Compounds and methods for the treatment of inflammatory and immune disorders

Abstract

2,5-Diaryl tetrahydrofurans, 2,5-diaryl tetrahydrothiophenes, 2,4-diaryl tetrahydrofurans, 2,4-diaryl tetrahydrothiophenes, 1,3-diaryl cyclopentanes, 2,4-diaryl pyrrolidines, and 2,5-diaryl pyrrolidines are disclosed that reduce the chemotaxis and respiratory burst leading to the formation of damaging oxygen radicals of polymorphonuclear leukocytes during an inflammatory or immune response. The compounds exhibit this biological activity by acting as PAF receptor antagonists, by inhibiting the enzyme 5-lipoxygenase, or by exhibiting dual activity, i. e., by acting as both a PAF receptor antagonist and inhibitor of 5-lipoxygenase. A method to treat disorders mediated by PAF or leukotrienes is also disclosed, that includes administering an effective amount of one or more of the above-identified compounds or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier.

We claim:  
     
         1 . A compound of the formula:  
       
         
           
           
               
               
           
         
       
       wherein: 
 X is O, S, S(O), S(O) 2 , CR 9 , or NR 10 ;  
 W is independently: 
 (1) —AN(OM)C(O)N(R 3 )R 4 , —AN(R 3 )C(O)N(OM)R 4 , —AN(OM)C(O)R 4 , —AC(O)N(OM)R 4 , —N(OM)C(O)N(R 3 )R 4 , —N(R 3 )C(O)N(OM)R 4 , —N(OM)C(O)R 4 , —C(O)N(OM)R 4 , —OR 6 N(R 5 )R 6 —(C 5 H 4 N)R 6 R 7 , —OR 6 N(COR 5 )R 6 —(C 5 H 4 N)R 6 R 7 , —OR 6 OC(O)N(COR 5 )R 6 —(C 5 H 4 N)R 6 R 7 , —OR 6 O(CO)N(CO 2 R 6 )R 6 (C 5 H 4 N)R 6 R 7 , —A(C 5 H 4 N)R 6 R 7 , or —OR 6 N(CO 2 R 5 )R 6 —(C 5 H 4 N)R 6 R 7 ;  
 (2) an amidohydroxyurea of the formula: —N(R 19 )C(O)C(R 19 ) 2 N(OM)C(O)NHR 20 , —C(O)N(R 19 )C(R 19 ) 2 N(OM)C(O)NHR 20 , —AN(R 19 )C(O)C(R 19 ) 2 N(OM)C(O)NHR 20 , —AC(O)N(R 19 )C(R 19 ) 2 N(OM)C(O)NHR 20 , —NHC(O)N(OM)C(R 19 ) 2 C(O)N(R 19 ) 2 ; or —NHC(O)N(OM)C(R 19 ) 2 N(R 19 )C(O)R 19 ;  
 (3) an oxalkane of the structure:  
                     
  wherein n and m are independently 1-4;  
 (4) a thioalkane of the structure:  
                     
  or (5) a quinolylinethoxy of the structure:  
                     
 
 n is 1 or 2;  
 m is 1, 2 or 3;  
 p is 0 or 1;  
 A is alkyl, alkenyl, alkynyl, alkyaryl, aralkyl, halo lower alkyl, halo lower alkenyl, halo lower alkynyl, —C 1-10 alkyl(oxy)C 1-10 alkyl, —C 1-10 alkyl(thio)C 1-10 alkyl, —N(R 3 )C(O)alkyl, —N(R 3 )C(O)alkenyl, —N(R 3 )C(O)alkynyl, —N(R 3 )C(O)(alkyl)oxy(alkyl), —N(R 3 )C(O)(alkyl)thio(alkyl), —N(R 3 )C(O)N(alkyl), —N(R 3 )C(O)N(alkenyl), —N(R 3 )C(O)N(alkynyl), —N(R 3 )C(O)N(alkyl)oxy(alkyl), —N(R 3 )C(O)N(alkyl)thio(alkyl), —N(R 3 )C(O 2 )alkyl, —N(R 3 )C(O 2 )alkenyl, —N(R 3 )C(O 2 )alkynyl, —N(R 3 )C(O 2 )(alkyl)oxy(alkyl), —N(R 3 )C(O 2 )(alkyl)thio(alkyl), —OC(O 2 )alkyl, —OC(O 2 )alkenyl, —OC(O 2 )alkynyl, —OC(O 2 )(alkyl)oxy(alkyl), —OC(O 2 )(alkyl)thio(alkyl), —N(R 3 )C(S)alkyl, —N(R 3 )C(S)alkenyl, —N(R 3 )C(S)alkynyl, —N(R 3 )C(S)(alkyl)oxy(alkyl), —N(R 3 )C(S)(alkyl)thio(alkyl), —N(R 3 )C(S)N(alkyl), —N(R 3 )C(S)N(alkenyl), —N(R 3 )C(S)N(alkynyl), —N(R 3 )C(S)N(alkyl)oxy(alkyl), —N(R 3 )C(S)N(alkyl)thio(alkyl), —N(R 3 )C(S)S(alkyl), —N(R 3 )C(S)S(alkenyl), —N(R 3 )C(S)S(alkynyl), —N(R 3 )C(S)S(alkyl)oxy(alkyl), —N(R 3 )C(S)S(alkyl)thio(alkyl), —SC(S)S(alkyl), —SC(S)S(alkenyl), —SC(S)S(alkynyl), —SC(S)S(alkyl)oxy(alkyl), and —SC(S)S(alkyl)thio(alkyl);  
 M is hydrogen, a pharmaceutically acceptable cation, or a metabolically cleavable leaving group;  
 Y is independently; 
 (a) hydrogen;  
 (b) R 1-6 , R 8 , R 10 , —OR 3 , —OR 11 , —OR 12 , R 3 S—, R 5 S, R 3 SO—, R 5 SO—, R 3 SO 2 —, R 5 SO 2 —, CF 3 O—, CF 3 S—, CF 3 SO—, —CF 3 SO 2 , —OCH 2 oxycyclopropyl, —OCH 2 C(O)OR 3 , —OCH 2 OR 3 , —OCH 2 C(O)R 3 , —OCH 2 C 3-8 cycloalkyl, —OCH 2 CH(R)R 3 , —OCH 2 cyclopropyl, —OCH 2 -aryl, —OCH 2 CH(OH)CH 2 OH, aryl-CH 2 —SO 2 —, (R 3 ) 2 CHCH 2 SO 2 —, —CH 2 CH(OH)CH 2 OH, CF 3 SO 2 —, R 3 R 4 N—, —OCH 2 CO 2 R 3 , —NR 3 COR 3 , —OCONH 2 , —OCONR 3 R 4 , —CONH 2 , —CONR 3 R 4 , —CR 3 R 3 R 4 , —SO 2 NR 3 R 4 , —SONR 3 R 4 , CH 3 OCH 2 ONR 3 R 6 , —SNR 3 R 4 , —CO 2 R 3 , —NR 3 R 4 SO 2 R 3 , —NR 3 R 4 SOR, —COR 3 , —CONR 3 , —NO 2 , —CN, —N(R 5 )CONR 3 R 4 , —CH 2 N(R 5 )CONR 3 R 4 , —R 6 NR 3 R 4 , —OR 6 NR 3 R 4 , —O(O)CR 5 , —O(O)CNR 3 R 4 ,  
                     
  —SR 6 NR 3 R 4 , —S(O)R 6 NR 3 R 4 , —SO 2 R 6 NR 3 R 4 ,  
                     
  —SR 6 OH; —S(O)R 6 OH; —SO 2 R 6 OH; —OR 6 OC(O)N(CO 2 R 6 )R 6 ; O-alkyl-N-(aryl)-C(O)-heterocycle;  
                     
 (c) a heterocycle, including but not limited to, pyrryl, furyl, pyridyl, 1,2,4-thiadiazolyl, pyrimidyl, thienyl, isothiazolyl, imidazolyl, tetrazolyl, pyrazinyl, pyrinidyl, quinolyl, isoquinolyl, benzothienyl, isobenzofuryl, pyrazolyl, indolyl, purinyl, carbozolyl, benzamidazolyl, and isoxazolyl, optionally substituted with a group described in Y section (b);  
 (d)  
                     
  wherein X′ is halo, —C(O)aryl, CF 3 , or OR 3 ; —NR 3 C(O)R 3 ; —OC(O)NH 2 ; —CR 3 R 3 R 4 ; —C(O)R 3 ; —CH 2 OR 3 ; —CH 2 CO 2 R 3 ; —CH 2 OC(O)R 3 ; R 3 CH(R 3 )CH 2 SO 3 —; —NHCH 2 COOR 3 ; halo such as F, Cl, Br and I; N+R 3 R 3 R 4 R 7 ; —NR 3 SO 2 R 3 ; —C(O)R 3 ; NO 2 ; or CN; or  
                     
                     
  wherein R 13 , R 14  and R 15  independently represents: BO— wherein B is —CH 2 -oxacyclopropyl, —CH 2 OR 3 , —CH 2 C(O)R 3 , —CH 2 CH(R 3 )R 3 , —CH 2 Aryl, —CH 2 CH(OH)—CH 2 OH; R 3 C(R 3 ) 2 CH 2 SO 2 ; or R 13 —R 14  or R 14 —R 15  are joined together to form a bridge such as —OCHR 2 CHR 2 —S(O) 2 — wherein n is 0 to 3; or  
                     where X′ is halo, —C(O)aryl, CF 3 , or OR 3 ; —CH 2 OR 3 ; —CH 2 CO 2 R 3 ; —CH 2 C(O)R 3 ; —NHCH 2 COOR 3 ; —N+R 3 R 3 R 4 R 7 .    R 1  and R 2  are independently hydrogen, halogen, or lower alkyl, halo lower alkyl, halo, —COOH, —CONR 16 R 17  wherein R 16  and R 17  independently represent C 1-6  alkyl and hydrogen, —COOR 3 , alkenyl, —C(O)R 3 ; —CH 2 OR 3 ; lower alkynyl, CH 2 NR 4 R 3 ; —CH 2 SR 3 ; ═O; —OR 3 ; or —NR 3 R 3 ;    R 3  and R 4  are independently cyclic and acyclic alkyl, alkenyl, alkynyl, aryl, aralkyl, alkyaryl, hydrogen, C 1-6  alkoxy-C 1-10  alkyl, C 1-6  alkylthio-C 1-10  alkyl, and C 1-10  substituted alkyl (wherein the substituent is independently hydroxy or carbonyl, located on any of C 1-10 );    R 5  is cyclic and acyclic lower alkyl, lower alkenyl, lower alkynyl, halo lower alkyl, halo lower alkenyl, halo lower alkynyl, aralkyl, or aryl;    R 6  is cyclic and acyclic lower alkyl, lower alkenyl, lower alkynyl, aralkyl, halo lower alkyl, halo lower alkenyl, halo lower alkynyl, or aryl;    R 7  is an organic or inorganic anion;    R 8  is halo alkyl, halo lower alkyl, halo lower alkenyl, halo lower alkynyl, lower alkenyl, lower alkynyl, aralkyl, or aryl;    R 9  is independently hydrogen, halogen, lower alkyl, halo lower alkyl, lower alkenyl, lower alkynyl, —CONR 3 R 4 , —C(O)R 5 , —CO 2 R 5 , —CH 2 OR 5 , —CH 2 NR 5 R 5 , —CH 2 SR 5 , ═O, ═NR 5 , —NR 3 R 4 , —NR 3 R 4 R 7 , or —OR 5 ;    R 10  is —R 3 , —R 8 , —C(O)N(OR 3 )R 3 , or —OR 3 ;    R 11  is phenyl-S(O) g -lower alkyl-; (R 3 O) d -phenyl-S(O) g -lower alkyl-; (CN) d -phenyl-S(O) g -lower alkyl-; (halo) d -phenyl-S(O) g -lower alkyl-; (R 3 COO) d -phenyl-S(O) g -lower alkyl-; (R 3 OCO) d -phenyl-S(O) g -lower alkyl-; (R 3 CO) d -phenyl-S(O) g -lower alkyl-; phenyl-O-lower alkyl-; (R 3 O) d -phenyl-O-lower alkyl-; (CN) d -phenyl-O-lower alkyl-; (halo) d -phenyl-O-lower alkyl-; (R 3 COO) d -phenyl-O-lower alkyl-; (R 3 OCO) d -phenyl-O-lower alkyl-; (R 3 R 3 N) d -phenyl-S(O) g -lower alkyl-; or (R 3 CO) d -phenyl-O-lower alkyl- where d is 1, 2, 3, 4 or 5; and g is 0, 1, or 2;    R 12  is selected from the group consisting of: alkyl; substituted alkyl wherein the substituent is selected from the group consisting of hydroxy and amino; -lower alkyl-O-R 18 , wherein R 18  is —PO 2 (OH)—M+ or —PO 3 (M+) 2 , wherein M+ is a pharmaceutically acceptable cation; —C(O)(CH 2 ) 2 CO 2 —M+, or —SO 3 —M+; -lower alkylcarbonyl-lower alkyl; -carboxy lower alkyl; -lower alkylamino-lower alkyl; N,N-di-substituted amino lower alkyl-, wherein the substituents each independently represent lower alkyl; pyridyl-lower alkyl; imidazolyl-lower alkyl; imidazolyl-Y-lower alkyl wherein Y is thio or amino; morpholinyl-lower alkyl; pyrrolidinyl-lower alkyl; thiazolinyl-lower alkyl; piperidinyl-lower alkyl; morpholinyl-lower hydroxyalkyl; N-pyrryl; piperazinyl-lower alkyl; N-substituted piperazinyl-lower alkyl, wherein the substituent is lower alkyl; triazolyl-lower alkyl; tetrazolyl-lower alkyl; tetrazolylamino-lower alkyl; or thiazolyl-lower alkyl;    R 19  is H, lower alkyl, or lower alkenyl; and    R 20  is H, halogen, lower alkoxy, or lower alkyl.    
 
 
     
     
         2 . A compound of the formula:  
       
         
           
           
               
               
           
         
       
       wherein: 
 X is O, S, S(O), S(O) 2 , or NR 10 ;  
 t is 1, 2, 3, or 4;  
 m is 1, 2, or 3;  
 Z is independently W or Y; and  
 all of the R groups are as defined in  claim 1 .  
 
     
     
         3 . A compound of the formula:  
       
         
           
           
               
               
           
         
         wherein Ar 5  is:  
         
           
             
             
                 
                 
             
           
         
         wherein Ar 6  is:  
         
           
             
             
                 
                 
             
           
         
          wherein: 
 v is 0, 1, or 2;  
 
         all R groups, t, m, and n are as defined in claims  1  and  2 ; and 
 Q is selected from the group consisting of substituted C 1  to C 12  alkyl wherein the substituent is selected from the group consisting of hydroxy and amino, alkylcarbonylalkyl, alkyl; lower alkyl S(O) m -lower alkyl in which m is 1 or 2; imidazolyl lower alkyl, morpholinyl lower alkyl, thiazolinyl lower alkyl, piperidinyl ower alkyl, imidazolylcarbonyl, morpholinyl carbonyl, amorpholinyl (lower alkyl) aminocarbonyl, N-pyrrylpyridinyl-lower alkyl; pyridylthio-lower alkyl; morpholinyl-lower alkyl; hydroxyphenylthio-lower alkyl; cyanophenylthio-lower alkyl; imidazolylthio-lower alkyl; triazolylthio-lower alkyl; triazolylphenylthio-lower alkyl; tetrazolylthio-lower alkyl; tetrazolylphenylthio-lower alkyl; aminophenylthio-lower alkyl; N,N-di-substituted aminophenylthio-lower alkyl wherein the amine substituents each independently represent lower alkyl amidinophenylthio-lower alkyl; phenylsultinyl-lower alkyl; or phenylsulfonyl lower alkyl; -lower alkyl-O-R 18 , wherein R 18  is —PO 2 (OH)—M+ or —PO 3 (M+) 2 , wherein M+ is a pharmaceutically acceptable cation; —C(O)(CH 2 ) 2 CO 2 —M+, or —SO 3 —M+; -lower alkylcarbonyl-lower alkyl; -carboxy lower alkyl; -lower alkylamino-lower alkyl; N,N-di-substituted amino lower alkyl-, wherein the substituents each independently represent lower alkyl; pyridyl-lower alkyl; imidazolyl-lower alkyl; imidazolyl-Y-lower alkyl wherein Y is thio or amino; morpholinyl-lower alkyl; pyrrolidinyl-lower alkyl; thiazolinyl-lower alkyl; piperidinyl-lower alkyl; morpholinyl-lower hydroxyalkyl; N-pyrryl; piperazinyl-lower alkyl; N-substituted piperazinyl-lower alkyl, wherein the amine substituent is lower alkyl; triazolyl-lower alkyl; tetrazolyl-lower alkyl; tetrazolylamino-lower alkyl; or thiazolyl-lower alkyl.  
 
       
     
     
         4 . A pharmaceutical composition comprising an effective amount of the compound of  claim 1  in a pharmaceutically acceptable carrier.  
     
     
         5 . The compound of  claim 2  further comprising a pharmaceutically acceptable carrier.  
     
     
         6 . The compound of  claim 3  further comprising a pharmaceutically acceptable carrier.  
     
     
         7 . A method for the treatment of disorders mediated by platelet activating factor or products of 5-lipoxygenase in an animal, comprising administering an effective amount, to reduce formation of oxygen radicals, of a compound of  claim 1  in a pharmaceutically acceptable carrier.  
     
     
         8 . The method of  claim 7 , wherein the animal is a mammal.  
     
     
         9 . The method of  claim 8 , wherein the mammal is a human.  
     
     
         10 . The method of  claim 8 , wherein the mammal is equine.  
     
     
         11 . The method of  claim 8 , wherein the mammal is canine.  
     
     
         12 . The method of  claim 8 , wherein the mammal is bovine.  
     
     
         13 . A method for the treatment of disorders mediated by platelet activating factor or products of 5-lipoxygenase in an animal, comprising administering an effective amount of a compound of  claim 2  in a pharmaceutically acceptable carrier.  
     
     
         14 . The method of  claim 13 , wherein the animal is a mammal.  
     
     
         15 . The method of  claim 14 , wherein the mammal is a human.  
     
     
         16 . The method of  claim 14 , wherein the mammal is equine.  
     
     
         17 . The method of  claim 14 , wherein the mammal is canine.  
     
     
         18 . The method of  claim 14 , wherein the mammal is bovine.  
     
     
         19 . A method for the treatment of disorders mediated by platelet activating factor or products of 5-lipoxygenase in an animal, comprising administering an effective amount of a compound of  claim 3  in a pharmaceutically acceptable carrier.  
     
     
         20 . The method of  claim 19 , wherein the animal is a mammal.  
     
     
         21 . The method of  claim 20 , wherein the mammal is a human.  
     
     
         22 . The method of  claim 20 , wherein the mammal is equine.  
     
     
         23 . The method of  claim 20 , wherein the mammal is canine.  
     
     
         24 . The method of  claim 20 , wherein the mammal is bovine.  
     
     
         25 . trans-2-[5-N′-methyl-N′-hydroxyureidylmethyl)-3-methoxy-4-p-chlorophenylthioethoxyphenyl]-5-(3,4,5-trimethoxyphenyl)tetrahydrofuran.