Phosphodiesterase 4 inhibitors

Abstract

Selective PDE4 inhibition is achieved by aryl and heteroaryl pyrazole compounds. The compounds exhibit improved PDE4 inhibition as compared to compounds such as rolipram and show selectivity with regard to inhibition of other classes of PDEs.

1 . A compound according to Formulas II or V: 
     
       
         
         
             
             
         
       
       wherein
 L is a single bond;
 C 1 -C 6  straight chain or branched alkylene, wherein a CH 2  group is optionally replaced by O, NH, NR 1 , or S, which is unsubstituted or substituted one or more times by oxo, halogen, hydroxy, cyano or combinations thereof; or 
 (CH 2 ) n CONH; (CH 2 ) n CON(C 1-6 -alkyl); (CH 2 ) n NHCO; (CH 2 ) n CONHSO 2 ; (CH 2 ) n SO 2 NH; (CH 2 ) n SO 2 ; or (CH 2 ) n CO 2 ; 
 
 n is 0 to 3; 
 R 1  is alkyl having 1 to 4 carbon atoms, which is unsubstituted or substituted one or more times by halogen; 
 R 3  is H,
 alkyl having 1 to 8 carbon atoms, which is unsubstituted or substituted one or more times by halogen, oxo, or combinations thereof wherein optionally one or more —CH 2 CH 2 — groups are replaced in each case by —CH═CH— or —C≡C— groups, 
 cycloalkyl having 3 to 8 carbon atoms, which is unsubstituted or substituted one or more times by halogen, oxo, alkyl, or combinations thereof, 
 aryl having 6 to 14 carbon atoms, which is unsubstituted or substituted one or more times by halogen, alkyl, hydroxy, alkoxy, halogenated alkyl, halogenated alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulphinyl, alkylsulphonyl, arylsulphinyl, arylsulphonyl, phenyl, halogenated phenyl, phenoxy, acyloxy, acylamido, imidazolyl, pyridinyl, morpholinyl, piperadinyl, piperazinyl, tetrazolyl, alkylsulphonimide, arylsulphonimide or combinations thereof, 
 heterocyclic group, which is saturated, partially saturated or fully unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is an N, O or S atom, which is unsubstituted or substituted one or more times by halogen, alkyl, hydroxy, alkoxy, halogenated alkyl, halogenated alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulphinyl, alkylsulphonyl, arylsulphinyl, arylsulphonyl, phenyl, halogenated phenyl, phenoxy, acyloxy, tetrazolyl, alkylsulphonimide, arylsulphonimide, aryl, oxo, acylamido, or combinations thereof, 
 arylalkyl having 7 to 16 carbon atoms, which is unsubstituted or substituted one or more times by halogen, alkyl, hydroxy, alkoxy, halogenated alkyl, halogenated alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulphinyl, alkylsulphonyl, arylsulphinyl, arylsulphonyl, phenyl, halogenated phenyl, phenoxy, acyloxy, acylamido, tetrazolyl, alkylsulphonimide, arylsulphonimide, or combinations thereof and/or substituted in the alkyl portion by halogen, oxo, cyano, or combinations thereof, 
 a heterocyclic-alkyl group, which is saturated, partially saturated or fully unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is an N, O or S atom, which is unsubstituted or substituted one or more times in the heterocyclic portion by halogen, alkyl, hydroxy, alkoxy, halogenated alkyl, halogenated alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulphinyl, alkylsulphonyl, arylsulphinyl, arylsulphonyl, phenyl, halogenated phenyl, phenoxy, acyloxy, tetrazolyl, alkylsulphonimide, arylsulphonimide, aryl, oxo, or combinations thereof and/or substituted in the alkyl portion by halogen, oxo, cyano, or combinations thereof, 
 cycloalkylalkyl having 4 to 16 carbon atoms, which is unsubstituted or substituted one or more times by halogen, oxo, alkyl or combinations thereof, or 
 alkoxyalkyl having 3 to 8 carbon atoms; 
 
 R 4  is alkyl having 1 to 6 carbon atoms, which is unsubstituted or substituted one or more times by halogen, oxo, or combinations thereof wherein optionally one or more —CH 2 CH 2 — groups are replaced in each case by —CH═CH— or —C≡C— groups; 
 R 7  is H, halogen, or alkyl having 1 to 6 carbon atoms wherein optionally one or more —CH 2 CH 2 — groups are replaced in each case by —CH═CH— or —C≡C— groups and wherein the alkyl is unsubstituted or substituted one or more times by halogen; and 
 R 8  is H, halogen, alkyl having 1 to 6 carbon atoms wherein optionally one or more —CH 2 CH 2 -groups are replaced in each case by —CH═CH— or —C≡C— groups and wherein the alkyl is unsubstituted or substituted one or more times by halogen or hydroxyl, carboxy, alkoxycarbonyl having 2 to 6 carbon atoms, —CO-alkyl having 2 to 6 carbon atoms, or phenyl; 
 
       or a pharmaceutically acceptable salt thereof,
 wherein said compound can be in the form of a mixture of enantiomers such as the racemate, or a mixture of diastereomers, or can be in the form of a single enantiomer or a single diastereomer. 
 
     
   
   
       2 . A compound according to  claim 1 , wherein said compound is selected from Formulas II or V: 
     
       
         
         
             
             
         
       
       wherein
 L is a single bond;
 C 1 -C 6  straight chain or branched alkylene, wherein a CH 2  group is optionally replaced by O, NH, NR 1 , or S, which is unsubstituted or substituted one or more times by oxo, halogen, hydroxy, cyano or combinations thereof; or 
 (CH 2 ) n CONH; (CH 2 ) n NHCO; (CH 2 ) n CONHSO 2 ; (CH 2 ) n SO 2 NH; (CH 2 ) n SO 2 ; or (CH 2 ) n CO 2 ; 
 
 n is 0 to 3; 
 R 1  is alkyl having 1 to 4 carbon atoms, which is unsubstituted or substituted one or more times by halogen; 
 R 3  is H,
 alkyl having 1 to 8 carbon atoms, which is unsubstituted or substituted one or more times by halogen, oxo, or combinations thereof wherein optionally one or more —CH 2 CH 2 — groups are replaced in each case by —CH═CH— or —C≡C— groups, 
 cycloalkyl having 3 to 8 carbon atoms, which is unsubstituted or substituted one or more times by halogen, oxo, alkyl, or combinations thereof, 
 aryl having 6 to 14 carbon atoms, which is unsubstituted or substituted one or more times by halogen, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulphinyl, alkylsulphonyl, phenoxy, and acyloxy, or combinations thereof, 
 heterocyclic group, which is saturated, partially saturated or fully unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is an N, O or S atom, which is unsubstituted or substituted one or more times in the heterocyclic portion by halogen, aryl, alkyl, alkoxy, cyano, halogenated alkyl, nitro, oxo, amino, alkylamino, dialkylamino, carboxy or combinations thereof and/or substituted in the alkyl portion by halogen, oxo, cyano, or combinations thereof, 
 arylalkyl having 7 to 16 carbon atoms, which is unsubstituted or substituted one or more times by halogen, CF 3 , OCF 3 , alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulphinyl, alkylsulphonyl, phenoxy, acylamido, and acyloxy, or combinations thereof, 
 a heterocyclic-alkyl group, which is saturated, partially saturated or fully unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is an N, O or S atom, which is unsubstituted or substituted one or more times in the heterocyclic portion by halogen, aryl, alkyl, alkoxy, cyano, halogenated alkyl, nitro, oxo, amino, alkylamino, dialkylamino, carboxy or combinations thereof and/or substituted in the alkyl portion by halogen, oxo, cyano, or combinations thereof, 
 cycloalkylalkyl having 4 to 16 carbon atoms, which is unsubstituted or substituted one or more times by halogen, oxo, alkyl or combinations thereof, or 
 alkoxyalkyl having 3 to 8 carbon atoms; 
 
 R 4  is alkyl having 1 to 6 carbon atoms, which is unsubstituted or substituted one or more times by halogen, oxo, or combinations thereof wherein optionally one or more —CH 2 CH 2 — groups are replaced in each case by —CH═CH— or —C≡C— groups; 
 R 7  is H, halogen, or alkyl having 1 to 6 carbon atoms wherein optionally one or more —CH 2 CH 2 — groups are replaced in each case by —CH═CH— or —C≡C— groups and wherein the alkyl is unsubstituted or substituted one or more times by halogen; 
 R 8  is H, halogen, or alkyl having 1 to 6 carbon atoms wherein optionally one or more —CH 2 CH 2 — groups are replaced in each case by —CH═CH— or —C≡C— groups and wherein the alkyl is unsubstituted or substituted one or more times by halogen; 
 
       or a pharmaceutically acceptable salt thereof,
 wherein said compound can be in the form of a mixture of enantiomers such as the racemate, or a mixture of diastereomers, or can be in the form of a single enantiomer or a single diastereomer. 
 
     
   
   
       3 . (canceled) 
   
   
       4 . A compound according to  claim 1 , wherein said compound is selected from Formula II. 
   
   
       5 . (canceled) 
   
   
       6 . (canceled) 
   
   
       7 . A compound according to  claim 1 , wherein said compound is selected from Formula V. 
   
   
       8 . (canceled) 
   
   
       9 . (canceled) 
   
   
       10 . (canceled) 
   
   
       11 . A compound according to  claim 1 , wherein R 1  is CH 3  or CF 2 H. 
   
   
       12 . A compound according to  claim 1 , wherein R 2  is alkyl, halogenated alkyl, cycloalkyl which is substituted or unsubstituted, cycloalkylalkyl which is substituted or unsubstituted, tetrahydrofuranyl, or arylalkyl which is substituted or unsubstituted. 
   
   
       13 . A compound according to  claim 1 , wherein R 2  is CH 3 , C 2 H 5 , isopropyl, CF 2 H, cyclobutyl, cyclopentyl, cyclopropylmethyl, or 3-tetrahydrofuranyl. 
   
   
       14 . (canceled) 
   
   
       15 . (canceled) 
   
   
       16 . (canceled) 
   
   
       17 . (canceled) 
   
   
       18 . (canceled) 
   
   
       19 . A compound according to  claim 1 , wherein R 3  is benzyl or phenethyl, which in each case is substituted or unsubstituted. 
   
   
       20 . A compound according to  claim 1 , wherein R 3  is benzyl, methylbenzyl, t.-butylbenzyl, methoxybenzyl, dimethoxybenzyl, carboxybenzyl, fluorobenzyl, difluorobenzyl, trifluoromethylbenzyl, trifluoromethoxybenzyl, chlorobenzyl, nitrobenzyl, methoxycarbonylbenzyl, or phenethyl. 
   
   
       21 . A compound according to  claim 1 , wherein R 4  is CH 3 . 
   
   
       22 . (canceled) 
   
   
       23 . (canceled) 
   
   
       24 . A compound according to  claim 1 , wherein X is CH. 
   
   
       25 . A compound according to  claim 1 , wherein X is N. 
   
   
       26 . A compound according to  claim 1 , wherein L is a bond, CH 2 , CH 2 CH 2 , CH 2 CO, CH 2 CO 2 , or CH 2 CONH. 
   
   
       27 . A compound according to  claim 1 , wherein subscript n is 0 or 1. 
   
   
       28 . A compound according to  claim 1 , wherein R 7  is H, and R 8  is H, CH 3 , C 2 H 5 , CF 3 , hydroxymethyl, 2-(2-hydroxy)propyl), carboxy, ethoxycarbonyl, CH 3 CO, or phenyl. 
   
   
       29 . (canceled) 
   
   
       30 . (canceled) 
   
   
       31 . (canceled) 
   
   
       32 . (canceled) 
   
   
       33 . (canceled) 
   
   
       34 . (canceled) 
   
   
       35 . (canceled) 
   
   
       36 . (canceled) 
   
   
       37 . (canceled) 
   
   
       38 . (canceled) 
   
   
       39 . (canceled) 
   
   
       40 . (canceled) 
   
   
       41 . (canceled) 
   
   
       42 . (canceled) 
   
   
       43 . (canceled) 
   
   
       44 . (canceled) 
   
   
       45 . (canceled) 
   
   
       46 . (canceled) 
   
   
       47 . (canceled) 
   
   
       48 . (canceled) 
   
   
       49 . (canceled) 
   
   
       50 . (canceled) 
   
   
       51 . (canceled) 
   
   
       52 . (canceled) 
   
   
       53 . (canceled) 
   
   
       54 . A compound according to  claim 1 , wherein R 7  and R 8  are each H. 
   
   
       55 . A compound according to  claim 1 , wherein said compound is selected from: 
     3-(2-Acetyl-7-methoxybenzofuran-4-yl)-1H-pyrazole; 
     3-(2-Acetyl-7-methoxybenzofuran-4-yl)-1-(2,3-difluorobenzyl)-1H-pyrazole; 
     3-(2-Acetyl-7-methoxybenzofuran-4-yl)-1-(4-methylsulfonylbenzyl)-1H-pyrazole; 
     3-(2-Acetyl-7-methoxybenzofuran-4-yl)-1-(2-methylbenzyl)-1H-pyrazole;
 and pharmaceutically acceptable salts thereof, wherein in each case the compound can be in the form of a mixture of enantiomers such as the racemate, or a mixture of diastereomers, or can be in the form of a single enantiomer or a single diastereomer. 
 
   
   
       56 . (canceled) 
   
   
       57 . (canceled) 
   
   
       58 . A pharmaceutical composition comprising a compound according to  claim 1  and a pharmaceutically acceptable carrier. 
   
   
       59 . (canceled) 
   
   
       60 . A method for enhancing cognition and/or treating psychosis in a patient comprising administering to said patient an effective amount of a compound according to  claim 1 . 
   
   
       61 . (canceled) 
   
   
       62 . (canceled) 
   
   
       63 . A method of  claim 60 , wherein the patient is suffering from cognition impairment or decline. 
   
   
       64 . A method according to  claim 60 , wherein said patient is suffering from memory impairment. 
   
   
       65 . (canceled) 
   
   
       66 . (canceled) 
   
   
       67 . (canceled) 
   
   
       68 . (canceled) 
   
   
       69 . (canceled) 
   
   
       70 . (canceled) 
   
   
       71 . A method of treating inflammation in a patient comprising administering to said patient an effective amount of a compound according to  claim 1 . 
   
   
       72 . (canceled) 
   
   
       73 . (canceled) 
   
   
       74 . (canceled) 
   
   
       75 . (canceled) 
   
   
       76 . (canceled)