Phosphodiesterase 4 inhibitors

Abstract

PDE4 inhibition is achieved by novel compounds of the Formula I: wherein R 1 and R 2 are as defined herein.

1 . A method for enhancing cognition in a patient in whom such enhancement is desired; for treating a patient suffering from cognition impairment or decline; for treating a patient having a disease involving decreased cAMP levels; for inhibiting PDE4 enzyme activity in a patient; or for treating a patient suffering from an allergic or inflammatory disease, resulting from decreased cyclic AMP levels, elevated phosphodiesterase 4 levels, or both; said method comprising administering to said patient an effective amount of a compound of Formula I: 
     
       
         
         
             
             
         
       
     
     wherein,
 R 1  is
 alkyl having 1 to 5 carbon atoms, which is substituted one or more times by halogen, hydroxy, or combinations thereof, and wherein a —CH 2 — group can be optionally replaced by —O—, —S—, or —NH—, 
 cycloalkyl having 3 to 6 carbon atoms, or 
 cycloalkylalkyl having 4 to 7 C atoms; and 
 
 R 2  is alkyl having 1 to 12 carbon atoms, which is unsubstituted or substituted one or more times by halogen, hydroxy, cyano or combinations thereof, wherein one or more —CH 2 — groups is each independently optionally replaced by —O—, —S—, or —NH—, and wherein optionally one or more —CH 2 CH 2 — groups is replaced in each case by —CH═CH— or —C≡C—,
 alkoxyalkyl having 3 to 12 carbon atoms, 
 cycloalkyl having 3 to 12 carbon atoms, which is unsubstituted or substituted one or more times by halogen, C 1-4  alkyl, halogenated C 1-4  alkyl, C 1-4  alkoxy, cyano or combinations thereof, 
 cycloalkylalkyl having 4 to 12 carbon atoms, which is unsubstituted or substituted one or more times by C 1-4  alkyl, halogenated C 1-4  alkyl, C 1-4  alkoxy, cyano, halogen, or combinations thereof, 
 aryl having 6 to 14 carbon atoms, which is unsubstituted or substituted one or more times by halogen, C 1-4  alkyl, halogenated C 1-4  alkyl, hydroxy, C 1-4 -alkoxy, halogenated C 1-4  alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, C 1-4  alkylamino, di-C 1-4 -alkylamino, C 1-4 -hydroxyalkyl, C 1-4 -hydroxyalkoxy, carboxy, cyano, —C(O)—NHOH, —C(O)—NH 2 , C 2-4 -acyl, C 2-4 -alkoxycarbonyl, C 1-4 -alkylthio, C 1-4 -alkylsulphinyl, C 1-4 -alkylsulphonyl, phenoxy, or combinations thereof, 
 arylalkyl having 7 to 16 carbon atoms, which is or substituted one or more times by halogen, halogenated C 1-4  alkyl, hydroxy, C 1-4 -alkoxy, halogenated C 1-4  alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, C 1-4  alkylamino, di-C 1-4 -alkylamino, C 1-4 -hydroxyalkyl, C 1-4 -hydroxyalkoxy, carboxy, cyano, —C(O)—NHOH, —C(O)—NH 2 , C 2-4 -acyl, C 2-4 -alkoxycarbonyl, C 1-4 -alkylthio, C 1-4 -alkylsulphinyl, C 1-4 -alkylsulphonyl, phenoxy, or combinations thereof, 
 heteroaryl having 5 to 10 ring atoms in which at least 1 ring atom is a heteroatom, which is unsubstituted or substituted one or more times by halogen, aryl, C 1-4  alkyl, halogenated C 1-4  alkyl, hydroxy, C 1-4 -alkoxy, halogenated C 1-4  alkoxy, cyano, trifluoromethyl, nitro, amino, C 1-4 -alkylamino, di-C 1-4 -alkylamino, carboxy, alkoxycarbonyl, —C(O)—NHOH, —C(O)—NH 2 , C 1-4 -alkylthio, C 1-4 -alkylsulphinyl, C 1-4 -alkylsulphonyl, or combinations thereof, 
 heteroarylalkyl wherein the heteroaryl portion has 5 to 10 ring atoms in which at least 1 ring atom is a heteroatom and the alkyl portion has 1 to 3 carbon atoms, the heteroaryl portion is unsubstituted or is substituted one or more times by halogen, aryl, C 1-4  alkyl, halogenated C 1-4  alkyl, hydroxy, C 1-4 -alkoxy, halogenated C 1-4  alkoxy, cyano, trifluoromethyl, nitro, amino, C 1-4 -alkylamino, di-C 1-4 -alkylamino, carboxy, alkoxycarbonyl, —C(O)—NHOH, —C(O)—NH 2 , C 1-4 -alkylthio, C 1-4 -alkylsulphinyl, C 1-4 -alkylsulphonyl, or combinations thereof, 
 heterocycle having 5 to 10 ring atoms in which at least 1 ring atom is a heteroatom, which is unsubstituted or is substituted one or more times by heterocycle-alkyl wherein the heterocycle portion has 5 to 10 ring atoms in which at least 1 ring atom is a heteroatom and the alkyl portion has 1 to 3 carbon atoms, the heterocycle portion is nonaromatic and is unsubstituted or is substituted one or more times by halogen, aryl, C 1-4  alkyl, halogenated C 1-4  alkyl, hydroxy, C 1-4 -alkoxy, halogenated C 1-4  alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, C 1-4 -alkylamino, di-C 1-4 -alkylamino, carboxy, alkoxycarbonyl, or combinations thereof, or 
 carbocycle which is a nonaromatic, monocyclic or bicyclic, group having 5 to 14 carbon atoms, which is unsubstituted or is substituted one or more times by halogen, C 1-4  alkyl, halogenated C 1-4  alkyl, hydroxy, C 1-4 -alkoxy, halogenated C 1-4  alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, C 1-4  alkylamino, di-C 1-4 -alkylamino, C 1-4 -hydroxyalkyl, C 1-4 -hydroxyalkoxy, carboxy, cyano, —C(O)—NHOH, —C(O)—NH 2 , C 2-4 -acyl, C 2-4 -alkoxycarbonyl, C 1-4 -alkylthio, C 1-4 -alkylsulphinyl, C 1-4 -alkylsulphonyl, phenoxy, or combinations thereof; and 
 
 or a pharmaceutically acceptable salt thereof, 
 with the proviso that 
 when R 1  is cyclopropyl, R 2  is not cyclopropylmethyl, or cyclopropylethyl. 
 
   
   
       2 . (canceled) 
   
   
       3 . A method according to  claim 1 , wherein R 1  is substituted alkyl. 
   
   
       4 . A method according to  claim 1 , wherein R 1  is cycloalkyl. 
   
   
       5 . A method according to  claim 1 , wherein R 1  is cycloalkylalkyl. 
   
   
       6 . A method according to  claim 1 , wherein R 2  is substituted or unsubstituted alkyl. 
   
   
       7 . A method according to  claim 1 , wherein R 2  is alkoxyalkyl. 
   
   
       8 . A method according to  claim 1 , wherein R 2  is substituted or unsubstituted cycloalkyl. 
   
   
       9 . A method according to  claim 1 , wherein R 2  is substituted or unsubstituted aryl. 
   
   
       10 . A method according to  claim 1 , wherein R 2  is substituted or unsubstituted arylalkyl. 
   
   
       11 . A method according to  claim 1 , wherein R 2  is substituted or unsubstituted heteroaryl. 
   
   
       12 . A method according to  claim 1 , wherein R 2  is substituted heteroarylalkyl. 
   
   
       13 . A method according to  claim 1 , wherein R 2  is substituted or unsubstituted heterocycle. 
   
   
       14 . A compound according to  claim 1 , wherein R 2  is substituted or unsubstituted heterocycle-alkyl. 
   
   
       15 . A compound according to  claim 1 , wherein R 2  is substituted or unsubstituted carbocycle. 
   
   
       16 . A method according to  claim 1 , wherein R 1  is cycloalkyl or cycloalkylalkyl. 
   
   
       17 . A method according to  claim 6 , wherein R 1  is cycloalkyl or cycloalkylalkyl. 
   
   
       18 . A method according to  claim 7 , wherein R 1  is cycloalkyl or cycloalkylalkyl. 
   
   
       19 . A method according to  claim 8 , wherein R 1  is cycloalkyl or cycloalkylalkyl. 
   
   
       20 . A method according to  claim 9 , wherein R 1  is cycloalkyl or cycloalkylalkyl. 
   
   
       21 . A method according to  claim 10 , wherein R 1  is cycloalkyl or cycloalkylalkyl. 
   
   
       22 . A method according to  claim 11 , wherein R 1  is cycloalkyl or cycloalkylalkyl. 
   
   
       23 . A method according to  claim 12 , wherein R 1  is cycloalkyl or cycloalkylalkyl. 
   
   
       24 . A method according to  claim 13 , wherein R 1  is cycloalkyl or cycloalkylalkyl. 
   
   
       25 . A method according to  claim 14 , wherein R 1  is cycloalkyl or cycloalkylalkyl. 
   
   
       26 . A method according to  claim 15 , wherein R 1  is cycloalkyl or cycloalkylalkyl. 
   
   
       27 . A method according to  claim 1 , wherein R 1  is cyclopropyl, cyclopentyl, or cyclopropylmethyl. 
   
   
       28 . A method according to  claim 1 , wherein R 1  is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. 
   
   
       29 . A method according to  claim 1 , wherein R 1  is cyclopropyl. 
   
   
       30 . A method according to  claim 1 , wherein R 2  is alkyl, arylalkyl, cycloalkyl, aryl, heteroaryl, heteroarylalkyl, or alkyl ether. 
   
   
       31 . A method according to  claim 1 , wherein R 2  is ethyl, isopropyl, butyl, tert-butyl, cyclopentyl, cyclohexyl, or cycloheptyl, which in each case is unsubstituted or substituted one or more times by F, Cl, CN, CF 3 , CH 3 , C 2 H 5 , isopropyl, OCH 3 , methylenedioxy, ethylenedioxy or combinations thereof, or arylalkyl which is substituted one or more times by F, Cl, CN, CF 3 —OCH 3  methylenedioxy, ethylenedioxy or combinations thereof. 
   
   
       32 . A method according to  claim 1 , wherein R 2  is substituted benzyl, phenethyl or phenpropyl. 
   
   
       33 . A method for enhancing cognition in a patient in whom such enhancement is desired; for treating a patient suffering from cognition impairment or decline; for treating a patient having a disease involving decreased cAMP levels; for inhibiting PDE4 enzyme activity in a patient; or for treating a patient suffering from an allergic or inflammatory disease, resulting from decreased cyclic AMP levels, elevated phosphodiesterase 4 levels, or both; said method comprising administering to said patient an effective amount of a compound of formula II 
     
       
         
         
             
             
         
       
     
     wherein
 R 1′  is methyl, ethyl, or cyclopropyl; and 
 R 2′  is cycloalkyl having 3 to 12 carbon atoms, which is unsubstituted or substituted one or more times by halogen, C 1-4  alkyl, halogenated C 1-4  alkyl, C 1-4  alkoxy, cyano or combinations thereof,
 aryl having 6 to 14 carbon atoms, which is unsubstituted or substituted one or more times by halogen, C 1-4  alkyl, halogenated C 1-4  alkyl, hydroxy, C 1-4 -alkoxy, halogenated C 1-4  alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, C 1-4  alkylamino, di-C 1-4 -alkylamino, C 1-4 -hydroxyalkyl, C 1-4 -hydroxyalkoxy, carboxy, cyano, —C(O)—NHOH, —C(O)—NH 2 , C 2-4 -acyl, C 2-4 -alkoxycarbonyl, C 1-4 -alkylthio, C 1-4 -alkylsulphinyl, C 1-4 -alkylsulphonyl, phenoxy, or combinations thereof, 
 heteroaryl having 5 to 10 ring atoms in which at least 1 ring atom is a heteroatom, which is unsubstituted or substituted one or more times by halogen, aryl, C 1-4  alkyl, halogenated C 1-4  alkyl, hydroxy, C 1-4 -alkoxy, halogenated C 1-4  alkoxy, cyano, trifluoromethyl, nitro, amino, C 1-4 -alkylamino, di-C 1-4 -alkylamino, carboxy, alkoxycarbonyl, —C(O)—NHOH, —C(O)—NH 2 , C 1-4 -alkylthio, C 1-4 -alkylsulphinyl, C 1-4 -alkylsulphonyl, or combinations thereof, 
 heterocycle having 5 to 10 ring atoms in which at least 1 ring atom is a heteroatom, which is unsubstituted or is substituted one or more times by halogen, aryl, C 1-4  alkyl, halogenated C 1-4  alkyl, hydroxy, C 1-4 -alkoxy, halogenated C 1-4  alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, C 1-4 -alkylamino, di-C 1-4 -alkylamino, carboxy, alkoxycarbonyl, or combinations thereof, or 
 carbocycle which is nonaromatic, monocyclic or bicyclic, group having 5 to 14 carbon atoms, which is unsubstituted or is substituted one or more times by halogen, C 1-4  alkyl, halogenated C 1-4  alkyl, hydroxy, C 1-4 -alkoxy, halogenated C 1-4  alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, C 1-4  alkylamino, di-C 1-4 -alkylamino, C 1-4 -hydroxyalkyl, C 1-4 -hydroxyalkoxy, carboxy, cyano, —C(O)—NHOH, —C(O)—NH 2 , C 2-4 -acyl, C 2-4 -alkoxycarbonyl, C 1-4 -alkylthio, C 1-4 -alkylsulphinyl, C 1-4 -alkylsulphonyl, phenoxy, or combinations thereof; 
 
 or a pharmaceutically acceptable salt thereof. 
 
   
   
       34 . A method for enhancing cognition in a patient in whom such enhancement is desired; for treating a patient suffering from cognition impairment or decline; for treating a patient having a disease involving decreased cAMP levels; for inhibiting PDE4 enzyme activity in a patient; or for treating a patient suffering from an allergic or inflammatory disease, resulting from decreased cyclic AMP levels, elevated phosphodiesterase 4 levels, or both; said method comprising administering to said patient an effective amount of a compound of Formula III: 
     
       
         
         
             
             
         
       
     
     wherein
 R 1″  is methyl, ethyl, or cyclopropyl; and 
 R 2″  is phenyl,
 phenyl which is substituted one or more times by halogen, C 1-4  alkyl, halogenated C 1-4  alkyl, hydroxy, C 1-4 -alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, C 1-4  alkylamino, di-C 1-4 -alkylamino, C 1-4 -hydroxyalkyl, C 1-4 -hydroxyalkoxy, carboxy, cyano, C 2-4 -acyl, C 2-4 -alkoxycarbonyl, C 1-4 -alkylthio, C 1-4 -alkylsulphinyl, C 1-4 -alkylsulphonyl, phenoxy, or combinations thereof, or 
 heteroaryl having 5 to 10 ring atoms in which at least 1 ring atom is a heteroatom, substituted heteroaryl having 5 to 10 ring atoms, in which at least 1 ring atom is a heteroatom, which is unsubstituted or substituted one or more times by halogen, aryl, C 1-4 -alkyl, C 1-4 -alkoxy, cyano, trifluoromethyl, nitro, amino, C 1-4 -alkylamino, di-C 1-4 -alkylamino or combinations thereof, 
 or when R 1  is methyl or cyclopropyl R 2  can also be cycloalkyl having 3 to 12 carbon atoms; 
 
 or a pharmaceutically acceptable salt thereof. 
 
   
   
       35 . A method for enhancing cognition in a patient in whom such enhancement is desired; for treating a patient suffering from cognition impairment or decline; for treating a patient having a disease involving decreased cAMP levels; for inhibiting PDE4 enzyme activity in a patient; or for treating a patient suffering from an allergic or inflammatory disease, resulting from decreased cyclic AMP levels, elevated phosphodiesterase 4 levels, or both; said method comprising administering to said patient an effective amount of a compound selected from:
 6-Cyclopropylamino-9-(2-fluorobenzyl)-2-trifluoromethylpurine   6-Cyclopropylamino-9-(4-fluorobenzyl)-2-trifluoromethylpurine   6-Cyclopropylamino-9-(2,6-difluorobenzyl)-2-trifluoromethylpurine   6-Cyclopropylamino-9-(2,3-difluorobenzyl)-2-trifluoromethylpurine   6-Cyclopropylamino-9-propyl 2-trifluoromethylpurine   6-Cyclopropylamino-9-cyclopentyl-2-trifluoromethylpurine   6-Cyclopropylamino-9-(3,4-dimethoxybenzyl)-2-trifluoromethylpurine   6-Cyclopropylamino-9-(3,4-methylenedioxybenzyl)-2-trifluoromethylpurine   6-Cyclopropylamino-9-(3-thiophenemethyl)-2-trifluoromethylpurine   6-Cyclopropylamino-9-cycloheptyl-2-trifluoromethylpurine   6-Methylamino-9-cyclopentyl-2-trifluoromethylpurine   6-Cyclopropylamino-9-cyclohexyl-2-trifluoromethylpurine   6-Methylamino-9-cycloheptyl-2-trifluoromethylpurine   6-Cyclopropylamino-9-cyclopentylmethyl-2-trifluoromethylpurine   6-Cyclopropylamino-9-phenyl-2-trifluoromethylpurine   6-Cyclopropylamino-9-(2-fluorophenyl)-2-trifluoromethylpurine   6-Cyclopropylamino-9-cyclobutyl-2-trifluoromethylpurine   6-Cyclopropylamino-9-(2-norboranane)-2-trifluoromethylpurine   6-Cyclopropylamino-9-(1-indanyl)-2-trifluoromethylpurine   6-Cyclopropylamino-9-(4-fluorophenyl)-2-trifluoromethylpurine   6-Cyclopropylamino-9-(4-chlorophenyl)-2-trifluoromethylpurine   6-Cyclopropylamino-9-(3-thienyl)-2-trifluoromethylpurine   6-Cyclopropylamino-9-(3-cyclopentyloxy-4-methoxybenzyl)-2-trifluoromethylpurine   6-Cyclopropylamino-9-(3,4-dimethoxyphenyl)-2-trifluoromethylpurine   6-Cyclopropylamino-9-(2,6-dichloro-4-pyridylmethyl)-2-trifluoromethylpurine   6-Cyclopropylamino-9-(4-methoxybenzyl)-2-trifluoromethylpurine   6-Cyclopropylamino-9-(3-methoxyphenyl)-2-trifluoromethylpurine   6-Cyclopropylamino-9-(4-methoxyphenyl)-2-trifluoromethylpurine   6-Cyclopropylamino-9-(3-nitrophenyl)-2-trifluoromethylpurine   6-Cyclopropylamino-9-(2-methoxyphenyl)-2-trifluoromethylpurine   6-Cyclopropylamino-9-(3-cyanophenyl)-2-trifluoromethylpurine   6-Cyclopropylamino-9-(2,4-dimethoxyphenyl)-2-trifluoromethylpurine   6-Cyclopropylamino-9-(3-nitrobenzyl)-2-trifluoromethylpurine   6-Cyclopropylamino-9-(6-methoxy-3-pyridyl)-2-trifluoromethylpurine   6-Cyclopropylamino-9-(4-pyridyl)-2-trifluoromethylpurine   6-Cyclopropylamino-9-(3-pyridyl)-2-trifluoromethylpurine   6-Cyclopropylamino-9-(4-dimethylaminophenyl)-2-trifluoromethylpurine   6-Cyclopropylamino-9-(3-aminophenyl)-2-trifluoromethylpurine   6-Methylamino-9-(2,4-dimethoxy-5-pyrimidyl)-2-trifluoromethylpurine   6-Methylamino-9-(2-methoxyphenyl)-2-trifluoromethylpurine   6-Methylamino-9-(4-methoxyphenyl)-2-trifluoromethylpurine   6-Methylamino-9-(3-acetylphenyl)-2-trifluoromethylpurine   6-Methylamino-9-(3-methoxyphenyl)-2-trifluoromethylpurine   6-Methylamino-9-(3-nitrophenyl)-2-trifluoromethylpurine   6-Cyclopropylamino-9-(3-furanyl)-2-trifluoromethylpurine   6-Cyclopropylamino-9-(4-ethoxyphenyl)-2-trifluoromethylpurine   6-Cyclopropylamino-9-(2-ethoxyphenyl)-2-trifluoromethylpurine   6-Cyclopropylamino-9-(3,4-methylenedioxyphenyl)-2-trifluoromethylpurine   6-Cyclopropylamino-9-(3-ethoxyphenyl)-2-trifluoromethylpurine   6-Methylamino-9-(3,4-dimethoxyphenyl)-2-trifluoromethylpurine; and   pharmaceutically acceptable salts thereof.   
   
   
       36 . A method according to  claim 35 , wherein said compound is selected from:
 6-Cyclopropylamino-9-(2,3-difluorobenzyl)-2-trifluoromethylpurine   6-Cyclopropylamino-9-cyclopentyl-2-trifluoromethylpurine   6-Cyclopropylamino-9-(3,4-dimethoxybenzyl)-2-trifluoromethylpurine   6-Cyclopropylamino-9-cycloheptyl-2-trifluoromethylpurine   6-Methylamino-9-cyclopentyl-2-trifluoromethylpurine   6-Cyclopropylamino-9-cyclohexyl-2-trifluoromethylpurine   6-Methylamino-9-cycloheptyl-2-trifluoromethylpurine   6-Cyclopropylamino-9-phenyl-2-trifluoromethylpurine   6-Cyclopropylamino-9-(2-fluorophenyl)-2-trifluoromethylpurine   6-Cyclopropylamino-9-cyclobutyl-2-trifluoromethylpurine   6-Cyclopropylamino-9-(2-norboranane)-2-trifluoromethylpurine   6-Cyclopropylamino-9-(4-fluorophenyl)-2-trifluoromethylpurine   6-Cyclopropylamino-9-(4-chlorophenyl)-2-trifluoromethylpurine   6-Cyclopropylamino-9-(3-thienyl)-2-trifluoromethylpurine   6-Cyclopropylamino-9-(3,4-dimethoxyphenyl)-2-trifluoromethylpurine   6-Cyclopropylamino-9-(2,6-dichloro-4-pyridylmethyl)-2-trifluoromethylpurine   6-Cyclopropylamino-9-(4-methoxybenzyl)-2-trifluoromethylpurine   6-Cyclopropylamino-9-(3-methoxyphenyl)-2-trifluoromethylpurine   6-Cyclopropylamino-9-(4-methoxyphenyl)-2-trifluoromethylpurine   6-Cyclopropylamino-9-(3-nitrophenyl)-2-trifluoromethylpurine   6-Cyclopropylamino-9-(2-methoxyphenyl)-2-trifluoromethylpurine   6-Cyclopropylamino-9-(3-cyanophenyl)-2-trifluoromethylpurine   6-Cyclopropylamino-9-(3-nitrobenzyl)-2-trifluoromethylpurine   6-Cyclopropylamino-9-(4-pyridyl)-2-trifluoromethylpurine   6-Methylamino-9-(2,4-dimethoxy-5-pyrimidyl)-2-trifluoromethylpurine   6-Methylamino-9-(4-methoxyphenyl)-2-trifluoromethylpurine   6-Methylamino-9-(3-acetylphenyl)-2-trifluoromethylpurine   6-Methylamino-9-(3-methoxyphenyl)-2-trifluoromethylpurine   6-Methylamino-9-(3-nitrophenyl)-2-trifluoromethylpurine   6-Cyclopropylamino-9-(3-ethoxyphenyl)-2-trifluoromethylpurine   6-Methylamino-9-(3,4-dimethoxyphenyl)-2-trifluoromethylpurine; and   pharmaceutically acceptable salts thereof.   
   
   
       37 - 73 . (canceled) 
   
   
       74 . A method according to  claim 1 , wherein said method is for enhancing cognition in a patient in whom such enhancement is desired. 
   
   
       75 . A method according to  claim 74 , wherein said compound is administered in an amount of 0.01-100 mg/kg of body weight/day. 
   
   
       76 . A method according to claim  37 , wherein said patient is a human. 
   
   
       77 . A method according to  claim 35 , wherein said method is for enhancing cognition in a patient in whom such enhancement is desired. 
   
   
       78 . A method according to  claim 77 , wherein said patient is a human. 
   
   
       79 . A method according to  claim 78 , wherein said compound is administered in an amount of 0.01-100 mg/kg of body weight/day. 
   
   
       80 . A method according to  claim 74 , wherein when R 1c  is methyl, then R 2c  is not arylalkyl, methyl or 2-butyl, and when R 1c  is H, then R 2c  is not benzyl. 
   
   
       81 . A method according to  claim 1 , wherein said method is for treating a patient suffering from cognition impairment or decline. 
   
   
       82 . A method according to  claim 81 , wherein said patient is a human. 
   
   
       83 . A method according to  claim 82 , wherein said patient is suffering from memory impairment. 
   
   
       84 . A method according to  claim 82 , wherein said compound is administered in an amount of 0.01-100 mg/kg of body weight/day. 
   
   
       85 . A method according to  claim 83 , wherein said patient is suffering from memory impairment due to Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeldt-Jakob disease, depression, aging, head trauma, stroke, CNS hypoxia, cerebral senility, multiinfarct dementia, HIV or cardiovascular disease. 
   
   
       86 . A according to  claim 35 , wherein said method is for treating a patient suffering from cognition impairment or decline. 
   
   
       87 . A method according to  claim 81 , wherein when R 1c  is methyl, then R 2c  is not arylalkyl, methyl or 2-butyl, and when R 1c  is H, then R 2 , is not benzyl. 
   
   
       88 . A method according to  claim 1 , wherein said method is for treating a patient having a disease involving decreased cAMP levels. 
   
   
       89 . A method according to  claim 1 , wherein said method is for inhibiting PDE4 enzyme activity in a patient. 
   
   
       90 . A method according to  claim 83 , wherein said method is for treating a patient suffering from memory impairment due to a neurodegenerative disease. 
   
   
       91 . A method according to  claim 83 , wherein said method is for treating a patient suffering from memory impairment due to an acute neurodegenerative disorder. 
   
   
       92 . A method according to  claim 1 , wherein said method is for treating a patient suffering from an allergic or inflammatory disease, resulting from decreased cyclic AMP levels, elevated phosphodiesterase 4 levels, or both. 
   
   
       93 . A method according to  claim 1 , wherein R 2  is cycloalkylalkyl. 
   
   
       94 . A method according to  claim 1 , wherein R 1  is cycloalkyl or cycloalkylalkyl. 
   
   
       95 . A method according to  claim 1 , wherein said compound is 6-cyclopropylamino-9-(2-methoxyphenyl)-2-trifluoromethylpurine, or a pharmaceutically acceptable salt thereof. 
   
   
       96 . A method according to  claim 83 , wherein said compound is 6-cyclopropylamino-9-(2-methoxyphenyl)-2-trifluoromethylpurine, or a pharmaceutically acceptable salt thereof. 
   
   
       97 . A method according to  claim 92 , wherein said compound is 6-cyclopropylamino-9-(2-methoxyphenyl)-2-trifluoromethylpurine, or a pharmaceutically acceptable salt thereof. 
   
   
       98 . A method according to  claim 1 , wherein said compound is 6-cyclopropylamino-9-(2-fluorobenzyl)-2-trifluoromethylpurine, or a pharmaceutically acceptable salt thereof 
   
   
       99 . A method according to  claim 83 , wherein said compound is 6-cyclopropylamino-9-(2-fluorobenzyl)-2-trifluoromethylpurine, or a pharmaceutically acceptable salt thereof. 
   
   
       100 . A method according to  claim 92 , wherein said compound 6-cyclopropylamino-9-(2-fluorobenzyl)-2-trifluoromethylpurine, or a pharmaceutically acceptable salt thereof.