Phosphodiesterase 4 inhibitors

Abstract

Selective PDE4 inhibition is achieved by 4-(substituted-phenyl)-2-pyrrolidinone compounds. The compounds exhibit improved PDE4 inhibition as compared to compounds like rolipram and show selectivity with regard to inhibition of other classes of PDEs. The compounds of the present invention are of formula I: wherein R 1 , R 2 , and R 3 are as defined herein.

1 . A compound of Formula I: 
     
       
         
         
             
             
         
       
     
     wherein
 X is O; 
 R 1  is alkyl having 1 to 8 carbon atoms wherein optionally one or more —CH 2 CH 2 — groups are replaced in each case by —CH═CH— or —C═C— groups,
 alkyl having 1 to 8 carbon atoms which is 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 having 1 to 4 carbon atoms or combinations thereof, 
 a heterocyclic group, which is saturated, partially saturated or fully unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is a N, O or S atom which is unsubstituted or substituted one or more times by halogen, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, alkylamino, dialkylamino, or combinations thereof, 
 aryl having 6 to 14 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, 
 arylalkyl having 8 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 partially unsaturated carbocyclic group having 5 to 14 carbon atoms, which is unsubstituted or substituted one or more times by halogen, alkyl, alkoxy, nitro, cyano, oxo, or combinations thereof, 
 arylalkenyl having 8 to 16 carbon atoms, wherein the alkenyl portion has up to 5 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, 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, wherein the heterocyclic portion is unsubstituted or substituted one or more times by halogen, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, alkylamino, dialkylamino, carboxy or combinations thereof and/or substituted in the alkyl portion by halogen, oxo, cyano, or combinations thereof, or 
 cycloalkylalkyl having 4 to 16 carbon atoms, which is unsubstituted or substituted one or more times by halogen, oxo, alkyl or combinations thereof, 
 
 R 2  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 wherein optionally one or more —CH 2 CH 2 — groups are replaced in each case by —CH═CH— or —C≡C— groups, 
 alkyl having 1 to 8 carbon atoms which is 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, 
 arylalkyl having 7 to 16 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, 
 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, wherein the heterocyclic portion is unsubstituted or substituted one or more times by halogen, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, alkylamino, dialkylamino, carboxy or combinations thereof and/or substituted in the alkyl portion by halogen, oxo, cyano, or combinations thereof, 
 alkoxyalkyl having 3 to 8 carbon atoms, 
 —C(O)R 4 , or 
 —CH 2 CONHR 5 ; 
 
 R 4  is alkyl having 1 to 12 carbon atoms wherein optionally one or more —CH 2 CH 2 — groups are replaced in each case by —CH═CH— or —C≡C— groups,
 alkyl having 1 to 12 carbon atoms which is 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, 
 cycloalkylalkyl having 4 to 16 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, 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, 
 arylalkyl having 8 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 group, which is saturated, partially saturated or fully unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is a N, O or S atom which is unsubstituted or substituted one or more times by halogen, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, alkylamino, dialkylamino, or combinations thereof, or 
 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, wherein the heterocyclic portion is unsubstituted or substituted one or more times by halogen, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, alkylamino, dialkylamino, carboxy or combinations thereof and/or substituted in the alkyl portion by halogen, oxo, cyano, or combinations thereof; and 
 
 R 5  is H,
 alkyl having 1 to 12 carbon atoms wherein optionally one or more —CH 2 CH 2 — groups are replaced in each case by —CH═CH— or —C≡C— groups, 
 alkyl having 1 to 12 carbon atoms which is 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, 
 cycloalkylalkyl having 4 to 16 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, 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, 
 arylalkyl having 8 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 group, which is saturated, partially saturated or fully unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is a N, O or S atom, which is unsubstituted or substituted one or more times by halogen, aryl, alkyl, alkoxy, alkoxycarbonyl, cyano, trifluoromethyl, nitro, oxo, amino, alkylamino, dialkylamino, or combinations thereof, or 
 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, wherein the heterocyclic portion is unsubstituted or substituted one or more times by halogen, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, alkylamino, dialkylamino, carboxy or combinations thereof and/or substituted in the alkyl portion by halogen, oxo, cyano, or combinations thereof; 
 
 
     and physiologically 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;
 with the proviso that:
 (a) when R 2  is CH 3  and R 3  is H, then R 1  is not methyl, ethyl, n-propyl, isopropyl, sec-butyl, n-butyl, isobutyl, neopentyl, n-pentyl, 2-methylbutyl, isopentyl, n-hexyl, phenyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, methylcyclopentyl, cyclopropylmethyl, cyclopentylmethyl, 2-propenyl, 2-propynyl, 3-methyl-2-butenyl, N-substituted 2-piperazinylethyl, norbornyl, 3-tetrahydrofuryl, 2-tetrahydrofuryl, 3-tetrahydrothienyl, 2-oxacyclopropyl, 2-oxacyclopenyl, 3-oxacyclopentyl, 2-chloroethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, 3-bromopropyl, 3-chloropropyl, or 4-bromobutyl; 
 (b) when R 1  is cyclopentyl, and R 2  is methyl, then R 3  is not H, acetyl, benzyl, 4-hydroxybenzyl, 4-acetoxybenzyl, 4-bromobenzyl, 3,4-dimethoxybenzyl, 4-methylthiobenzyl, 4-cyanobenzyl, 2-aminobenzyl, 3-aminobenzyl, 4-aminobenzyl, 4-dimethylaminobenzyl, 2,4-diaminobenzyl, 4-amino-3,5-dimethoxybenzyl, 3-carboxybenzyl, 3-methoxycarbonylbenzyl, 4-methoxycarbonylbenzyl, 4-methylsulfinylbenzyl, 4-methylsulfonylbenzyl, 2-nitrobenzyl, 3-nitrobenzyl, 4-nitrobenzyl, 2,4-dinitrobenzyl, 2-nitro-4-aminobenzyl, 2-amino-4-nitrobenzyl, morpholinoethyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 4-(6-fluoroquinolyl)methyl, 2-(7-chloroquinolyl)methyl, 2-imidazoylmethyl, or substituted imidazoylmethyl; 
 (c) when R 1  is CH 3 , and R 3  is H, then R 2  is not methyl, ethyl, or butyl; 
 (d) when R 3  is H, then R 1  and R 2  are not both ethyl or isobutyl; and 
 (e) when R 3  and R 2  are both difluoromethyl, then R 3  is not 4-aminobenzyl, or 4-amino-3,5-dimethoxybenzyl. 
 
 
 
   
   
       2 - 4 . (canceled) 
   
   
       5 . A compound of Formula I: 
     
       
         
         
             
             
         
       
     
     wherein
 X is O; 
 R 1  is alkyl having 1 to 8 carbon atoms wherein optionally one or more —CH 2 CH 2 — groups are replaced in each case by —CH═CH— or —C≡C— groups,
 alkyl having 1 to 8 carbon atoms which is 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 having 1 to 4 carbon atoms or combinations thereof, 
 a heterocyclic group, which is saturated, partially saturated or fully unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is a N, O or S atom, which is unsubstituted or substituted one or more times by halogen, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, alkylamino, dialkylamino, or combinations thereof, 
 aryl having 6 to 14 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, 
 arylalkyl having 8 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 partially unsaturated carbocyclic group having 5 to 14 carbon atoms which is unsubstituted or substituted one or more times by halogen, alkyl, alkoxy, nitro, cyano, oxo, or combinations thereof, 
 arylalkenyl having 8 to 16 carbon atoms, wherein the alkenyl portion has up to 5 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, 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, wherein the heterocyclic portion is unsubstituted or substituted one or more times by halogen, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, alkylamino, dialkylamino, carboxy or combinations thereof and/or substituted in the alkyl portion by halogen, oxo, cyano, or combinations thereof, or 
 cycloalkylalkyl having 4 to 16 carbon atoms which is unsubstituted or substituted one or more times by halogen, oxo, alkyl or combinations thereof, 
 
 R 2  is CHF 2 ; 
 R 3  is H,
 arylalkyl having 7 to 16 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, 
 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, wherein the heterocyclic portion is unsubstituted or substituted one or more times by halogen, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, alkylamino, dialkylamino, carboxy or combinations thereof and/or substituted in the alkyl portion by halogen, oxo, cyano, or combinations thereof, 
 alkoxyalkyl having 3 to 8 carbon atoms, 
 —C(O)R 4 , or 
 —CH 2 CONHR 5 ; 
 
 R 4  is aryl having 6 to 14 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, or
 a heterocyclic group, which is saturated, partially saturated or fully unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is a N, O or S atom, which is unsubstituted or substituted one or more times by halogen, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, alkylamino, dialkylamino, or combinations thereof; and 
 
 R 5  is aryl having 6 to 14 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, or
 a heterocyclic group, which is saturated, partially saturated or fully unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is a N, O or S atom, which is unsubstituted or substituted one or more times by halogen, aryl, alkyl, alkoxy, alkoxycarbonyl, cyano, trifluoromethyl, nitro, oxo, amino, alkylamino, dialkylamino, or combinations thereof; 
 
 
     and physiologically 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; 
 with the proviso that:
 (a) when R 1  and R 2  are both difluoromethyl, then R 3  is not 4-aminobenzyl, or 4-amino-3,5-dimethoxybenzyl. 
 
 
   
   
       6 . A compound according to  claim 1 , wherein R 1  is optionally substituted cycloalkyl, cycloalkylalkyl, aryl, a heterocyclic group, arylalkyl, or a partially unsaturated carbocyclic group, or is CHF 2 . 
   
   
       7 . A compound according to  claim 6 , wherein R 1  is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentylethyl, cyclopropylmethyl, phenyl, napthyl, phenethyl, phenpropyl, furanyl, pyrazinyl, pyrimidinyl, pyridyl, quinolinyl, isoquinolinyl, thienyl, indanyl, tetrahydrofuranyl, phenylpropenyl, phenyl substituted by one or more substituents selected from oxo, F, Cl, CF 3 , alkyl, alkoxy, CN, vinyl, methylenedioxy, COOH, and combinations thereof, or phenethyl substituted by one or more substituents selected from oxo, F, Cl, CF 3 , alkyl, alkoxy, CN, vinyl, methylenedioxy, COOH, and combinations thereof. 
   
   
       8 . A compound according to  claim 1 , wherein when R 3  is other than H, R 1  is CHF 2 , cycloalkyl, cycloalkylalkyl, aryl, arylalkyl or a heterocyclic group. 
   
   
       9 . A compound according to  claim 1 , wherein when R 3  is other than H, R 1  is CHF 2  or is optionally substituted cyclopentyl, phenethyl, 3-tetrahydrofuranyl, or cyclopropylmethyl. 
   
   
       10 . A compound according to  claim 1 , wherein R 2  is substituted or unsubstituted alkyl having 1 to 4 carbon atoms. 
   
   
       11 . A compound according to  claim 10 , wherein R 2  is CHF 2  or CH 3 . 
   
   
       12 . A compound according to  claim 1 , wherein R 3  is H, substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl, CH 2 CONHR 5  or COR 4 . 
   
   
       13 . A compound according to  claim 12 , wherein R 3  is H, substituted benzyl or CH 2 CONHR 5 . 
   
   
       14 . A compound according to  claim 12 , wherein R 3  is methyl, ethyl, propyl, n-butyl, methylbenzyl, fluorobenzyl, difluorobenzyl, chlorobenzyl, methoxy, benzyl, cyanobenzyl, dichlorobenzyl, chlorofluorobenzyl, trifluoromethylbenzyl, or bis(trifluoromethyl)benzyl. 
   
   
       15 . A compound according to  claim 1 , wherein R 3  is COR 4  and R 4  is an optionally substituted aryl or heterocyclic group. 
   
   
       16 . A compound according to  claim 15 , wherein R 4  is phenyl or phenyl substituted by one or more substituents selected from F, Cl, CH 3 , C 2 H 5 , OCH 3 , COOH, CN and combinations thereof. 
   
   
       17 . (canceled) 
   
   
       18 . (canceled) 
   
   
       19 . A compound according to  claim 6 , wherein R 2  is CH 3  or CHF 2 . 
   
   
       20 . A compound according to  claim 1 , wherein R 2  is CH 3  or CHF 2 , R 1  is CHF 2 , cyclopentyl, tetrahydrofuran, phenethyl or cyclopropylmethyl, and R 3  is not H. 
   
   
       21 - 30 . (canceled) 
   
   
       31 . A compound according to  claim 1 , wherein the compound of formula I is selected from: 
     4-[4-Methoxy-3-(4-methoxyphenoxy)phenyl]-2-pyrrolidone, 
     4-[4-Methoxy-3-(3-thienyloxy)phenyl]-2-pyrrolidone, 
     4-[3-(4-Fluorophenoxy)-4-methoxyphenyl]-2-pyrrolidone, 
     4-(3-(3-Cyclohexyl-1-propyloxy)-4-methoxyphenyl)-2-pyrrolidone, 
     4-(4-Methoxy-3-(2-phenylethoxy)phenyl)-2-pyrrolidone, 
     4-(4-Methoxy-3-(3-phenyl-1-propoxy)phenyl)-2-pyrrolidone, 
     4-(3-Cyclopentyloxy-4-methoxyphenyl)-1-(2-chloro-4-fluorobenzyl)-2-pyrrolidone, 
     Methyl 4-(3-cyclopentyloxy-4-methoxyphenyl)-2-pyrrolidone-1-acetate, 
     4-(3-Cyclopentyloxy-4-methoxyphenyl)-1-cyanomethyl-2-pyrrolidone, 
     4-(3-Cyclopentyloxy-4-methoxyphenyl)-1-cyclopentyl-2-pyrrolidone, 
     4-(3-Cyclopentyloxy-4-methoxyphenyl)-1-(4-methoxybenzoyl)-2-pyrrolidone, 
     4(S)-(3-Cyclopentyloxy-4-difluoromethoxyphenyl)-1-(N-(2-(6-methylpyridyl))-aminocarbonylmethyl)-2-pyrrolidone, 
     1-(N-(2,3-Difluorophenyl)-aminocarbonylmethyl)-4(S)-(4-methoxy-3-(3(R)-tetrahydrofuryloxy)phenyl)-2-pyrrolidone, 
     4(S)-(4-Methoxy-3-(3(R)-tetrahydrofuryloxy)phenyl)-1-(N-(2-methylphenyl)-aminocarbonylmethyl)-2-pyrrolidone, 
     4(S)-(4-Methoxy-3-(3(R)-tetrahydrofuryloxy)phenyl)-1-(N-(2-(6-methylpyridinyl))-aminocarbonylmethyl)-2-pyrrolidone, and
 physiologically 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. 
 
   
   
       32 . A compound according to  claim 1 , wherein the compound of formula I is selected from: 
     (4S)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-1-(2-methylbenzyl)-2-pyrrolidone, 
     (4S)-1-(2-Chlorobenzyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-2-pyrrolidone, 
     (4S)-1-(4-Chlorobenzyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-2-pyrrolidone, 
     (4S)-1-(3-Chlorobenzyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-2-pyrrolidone, 
     (4S)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-1-(3-methoxybenzyl)-2-pyrrolidone, 
     (4S)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-1-(2-fluorobenzyl)-2-pyrrolidone, 
     (4S)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-1-(3-fluorobenzyl)-2-pyrrolidone, 
     (4S)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-1-(4-fluorobenzyl)-2-pyrrolidone, 
     (4S)-1-(4-Cyanobenzyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-2-pyrrolidone, 
     (4S)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-1-(2-trifluoromethylbenzyl)-2-pyrrolidone, 
     (4S)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-1-(3-trifluoromethylbenzyl)-2-pyrrolidone, 
     (4S)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-1-(4-trifluoromethylbenzyl)-2-pyrrolidone, 
     (4S)-1-(3,5-bistrifluoromethylbenzyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-2-pyrrolidone, 
     (4S)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-1-(3,4-difluorobenzyl)-2-pyrrolidone, 
     (4S)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-1-(3,5-difluorobenzyl)-2-pyrrolidone, 
     (4S)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-1-(2,4-difluorobenzyl)-2-pyrrolidone, 
     (4S)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-1-(2,6-difluorobenzyl)-2-pyrrolidone, 
     (4S)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-1-(2,3-difluorobenzyl)-2-pyrrolidone, 
     (4S)-1-(2-Chloro-4-fluorobenzyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-2-pyrrolidone, 
     (4S)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-1-(3,4-dichlorobenzyl)-2-pyrrolidone, 
     (4S)-1-(4-tert-Butylbenzyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-2-pyrrolidone, 
     (4S)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-1-ethyl-2-pyrrolidone, 
     (4S)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-1-propyl-2-pyrrolidone, 
     (4S)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-1-butyl-2-pyrrolidone, 
     (4S)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-1-(2-methoxyethyl)-2-pyrrolidone, 
     (4S)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-1-(2-phenylbenzyl)-2-pyrrolidone, 
     (4R)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-1-(2-methylbenzyl)-2-pyrrolidone, 
     (4R)-1-(2-Chlorobenzyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-2-pyrrolidone, 
     (4R)-1-(4-Chlorobenzyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-2-pyrrolidone, 
     (4R)-1-(3-Chlorobenzyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-2-pyrrolidone, 
     (4R)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-1-(3-methoxybenzyl)-2-pyrrolidone, 
     (4R)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-1-(2-fluorobenzyl)-2-pyrrolidone, 
     (4R)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-1-(3-fluorobenzyl)-2-pyrrolidone, 
     (4R)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-1-(4-fluorobenzyl)-2-pyrrolidone, 
     (4R)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-1-(2-trifluoromethylbenzyl)-2-pyrrolidone, 
     (4R)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-1-(3-trifluoromethylbenzyl)-2-pyrrolidone, 
     (4R)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-1-(4-trifluoromethylbenzyl)-2-pyrrolidone, 
     (4R)-1-(3,5-bistrifluoromethylbenzyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-2-pyrrolidone, 
     (4R)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-1-(3,4-difluorobenzyl)-2-pyrrolidone, 
     (4R)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-1-(3,5-difluorobenzyl)-2-pyrrolidone, 
     (4R)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-1-(2,4-difluorobenzyl)-2-pyrrolidone, 
     (4R)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-1-(2,6-difluorobenzyl)-2-pyrrolidone, 
     (4R)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-1-(2,3-difluorobenzyl)-2-pyrrolidone, 
     (4R)-1-(2-Chloro-4-fluorobenzyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-2-pyrrolidone, 
     (4R)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-1-(3,4-dichlorobenzyl)-2-pyrrolidone, 
     (4R)-1-(4-tert-Butylbenzyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-2-pyrrolidone, 
     (4R)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-1-ethyl-2-pyrrolidone, 
     (4R)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-1-propyl-2-pyrrolidone, 
     (4R)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-1-butyl-2-pyrrolidone, 
     (4R)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-1-(2-methoxyethyl)-2-pyrrolidone, 
     (4R)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-1-(2-phenylbenzyl)-2-pyrrolidone, 
     (4S)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-1-(N-(2,6-dimethylphenyl)-aminocarbonylmethyl)-2-pyrrolidone, 
     (4R)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-1-(N-(2,6-dimethylphenyl)-aminocarbonylmethyl)-2-pyrrolidone, 
     4-(3-Cyclopentyloxy-4-methoxyphenyl)-1-(N-(2-methylphenyl)-aminocarbonylmethyl)-2-pyrrolidone, 
     (4R)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-1-(N-(2-methylphenyl)-aminocarbonylmethyl)-2-pyrrolidone, 
     (4S)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-1-(N-(2-methylphenyl)-aminocarbonylmethyl)-2-pyrrolidone, 
     4-(3-Cyclopentyloxy-4-methoxyphenyl)-1-(N-(2,3-difluorophenyl)-aminocarbonylmethyl)-2-pyrrolidone, 
     4-(3-Cyclopentyloxy-4-methoxyphenyl)-1-(N-(3-chlorophenyl)-aminocarbonylmethyl)-2-pyrrolidone, 
     4-(3-Cyclopentyloxy-4-methoxyphenyl)-1-(N-(4-pyridyl)-aminocarbonylmethyl)-2-pyrrolidone, 
     4-(3-Cyclopentyloxy-4-methoxyphenyl)-1-(N-(4-methoxyphenyl)-aminocarbonylmethyl)-2-pyrrolidone, 
     4-(3-Cyclopentyloxy-4-methoxyphenyl)-1-(N-(4-chloro-2-fluorophenyl)-aminocarbonylmethyl)-2-pyrrolidone, 
     4-(3-Cyclopentyloxy-4-methoxyphenyl)-1-(N-(3-methylphenyl)-aminocarbonylmethyl)-2-pyrrolidone, 
     4-(3-Cyclopentyloxy-4-methoxyphenyl)-1-(N-(4-methylphenyl)-aminocarbonylmethyl)-2-pyrrolidone, 
     4-(3-Cyclopentyloxy-4-methoxyphenyl)-1-(N-(4-nitrophenyl)-aminocarbonylmethyl)-2-pyrrolidone, 
     4-(3-Cyclopentyloxy-4-difluoromethoxyphenyl)-1-(N-(2,3-difluorophenyl)-aminocarbonylmethyl)-2-pyrrolidone, 
     4(S)-(3-Cyclopentyloxy-4-difluoromethoxyphenyl)-1-(N-(2-(6-methylpyridyl))-aminocarbonylmethyl)-2-pyrrolidone, 
     4(S)-(4-Methoxy-3-(3(R)-tetrahydrofuryloxy)phenyl)-1-(N-(2-(6-methylpyridyl))-aminocarbonylmethyl)-2-pyrrolidone, 
     1-(N-(2,3-Difluorophenyl)-aminocarbonylmethyl)-4(S)-(4-methoxy-3-(3(R)-tetrahydrofuryloxy)phenyl)-2-pyrrolidone, 
     1-(N-(2-(6-Aminopyridyl))-aminocarbonylmethyl)-4(S)-(3-cyclopentyloxy-4-methoxyphenyl)-2-pyrrolidone, 
     4(S)-(3-Cyclopentyloxy-4-methoxyphenyl)-1-(N-(2-(6-ethylpyridyl))-aminocarbonylmethyl)-2-pyrrolidone, 
     4(S)-(3-Cyclopentyloxy-4-methoxyphenyl)-1-(N-(2-(4,6-dimethylpyridyl))-aminocarbonylmethyl)-2-pyrrolidone, 
     1-(N-(2-(6-Bromopyridyl))-aminocarbonylmethyl)-4(S)-(3-cyclopentyloxy-4-methoxyphenyl)-2-pyrrolidone, 
     1-(N-(2-(6-Bromopyridyl))-aminocarbonylmethyl)-4(S)-(4-methoxy-3-(3(R)-tetrahydrofuryloxy)phenyl)-2-pyrrolidone, 
     4(S)-(4-Methoxy-3-(3(R)-tetrahydrofuryloxy)phenyl)-1-(N-(2-methylphenyl)-aminocarbonylmethyl)-2-pyrrolidone, 
     4(S)-(3-Cyclopentyloxy-4-methoxyphenyl)-1-(N-(3-(2-methoxypyridyl))-aminocarbonylmethyl)-2-pyrrolidone, 
     1-(N-(6-(3-Bromo-2-methylpyridyl))-aminocarbonylmethyl)-4(S)-(3-cyclopentyloxy-4-methoxyphenyl)-2-pyrrolidone, 
     4(S)-(3-Cyclopentyloxy-4-methoxyphenyl)-1-(N-(3-(4-methoxycarbonyl)-pyridyl)-aminocarbonylmethyl)-2-pyrrolidone, 
     4(S)-(3-Cyclopentyloxy-4-methoxyphenyl)-1-(N-(2-(6-methylpyridyl))-aminocarbonylmethyl)-2-pyrrolidone, 
     1-(N-(3-(2-Cyanopyridyl))-aminocarbonylmethyl)-4(S)-(3-cyclopentyloxy-4-methoxyphenyl)-2-pyrrolidone, or 
     4(S)-(4-Methoxy-3-(3(R)-tetrahydrofuryloxy)phenyl)-1-(N-(2-(6-methylpyridinyl))-aminocarbonylmethyl)-2-pyrrolidone, and
 physiologically 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. 
 
   
   
       33 - 61 . (canceled)