Alkyne-aryl phosphodiesterase-4 inhibitors

Abstract

Compounds represented by Formula (I) or a pharmaceutically acceptable salt thereof, are phosphodiesterase 4 inhibitors useful in the treatment of asthma and inflammation.

1 - 28 . (canceled).  
     
     
         29 . A method of treatment or prevention of asthma; chronic bronchitis; chronic obstructive pulmonary disease; adult respiratory distress syndrome; infant respiratory distress syndrome; cough; chronic obstructive pulmonary disease in animals; adult respiratory distress syndrome; ulcerative colitis; Crohn's disease; hypersecretion of gastric acid; bacterial, fungal or viral induced sepsis or septic shock; endotoxic shock; laminitis or colic in horses; spinal cord trauma; head injury; neurogenic inflammation; pain; reperfusion injury of the brain; psoriatic arthritis; rheumatoid arthritis; ankylosing spondylitis; osteoarthritis; inflammation; or cytokine-mediated chronic tissue degeneration; 
 allergic rhinitis, allergic conjunctivitis, eosinophilic granuloma, osteoporosis, arterial restenosis, atherosclerosis, reperfiision injury of the myocardium chronic glomerulonephritis, vernal conjunctivitis, cachexia, transplant rejection, or graft versus host disease; or    memory impairment, monopolar depression, Parkinson disease, Alzheimer's disease, acute and chronic multiple sclerosis, psoriasis, benign or malignant proliferative skin diseases, atopic dermatitis, urticaria, cancer, tumor growth or cancerous invasion of normal tissues:    comprising the step of administering a therapeutically effective amount, or a prophylactically effective amount, of the compound for Formula (I)                          or a pharmaceutically acceptable salt thereof,    wherein:    R is H, —C 1-6 alkyl or —C 3-6 cycloalkyl;    R 1  is H, or a —C 1-6 alkyl, —C 3-6 cycloalkyl, —C 1-6  alkoxy, —C 2-6 alkenyl, —C 3-6 alkynyl, —C(O)—C 1-6 alkyl, C(O)-aryl, C 0-6 alkyl)SO n —(C 1-6 alkyl), —(C 0-6 alkyl)SO n -(aryl), phenyl, wherein aryl is selected from phenyl or naphthyl and wherein any of the groups is optionally substituted with 1-3 independent —C 1-6 alkyl, —C 1-6 alkoxy, OH, —N(C 0-6 alkyl)(C 0-6 alkyl), —(C 0-6 alkyl)SO n C 1-6 alkyl), nitro, CN, ═N—O—C 1-6 alkyl, —O—N═C 1-6 alkyl, or halogen substituents;    R 2  is absent, H, halogen, —C 1-6 alkyl, —C 3-6 cycloalkyl, —C 1-6 alkyl(C 3-6 cycloalkyl)(C 3-6 cycloalkyl), —C 1-6 alkoxy, phenyl, nitro, CN, ═N—O—C 1-6 alkyl, —O—N═C 1-6 alkyl, —N(C 0-6 alkyl)(C 0-6 alkyl), —NHSO n —(C 1-6 alkyl), —NHC(O)C 1-6 alkyl, —C(O)C 1-6 alkyl, —C(O)—O—C 1-6 alkyl, —C 1-6 alkyl(═N—OH), —C(N═NOH)C 1-6 alkyl, —C 0-6 alkyl(oxy)C 1-6 alkyl-phenyl, —SO n NH(C 0-6 alkyl), or —(C 0-6 alkyl)SO n —(C 1-6 alkyl), wherein the phenyl, is optionally substituted with halogen, —C 1-6 alkyl, —C 1-6 alkoxy, hydroxy, —N(C 0-6 alkyl)(C 0-6 alkyl), or —C(O)—O—C 1-6  alkyl, and any alkyl is optionally substituted with 1-6 independent halogen or —OH substituents;    n is 0, 1, or 2;    R 3  is absent, H, OH, —N(C 0-6 alkyl)(C 0-6 alkyl), halogen or C 1-6 alkyl, wherein any alkyl is optionally substituted with 1-6 independent halogen, OH, or —N(C 0-6 alkyl)(C 0-6 alkyl) substituents;    R 4 , R 5 , R 6 , and R 7  each independently is H, halogen, —C 1-6 alkyl, —C 1-6 alkoxy, —SO n —(C 1-6 alkyl), nitro, CN, or —N(C 0-6 alkyl)(C 0-6 alkyl), and any alkyl is optionally substituted with 1-6 independent halogen or —OH substituents; and    R 8  is pyridyl or pyridonyl, or pyridyl N-oxide.    
     
     
         30 . A method according to  claim 29  wherein: 
 R 8  is pyridyl, or pyridyl N-oxide.    
     
     
         31 . A method according to  claim 29  wherein: 
 R is Hydrogen.    
     
     
         32 . A method according to  claim 29  wherein R 4 , R 5 , R 6  and R 7  are each hydrogen.  
     
     
         33 . A method according to  claim 29  wherein R 1  is —C 3-6 cycloalkyl.  
     
     
         34 . A method according to  claim 29  wherein R is Hydrogen; and  
       R 4 , R 5 , R 6  and R 7  are each hydrogen.  
     
     
         35 . A method according to  claim 34  wherein R 8  is pyridyl or pyridyl N-oxide.  
     
     
         36 . A method according to  claim 34  wherein R 1  is 3 cycloalkyl.  
     
     
         37 . A method according to  claim 29  wherein the compound is selected from 
 N-Isopropyl-1-[3-(2-pyridinylethynyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide;    N-Isopropyl-1-[3-(4-pyridinylethynyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide;    N-Isopropyl-1-[3-(1-oxido-4-pyridinylethynyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide;    N-Isopropyl-1-[3-(3-pyridinylethynyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide;    N-Isopropyl-1-[3-(1-oxido-3-pyridinylethynyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide;    N-Cyclopropyl-1-[3-(3-pyridinylethynyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide;    N-Cyclopropyl-1-[3-(1-oxido-3-pyridinylethynyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide;    N-Isopropyl-1-[3-(6-amino-3-pyridinylethynyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide;    N-Isopropyl-1-{3-[5-(1-hydroxy-1-methylethyl)-1-oxido-3-pyridinylethynyl]phenyl}-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide;    N-Isopropyl-1-{3-[6-(1-hydroxy-1-methylethyl)-3-pyridinylethynyl]phenyl}-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide;    N-Isopropyl-1-{3-[6-(1-hydroxy-1-methylethyl)-1-oxido-3-pyridinylethynyl]phenyl}-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide;    N-Isopropyl-1-{3-[4-(1-hydroxy-1-methylethyl)-2-pyridinylethynyl]phenyl}-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide;    N-Isopropyl-1-{3-[5-(1-hydroxy-1-methylethyl)-2-pyridinylethynyl]phenyl}-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide;    N-Isopropyl-1-{3-[6-(1-hydroxy-1-methylethyl)-2-pyridinylethynyl]phenyl}-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide;    N-Cyclopropyl-1-{3-[6-(1-hydroxy-1-methylethyl)-1-oxido-3-pyridinylethynyl]phenyl}-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide;    1-[3-(1-Oxido-3-pyridinylethynyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide; or    1-[3-(1-Oxido-3-pyridinylethynyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxylic acid; 
 or a pharmaceutically acceptable salt thereof.  
   
     
     
         38 . A method according to  claim 29  wherein the compound is N-Cyclopropyl-1-[3-(3-pyridinylethynyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide; 
 or a pharmaceutically acceptable salt thereof.    
     
     
         39 . A method according to  claim 29  wherein the compound is N-Cyclopropyl-1-[3-(1-oxido-3-pyridinylethynyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide; 
 or a pharmaceutically acceptable salt thereof.    
     
     
         40 . A method according to  claim 29  selected from asthma; chronic bronchitis; chronic obstructive pulmonary disease; adult respiratory distress syndrome; infant respiratory distress syndrome; cough and adult respiratory distress syndrome; arthritis; rheumatoid arthritis; osteoarthritis and inflammation.  
     
     
         41 . A method according to  claim 29  selected from 
 memory impairment, monopolar depression, Parkinson disease and Alzheimer's disease.