Therapeutic Morpholino-Substituted Compounds

Abstract

Morpholino-substituted pyridopyrimidine, quinolone, and benzopyranone derivatives inhibit phosphoinositide (PI) 3-kinase, an enzyme that regulates platelet-adhesion processes. As a consequence, the compounds in question have anti-thrombotic activity, as well as other pharmaceutical properties. The compounds claimed are represented by formula (I), (II) and (III). PI 3-kinase generates 3-phosphorylated PI second messengers which stimulate platelet adhesion under blood-flow conditions. Because platelet adhesion is a necessary step in the formation of a thrombus, inhibition by these compounds of PI 3-kinase under such conditions inhibits or prevents thrombus formation. The compounds are useful in treating PI 3-kinase-dependent conditions including cardiovascular diseases such as coronary artery occlusion, stroke, acute coronary syndrome, acute myocardial infarction, vascular restenosis, atherosclerosis, and unstable angina; respiratory diseases such as asthma, chronic obstructive pulmonary diseases (COPD), and bronchitis; inflammatory disorders; neoplasms including cancers such as glioma, prostate cancer, small cell lung cancer, and breast cancer; and diseases linked to disordered white blood cell function, such as autoimmune and inflammatory diseases.

1 - 78 . (canceled) 
   
   
       79 . A method for treating cardiovascular disease in a patient comprising administering to the patient a therapeutically effective amount of a compound having formula (II), or a salt thereof: 
     
       
         
         
             
             
         
       
     
     wherein
 R and R 2  are independently H, OH, F, Cl, Br, I, C 1 -C 6  alkyl, aryl or (CH 2 ) n -aryl; 
 R 12  is C 3 -C 6  cycloalkyl, CH═CH-aryl, C≡C-aryl, (CHR 3 ) n -aryl, NR 3 -cycloalkyl, NR 3 —(CHR 3 ) n -aryl, (CHR 3 ) n —NR 3 -aryl, (CHR 3 ) n —NR 3 -cycloalkyl, (CHR 3 )—O-aryl, (CHR 3 ) n —O-cycloalkyl, O—(CHR 3 ) n -aryl, S—(CHR 3 ) n -aryl, 4-methylbenzensulfonate, or CO-aryl, wherein n is 0, 1, or 2 and alkyl, cycloalkyl or aryl is optionally substituted with F, Cl, Br, I, CN, CO 2 H, CO 2 R 3 , NO 2 , CF 3 , substituted or unsubstituted C 1 -C 6  alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, OCF 3 , OR 3 , OSO 2 -aryl, substituted or unsubstituted amine, NHCOR 3 , NHSO 2 R 3 , CONHR 3 , or SO 2 NHR 3 ; and 
 R 3  is H, or substituted or unsubstituted C 1 -C 6  alkyl, substituted or unsubstituted aryl. 
 
   
   
       80 . The method of  claim 79  wherein R 12  is chosen from: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       81 . The method of  claim 79  wherein R is H, R 12  is phenoxy and R 2  is H. 
   
   
       82 . The method of  claim 79  wherein R is H, R 12  is 2-methylphenoxy and R 2  is H. 
   
   
       83 . The method of  claim 79  wherein R is H, R 12  is 2-methyl-4-fluorophenoxy, and R 2  is H. 
   
   
       84 . The method of  claim 79  wherein the compound is in the form of a dose. 
   
   
       85 . The method of  claim 84  wherein the dose is in the form of a tablet, capsule, intravenous formulation, intranasal formulation, transdermal formulation, formulation for muscular injection, syrup, suppository, aerosol, or pessary. 
   
   
       86 . The method of  claim 85  wherein the tablet is formulated for oral, sublingual, or buccal administration. 
   
   
       87 . The method of  claim 84  wherein the dose contains from about 5 to about 500 mg of the compound. 
   
   
       88 . The method of  claim 84  wherein the dose contains from about 25 to about 300 mg of the compound. 
   
   
       89 . The method of  claim 79  wherein the compound has the following formula: 
     
       
         
         
             
             
         
       
     
     wherein
 R and R 2  are independently H, OH, F, Cl, Br, I, C 1 -C 6  alkyl, aryl or (CH 2 ) n -aryl; and 
 R 12  is OH, F, Cl, Br, I or CHO. 
 
   
   
       90 . The method of  claim 79  wherein the compound is chosen from: 
     8-(4-fluoro-2-methylphenoxy)-2-morpholinoquinolin-4(1H)-one (TGX 155); 
     8-(m-tolyloxy)-2-morpholinoquinolin-4(1H)-one (TGX 127); 
     8-(o-tolyloxy)-2-morpholinoquinolin-4(1H)-one (TGX 115); 
     8-(4-fluorophenoxy)-2-morpholinoquinolin-4(1H)-one (TGX 121); 
     2-morpholino-8-(phenylthio)quinolin-4(1H)-one (TGX 111); 
     2-morpholino-8-phenoxyquinolin-4(1H)-one (TGX 084); 
     8-(4-chloro-2-methylphenoxy)-2-morpholinoquinolin-4(1H)-one (TGX 180); 
     8-(2-fluorophenoxy)-2-morpholinoquinolin-4(1H)-one (TGX 143); 
     8-(p-tolyloxy)-2-morpholinoquinolin-4(1H)-one (TGX 113); 
     methyl 3-(1,4-dihydro-2-morpholino-4-oxoquinolin-8-yloxy)benzoate (TGX 149); 
     sodium 3-(1,4-dihydro-2-morpholino-4-oxoquinolin-8-yloxy)benzoate (TGX 152); 
     3-(1,4-dihydro-2-morpholino-4-oxoquinolin-8-yloxy)benzoic acid (TGX 151); 
     1-methyl-2-morpholino-8-phenoxyquinolin-4(1H)-one (TGX 171); 
     8-(4-fluorobenzyl)-2-morpholinoquinolin-4(1H)-one (TGX 099); 
     8-(4-methylbenzyl)-2-morpholinoquinolin-4(1H)-one (TGX 106); 
     8-benzyl-2-morpholinoquinolin-4(1H)-one (TGX 057); 
     2-morpholino-8-phenylquinolin-4(1H)-one (TGX 070); 
     1-methyl-2-morpholino-8-phenylquinolin-4(1H)-one (TGX 071); 
     8-acetylphenyl-2-morpholinoquinolin-4(1H)-one (TGX 086); 
     8-benzyl-1-methyl-2-morpholinoquinolin-4(1H)-one (TGX 074); and 
     1,4-dihydro-1-methyl-2-morpholino-4-oxoquinolin-8-yl 4-methylbenzenesulfonate (TGX 138). 
   
   
       91 . A method for treating respiratory disease in a patient comprising administering to the patient a therapeutically effective amount of a compound having formula (II), or a salt thereof: 
     
       
         
         
             
             
         
       
     
     wherein
 R and R 2  are independently H, OH, F, Cl, Br, I, C 1 -C 6  alkyl, aryl or (CH 2 ) n -aryl; 
 R 12  is C 3 -C 6  cycloalkyl, CH═CH-aryl, C≡C-aryl, (CHR 3 ) n -aryl, NR 3 -cycloalkyl, NR 3 —(CHR 3 ) n -aryl, (CHR 3 ) n —NR 3 -aryl, (CHR 3 ) n —NR 3 -cycloalkyl, (CHR 3 )—O-aryl, (CHR 3 ) n —O-cycloalkyl, O—(CHR 3 ) n -aryl, S—(CHR 3 ) n -aryl, 4-methylbenzensulfonate, or CO-aryl, wherein n is 0, 1, or 2 and alkyl, cycloalkyl or aryl is optionally substituted with F, Cl, Br, I, CN, CO 2 H, CO 2 R 3 , NO 2 , CF 3 , substituted or unsubstituted C 1 -C 6  alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, OCF 3 , OR 3 , OSO 2 -aryl, substituted or unsubstituted amine, NHCOR 3 , NHSO 2 R 3 , CONHR 3 , or SO 2 NHR 3 ; and 
 R 3  is H, or substituted or unsubstituted C 1 -C 6  alkyl, substituted or unsubstituted aryl. 
 
   
   
       92 . The method of  claim 91  wherein R 12  is chosen from: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       93 . The method of  claim 91  wherein R is H, R 12  is phenoxy and R 2  is H. 
   
   
       94 . The method of  claim 91  wherein R is H, R 12  is 2-methylphenoxy and R 2  is H. 
   
   
       95 . The method of  claim 91  wherein R is H, R 12  is 2-methyl-4-fluorophenoxy, and R 2  is H. 
   
   
       96 . The method of  claim 91  wherein the compound is in the form of a dose. 
   
   
       97 . The method of  claim 96  wherein the dose is in the form of a tablet, capsule, intravenous formulation, intranasal formulation, transdermal formulation, formulation for muscular injection, syrup, suppository, aerosol, or pessary. 
   
   
       98 . The method of  claim 97  wherein the tablet is formulated for oral, sublingual, or buccal administration. 
   
   
       99 . The method of  claim 96  wherein the dose contains from about 5 to about 500 mg of the compound. 
   
   
       100 . The method of  claim 96  wherein the dose contains from about 25 to about 300 mg of the compound. 
   
   
       101 . The method of  claim 91  wherein the compound has the following formula: 
     
       
         
         
             
             
         
       
     
     wherein
 R and R 2  are independently H, OH, F, Cl, Br, I, C 1 -C 6  alkyl, aryl or (CH 2 ) n -aryl; and 
 R 12  is OH, F, Cl, Br, I or CHO. 
 
   
   
       102 . The method of  claim 91  wherein the compound is chosen from: 
     8-(4-fluoro-2-methylphenoxy)-2-morpholinoquinolin-4(1H)-one (TGX 155); 
     8-(m-tolyloxy)-2-morpholinoquinolin-4(1H)-one (TGX 127); 
     8-(o-tolyloxy)-2-morpholinoquinolin-4(1H)-one (TGX 115); 
     8-(4-fluorophenoxy)-2-morpholinoquinolin-4(1H)-one (TGX 121); 
     2-morpholino-8-(phenylthio)quinolin-4(1H)-one (TGX 111); 
     2-morpholino-8-phenoxyquinolin-4(1H)-one (TGX 084); 
     8-(4-chloro-2-methylphenoxy)-2-morpholinoquinolin-4(1H)-one (TGX 180); 
     8-(2-fluorophenoxy)-2-morpholinoquinolin-4(1H)-one (TGX 143); 
     8-(p-tolyloxy)-2-morpholinoquinolin-4(1H)-one (TGX 113); 
     methyl 3-(1,4-dihydro-2-morpholino-4-oxoquinolin-8-yloxy)benzoate (TGX 149); 
     sodium 3-(1,4-dihydro-2-morpholino-4-oxoquinolin-8-yloxy)benzoate (TGX 152); 
     3-(1,4-dihydro-2-morpholino-4-oxoquinolin-8-yloxy)benzoic acid (TGX 151); 
     1-methyl-2-morpholino-8-phenoxyquinolin-4(1H)-one (TGX 171); 
     8-(4-fluorobenzyl)-2-morpholinoquinolin-4(1H)-one (TGX 099); 
     8-(4-methylbenzyl)-2-morpholinoquinolin-4(1H)-one (TGX 106); 
     8-benzyl-2-morpholinoquinolin-4(1H)-one (TGX 057); 
     2-morpholino-8-phenylquinolin-4(1H)-one (TGX 070); 
     1-methyl-2-morpholino-8-phenylquinolin-4(1H)-one (TGX 071); 
     8-acetylphenyl-2-morpholinoquinolin-4(1H)-one (TGX 086); 
     8-benzyl-1-methyl-2-morpholinoquinolin-4(1H)-one (TGX 074); and 
     1,4-dihydro-1-methyl-2-morpholino-4-oxoquinolin-8-yl 4-methylbenzenesulfonate (TGX 138).