Benzylated pde4 inhibitors

Abstract

The present invention is directed to a method for reducing the emetogenic effects of PDE inhibitors, and more particularly is directed to compounds having PDE4 inhibition activity with little or no emetogenic side-effects, and chemical methods including benzylation for preparing such compounds. A benzyl group may be attached to either a carbon or nitrogen atom of a PDE4 inhibitor. Suitable benzylation chemistry is to extract a hydrogen from a PDE4 inhibitor, preferably with a base, and then react the resulting nucleophilic PDE4 inhibitor with a benzylating agent, e.g., benzyl bromide or a derivative thereof.

1 . A compound of the formula 
       
         
           
           
               
               
           
         
         and isolated stereoisomers, salts and solvates thereof, wherein 
         Bzl is a benzyl group of the formula 
       
       
         
           
           
               
               
           
         
         wherein each of the numerals 1, 2, 3, 4 and 5 may be carbon or nitrogen, with the proviso that the ring is aromatic and contains at least 3 carbon atoms, and with the proviso that numerals 1, 2, 3, 4 and 5 can not all be carbon; 
         n is 5 and R 1  at each occurrence is independently selected from halogen, nitro, R 2 , NR 2   (m) , and OR 2  wherein m=0, 1, 2, or 3 and R 2  at each occurrence is independently selected from H, C 1 -C 8 alkyl, alkoxyalkyl having 3-7 carbons in the alkoxy portion and 2-4 carbons in the alkyl portion, phenoxyalkyl having 2-6 carbons in the alkyl portion, C 3 -C 7 cycloalkyl, C 6 -C 9 polycycloalkyl, alkylcycloalkyl, hydroxyalkyl, carboxylate, alkylcarboxylate, carboxyl, alkyl carboxyl, amide, alkylamide, aryl, heteroaryl, heteroalkyl, heterocycloalkyl, phenylalkyl having 1-8 carbons in the alkyl portion, phenylaminoalkyl having 2-6 carbons in the alkyl portion and the amino may be optionally substituted with C 1 -C 4 alkyl and indanyl; wherein the alkyl portion of an R 2  group may be optionally substituted with one or more fluorine atoms, hydroxyl or C 1 -C 8 alkoxy; and the aryl portion of an R 2  group may be optionally substituted with C 1 -C 8 alkyl, C 1 -C 8 alkoxy or halogen; 
         A is selected from a direct bond, optionally substituted C 1 -C 5 alkylene, optionally substituted C 2 -C 5 alkenyl and optionally substituted phenylene; 
         p is 5 and R 3  at each occurrence is independently selected from halogen, nitro, R 4 , NR 4   (q) , and OR 4  wherein q=0, 1, 2, or 3 and R 4  at each occurrence is independently selected from H, C 1 -C 8 alkyl, alkoxyalkyl having 3-7 carbons in the alkoxy portion and 2-4 carbons in the alkyl portion, phenoxyalkyl having 2-6 carbons in the alkyl portion, C 3 -C 7 cycloalkyl, C 6 -C 9 polycycloalkyl, alkylcycloalkyl, hydroxyalkyl, carboxylate, alkylcarboxylate, carboxyl, alkyl carboxyl, amide, alkylamide, aryl, heteroaryl, heteroalkyl, heterocycloalkyl, phenylalkyl having 1-8 carbons in the alkyl portion, phenylaminoalkyl having 2-6 carbons in the alkyl portion and the amino may be optionally substituted with C 1 -C 4 alkyl and indanyl; wherein the alkyl portion of an R 4  group may be optionally substituted with one or more fluorine atoms, hydroxyl or C 1 -C 8 alkoxy; and the aryl portion of an R 4  group may be optionally substituted with C 1 -C 8 alkyl, C 1 -C 8 alkoxy or halogen; 
         with the proviso that R 3  at the para position relative to A is alkoxy, and R 3  at one meta position is selected from alkyl having at least 3 carbons and alkoxy having at least 3 carbons. 
       
     
     
         2 . The compound of  claim 1  wherein each of the numerals 1, 2, 3, 4 and 5 may be carbon or nitrogen, with the proviso that the ring is aromatic and contains at least 4 carbon atoms; and
 n is 5 and R 1  at each occurrence is independently selected from halogen, nitro, R 2 , and OR 2  wherein and R 2  at each occurrence is independently selected from H, C 1 -C 8 alkyl, alkoxyalkyl having 3-7 carbons in the alkoxy portion and 2-4 carbons in the alkyl portion, phenoxyalkyl having 2-6 carbons in the alkyl portion, C 3 -C 7 cycloalkyl, C 6 -C 9 polycycloalkyl, alkylcycloalkyl, hydroxyalkyl, carboxylate, alkylcarboxylate, carboxyl, alkyl carboxyl, amide, alkylamide, phenyl, phenylalkyl having 1-8 carbons in the alkyl portion, phenylaminoalkyl having 2-6 carbons in the alkyl portion and the amino may be optionally substituted with C 1 -C 4 alkyl and indanyl; wherein the alkyl portion of an R 2  group may be optionally substituted with one or more fluorine atoms, hydroxyl or C 1 -C 8 alkoxy; and the phenyl portion of an R 2  group may be optionally substituted with C 1 -C 8 alkyl, C 1 -C 8 alkoxy or halogen.   
     
     
         3 . The compound of  claim 1  wherein each of the numerals 1, 2, 3, 4 and 5 may be carbon or nitrogen, with the proviso that the ring is aromatic and contains at least 3 carbon atoms; and
 n is 5 and R 1  at each occurrence is independently selected from halogen, nitro, R 2 , NR 2   (m) , and OR 2  wherein m=0, 1, 2, or 3 and R 2  at each occurrence is independently selected from H, C 1 -C 8 alkyl, alkoxyalkyl having 3-7 carbons in the alkoxy portion and 2-4 carbons in the alkyl portion, phenoxyalkyl having 2-6 carbons in the alkyl portion, C 3 -C 7 cycloalkyl, C 6 -C 9 polycycloalkyl, alkylcycloalkyl, hydroxyalkyl, carboxylate, alkylcarboxylate, carboxyl, alkyl carboxyl, amide, alkylamide, aryl, heteroaryl, heteroalkyl, heterocycloalkyl, phenylalkyl having 1-8 carbons in the alkyl portion, phenylaminoalkyl having 2-6 carbons in the alkyl portion and the amino may be optionally substituted with C 1 -C 4 alkyl and indanyl; wherein the alkyl portion of an R 2  group may be optionally substituted with one or more fluorine atoms, hydroxyl or C 1 -C 8 alkoxy; and the aryl portion of an R 2  group may be optionally substituted with C 1 -C 8 alkyl, C 1 -C 8 alkoxy or halogen; with the proviso that either (a) at least one R 1  is OR 2 , or (b) the benzyl ring contains at least two R 1  groups that are not hydrogen.   
     
     
         4 . The compound of  claim 1  wherein the phenyl group to which (R 3 ) p  is attached has the formula 
       
         
           
           
               
               
           
         
         wherein R 7  is selected from methyl, ethyl, difluoromethyl and trifluoromethyl; and R 8  is selected from C 3 -C 8 alkyl, alkoxyalkyl having 3-7 carbons in the alkoxy portion and 2-4 carbons in the alkyl portion, phenoxyalkyl having 2-6 carbons in the alkyl portion, C 3 -C 7 cycloalkyl, C 6 -C 9 polycycloalkyl, phenylalkyl having 1-8 carbons in the alkyl portion, phenylaminoalkyl having 2-6 carbons in the alkyl portion and the amino may be optionally substituted with C 1 -C 4 alkyl and indanyl; wherein the alkyl portion of an R 2  group may be optionally substituted with one or more fluorine atoms, hydroxyl or C 1 -C 4 alkoxy; and the aryl portion (e.g., phenyl) of an R 2  group may be optionally substituted with C 1 -C 4 alkyl, C 1 -C 4 alkoxy or halogen. 
       
     
     
         5 . The compound of  claim 4  wherein R 8  is not cyclopentyl. 
     
     
         6 . The compound of  claim 1  wherein A is a direct bond; and in at least one occurrence, R 3  is OR 4  wherein R 4  is selected from C 1 -C 8 alkyl, C 3 -C 7 cycloalkyl, and C 6 -C 9 polycycloalkyl. 
     
     
         7 . The compound of  claim 1  having the formula 
       
         
           
           
               
               
           
         
       
     
     
         8 . The compound of  claim 1  wherein A is selected from a direct bond, C 1 -C 5 alkylene, C 2 -C 5 alkenyl and phenylene. 
     
     
         9 . The compound of  claim 1  wherein, at the meta position relative to the A group on the R 3 -substituted phenyl ring, R 3  is alkoxy having at least three carbon atoms, excluding cyclopentyloxy, and at the para position R 1  is not hydrogen. 
     
     
         10 . The compound of  claim 1  wherein aryl is a phenyl ring. 
     
     
         11 . A compound of the formula 
       
         
           
           
               
               
           
         
         and isolated stereoisomers, salts and solvates thereof, wherein 
         Bzl is a benzyl group of the formula 
       
       
         
           
           
               
               
           
         
         wherein each of the numerals 1, 2, 3, 4 and 5 may be carbon or nitrogen, with the proviso that the ring is aromatic and contains at least 3 carbon atoms; 
         n is 5 and R 1  at each occurrence is independently selected from halogen, nitro, R 2 , NR 2   (m) , and OR 2  wherein m=0, 1, 2, or 3 and R 2  at each occurrence is independently selected from H, C 1 -C 8 alkyl, alkoxyalkyl having 3-7 carbons in the alkoxy portion and 2-4 carbons in the alkyl portion, phenoxyalkyl having 2-6 carbons in the alkyl portion, C 3 -C 7 cycloalkyl, C 6 -C 9 polycycloalkyl, alkylcycloalkyl, hydroxyalkyl, carboxylate, alkylcarboxylate, carboxyl, alkyl carboxyl, amide, alkylamide, aryl, heteroaryl, heteroalkyl, heterocycloalkyl, phenylalkyl having 1-8 carbons in the alkyl portion, phenylaminoalkyl having 2-6 carbons in the alkyl portion and the amino may be optionally substituted with C 1 -C 4 alkyl and indanyl; wherein the alkyl portion of an R 2  group may be optionally substituted with one or more fluorine atoms, hydroxyl or C 1 -C 8 alkoxy; and the aryl portion of an R 2  group may be optionally substituted with C 1 -C 8 alkyl, C 1 -C 8 alkoxy or halogen; 
         A is selected from a direct bond, optionally substituted C 1 -C 5 alkylene, optionally substituted C 2 -C 5 alkenyl and optionally substituted phenylene; 
         p is 5 and R 3  at each occurrence is independently selected from halogen, nitro, R 4 , NR 4   (q) , and OR 4  wherein q=0, 1, 2, or 3 and R 4  at each occurrence is independently selected from H, C 1 -C 8 alkyl, alkoxyalkyl having 3-7 carbons in the alkoxy portion and 2-4 carbons in the alkyl portion, phenoxyalkyl having 2-6 carbons in the alkyl portion, C 3 -C 7 cycloalkyl, C 6 -C 9 polycycloalkyl, alkylcycloalkyl, hydroxyalkyl, carboxylate, alkylcarboxylate, carboxyl, alkyl carboxyl, amide, alkylamide, aryl, heteroaryl, heteroalkyl, heterocycloalkyl, phenylalkyl having 1-8 carbons in the alkyl portion, phenylaminoalkyl having 2-6 carbons in the alkyl portion and the amino may be optionally substituted with C 1 -C 4 alkyl and indanyl; wherein the alkyl portion of an R 4  group may be optionally substituted with one or more fluorine atoms, hydroxyl or C 1 -C 8 alkoxy; and the aryl portion of an R 4  group may be optionally substituted with C 1 -C 8 alkyl, C 1 -C 8 alkoxy or halogen; with the provisos that, at the meta position relative to the A group on the R 3 -substituted phenyl ring, R 3  is alkoxy having at least three carbon atoms, excluding cyclopentyloxy, and at the para position R 1  is not hydrogen. 
       
     
     
         12 . The compound of  claim 11  wherein each of the numerals 1, 2, 3, 4 and 5 may be carbon or nitrogen, with the proviso that the ring is aromatic and contains at least 4 carbon atoms; and
 n is 5 and R 1  at each occurrence is independently selected from halogen, nitro, R 2 , and OR 2  wherein and R 2  at each occurrence is independently selected from H, C 1 -C 8 alkyl, alkoxyalkyl having 3-7 carbons in the alkoxy portion and 2-4 carbons in the alkyl portion, phenoxyalkyl having 2-6 carbons in the alkyl portion, C 3 -C 7 cycloalkyl, C 6 -C 9 polycycloalkyl, alkylcycloalkyl, hydroxyalkyl, carboxylate, alkylcarboxylate, carboxyl, alkyl carboxyl, amide, alkylamide, phenyl, phenylalkyl having 1-8 carbons in the alkyl portion, phenylaminoalkyl having 2-6 carbons in the alkyl portion and the amino may be optionally substituted with C 1 -C 4 alkyl and indanyl; wherein the alkyl portion of an R 2  group may be optionally substituted with one or more fluorine atoms, hydroxyl or C 1 -C 8 alkoxy; and the phenyl portion of an R 2  group may be optionally substituted with C 1 -C 8 alkyl, C 1 -C 8 alkoxy or halogen.   
     
     
         13 . The compound of  claim 11  wherein each of the numerals 1, 2, 3, 4 and 5 may be carbon or nitrogen, with the proviso that the ring is aromatic and contains at least 3 carbon atoms; and
 n is 5 and R 1  at each occurrence is independently selected from halogen, nitro, R 2 , NR 2   (m) , and OR 2  wherein m=0, 1, 2, or 3 and R 2  at each occurrence is independently selected from H, C 1 -C 8 alkyl, alkoxyalkyl having 3-7 carbons in the alkoxy portion and 2-4 carbons in the alkyl portion, phenoxyalkyl having 2-6 carbons in the alkyl portion, C 3 -C 7 cycloalkyl, C 6 -C 9 polycycloalkyl, alkylcycloalkyl, hydroxyalkyl, carboxylate, alkylcarboxylate, carboxyl, alkyl carboxyl, amide, alkylamide, aryl, heteroaryl, heteroalkyl, heterocycloalkyl, phenylalkyl having 1-8 carbons in the alkyl portion, phenylaminoalkyl having 2-6 carbons in the alkyl portion and the amino may be optionally substituted with C 1 -C 4 alkyl and indanyl; wherein the alkyl portion of an R 2  group may be optionally substituted with one or more fluorine atoms, hydroxyl or C 1 -C 8 alkoxy; and the aryl portion of an R 2  group may be optionally substituted with C 1 -C 8 alkyl, C 1 -C 8 alkoxy or halogen; with the proviso that either (a) at least one R 1  is OR 2 , or (b) the benzyl ring contains at least two R 1  groups that are not hydrogen.   
     
     
         14 . The compound of  claim 11  wherein each of the numerals 1, 2, 3, 4 and 5 is carbon; and
 n is 5 and R 1  at each occurrence is independently selected from halogen, nitro, R 2 , NR 2   (m) , and OR 2  wherein m=0, 1, 2, or 3 and R 2  at each occurrence is independently selected from H, C 1 -C 8 alkyl, alkoxyalkyl having 3-7 carbons in the alkoxy portion and 2-4 carbons in the alkyl portion, phenoxyalkyl having 2-6 carbons in the alkyl portion, C 3 -C 7 cycloalkyl, C 6 -C 9 polycycloalkyl, alkylcycloalkyl, hydroxyalkyl, carboxylate, alkylcarboxylate, carboxyl, alkyl carboxyl, amide, alkylamide, aryl, heteroaryl, heteroalkyl, heterocycloalkyl, phenylalkyl having 1-8 carbons in the alkyl portion, phenylaminoalkyl having 2-6 carbons in the alkyl portion and the amino may be optionally substituted with C 1 -C 4 alkyl and indanyl; wherein the alkyl portion of an R 2  group may be optionally substituted with one or more fluorine atoms, hydroxyl or C 1 -C 8 alkoxy; and the aryl portion of an R 2  group may be optionally substituted with C 1 -C 8 alkyl, C 1 -C 8 alkoxy or halogen; with the proviso that R 1  is hydrogen at either 1, 2, or 3 occurrences of n, but not 4 or 5 occurrences.   
     
     
         15 . The compound of  claim 11  wherein the phenyl group to which (R 3 ) p  is attached has the formula 
       
         
           
           
               
               
           
         
         wherein R 7  is selected from methyl, ethyl, difluoromethyl and trifluoromethyl; and R 8  is selected from C 3 -C 8 alkyl, alkoxyalkyl having 3-7 carbons in the alkoxy portion and 2-4 carbons in the alkyl portion, phenoxyalkyl having 2-6 carbons in the alkyl portion, C 3 -C 7 cycloalkyl, C 6 -C 9 polycycloalkyl, phenylalkyl having 1-8 carbons in the alkyl portion, phenylaminoalkyl having 2-6 carbons in the alkyl portion and the amino may be optionally substituted with C 1 -C 4 alkyl and indanyl; wherein the alkyl portion of an R 2  group may be optionally substituted with one or more fluorine atoms, hydroxyl or C 1 -C 4 alkoxy; and the aryl portion (e.g., phenyl) of an R 2  group may be optionally substituted with C 1 -C 4 alkyl, C 1 -C 4 alkoxy or halogen. 
       
     
     
         16 . The compound of  claim 11  wherein each of the numerals 1, 2, 3, 4 and 5 is carbon. 
     
     
         17 . The compound of  claim 11  wherein n is 5 and R 1  at each occurrence is independently selected from halogen, nitro, R 2 , NR 2   (m) , and OR 2  wherein m=0, 1, 2, or 3 and R 2  at each occurrence is independently selected from H, C 1 -C 8 alkyl, alkoxyalkyl having 3-7 carbons in the alkoxy portion and 2-4 carbons in the alkyl portion, phenoxyalkyl having 2-6 carbons in the alkyl portion, C 3 -C 7 cycloalkyl, C 6 -C 9 polycycloalkyl, alkylcycloalkyl, hydroxyalkyl, carboxylate, alkylcarboxylate, carboxyl, alkyl carboxyl, amide, alkylamide, phenyl, phenylalkyl having 1-8 carbons in the alkyl portion, phenylaminoalkyl having 2-6 carbons in the alkyl portion and the amino may be optionally substituted with C 1 -C 4 alkyl and indanyl; wherein the alkyl portion of an R 2  group may be optionally substituted with one or more fluorine atoms, hydroxyl or C 1 -C 8 alkoxy; and the phenyl portion of an R 2  group may be optionally substituted with C 1 -C 8 alkyl, C 1 -C 8 alkoxy or halogen. 
     
     
         18 . The compound of  claim 11  wherein each of the numerals 1, 2, 3, 4 and 5 may be carbon or nitrogen, with the proviso that the ring is aromatic and contains at least 3 carbon atoms; n is 5 and R 1  at each occurrence is independently selected from halogen and OR 2  wherein R 2  at each occurrence is independently selected from H and C 1 -C 8 alkyl; with the provisos that the benzyl ring contain no more than three hydrogen substituents and no more than one methoxy substituent. 
     
     
         19 . The compound of  claim 11  wherein A is a direct bond; p is 1, 2, or 3; and in at least one occurrence, R 3  is OR 4  wherein R 4  is selected from C 1 -C 8 alkyl, C 3 -C 7 cycloalkyl, and C 6 -C 9 polycycloalkyl. 
     
     
         20 . The compound of  claim 11  wherein A is selected from a direct bond, C 1 -C 5 alkylene, C 2 -C 5 alkenyl and phenylene. 
     
     
         21 . The compound of  claim 11  wherein each of the numerals 1, 2, 3, 4 and 5 is carbon; and
 n is 5 and R 1  at each occurrence is independently selected from halogen, nitro, R 2 , NR 2   (m) , and OR 2  wherein m=0, 1, 2, or 3 and R 2  at each occurrence is independently selected from H, C 1 -C 8 alkyl, alkoxyalkyl having 3-7 carbons in the alkoxy portion and 2-4 carbons in the alkyl portion, phenoxyalkyl having 2-6 carbons in the alkyl portion, C 3 -C 7 cycloalkyl, C6-C 9 polycycloalkyl, alkylcycloalkyl, hydroxyalkyl, carboxylate, alkylcarboxylate, carboxyl, alkyl carboxyl, amide, alkylamide, aryl, heteroaryl, heteroalkyl, heterocycloalkyl, phenylalkyl having 1-8 carbons in the alkyl portion, phenylaminoalkyl having 2-6 carbons in the alkyl portion and the amino may be optionally substituted with C 1 -C 4 alkyl and indanyl; wherein the alkyl portion of an R 2  group may be optionally substituted with one or more fluorine atoms, hydroxyl or C 1 -C 8 alkoxy; and the aryl portion of an R 2  group may be optionally substituted with C 1 -C 8 alkyl, C 1 -C 8 alkoxy or halogen; with the proviso that at least one R 1  is halogen.   
     
     
         22 . The compound of  claim 11  wherein aryl is a phenyl ring. 
     
     
         23 . A compound of the formula 
       
         
           
           
               
               
           
         
         and isolated stereoisomers, salts and solvates thereof, wherein 
         Bzl is a benzyl group of the formula 
       
       
         
           
           
               
               
           
         
         wherein each of the numerals 1, 2, 3, 4 and 5 may be carbon or nitrogen, with the proviso that the ring is aromatic and contains at least 3 carbon atoms; 
         n is 5 and R 1  at each occurrence is independently selected from hydrogen and OR 2  wherein R 2  at each occurrence is independently selected from H and C 1 -C 8 alkyl; with the provisos that the benzyl ring contain no more than three hydrogen substituents and no more than one methoxy substituent; 
         A is selected from a direct bond, optionally substituted C 1 -C 5 alkylene, optionally substituted C 2 -C 5 alkenyl and optionally substituted phenylene; 
         p is 5 and R 3  at each occurrence is independently selected from halogen, nitro, R 4 , NR 4   (q) , and OR 4  wherein q=0, 1, 2, or 3 and R 4  at each occurrence is independently selected from H, C 1 -C 8 alkyl, alkoxyalkyl having 3-7 carbons in the alkoxy portion and 2-4 carbons in the alkyl portion, phenoxyalkyl having 2-6 carbons in the alkyl portion, C 3 -C 7 cycloalkyl, C 6 -C 9 polycycloalkyl, alkylcycloalkyl, hydroxyalkyl, carboxylate, alkylcarboxylate, carboxyl, alkyl carboxyl, amide, alkylamide, aryl, heteroaryl, heteroalkyl, heterocycloalkyl, phenylalkyl having 1-8 carbons in the alkyl portion, phenylaminoalkyl having 2-6 carbons in the alkyl portion and the amino may be optionally substituted with C 1 -C 4 alkyl and indanyl; wherein the alkyl portion of an R 4  group may be optionally substituted with one or more fluorine atoms, hydroxyl or C 1 -C 8 alkoxy; and the aryl portion of an R 4  group may be optionally substituted with C 1 -C 8 alkyl, C 1 -C 8 alkoxy or halogen. 
       
     
     
         24 . The compound of  claim 23  wherein R 3  is OR 4  in at least one occurrence wherein R 4  is selected from C 1 -C 8 alkyl, C 3 -C 7 cycloalkyl, and C 6 -C 9 polycycloalkyl. 
     
     
         25 . The compound of  claim 23  wherein the phenyl group to which (R 3 ) p  is attached has the formula 
       
         
           
           
               
               
           
         
         wherein R 7  is selected from methyl, ethyl, difluoromethyl and trifluoromethyl; and R 8  is selected from C 3 -C 8 alkyl, alkoxyalkyl having 3-7 carbons in the alkoxy portion and 2-4 carbons in the alkyl portion, phenoxyalkyl having 2-6 carbons in the alkyl portion, C 3 -C 7 cycloalkyl, C6-C 9 polycycloalkyl, phenylalkyl having 1-8 carbons in the alkyl portion, phenylaminoalkyl having 2-6 carbons in the alkyl portion and the amino may be optionally substituted with C 1 -C 4 alkyl and indanyl; wherein the alkyl portion of an R 2  group may be optionally substituted with one or more fluorine atoms, hydroxyl or C 1 -C 4 alkoxy; and the aryl portion (e.g., phenyl) of an R 2  group may be optionally substituted with C 1 -C 4 alkyl, C 1 -C 4 alkoxy or halogen. 
       
     
     
         26 . The compound of  claim 25  wherein R 8  is not cyclopentyl. 
     
     
         27 . The compound of  claim 23  wherein each of the numerals 1, 2, 3, 4 and 5 is carbon. 
     
     
         28 . The compound of  claim 23  wherein A is a direct bond; and in at least one occurrence, R 3  is OR 4  wherein R 4  is selected from C 1 -C 8 alkyl, C 3 -C 7 cycloalkyl, and C 6 -C 9 polycycloalkyl. 
     
     
         29 . The compound of  claim 28  wherein p is 1, 2, or 3. 
     
     
         30 . The compound of  claim 23  having the formula 
       
         
           
           
               
               
           
         
       
     
     
         31 . The compound of  claim 23  wherein A is selected from a direct bond, C 1 -C 5 alkylene, C 2 -C 5 alkenyl and phenylene. 
     
     
         32 . The compound of  claim 23  wherein at least one R 1  is OR 2 . 
     
     
         33 . The compound of  claim 23  wherein, at the meta position relative to the A group on the R 3 -substituted phenyl ring, R 3  is alkoxy having at least three carbon atoms, excluding cyclopentyloxy, and at the para position R 1  is not hydrogen. 
     
     
         34 . The compound of  claim 23  wherein each of the numerals 1, 2, 3, 4 and 5 is carbon; and
 n is 5 and R 1  at each occurrence is independently selected from halogen, nitro, R 2 , NR 2   (m) , and OR 2  wherein m=0, 1, 2, or 3 and R 2  at each occurrence is independently selected from H, C 1 -C 8 alkyl, alkoxyalkyl having 3-7 carbons in the alkoxy portion and 2-4 carbons in the alkyl portion, phenoxyalkyl having 2-6 carbons in the alkyl portion, C 3 -C 7 cycloalkyl, C 6 -C 9 polycycloalkyl, alkylcycloalkyl, hydroxyalkyl, carboxylate, alkylcarboxylate, carboxyl, alkyl carboxyl, amide, alkylamide, aryl, heteroaryl, heteroalkyl, heterocycloalkyl, phenylalkyl having 1-8 carbons in the alkyl portion, phenylaminoalkyl having 2-6 carbons in the alkyl portion and the amino may be optionally substituted with C 1 -C 4 alkyl and indanyl; wherein the alkyl portion of an R 2  group may be optionally substituted with one or more fluorine atoms, hydroxyl or C 1 -C 8 alkoxy; and the aryl portion of an R 2  group may be optionally substituted with C 1 -C 8 alkyl, C 1 -C 8 alkoxy or halogen; with the proviso that at least one R 1  is halogen.   
     
     
         35 . The compound of  claim 23  wherein aryl is a phenyl ring. 
     
     
         36 . A method for treating or preventing an inflammatory condition or disease in a patient, comprising administering to the patient in need thereof an amount of a compound according to  claim 1 , where the amount is effective to treat or prevent the inflammatory condition or disease of the patient. 
     
     
         37 . The method of  claim 36  wherein the compound 1 is a PDE4 inhibitor, and the PDE4 inhibitor inhibits an enzyme selected from phosphodiesterase 4 A, B, C or D or any combination thereof including all splice variants of PDE4 A, B, C and D. 
     
     
         38 . The method of  claim 36  wherein the inflammatory condition or disease is selected from an autoimmune condition or disease; acute or chromic inflammation of bone and/or cartilage compartments of joints; arthritis selected from rheumatoid arthritis, gouty arthritis and juvenile rheumatoid arthritis; asthma; a condition or disease associated with the disregulation of T-cells; a condition or disease associated with elevated levels of inflammatory cytokines; multiple sclerosis; pulmonary sarcadosis; ocular inflammation or allergy; inflammatory bowel disease; inflammatory cutaneous disease; chronic obstructive pulmonary disease (COPD), bronchitis, emphysema; and acute respiratory distress syndrome (ARDS). 
     
     
         39 . A method for treating or preventing a disease or condition in a patient, where the disease or condition is associated with pathological conditions that are modulated by inhibiting enzymes associated with secondary cellular messengers, the method comprising administering to the patient in need thereof an amount of a compound according to  claim 1 , wherein the amount is effective to treat or prevent a disease or condition associated with pathological conditions that are modulated by inhibiting enzymes associated with secondary cellular messengers. 
     
     
         40 . The method of  claim 39  wherein the enzymes include a cyclic AMP phosphodiesterase. 
     
     
         41 . The method of  claim 39  wherein the enzymes include phosphodiesterase 4. 
     
     
         42 . A method of treating or preventing transplant rejection in a patient, the method comprising administering to the patient in need thereof an amount of a compound according to  claim 1 , where the amount is effective to treat or prevent transplant rejection in the patient. 
     
     
         43 . The method of  claim 42  wherein the transplant rejection is due to graft versus host disease. 
     
     
         44 . A method of treating or preventing uncontrolled cellular proliferation in a patient, the method comprising administering to the patient in need thereof an amount of a compound according to  claim 1 , where the amount is effective to treat or prevent uncontrolled cellular proliferation in the patient. 
     
     
         45 . The method of  claim 44  wherein the uncontrolled cellular proliferation is caused by a cancer selected from leukemia and solid tumors. 
     
     
         46 . A method of treating or preventing a condition associated with the central nervous system (CNS) in a patient, the method comprising administering to the patient in need thereof an amount of a compound according to  claim 1 , where the amount is effective to treat or prevent a condition associated with the central nervous system (CNS) in the patient. 
     
     
         47 . The method of  claim 46  wherein the condition is depression. 
     
     
         48 . The method of  claim 46  wherein the condition is long-term memory potentiation and learning enhancement. 
     
     
         49 . A method of treating or preventing a disease associated with viral infection in a patient, the method comprising administering to the patient in need thereof an amount of a compound according to  claim 1 , where the amount is effective to treat or prevent the disease associated with viral infection in the patient. 
     
     
         50 . The method of  claim 49  wherein the viral infection is due to human immunodeficiency virus (HIV) and the disease is acquired immunodeficiency syndrome (AIDS). 
     
     
         51 . A method of treating or preventing a disease associated with a parasitic infection in a patient, the method comprising administering to the patient in need thereof an amount of a compound according to  claim 1 , where the amount is effective to treat or prevent the disease associated with the parasitic infection. 
     
     
         52 . The method of  claim 51  wherein the parasitic infection is due to the trypanosoma brucei and the disease is African sleeping sickness disease. 
     
     
         53 . A method of treating or preventing cystic fibrosis in a patient, the method comprising administering to the patient in need thereof an amount of a compound according to  claim 1 , where the amount is effective to treat or prevent cystic fibrosis. 
     
     
         54 . A method for treating or preventing an inflammatory condition or disease in a patient, comprising administering to the patient in need thereof an amount of a compound according to  claim 11 , where the amount is effective to treat or prevent the inflammatory condition or disease of the patient. 
     
     
         55 . The method of  claim 54  wherein the compound is a PDE4 inhibitor, and the PDE4 inhibitor inhibits an enzyme selected from phosphodiesterase 4 A, B, C or D or any combination thereof including all splice variants of PDE4 A, B, C and D. 
     
     
         56 . The method of  claim 54  wherein the inflammatory condition or disease is selected from an autoimmune condition or disease; acute or chromic inflammation of bone and/or cartilage compartments of joints; arthritis selected from rheumatoid arthritis, gouty arthritis and juvenile rheumatoid arthritis; asthma; a condition or disease associated with the disregulation of T-cells; a condition or disease associated with elevated levels of inflammatory cytokines; multiple sclerosis; pulmonary sarcadosis; ocular inflammation or allergy; inflammatory bowel disease; inflammatory cutaneous disease; chronic obstructive pulmonary disease (COPD), bronchitis, emphysema; and acute respiratory distress syndrome (ARDS). 
     
     
         57 . A method for treating or preventing a disease or condition in a patient, where the disease or condition is associated with pathological conditions that are modulated by inhibiting enzymes associated with secondary cellular messengers, the method comprising administering to the patient in need thereof an amount of a compound according to  claim 11 , wherein the amount is effective to treat or prevent a disease or condition associated with pathological conditions that are modulated by inhibiting enzymes associated with secondary cellular messengers. 
     
     
         58 . The method of  claim 57  wherein the enzymes include a cyclic AMP phosphodiesterase. 
     
     
         59 . The method of  claim 57  wherein the enzymes include phosphodiesterase 4. 
     
     
         60 . A method of treating or preventing transplant rejection in a patient, the method comprising administering to the patient in need thereof an amount of a compound according to  claim 11 , where the amount is effective to treat or prevent transplant rejection in the patient. 
     
     
         61 . The method of  claim 60  wherein the transplant rejection is due to graft versus host disease. 
     
     
         62 . A method of treating or preventing uncontrolled cellular proliferation in a patient, the method comprising administering to the patient in need thereof an amount of a compound according to  claim 11 , where the amount is effective to treat or prevent uncontrolled cellular proliferation in the patient. 
     
     
         63 . The method of  claim 62  wherein the uncontrolled cellular proliferation is caused by a cancer selected from leukemia and solid tumors. 
     
     
         64 . A method of treating or preventing a condition associated with the central nervous system (CNS) in a patient, the method comprising administering to the patient in need thereof an amount of a compound according to  claim 11 , where the amount is effective to treat or prevent a condition associated with the central nervous system (CNS) in the patient. 
     
     
         65 . The method of  claim 64  wherein the condition is depression. 
     
     
         66 . The method of  claim 64  wherein the condition is long-term memory potentiation and learning enhancement. 
     
     
         67 . A method of treating or preventing a disease associated with viral infection in a patient, the method comprising administering to the patient in need thereof an amount of a compound according to  claim 11 , where the amount is effective to treat or prevent the disease associated with viral infection in the patient. 
     
     
         68 . The method of  claim 67  wherein the viral infection is due to human immunodeficiency virus (HIV) and the disease is acquired immunodeficiency syndrome (AIDS). 
     
     
         69 . A method of treating or preventing a disease associated with a parasitic infection in a patient, the method comprising administering to the patient in need thereof an amount of a compound according to  claim 11 , where the amount is effective to treat or prevent the disease associated with the parasitic infection. 
     
     
         70 . The method of  claim 69  wherein the parasitic infection is due to the trypanosoma brucei and the disease is African sleeping sickness disease. 
     
     
         71 . A method of treating or preventing cystic fibrosis in a patient, the method comprising administering to the patient in need thereof an amount of a compound according to  claim 11 , where the amount is effective to treat or prevent cystic fibrosis. 
     
     
         72 . A method for treating or preventing an inflammatory condition or disease in a patient, comprising administering to the patient in need thereof an amount of a compound according to  claim 23 , where the amount is effective to treat or prevent the inflammatory condition or disease of the patient. 
     
     
         73 . The method of  claim 72  wherein the compound is a PDE4 inhibitor, and the PDE4 inhibitor inhibits an enzyme selected from phosphodiesterase 4 A, B, C or D or any combination thereof including all splice variants of PDE4 A, B, C and D. 
     
     
         74 . The method of  claim 72  wherein the inflammatory condition or disease is selected from an autoimmune condition or disease; acute or chromic inflammation of bone and/or cartilage compartments of joints; arthritis selected from rheumatoid arthritis, gouty arthritis and juvenile rheumatoid arthritis; asthma; a condition or disease associated with the disregulation of T-cells; a condition or disease associated with elevated levels of inflammatory cytokines; multiple sclerosis; pulmonary sarcadosis; ocular inflammation or allergy; inflammatory bowel disease; inflammatory cutaneous disease; chronic obstructive pulmonary disease (COPD), bronchitis, emphysema; and acute respiratory distress syndrome (ARDS). 
     
     
         75 . A method for treating or preventing a disease or condition in a patient, where the disease or condition is associated with pathological conditions that are modulated by inhibiting enzymes associated with secondary cellular messengers, the method comprising administering to the patient in need thereof an amount of a compound according to  claim 11 , wherein the amount is effective to treat or prevent a disease or condition associated with pathological conditions that are modulated by inhibiting enzymes associated with secondary cellular messengers. 
     
     
         76 . The method of  claim 75  wherein the enzymes include a cyclic AMP phosphodiesterase. 
     
     
         77 . The method of  claim 75  wherein the enzymes include phosphodiesterase 4. 
     
     
         78 . A method of treating or preventing transplant rejection in a patient, the method comprising administering to the patient in need thereof an amount of a compound according to  claim 23 , where the amount is effective to treat or prevent transplant rejection in the patient. 
     
     
         79 . The method of  claim 78  wherein the transplant rejection is due to graft versus host disease. 
     
     
         80 . A method of treating or preventing uncontrolled cellular proliferation in a patient, the method comprising administering to the patient in need thereof an amount of a compound according to  claim 23 , where the amount is effective to treat or prevent uncontrolled cellular proliferation in the patient. 
     
     
         81 . The method of  claim 80  wherein the uncontrolled cellular proliferation is caused by a cancer selected from leukemia and solid tumors. 
     
     
         82 . A method of treating or preventing a condition associated with the central nervous system (CNS) in a patient, the method comprising administering to the patient in need thereof an amount of a compound according to  claim 23 , where the amount is effective to treat or prevent a condition associated with the central nervous system (CNS) in the patient. 
     
     
         83 . The method of  claim 82  wherein the condition is depression. 
     
     
         84 . The method of  claim 82  wherein the condition is long-term memory potentiation and learning enhancement. 
     
     
         85 . A method of treating or preventing a disease associated with viral infection in a patient, the method comprising administering to the patient in need thereof an amount of a compound according to  claim 82 , where the amount is effective to treat or prevent the disease associated with viral infection in the patient. 
     
     
         86 . The method of  claim 85  wherein the viral infection is due to human immunodeficiency virus (HIV) and the disease is acquired immunodeficiency syndrome (AIDS). 
     
     
         87 . A method of treating or preventing a disease associated with a parasitic infection in a patient, the method comprising administering to the patient in need thereof an amount of a compound according to  claim 23 , where the amount is effective to treat or prevent the disease associated with the parasitic infection. 
     
     
         88 . The method of  claim 87  wherein the parasitic infection is due to the trypanosoma brucei and the disease is African sleeping sickness disease. 
     
     
         89 . A method of treating or preventing cystic fibrosis in a patient, the method comprising administering to the patient in need thereof an amount of a compound according to  claim 23 , where the amount is effective to treat or prevent cystic fibrosis.