharmaceutically acceptable derivatives, to processes and intermediates for their preparation, to pharmaceutical compositions containing them and to their activity and use in the treatment of inflammatory diseases and conditions in humans and animals, especially those diseases associated with excessive secretion of TNF-α, IL-1, IL-8, IL-2 or IL-5; and/or inhibitor of excessive lymphocyte proliferation; and/or excessive granulocyte degranulation.

What is claimed is: 
     
         1 . A compound of Formula (I) 
       
         
           
           
               
               
           
         
         wherein: 
         A is a bivalent radical selected from —C(O)—, —N(R 7 )CH 2 —, —CH 2 N(R 7 )—, —CH(OH)— and —C(═NOR 7 )—; 
         R 1  is —OC(O)(CH 2 ) n NR 8 R 9 , —O—(CH 2 ) n NR 8 R 9 , —OC(O)N(R 7 )(CH 2 ) n NR 8 R 9 , 
       
       
         
           
           
               
               
           
         
         
           —O(CH 2 ) n CN , —OC(O)(CH 2 ) n  N (CH 2 ) n NR 8 R 9 , or 
           —OC(O)CH═CH 2  with the proviso that if R 1  is —OC(O)CH═CH 2,  R 3  cannot be methyl; 
         
         R 2  is hydrogen or a hydroxyl protecting group; 
         R 3  is C 1-4  alkyl substituted at terminal carbon atom with CN or NH 2  group, or C 1-5  alkanoyl; 
         R 4  is hydrogen, C 1-4  alkyl, or C 2-6  alkenyl; 
         R 5  is hydroxy, methoxy group, —OC(O)(CH 2 ) n NR 8 R 9 , —O—(CH 2 ) n NR 8 R 9 , or —O(CH 2 ) n CN; 
         R 6  is hydroxy; or 
         R 5  and R 6  taken together with the intervening atoms form a cyclic group having the following structure: 
       
       
         
           
           
               
               
           
         
         wherein Y is a bivalent radical selected from —CH 2 —, —CH(CN)—, —O—, —N(R 7 )— and —CH(SR 7 )—; 
         R 7  is hydrogen or C 1-6  olkyl; 
         R 8  and R 9  are each independently hydrogen, C 3-7  cycloalkyl, or C 1-18  alkyl, wherein C 1-18  alkyl is:
 (i) uninterrupted or interrupted by 1-3 bivalent radical groups selected from —O—, —S— and —N(R 7 )—; and/or 
 (ii) unsubstituted or substituted by 1-3 groups selected from halogen, OH, NH 2 , N—(C 1 -C 6 )alkylamino, N,N-di(C 1 -C 6 -alkyl)amino, CN, NO 2 , OCH 3 , a C 3-8  membered non-aromatic ring which is saturated or unsaturated, a non-aromatic heterocyclic ring containing 2-6 carbon atoms which is saturated or unsaturated containing from 1-2 heteroatoms selected from oxygen, sulphur and nitrogen, alkylcarbonylalkoxy and alkoxycarbonylamino; or 
 
         R 8  and R 9  taken together with nitrogen to which they are attached form a non-aromatic heterocyclic ring containing 2-6 carbon atoms which is:
 (iii) saturated or unsaturated containing from 0 or 1 additional heteroatoms selected from oxygen, sulphur and nitrogen; and/or 
 (iv) unsubstituted or substituted by 1-2 groups selected from C 1-5 alkanoyl and C 1-8  alkyl, wherein C 1-8  alkyl is uninterrupted or is interrupted by 1-3 bivalent radical groups selected from —O—, —S— and —N(R 7 )—, and/or being unsubstituted or substituted by 1-2 groups selected from OH, NH 2 , a non-aromatic heterocyclic ring containing 2-6 carbon atoms which is unsubstituted or is substituted by group selected from C 1-4  alkyl, halo, NH 2 , OH, SH, C 1-6  alkoxy and C 1-4  hydroxyalkyl, a C 3-7  cycloalkyl which is unsubstituted or is substituted by group selected from C 1-4  alkyl, halo, NH 2 , OH, SH, C 1-6  alkoxy and C 1-4  hydroxyalkyl; 
 
         n is an integer from 1 to 8; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         2 . A compound of Formula (I) according to  claim 1  wherein A is a bivalent radical selected from —C(O)—, —CH(OH)— and —C(═NOR 7 )—. 
     
     
         3 . A compound of Formula (I) according to  claim 1  wherein A is a bivalent radical selected from —N(R 7 )CH 2 — and —CH 2 N(R 7 )—. 
     
     
         4 . A compound of Formula (I) according to  claim 1  wherein R 3  is C 1-4 aminoalkyl. 
     
     
         5 . A compound of Formula (I) according to  claim 1  wherein R 3  is C 1-4  cyanoalkyl. 
     
     
         6 . A compound of Formula (I) according to  claim 1  wherein R 3  is C 1-5 alkanoyl. 
     
     
         7 . A compound of Formula (I) according to  claim 1  wherein R 5  and R 6  taken together with the intervening atoms form a cyclic group having the following structure: 
       
         
           
           
               
               
           
         
         wherein Y is a bivalent radical selected from —O— and —N(R 7 )—. 
       
     
     
         8 . A compound of Formula (I) according to  claim 1 , wherein R 8  and R 9  taken together with nitrogen to which they are attached form a C 5-7  membered saturated non-aromatic heterocyclic ring. 
     
     
         9 . A pharmaceutical composition comprising a compound of Formula (I) according to  claim 1  or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent or carrier. 
     
     
         10 . A method of treating an inflammatory disease, disorder or condition characterized by or associated with an undesirable inflammatory immune response, or an excessive secretion of TNF-α, IL-1, IL-6 and IL-8 which comprises administering to a subject in need thereof a therapeutically effective amount of a compound according to  claim 1 . 
     
     
         11 . A method of treating an inflammatory condition or immune or anaphylactic disorder associated with infiltration of leukocytes into inflamed organ or tissue comprising administering to a subject in need thereof a therapeutically effective amount of a compound of  claim 1 . 
     
     
         12 . The method according to  claim 11 , wherein the inflammatory condition or immune disorder is selected from the group consisting of asthma, COPD, diffuse panbronchiolitis, adult respiratory distress syndrome, inflammatory bowel disease, Crohn's disease, chronic bronchitis, and cystic fibrosis. 
     
     
         13 . A method according to  claim 1 , wherein said inflammatory condition or immune disorder is selected from the group consisting of an inflammatory condition or immune disorder of the lungs, joints, eyes, bowel, skin, and heart. 
     
     
         14 . A method according to  claim 13 , wherein said inflammatory condition or immune disorder is selected from the group consisting of asthma, adult respiratory distress syndrome, bronchitis, bronchiectasis, bronchiolitis obliterans, cystic fibrosis, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, osteomyelitis, sinusitis, nasal polyps, gouty arthritis, uveitis, conjunctivitis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, distal proctitis, psoriasis, eczema, dermatitis, acne, coronary infarct damage, chronic inflammation, endotoxin shock, chronic sinusitis, pulmonary fibrosis, diffuse panbronchiolitis, and smooth muscle proliferation disorders. 
     
     
         15 . A method of inhibiting one or more inflammatory processes selected from the group consisting of: proinflammatory cytokine production, lymphocyte proliferation, granulocyte degranulation, t-cell proliferation, neutrophilia, and oedema comprising exposing an organ or tissue afflicted with inflammation to an amount of a compound according to  claim 1  effective to inhibit said inflammatory process. 
     
     
         16 . The method of  claim 15 , wherein the inflammatory process comprises lymphocyte proliferation.