US2005272803A1PendingUtilityA1
Phosphodiesterase 4 inhibitors
Est. expiryOct 16, 2021(expired)· nominal 20-yr term from priority
A61P 43/00A61P 9/10A61P 3/10A61P 37/08A61P 37/02A61P 29/00A61P 25/14A61P 25/16A61P 3/04A61P 25/28A61P 27/02A61P 25/00A61P 35/02A61P 31/18A61P 27/16A61P 25/18A61P 25/24A61P 31/16C07D 413/12A61P 17/02A61P 17/06A61P 1/04C07D 207/26C07D 401/12C07D 405/12C07D 403/12C07D 409/12A61P 19/02A61P 17/14A61P 17/00A61P 11/08A61P 13/10A61P 19/08C07D 417/12A61P 11/00A61P 17/04A61P 13/12A61P 11/06A61K 31/40C07D 207/27
50
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Claims
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.
Claims
exact text as granted — not AI-modified1 . 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, which is unsubstituted or substituted one or more times in the heteroaryl portion 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,
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 heteroaryl portion 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, which is unsubstituted or substituted one or more times in the heteroaryl portion 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═ 32 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, which is unsubstituted or substituted one or more times in the heteroaryl portion 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,
with the proviso that:
(a) when X is O , 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 X is O, 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-methylsufonylbenzyl, 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 X is O, R 1 is CH 3 , and R 3 is H, then R 2 is not methyl, ethyl, or butyl;
(d) when X is O and R 3 is H, then R 1 and R 2 are not both ethyl or isobutyl; and
(e) when X is O, and R 1 and R 2 are both difluoromethyl, then R 3 is not 4-aminobenzyl, or 4-amino-3,5-dimethoxybenzyl.
2 . (canceled)
3 . (canceled)
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, which is unsubstituted or substituted one or more times in the heteroaryl portion 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,
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 heteroaryl portion 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;
with the proviso that:
(a) when X is O, and 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, 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 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 (CF 3 ) 2 benzyl.
15 . A compound according to claim 1 , wherein R 3 is COR 4 and R 4 is 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 . A compound according to claim 1 , wherein R 2 is CH 3 or CHF 2 , R 3 is H, and R 1 is phenethyl which is unsubstituted or the phenyl portion is substituted by F, Cl, Br, I, CN, C 1-4 -alkyl and/or C 1-4 -alkoxy, phenpropyl which is unsubstituted or the phenyl portion is substituted by F, Cl, Br, I, CN, C 1-4 -alkyl and/or C 1-4 -alkoxy, phenylbutyl which is unsubstituted or the phenyl portion is substituted by F, Cl, Br, I, CN, C 1-4 -alkyl and/or C 1-4 -alkoxy, or 3-phenyl-2-propenyl.
22 . A compound according to claim 1 , wherein R 1 is 3(R)-tetrahydrofuranyl, R 2 is CH 3 or CHF 2 , and R 3 is arylalkyl in which the aryl group is substituted by F, Br, Cl, I, alkyl or alkoxy.
23 . A compound according to claim 1 , wherein R 1 is CHF 2 , cyclopentyl, tetrahydrofuran, phenethyl, or cyclopropylmethyl, R 2 is CH 3 or CHF 2 , and R 3 is arylalkyl in which the aryl group is substituted by F, Br, Cl, I, alkyl or alkoxy.
24 . A compound according to claim 1 , wherein R 1 is cyclopentyl, tetrahydrofuran, cyclopropylmethyl or CHF 2 , R 2 is CH 3 or CHF 2 , and R 3 is methylbenzyl, methoxybenzyl, chlorobenzyl, fluorobenzyl, trifluorobenzyl, difluorobenzyl, dichlorobenzyl, fluorochlorobenzyl, or bis(trifluoromethyl)benzyl.
25 . A compound according to claim 1 , wherein R 1 is CHF 2 , cycloalkyl, cycloalkylalkyl, arylalkyl, heterocyclic group, or heterocyclic alkyl group, R 2 is CH 3 or CHF 2 , and R 3 is CH 2 CONHR 5 .
26 . A compound according to claim 1 , wherein R 1 is CHF 2 , cyclopentyl, tetrahydrofuran, phenethyl, or cyclopropylmethyl, R 2 is CH 3 or CHF 2 , and R 3 is CH 2 CONHR 5 .
27 . A compound according to claim 1 , wherein R 1 is CHF 2 , cycloalkyl, cycloalkylalkyl, heterocyclic group, or heterocyclicalkyl group, R 2 is CH 3 or CHF 2 , R 3 is CH 2 CONHR 5 , and R 5 is substituted or unsubstituted phenyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl.
28 . A compound according to claim 1 , wherein R 1 is cycloalkyl, heterocyclic group, or heterocyclicalkyl group, R 2 is CH 3 or CHF 2 , R 3 is CH 2 CONHR 5 , and R 5 is 2-methylphenyl, 2,6-dimethylphenyl, 2,3-difluorophenyl, 4-fluorophenyl, 4-pyridyl, 2-pyridyl, 6-methyl-2-pyridyl, 6-amino-2-pyridyl, 6-ethyl-2-pyridyl, 4,6-dimethyl-2-pyridyl, 6-bromo-2-pyridyl, 6-methyl-5-bromo-2-pyridyl, 2-methoxy-3-pyridyl, 4-CH 3 O—CO-3-pyridyl, or 2-cyano-3-pyridyl.
29 . A compound according to claim 1 , wherein R 1 is CHF 2 , cyclopentyl, tetrahydrofuran, or cyclopropylmethyl, R 2 is CH 3 or CHF 2 , R 3 is CH 2 CONHR 5 , and R 5 is substituted or unsubstituted phenyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl.
30 . A compound according to claim 1 , wherein R 1 is CHF 2 , cyclopentyl, tetrahydrofuran, or cyclopropylmethyl, R 2 is CH 3 or CHF 2 , R 3 is CH 2 CONHR 5 , and R 5 is 2-methylphenyl, 2,6-dimethylphenyl, 2,3-difluorophenyl, 4-fluorophenyl, 4-pyridyl, 2-pyridyl, 6-methyl-2-pyridyl, 6-amino-2-pyridyl, 6-ethyl-2-pyridyl, 4,6-dimethyl-2-pyridyl, 6-bromo-2-pyridyl, 6-methyl-5-bromo-2-pyridyl, 2-methoxy-3-pyridyl, 4-CH 3 O—CO-3-pyridyl, or 2-cyano-3-pyridyl.
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)-tetra hydrofuryloxy)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, or
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-4methoxyphenyl)-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)-2pyrrolidone, 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)-amino carbonylmethyl)-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)-tetra hydrofuryloxy)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, or
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 . A method for enhancing cognition in a patient in whom such enhancement is desired comprising administering to said patient an effective amount of a compound according to 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═ 32 CH— or —C≡ 32 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, which is unsubstituted or substituted one or more times in the heteroaryl portion 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, alklylsulphonyl, phenoxy, and acyloxy or combinations thereof,
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 heteroaryl portion 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, which is unsubstituted or substituted one or more times in the heteroaryl portion 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, which is unsubstituted or substituted one or more times in the heteroaryl portion 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.
34 . A method according to claim 33 , wherein said patient is a human.
35 . A method according to claim 34 , wherein said compound is administered in an amount of 0.0001-100 mg/kg of body weight/day.
36 . A method according to claim 33 , wherein R 2 is CH 3 or CHF 2 .
37 . A method according to claim 33 , 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.
38 . A method according to claim 33 , wherein R 2 is CH 3 or CHF 2 , R 3 is H, and R 1 is phenethyl which is unsubstituted or the phenyl portion is substituted by F, Cl, Br, I, CN, C 1-4 -alkyl and/or C 1-4 -alkoxy, phenpropyl which is unsubstituted or the phenyl portion is substituted by F, Cl, Br, I, CN, C 1-4 -alkyl and/or C 1-4 -alkoxy, phenylbutyl which is unsubstituted or the phenyl portion is substituted by F, Cl, Br, I, CN, C 1-4 -alkyl and/or C 1-4 -alkoxy, or 3-phenyl-2-propenyl.
39 . A method according to claim 33 , wherein R 1 is 3(R)-tetrahydrofuranyl, R 2 is CH 3 or CHF 2 , and R 3 is arylalkyl in which the aryl group is substituted by F, Br, Cl, I, alkyl or alkoxy.
40 . A method according to claim 33 , wherein R 1 is CHF 2 , cyclopentyl, tetrahydrofuran, phenethyl or cyclopropylmethyl, R 2 is CH 3 or CHF 2 , and R 3 is arylalkyl in which the aryl group is substituted by F, Br, Cl, I, alkyl or alkoxy.
41 . A method according to claim 33 , wherein R 1 is cyclopentyl, tetrahydrofuran, cyclopropylmethyl or CHF 2 , R 2 is CH 3 or CHF 2 , and R 3 is methylbenzyl, methoxybenzyl, chlorobenzyl, fluorobenzyl, trifluorobenzyl, difluorobenzyl, dichlorobenzyl, fluorochlorobenzyl, or bis(trifluoromethyl)benzyl.
42 . A method according to claim 33 , wherein R 1 is CHF 2 , cycloalkyl, cycloalkylalkyl, arylalkyl, heterocyclic group, or heterocyclic alkyl group, R 2 is CH 3 or CHF 2 , and R 3 is CH 2 CONHR 5 .
43 . A method according to claim 33 , wherein R 1 is cyclopentyl, CHF 2 tetrahydrofuran, phenethyl or cyclopropylmethyl, R 2 is CH 3 or CHF 2 , and R 3 is CH 2 CONHR 5 .
44 . A method according to claim 33 , wherein R 1 is CHF 2 , cycloalkyl, cycloalkylalkyl, heterocyclic group, or heterocyclicalkyl group, R 2 is CH 3 or CHF 2 , R 3 is CH 2 CONHR 5 , and R 5 is substituted or unsubstituted phenyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl.
45 . A method according to claim 33 , wherein R 1 is CHF 2 , cycloalkyl, cycloalkylalkyl, heterocyclic group, or heterocyclicalkyl group, R 2 is CH 3 or CHF 2 , R 3 is CH 2 CONHR 5 , and R 5 is 2-methylphenyl, 2,6-dimethylphenyl, 2,3-difluorophenyl, 4-fluorophenyl, 4-pyridyl, 2-pyridyl, 6-methyl-2-pyridyl, 6-amino-2-pyridyl, 6-ethyl-2-pyridyl, 4,6-dimethyl-2-pyridyl, 6-bromo-2-pyridyl, 6-methyl-5-bromo-2-pyridyl, 2-methoxy-3-pyridyl, 4-CH 3 O—CO-3-pyridyl, or 2-cyano-3-pyridyl.
46 . A method according to claim 33 , wherein R 1 is CHF 2 , cyclopentyl, tetrahydrofuran, or cyclopropylmethyl, R 2 is CH 3 or CHF 2 , R 3 is CH 2 CONHR 5 , and R 5 is substituted or unsubstituted phenyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl.
47 . A method according to claim 33 , wherein R 1 is CHF 2 , cyclopentyl, tetrahydrofuran, or cyclopropylmethyl, R 2 is CH 3 or CHF 2 , R 3 is CH 2 CONHR 5 , and R 5 is 2-methylphenyl, 2,6-dimethylphenyl, 2,3-difluorophenyl, 4-fluorophenyl, 4-pyridyl, 2-pyridyl, 6-methyl-2pyridyl, 6-amino-2-pyridyl, 6-ethyl-2-pyridyl, 4,6-dimethyl-2-pyridyl, 6-bromo-2-pyridyl, 6-methyl-5-bromo-2-pyridyl, 2-methoxy-3-pyridyl, 4-CH 3 O—CO-3-pyridyl, or 2-cyano-3-pyridyl.
48 . A method according to claim 33 , 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)-tetra hydrofuryloxy)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, or
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.
49 . A method according to claim 33 , 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)-amino carbonylmethyl)-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)-tetra hydrofuryloxy)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, or
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.
50 . A method of treating a patient suffering from cognition impairment or decline comprising administering to said patient an effective amount of a compound according to 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, which is unsubstituted or substituted one or more times in the heteroaryl portion 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,
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 heteroaryl portion 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 4to 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, which is unsubstituted or substituted one or more times in the heteroaryl portion 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, which is unsubstituted or substituted one or more times in the heteroaryl portion 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.
51 . A method according to claim 50 , wherein said patient is a human.
52 . A method according to claim 51 , wherein said patient is suffering from memory impairment.
53 . A method according to claim 50 , wherein said compound is administered in an amount of 0.0001-100 mg/kg of body weight/day.
54 . A method according to claim 50 , wherein said patient is suffering from memory impairment due to Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeld-Jakob disease, depression, aging, head trauma, stroke, CNS hypoxia, cerebral senility, multiinfarct dementia, HIV or cardiovascular disease.
55 . A method for treating a patient having a disease involving decreased cAMP levels comprising administering to said patient an effective amount of a compound according to formula I′:
wherein
X is O;
R 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, cyan, 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 heteroaryl portion 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,
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 heteroaryl portion 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, which is unsubstituted or substituted one or more times in the heteroaryl portion 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, which is unsubstituted or substituted one or more times in the heteroaryl portion 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.
56 . A method of inhibiting PDE4 enzyme activity in a patient comprising administering to said patient an effective amount of a compound according to 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, which is unsubstituted or substituted one or more times in the heteroaryl portion 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,
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 heteroaryl portion 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, which is unsubstituted or substituted one or more times in the heteroaryl portion 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, which is unsubstituted or substituted one or more times in the heteroaryl portion 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,
with the provisos that:
(a) when X is O, 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 X is O, 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-methylsufonylbenzyl, 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 X is O, R 1 is CH 3 , and R 3 is H, then R 2 is not methyl, ethyl, or butyl;
(d) when X is O and R 3 is H, then R 1 and R 2 are not both ethyl or isobutyl; and
(e) when X is O, and R 1 and R 2 are both difluoromethyl, then R 3 is not 4-aminobenzyl, or 4-amino-3,5-dimethoxybenzyl.
57 . A method of treating a patient suffering from memory impairment due to a neurodegenerative disease comprising administering to said patient an effective amount of a compound according to 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, which is unsubstituted or substituted one or more times in the heteroaryl portion 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,
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 heteroaryl portion 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, which is unsubstituted or substituted one or more times in the heteroaryl portion 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 57 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, which is unsubstituted or substituted one or more times in the heteroaryl portion 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.
58 . A method of treating a patient suffering from memory impairment due to an acute neurodegenerative disorder comprising administering to said patient an effective amount of a compound according to 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 which is unsubstituted or substituted one or more times by halogen, alkyl, alkoxy, nitro, cyano, oxo, or combinations thereof,
arylalkenyl having 8to 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, which is unsubstituted or substituted one or more times in the heteroaryl portion 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,
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 heteroaryl portion 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, which is unsubstituted or substituted one or more times in the heteroaryl portion 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, which is unsubstituted or substituted one or more times in the heteroaryl portion 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.
59 . A method of treating a patient suffering from an allergic or inflammatory disease comprising administering to said patient an effective amount of a compound according to 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, which is unsubstituted or substituted one or more times in the heteroaryl portion 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,
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 heteroaryl portion 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, which is unsubstituted or substituted one or more times in the heteroaryl portion 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, which is unsubstituted or substituted one or more times in the heteroaryl portion 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,
with the proviso that:
(a) when X is O, 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 X is O, 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-methylsufonylbenzyl, 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 X is O, R 1 is CH 3 , and R 3 is H, then R 2 is not methyl, ethyl, or butyl;
(d) when X is O and R 3 is H, then R 1 and R 2 are not both ethyl or isobutyl; and
(e) when X is O, and R 1 and R 2 are both difluoromethyl, then R 1 is not 4-aminobenzyl, or 4-amino-3,5-dimethoxybenzyl.
60 . A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.
61 . A composition according to claim 60 , wherein said composition contains 0.01-1000 mg of said compound.Cited by (0)
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