U.S. patent application number 12/564636 was filed with the patent office on 2010-01-14 for phosphodiesterase 4 inhibitors.
Invention is credited to Hans-Jurgen Ernst Hess, Allen Hopper, Ruiping LIU, Yujing Rong, Ashok Tehim.
Application Number | 20100010020 12/564636 |
Document ID | / |
Family ID | 26952286 |
Filed Date | 2010-01-14 |
United States Patent
Application |
20100010020 |
Kind Code |
A1 |
LIU; Ruiping ; et
al. |
January 14, 2010 |
PHOSPHODIESTERASE 4 INHIBITORS
Abstract
PDE4 inhibition is achieved by novel compounds of the Formula I:
##STR00001## wherein R.sup.1 and R.sup.2 are as defined herein.
Inventors: |
LIU; Ruiping; (Huntington,
NY) ; Hess; Hans-Jurgen Ernst; (Old Lyme, CT)
; Hopper; Allen; (Glen Rock, NJ) ; Tehim;
Ashok; (Ridgewood, NJ) ; Rong; Yujing;
(Monmouth Junction, NJ) |
Correspondence
Address: |
MILLEN, WHITE, ZELANO & BRANIGAN, P.C.
2200 CLARENDON BLVD., SUITE 1400
ARLINGTON
VA
22201
US
|
Family ID: |
26952286 |
Appl. No.: |
12/564636 |
Filed: |
September 22, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11956871 |
Dec 14, 2007 |
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12564636 |
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10067996 |
Feb 8, 2002 |
7342021 |
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11956871 |
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Current U.S.
Class: |
514/263.4 |
Current CPC
Class: |
C07D 473/40 20130101;
A61P 25/28 20180101; A61P 25/14 20180101; A61P 29/00 20180101; A61P
37/08 20180101; A61P 25/00 20180101; A61P 9/00 20180101; A61P 43/00
20180101; A61P 9/10 20180101; A61P 31/18 20180101; A61P 25/24
20180101; A61P 25/16 20180101; A61P 37/00 20180101; A61P 25/18
20180101 |
Class at
Publication: |
514/263.4 |
International
Class: |
A61K 31/52 20060101
A61K031/52; A61P 25/28 20060101 A61P025/28 |
Claims
1. A method for enhancing cognition in a patient in whom such
enhancement is desired; for treating a patient suffering from
cognition impairment or decline; for treating a patient having a
disease involving decreased cAMP levels; for inhibiting PDE4 enzyme
activity in a patient; or for treating a patient suffering from an
allergic or inflammatory disease, resulting from decreased cyclic
AMP levels, elevated phosphodiesterase 4 levels, or both; said
method comprising administering to said patient an effective amount
of a compound of Formula I: ##STR00015## wherein, R.sup.1 is alkyl
having 1 to 5 carbon atoms, which is substituted one or more times
by halogen, hydroxy, or combinations thereof, and wherein a
--CH.sub.2-- group can be optionally replaced by --O--, --S--, or
--NH--, cycloalkyl having 3 to 6 carbon atoms, or cycloalkylalkyl
having 4 to 7 C atoms; and R.sup.2 is alkyl having 1 to 12 carbon
atoms, which is unsubstituted or substituted one or more times by
halogen, hydroxy, cyano or combinations thereof, wherein one or
more --CH.sub.2-- groups is each independently optionally replaced
by --O--, --S--, or --NH--, and wherein optionally one or more
--CH.sub.2CH.sub.2-- groups is replaced in each case by
--CH.dbd.CH-- or --C.ident.C--, alkoxyalkyl having 3 to 12 carbon
atoms, cycloalkyl having 3 to 12 carbon atoms, which is
unsubstituted or substituted one or more times by halogen,
C.sub.1-4 alkyl, halogenated C.sub.1-4 alkyl, C.sub.1-4 alkoxy,
cyano or combinations thereof, cycloalkylalkyl having 4 to 12
carbon atoms, which is unsubstituted or substituted one or more
times by C.sub.1-4 alkyl, halogenated C.sub.1-4 alkyl, C.sub.1-4
alkoxy, cyano, halogen, or combinations thereof, aryl having 6 to
14 carbon atoms, which is unsubstituted or substituted one or more
times by halogen, C.sub.1-4 alkyl, halogenated C.sub.1-4 alkyl,
hydroxy, C.sub.1-4-alkoxy, halogenated C.sub.1-4 alkoxy, nitro,
methylenedioxy, ethylenedioxy, amino, C.sub.1-4 alkylamino,
di-C.sub.1-4-alkylamino, C.sub.1-4-hydroxyalkyl,
C.sub.1-4-hydroxyalkoxy, carboxy, cyano, --C(O)--NHOH,
--C(O)--NH.sub.2, C.sub.2-4-acyl, C.sub.2-4-alkoxycarbonyl,
C.sub.1-4-alkylthio, C.sub.1-4-alkylsulphinyl,
C.sub.1-4-alkylsulphonyl, phenoxy, or combinations thereof,
arylalkyl having 7 to 16 carbon atoms, which is or substituted one
or more times by halogen, halogenated C.sub.1-4 alkyl, hydroxy,
C.sub.1-4-alkoxy, halogenated C.sub.1-4 alkoxy, nitro,
methylenedioxy, ethylenedioxy, amino, C.sub.1-4 alkylamino,
di-C.sub.1-4-alkylamino, C.sub.1-4-hydroxyalkyl,
C.sub.1-4-hydroxyalkoxy, carboxy, cyano, --C(O)--NHOH,
--C(O)--NH.sub.2, C.sub.2-4-acyl, C.sub.2-4-alkoxycarbonyl,
C.sub.1-4-alkylthio, C.sub.1-4-alkylsulphinyl,
C.sub.1-4-alkylsulphonyl, phenoxy, or combinations thereof,
heteroaryl having 5 to 10 ring atoms in which at least 1 ring atom
is a heteroatom, which is unsubstituted or substituted one or more
times by halogen, aryl, C.sub.1-4 alkyl, halogenated C.sub.1-4
alkyl, hydroxy, C.sub.1-4-alkoxy, halogenated C.sub.1-4 alkoxy,
cyano, trifluoromethyl, nitro, amino, C.sub.1-4-alkylamino,
di-C.sub.1-4-alkylamino, carboxy, alkoxycarbonyl, --C(O)--NHOH,
--C(O)--NH.sub.2, C.sub.1-4-alkylthio, C.sub.1-4-alkylsulphinyl,
C.sub.1-4-alkylsulphonyl, or combinations thereof, heteroarylalkyl
wherein the heteroaryl portion has 5 to 10 ring atoms in which at
least 1 ring atom is a heteroatom and the alkyl portion has 1 to 3
carbon atoms, the heteroaryl portion is unsubstituted or is
substituted one or more times by halogen, aryl, C.sub.1-4 alkyl,
halogenated C.sub.1-4 alkyl, hydroxy, C.sub.1-4-alkoxy, halogenated
C.sub.1-4 alkoxy, cyano, trifluoromethyl, nitro, amino,
C.sub.1-4-alkylamino, di-C.sub.1-4-alkylamino, carboxy,
alkoxycarbonyl, --C(O)--NHOH, --C(O)--NH.sub.2,
C.sub.1-4-alkylthio, C.sub.1-4-alkylsulphinyl,
C.sub.1-4-alkylsulphonyl, or combinations thereof, heterocycle
having 5 to 10 ring atoms in which at least 1 ring atom is a
heteroatom, which is unsubstituted or is substituted one or more
times by heterocycle-alkyl wherein the heterocycle portion has 5 to
10 ring atoms in which at least 1 ring atom is a heteroatom and the
alkyl portion has 1 to 3 carbon atoms, the heterocycle portion is
nonaromatic and is unsubstituted or is substituted one or more
times by halogen, aryl, C.sub.1-4 alkyl, halogenated C.sub.1-4
alkyl, hydroxy, C.sub.1-4-alkoxy, halogenated C.sub.1-4 alkoxy,
cyano, trifluoromethyl, nitro, oxo, amino, C.sub.1-4-alkylamino,
di-C.sub.1-4-alkylamino, carboxy, alkoxycarbonyl, or combinations
thereof, or carbocycle which is a nonaromatic, monocyclic or
bicyclic, group having 5 to 14 carbon atoms, which is unsubstituted
or is substituted one or more times by halogen, C.sub.1-4 alkyl,
halogenated C.sub.1-4 alkyl, hydroxy, C.sub.1-4-alkoxy, halogenated
C.sub.1-4 alkoxy, nitro, methylenedioxy, ethylenedioxy, amino,
C.sub.1-4 alkylamino, di-C.sub.1-4-alkylamino,
C.sub.1-4-hydroxyalkyl, C.sub.1-4-hydroxyalkoxy, carboxy, cyano,
--C(O)--NHOH, --C(O)--NH.sub.2, C.sub.2-4-acyl,
C.sub.2-4-alkoxycarbonyl, C.sub.1-4-alkylthio,
C.sub.1-4-alkylsulphinyl, C.sub.1-4-alkylsulphonyl, phenoxy, or
combinations thereof; and or a pharmaceutically acceptable salt
thereof, with the proviso that when R.sup.1 is cyclopropyl, R.sup.2
is not cyclopropylmethyl, or cyclopropylethyl.
2. (canceled)
3. A method according to claim 1, wherein R.sup.1 is substituted
alkyl.
4. A method according to claim 1, wherein R.sup.1 is
cycloalkyl.
5. A method according to claim 1, wherein R.sup.1 is
cycloalkylalkyl.
6. A method according to claim 1, wherein R.sup.2 is substituted or
unsubstituted alkyl.
7. A method according to claim 1, wherein R.sup.2 is
alkoxyalkyl.
8. A method according to claim 1, wherein R.sup.2 is substituted or
unsubstituted cycloalkyl.
9. A method according to claim 1, wherein R.sup.2 is substituted or
unsubstituted aryl.
10. A method according to claim 1, wherein R.sup.2 is substituted
or unsubstituted arylalkyl.
11. A method according to claim 1, wherein R.sup.2 is substituted
or unsubstituted heteroaryl.
12. A method according to claim 1, wherein R.sup.2 is substituted
heteroarylalkyl.
13. A method according to claim 1, wherein R.sup.2 is substituted
or unsubstituted heterocycle.
14. A compound according to claim 1, wherein R.sup.2 is substituted
or unsubstituted heterocycle-alkyl.
15. A compound according to claim 1, wherein R.sup.2 is substituted
or unsubstituted carbocycle.
16. A method according to claim 1, wherein R.sup.1 is cycloalkyl or
cycloalkylalkyl.
17. A method according to claim 6, wherein R.sup.1 is cycloalkyl or
cycloalkylalkyl.
18. A method according to claim 7, wherein R.sup.1 is cycloalkyl or
cycloalkylalkyl.
19. A method according to claim 8, wherein R.sup.1 is cycloalkyl or
cycloalkylalkyl.
20. A method according to claim 9, wherein R.sup.1 is cycloalkyl or
cycloalkylalkyl.
21. A method according to claim 10, wherein R.sup.1 is cycloalkyl
or cycloalkylalkyl.
22. A method according to claim 11, wherein R.sup.1 is cycloalkyl
or cycloalkylalkyl.
23. A method according to claim 12, wherein R.sup.1 is cycloalkyl
or cycloalkylalkyl.
24. A method according to claim 13, wherein R.sup.1 is cycloalkyl
or cycloalkylalkyl.
25. A method according to claim 14, wherein R.sup.1 is cycloalkyl
or cycloalkylalkyl.
26. A method according to claim 15, wherein R.sup.1 is cycloalkyl
or cycloalkylalkyl.
27. A method according to claim 1, wherein R.sup.1 is cyclopropyl,
cyclopentyl, or cyclopropylmethyl.
28. A method according to claim 1, wherein R.sup.1 is cyclopropyl,
cyclobutyl, cyclopentyl or cyclohexyl.
29. A method according to claim 1, wherein R.sup.1 is
cyclopropyl.
30. A method according to claim 1, wherein R.sup.2 is alkyl,
arylalkyl, cycloalkyl, aryl, heteroaryl, heteroarylalkyl, or alkyl
ether.
31. A method according to claim 1, wherein R.sup.2 is ethyl,
isopropyl, butyl, tert-butyl, cyclopentyl, cyclohexyl, or
cycloheptyl, which in each case is unsubstituted or substituted one
or more times by F, Cl, CN, CF.sub.3, CH.sub.3, C.sub.2H.sub.5,
isopropyl, OCH.sub.3, methylenedioxy, ethylenedioxy or combinations
thereof, or arylalkyl which is substituted one or more times by F,
Cl, CN, CF.sub.3--OCH.sub.3 methylenedioxy, ethylenedioxy or
combinations thereof.
32. A method according to claim 1, wherein R.sup.2 is substituted
benzyl, phenethyl or phenpropyl.
33. A method for enhancing cognition in a patient in whom such
enhancement is desired; for treating a patient suffering from
cognition impairment or decline; for treating a patient having a
disease involving decreased cAMP levels; for inhibiting PDE4 enzyme
activity in a patient; or for treating a patient suffering from an
allergic or inflammatory disease, resulting from decreased cyclic
AMP levels, elevated phosphodiesterase 4 levels, or both; said
method comprising administering to said patient an effective amount
of a compound of formula II ##STR00016## wherein R.sup.1' is
methyl, ethyl, or cyclopropyl; and R.sup.2' is cycloalkyl having 3
to 12 carbon atoms, which is unsubstituted or substituted one or
more times by halogen, C.sub.1-4 alkyl, halogenated C.sub.1-4
alkyl, C.sub.1-4 alkoxy, cyano or combinations thereof, aryl having
6 to 14 carbon atoms, which is unsubstituted or substituted one or
more times by halogen, C.sub.1-4 alkyl, halogenated C.sub.1-4
alkyl, hydroxy, C.sub.1-4-alkoxy, halogenated C.sub.1-4 alkoxy,
nitro, methylenedioxy, ethylenedioxy, amino, C.sub.1-4 alkylamino,
di-C.sub.1-4-alkylamino, C.sub.1-4-hydroxyalkyl,
C.sub.1-4-hydroxyalkoxy, carboxy, cyano, --C(O)--NHOH,
--C(O)--NH.sub.2, C.sub.2-4-acyl, C.sub.2-4-alkoxycarbonyl,
C.sub.1-4-alkylthio, C.sub.1-4-alkylsulphinyl,
C.sub.1-4-alkylsulphonyl, phenoxy, or combinations thereof,
heteroaryl having 5 to 10 ring atoms in which at least 1 ring atom
is a heteroatom, which is unsubstituted or substituted one or more
times by halogen, aryl, C.sub.1-4 alkyl, halogenated C.sub.1-4
alkyl, hydroxy, C.sub.1-4-alkoxy, halogenated C.sub.1-4 alkoxy,
cyano, trifluoromethyl, nitro, amino, C.sub.1-4-alkylamino,
di-C.sub.1-4-alkylamino, carboxy, alkoxycarbonyl, --C(O)--NHOH,
--C(O)--NH.sub.2, C.sub.1-4-alkylthio, C.sub.1-4-alkylsulphinyl,
C.sub.1-4-alkylsulphonyl, or combinations thereof, heterocycle
having 5 to 10 ring atoms in which at least 1 ring atom is a
heteroatom, which is unsubstituted or is substituted one or more
times by halogen, aryl, C.sub.1-4 alkyl, halogenated C.sub.1-4
alkyl, hydroxy, C.sub.1-4-alkoxy, halogenated C.sub.1-4 alkoxy,
cyano, trifluoromethyl, nitro, oxo, amino, C.sub.1-4-alkylamino,
di-C.sub.1-4-alkylamino, carboxy, alkoxycarbonyl, or combinations
thereof, or carbocycle which is nonaromatic, monocyclic or
bicyclic, group having 5 to 14 carbon atoms, which is unsubstituted
or is substituted one or more times by halogen, C.sub.1-4 alkyl,
halogenated C.sub.1-4 alkyl, hydroxy, C.sub.1-4-alkoxy, halogenated
C.sub.1-4 alkoxy, nitro, methylenedioxy, ethylenedioxy, amino,
C.sub.1-4 alkylamino, di-C.sub.1-4-alkylamino,
C.sub.1-4-hydroxyalkyl, C.sub.1-4-hydroxyalkoxy, carboxy, cyano,
--C(O)--NHOH, --C(O)--NH.sub.2, C.sub.2-4-acyl,
C.sub.2-4-alkoxycarbonyl, C.sub.1-4-alkylthio,
C.sub.1-4-alkylsulphinyl, C.sub.1-4-alkylsulphonyl, phenoxy, or
combinations thereof; or a pharmaceutically acceptable salt
thereof.
34. A method for enhancing cognition in a patient in whom such
enhancement is desired; for treating a patient suffering from
cognition impairment or decline; for treating a patient having a
disease involving decreased cAMP levels; for inhibiting PDE4 enzyme
activity in a patient; or for treating a patient suffering from an
allergic or inflammatory disease, resulting from decreased cyclic
AMP levels, elevated phosphodiesterase 4 levels, or both; said
method comprising administering to said patient an effective amount
of a compound of Formula III: ##STR00017## wherein R.sup.1'' is
methyl, ethyl, or cyclopropyl; and R.sup.2'' is phenyl, phenyl
which is substituted one or more times by halogen, C.sub.1-4 alkyl,
halogenated C.sub.1-4 alkyl, hydroxy, C.sub.1-4-alkoxy, nitro,
methylenedioxy, ethylenedioxy, amino, C.sub.1-4 alkylamino,
di-C.sub.1-4-alkylamino, C.sub.1-4-hydroxyalkyl,
C.sub.1-4-hydroxyalkoxy, carboxy, cyano, C.sub.2-4-acyl,
C.sub.2-4-alkoxycarbonyl, C.sub.1-4-alkylthio,
C.sub.1-4-alkylsulphinyl, C.sub.1-4-alkylsulphonyl, phenoxy, or
combinations thereof, or heteroaryl having 5 to 10 ring atoms in
which at least 1 ring atom is a heteroatom, substituted heteroaryl
having 5 to 10 ring atoms, in which at least 1 ring atom is a
heteroatom, which is unsubstituted or substituted one or more times
by halogen, aryl, C.sub.1-4-alkyl, C.sub.1-4-alkoxy, cyano,
trifluoromethyl, nitro, amino, C.sub.1-4-alkylamino,
di-C.sub.1-4-alkylamino or combinations thereof, or when R.sup.1 is
methyl or cyclopropyl R.sup.2 can also be cycloalkyl having 3 to 12
carbon atoms; or a pharmaceutically acceptable salt thereof.
35. A method for enhancing cognition in a patient in whom such
enhancement is desired; for treating a patient suffering from
cognition impairment or decline; for treating a patient having a
disease involving decreased cAMP levels; for inhibiting PDE4 enzyme
activity in a patient; or for treating a patient suffering from an
allergic or inflammatory disease, resulting from decreased cyclic
AMP levels, elevated phosphodiesterase 4 levels, or both; said
method comprising administering to said patient an effective amount
of a compound selected from:
6-Cyclopropylamino-9-(2-fluorobenzyl)-2-trifluoromethylpurine
6-Cyclopropylamino-9-(4-fluorobenzyl)-2-trifluoromethylpurine
6-Cyclopropylamino-9-(2,6-difluorobenzyl)-2-trifluoromethylpurine
6-Cyclopropylamino-9-(2,3-difluorobenzyl)-2-trifluoromethylpurine
6-Cyclopropylamino-9-propyl 2-trifluoromethylpurine
6-Cyclopropylamino-9-cyclopentyl-2-trifluoromethylpurine
6-Cyclopropylamino-9-(3,4-dimethoxybenzyl)-2-trifluoromethylpurine
6-Cyclopropylamino-9-(3,4-methylenedioxybenzyl)-2-trifluoromethylpurine
6-Cyclopropylamino-9-(3-thiophenemethyl)-2-trifluoromethylpurine
6-Cyclopropylamino-9-cycloheptyl-2-trifluoromethylpurine
6-Methylamino-9-cyclopentyl-2-trifluoromethylpurine
6-Cyclopropylamino-9-cyclohexyl-2-trifluoromethylpurine
6-Methylamino-9-cycloheptyl-2-trifluoromethylpurine
6-Cyclopropylamino-9-cyclopentylmethyl-2-trifluoromethylpurine
6-Cyclopropylamino-9-phenyl-2-trifluoromethylpurine
6-Cyclopropylamino-9-(2-fluorophenyl)-2-trifluoromethylpurine
6-Cyclopropylamino-9-cyclobutyl-2-trifluoromethylpurine
6-Cyclopropylamino-9-(2-norboranane)-2-trifluoromethylpurine
6-Cyclopropylamino-9-(1-indanyl)-2-trifluoromethylpurine
6-Cyclopropylamino-9-(4-fluorophenyl)-2-trifluoromethylpurine
6-Cyclopropylamino-9-(4-chlorophenyl)-2-trifluoromethylpurine
6-Cyclopropylamino-9-(3-thienyl)-2-trifluoromethylpurine
6-Cyclopropylamino-9-(3-cyclopentyloxy-4-methoxybenzyl)-2-trifluoromethyl-
purine
6-Cyclopropylamino-9-(3,4-dimethoxyphenyl)-2-trifluoromethylpurine
6-Cyclopropylamino-9-(2,6-dichloro-4-pyridylmethyl)-2-trifluoromethylpuri-
ne 6-Cyclopropylamino-9-(4-methoxybenzyl)-2-trifluoromethylpurine
6-Cyclopropylamino-9-(3-methoxyphenyl)-2-trifluoromethylpurine
6-Cyclopropylamino-9-(4-methoxyphenyl)-2-trifluoromethylpurine
6-Cyclopropylamino-9-(3-nitrophenyl)-2-trifluoromethylpurine
6-Cyclopropylamino-9-(2-methoxyphenyl)-2-trifluoromethylpurine
6-Cyclopropylamino-9-(3-cyanophenyl)-2-trifluoromethylpurine
6-Cyclopropylamino-9-(2,4-dimethoxyphenyl)-2-trifluoromethylpurine
6-Cyclopropylamino-9-(3-nitrobenzyl)-2-trifluoromethylpurine
6-Cyclopropylamino-9-(6-methoxy-3-pyridyl)-2-trifluoromethylpurine
6-Cyclopropylamino-9-(4-pyridyl)-2-trifluoromethylpurine
6-Cyclopropylamino-9-(3-pyridyl)-2-trifluoromethylpurine
6-Cyclopropylamino-9-(4-dimethylaminophenyl)-2-trifluoromethylpurine
6-Cyclopropylamino-9-(3-aminophenyl)-2-trifluoromethylpurine
6-Methylamino-9-(2,4-dimethoxy-5-pyrimidyl)-2-trifluoromethylpurine
6-Methylamino-9-(2-methoxyphenyl)-2-trifluoromethylpurine
6-Methylamino-9-(4-methoxyphenyl)-2-trifluoromethylpurine
6-Methylamino-9-(3-acetylphenyl)-2-trifluoromethylpurine
6-Methylamino-9-(3-methoxyphenyl)-2-trifluoromethylpurine
6-Methylamino-9-(3-nitrophenyl)-2-trifluoromethylpurine
6-Cyclopropylamino-9-(3-furanyl)-2-trifluoromethylpurine
6-Cyclopropylamino-9-(4-ethoxyphenyl)-2-trifluoromethylpurine
6-Cyclopropylamino-9-(2-ethoxyphenyl)-2-trifluoromethylpurine
6-Cyclopropylamino-9-(3,4-methylenedioxyphenyl)-2-trifluoromethylpurine
6-Cyclopropylamino-9-(3-ethoxyphenyl)-2-trifluoromethylpurine
6-Methylamino-9-(3,4-dimethoxyphenyl)-2-trifluoromethylpurine; and
pharmaceutically acceptable salts thereof.
36. A method according to claim 35, wherein said compound is
selected from:
6-Cyclopropylamino-9-(2,3-difluorobenzyl)-2-trifluoromethylpurine
6-Cyclopropylamino-9-cyclopentyl-2-trifluoromethylpurine
6-Cyclopropylamino-9-(3,4-dimethoxybenzyl)-2-trifluoromethylpurine
6-Cyclopropylamino-9-cycloheptyl-2-trifluoromethylpurine
6-Methylamino-9-cyclopentyl-2-trifluoromethylpurine
6-Cyclopropylamino-9-cyclohexyl-2-trifluoromethylpurine
6-Methylamino-9-cycloheptyl-2-trifluoromethylpurine
6-Cyclopropylamino-9-phenyl-2-trifluoromethylpurine
6-Cyclopropylamino-9-(2-fluorophenyl)-2-trifluoromethylpurine
6-Cyclopropylamino-9-cyclobutyl-2-trifluoromethylpurine
6-Cyclopropylamino-9-(2-norboranane)-2-trifluoromethylpurine
6-Cyclopropylamino-9-(4-fluorophenyl)-2-trifluoromethylpurine
6-Cyclopropylamino-9-(4-chlorophenyl)-2-trifluoromethylpurine
6-Cyclopropylamino-9-(3-thienyl)-2-trifluoromethylpurine
6-Cyclopropylamino-9-(3,4-dimethoxyphenyl)-2-trifluoromethylpurine
6-Cyclopropylamino-9-(2,6-dichloro-4-pyridylmethyl)-2-trifluoromethylpuri-
ne 6-Cyclopropylamino-9-(4-methoxybenzyl)-2-trifluoromethylpurine
6-Cyclopropylamino-9-(3-methoxyphenyl)-2-trifluoromethylpurine
6-Cyclopropylamino-9-(4-methoxyphenyl)-2-trifluoromethylpurine
6-Cyclopropylamino-9-(3-nitrophenyl)-2-trifluoromethylpurine
6-Cyclopropylamino-9-(2-methoxyphenyl)-2-trifluoromethylpurine
6-Cyclopropylamino-9-(3-cyanophenyl)-2-trifluoromethylpurine
6-Cyclopropylamino-9-(3-nitrobenzyl)-2-trifluoromethylpurine
6-Cyclopropylamino-9-(4-pyridyl)-2-trifluoromethylpurine
6-Methylamino-9-(2,4-dimethoxy-5-pyrimidyl)-2-trifluoromethylpurine
6-Methylamino-9-(4-methoxyphenyl)-2-trifluoromethylpurine
6-Methylamino-9-(3-acetylphenyl)-2-trifluoromethylpurine
6-Methylamino-9-(3-methoxyphenyl)-2-trifluoromethylpurine
6-Methylamino-9-(3-nitrophenyl)-2-trifluoromethylpurine
6-Cyclopropylamino-9-(3-ethoxyphenyl)-2-trifluoromethylpurine
6-Methylamino-9-(3,4-dimethoxyphenyl)-2-trifluoromethylpurine; and
pharmaceutically acceptable salts thereof.
37-73. (canceled)
74. A method according to claim 1, wherein said method is for
enhancing cognition in a patient in whom such enhancement is
desired.
75. A method according to claim 74, wherein said compound is
administered in an amount of 0.01-100 mg/kg of body weight/day.
76. A method according to claim 37, wherein said patient is a
human.
77. A method according to claim 35, wherein said method is for
enhancing cognition in a patient in whom such enhancement is
desired.
78. A method according to claim 77, wherein said patient is a
human.
79. A method according to claim 78, wherein said compound is
administered in an amount of 0.01-100 mg/kg of body weight/day.
80. A method according to claim 74, wherein when R.sup.1c is
methyl, then R.sup.2c is not arylalkyl, methyl or 2-butyl, and when
R.sup.1c is H, then R.sup.2c is not benzyl.
81. A method according to claim 1, wherein said method is for
treating a patient suffering from cognition impairment or
decline.
82. A method according to claim 81, wherein said patient is a
human.
83. A method according to claim 82, wherein said patient is
suffering from memory impairment.
84. A method according to claim 82, wherein said compound is
administered in an amount of 0.01-100 mg/kg of body weight/day.
85. A method according to claim 83, wherein said patient is
suffering from memory impairment due to Alzheimer's disease,
schizophrenia, Parkinson's disease, Huntington's disease, Pick's
disease, Creutzfeldt-Jakob disease, depression, aging, head trauma,
stroke, CNS hypoxia, cerebral senility, multiinfarct dementia, HIV
or cardiovascular disease.
86. A according to claim 35, wherein said method is for treating a
patient suffering from cognition impairment or decline.
87. A method according to claim 81, wherein when R.sup.1c is
methyl, then R.sup.2c is not arylalkyl, methyl or 2-butyl, and when
R.sup.1c is H, then R.sup.2, is not benzyl.
88. A method according to claim 1, wherein said method is for
treating a patient having a disease involving decreased cAMP
levels.
89. A method according to claim 1, wherein said method is for
inhibiting PDE4 enzyme activity in a patient.
90. A method according to claim 83, wherein said method is for
treating a patient suffering from memory impairment due to a
neurodegenerative disease.
91. A method according to claim 83, wherein said method is for
treating a patient suffering from memory impairment due to an acute
neurodegenerative disorder.
92. A method according to claim 1, wherein said method is for
treating a patient suffering from an allergic or inflammatory
disease, resulting from decreased cyclic AMP levels, elevated
phosphodiesterase 4 levels, or both.
93. A method according to claim 1, wherein R.sup.2 is
cycloalkylalkyl.
94. A method according to claim 1, wherein R.sup.1 is cycloalkyl or
cycloalkylalkyl.
95. A method according to claim 1, wherein said compound is
6-cyclopropylamino-9-(2-methoxyphenyl)-2-trifluoromethylpurine, or
a pharmaceutically acceptable salt thereof.
96. A method according to claim 83, wherein said compound is
6-cyclopropylamino-9-(2-methoxyphenyl)-2-trifluoromethylpurine, or
a pharmaceutically acceptable salt thereof.
97. A method according to claim 92, wherein said compound is
6-cyclopropylamino-9-(2-methoxyphenyl)-2-trifluoromethylpurine, or
a pharmaceutically acceptable salt thereof.
98. A method according to claim 1, wherein said compound is
6-cyclopropylamino-9-(2-fluorobenzyl)-2-trifluoromethylpurine, or a
pharmaceutically acceptable salt thereof
99. A method according to claim 83, wherein said compound is
6-cyclopropylamino-9-(2-fluorobenzyl)-2-trifluoromethylpurine, or a
pharmaceutically acceptable salt thereof.
100. A method according to claim 92, wherein said compound
6-cyclopropylamino-9-(2-fluorobenzyl)-2-trifluoromethylpurine, or a
pharmaceutically acceptable salt thereof.
Description
[0001] This application claims benefit of U.S. Provisional
application Ser. No. 60/267,195, filed Feb. 8, 2001, and U.S.
Provisional application Ser. No. 60/344, 824, filed Jan. 7,
2002.
FIELD OF THE INVENTION
[0002] The present invention relates generally to the field of
phosphodiesterase 4 (PDE4) enzyme inhibition. More specifically
this invention relates to selective PDE4 inhibition by novel
adenine analogs, methods of preparing such compounds, compositions
containing such compounds, and methods of use thereof.
BACKGROUND OF THE INVENTION
[0003] The cyclic nucleotide specific phosphodiesterases (PDEs)
represent a family of enzymes that catalyze the hydrolysis of
various cyclic nucleoside monophosphates (including cAMP and cGMP).
These cyclic nucleotides act as second messengers within cells, and
as messengers, carry impulses from cell surface receptors having
bound various hormones and neurotransmitters. PDEs act to regulate
the level of cyclic nucleotides within cells and maintain cyclic
nucleotide homeostasis by degrading such cyclic mononucleotides
resulting in termination of their messenger role.
[0004] PDE enzymes can be grouped into eleven families according to
their specificity toward hydrolysis of cAMP or cGMP, their
sensitivity to regulation by calcium, calmodulin or cGMP, and their
selective inhibition by various compounds. For example, PDE 1 is
stimulated by Ca.sup.2+/calmodulin. PDE 2 is cGMP-dependent, and is
found in the heart and adrenals. PDE 3 is cGMP dependent, and
inhibition of this enzyme creates positive inotropic activity. PDE
4 is cAMP specific, and its inhibition causes airway relaxation,
antiinflammatory and antidepressant activity. PDE 5 appears to be
important in regulating cGMP content in vascular smooth muscle, and
therefore PDE 5 inhibitors may have cardiovascular activity. Since
the PDEs possess distinct biochemical properties, it is likely that
they are subject to a variety of different forms of regulation.
[0005] PDE4 is distinguished by various kinetic properties
including low Michaelis constant for cAMP and sensitivity to
certain drugs. The PD4 enzyme family consists of four genes, which
produce 4 isoforms of the PDE4 enzyme designated PDE4A, PDE4B,
PDE4C, and PDE4D [See: Wang et al., Expression, Purification, and
Characterization of human cAMP-Specific Phosphodiesterase (PDE4)
Subtypes A, B, C, and D, Biochem. Biophys. Res. Comm., 234, 320-324
(1997)] In addition, various splice variants of each PDE4 isoform
have been identified.
[0006] PDE4 isoenzymes are localized in the cytosol of cells and
are unassociated with any known membranous structures. PDE4
isoenzymes specifically inactivate cAMP by catalyzing its
hydrolysis to adenosine 5'-monophosphate (AMP). Regulation of cAMP
activity is important in many biological processes, including
inflammation and memory. Inhibitors of PDE4 isoenzymes such as
rolipram, piclamilast, CDP-840 and ariflo are powerful
antiinflammatory agents and therefore may be useful in treating
diseases where inflammation is problematic such as asthma or
arthritis. Further, rolipram improves the cognitive performance of
rats and mice in learning paradigms.
##STR00002##
[0007] In addition to such compounds as rolipram, xanthine
derivatives such as pentoxifylline, denbufylline, and theophylline
inhibit PDE4 and have received considerable attention of late for
their cognition enhancing effects. cAMP and cGMP are second
messengers at mediate cellular responses to many different hormones
and neurotransmitters. Thus, therapeutically significant effects
may result from PDE inhibition and the resulting increase in
intracellular cAMP or cGMP in key cells, such as those located in
the nervous system and elsewhere in the body.
[0008] Rolipram, previously in development as an anti-depressant,
selectively inhibits the PDE4 enzyme and has become a standard
agent in the classification of PDE enzyme subtypes Early work in
the PDE4 field focused on depression and inflammation, and has
subsequently been extended to include indications such as dementia.
[see "The PDE IV Family Of Calcium-Phosphodiesterases Enzymes,"
John A. Lowe, III, et al., Drugs of the Future 1992, 17(9):799-807
for a general review). Further clinical developments of rolipram
and other first-generation PDE4 inhibitors were terminated due to
the side effect profile of these compounds. The primary side effect
in prates is emesis, while the primary side effects in rodents are
testicular degranulation, weakening of vascular smooth muscle,
psychotrophic effects, increased gastric acid secretion and stomach
erosion.
SUMMARY OF THE INVENTION
[0009] The present invention relates to novel adenine compounds
that inhibit PDE4 enzymes, and especially have improved side effect
profiles, e.g., are relatively non-emetic, (e.g., as compared to
the previously discussed prior a compounds). In particular, the
present invention relates to novel
9-substituted-2-trifluoromethyladenine compounds that possess PDE4
inhibitory activity. Preferably, the compounds selectively inhibit
PDE4 enzymes. The compounds of this invention at the same time
facilitate entry into cells, especially cells of the nervous
system.
[0010] Still further, the present invention provides methods for
synthesizing compounds with such activity and selectivity as well
as methods of (and corresponding pharmaceutical compositions for)
treating a patient, e.g., mammals, including humans, requiring PDE
inhibition, especially PDE4 inhibition, for a disease state that
involves elevated intracellular PDE 4 levels or decreased cAMP
levels, e.g., involving neurological syndromes, especially those
states associated with memory impairment, most especially long term
memory impairment, as where such memory impairment is due in part
to catabolism of intracellular cAMP levels by PDE 4 enzymes, or
where such memory impairment may be improved by effectively
inhibiting PDE4 enzyme activity.
[0011] In a preferred aspect, the compounds of the invention
improve such diseases by inhibiting PDE4 enzymes at doses which do
not induce emesis.
[0012] Upon further study of the specification and appended claims,
further aspects, objects and advantages of this invention will
become apparent to those skilled in the art.
[0013] The present invention includes compounds of Formula I:
##STR00003##
[0014] wherein, [0015] R.sup.1 is H, [0016] alkyl having 1 to 5
carbon atoms, which is unsubstituted or substituted one or more
times by halogen, hydroxy, or combinations thereof, and wherein a
--CH.sub.2-- group can be optionally replaced by --O--, --S--, or
--NH--, [0017] cycloalkyl having 3 to 6 carbon atoms, or [0018]
cycloalkylalkyl having 4 to 7 C atoms; [0019] R.sup.2 is alkyl
having 1 to 12 carbon atoms, which is unsubstituted or substituted
one or more times by halogen, hydroxy, cyano or combinations
thereof, wherein one or more --CH.sub.2-- groups is each
independently optionally replaced by --O--, --S--, or --NH--, and
wherein optionally one or more --CH.sub.2CH.sub.2-- groups is
replaced in each case by --CH.dbd.CH-- or --C.ident.C--, [0020]
alkyl ether having 3 to 12 carbon atoms, [0021] cycloalkyl having 3
to 12 carbon atoms, which is unsubstituted or substituted one or
more times by halogen, C.sub.1-4 alkyl, halogenated C.sub.1-4
alkyl, C.sub.1-4 alkoxy, cyano or combinations thereof, [0022]
cycloalkylalkyl having 4 to 12 C atoms, which is unsubstituted or
substituted one or more times by C.sub.1-4 alkyl, halogenated
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, cyano, halogen, or combinations
thereof, [0023] aryl having 6 to 14 carbon atoms, which is
unsubstituted or substituted one or more times by halogen,
C.sub.1-4 alkyl, halogenated C.sub.1-4 alkyl, hydroxy,
C.sub.1-4-alkoxy, halogenated C.sub.1-4 alkoxy, nitro,
methylenedioxy, ethylenedioxy, amino, C.sub.1-4 alkylamino,
di-C.sub.1-4-alkylamino, C.sub.1-4-hydroxyalkyl,
C.sub.1-4-hydroxyalkoxy, carboxy, cyano, hydroxamic acid,
carboxamide, C.sub.2-4-acyl, C.sub.2-4-alkoxycarbonyl,
C.sub.1-4-alkylthio, C.sub.1-4-alkylsulphinyl,
C.sub.1-4-alkylsulphonyl, phenoxy, or combinations thereof, [0024]
arylalkyl having 7 to 16 carbon atoms, which is unsubstituted or
substituted one or more times by halogen, C.sub.1-4 alkyl,
halogenated C.sub.1-4 alkyl, hydroxy, C.sub.1-4-alkoxy, halogenated
C.sub.1-4 alkoxy, nitro, methylenedioxy, ethylenedioxy, amino,
C.sub.1-4 alkylamino, di-C.sub.1-4-alkylamino,
C.sub.1-4-hydroxyakyl, C.sub.1-4-hydroxyalkoxy, carboxy, cyano,
hydroxamic acid, carboxamide, C.sub.2-4-acyl,
C.sub.2-4-alkoxycarbonyl, C.sub.1-4-alkylthio, C.sub.1-4
alkylsulphinyl, C.sub.1-4-alkylsulphonyl, phenoxy, or combinations
thereof, [0025] heteroaryl having 5 to 10 ring atoms in which at
least 1 ring atom is a heteroatom, which is unsubstituted or
substituted one or more times by halogen, aryl, C.sub.1-4 alkyl,
halogenated C.sub.1-4 alkyl, hydroxy, C.sub.1-4-alkoxy, halogenated
C.sub.1-4 alkoxy; cyano, trifluoromethyl, nitro, oxo, amino,
C.sub.1-4-alkylamino, di-C.sub.1-4-alkylamino, carboxy,
alkoxycarbonyl, hydroxamic acid, carboxamide, C.sub.1-4-alkylthio,
C.sub.1-4-alkylsulphinyl, C.sub.1-4-alkylsulphonyl, or combinations
thereof, [0026] heteroarylalkyl wherein the heteroaryl portion has
5 to 10 ring atoms in which at least 1 ring atom is a heteroatom
and the alkyl portion has 1 to 3 carbon atoms, the heteroaryl
portion is unsubstituted or is substituted one or more times in by
halogen, aryl, C.sub.1-4 alkyl, halogenated C.sub.1-4 alkyl,
hydroxy, C.sub.1-4-alkoxy, halogenated C.sub.1-4 alkoxy, cyano,
trifluoromethyl, nitro, oxo, amino, C.sub.1-4-alkylamino,
di-C.sub.1-4-alkylamino, carboxy, alkoxycarbonyl, hydroxamic acid,
carboxamide, C.sub.1-4-alkylthio, C.sub.1-4-alkylsulphinyl,
C.sub.1-4-alkylsulphonyl, or combinations thereof, [0027]
heterocycle having 5 to 10 ring atoms in which at least 1 ring atom
is a heteroatom, which is unsubstituted or is substituted one or
more times by halogen, aryl, C.sub.1-4 alkyl, halogenated C.sub.1-4
alkyl, hydroxy, C.sub.1-4-alkoxy, halogenated C.sub.1-4 alkoxy,
cyano, trifluoromethyl, nitro, oxo, amino, C.sub.1-4-alkylamino,
di-C.sub.1-4-alkylamino, carboxy, alkoxycarbonyl, or combinations
thereof (e.g., piperidinyl, imidazolinyl, imidazolidinyl,
pyrrolinyl, pyrrolidinyl, morpholinyl, piperazinyl, and indolinyl),
[0028] heterocycle-alkyl wherein the heterocycle portion has 5 to
10 ring atoms in which at least 1 ring atom is a heteroatom and the
alkyl portion has 1 to 3 carbon atoms, the heterocycle portion is
nonarmoatic and is unsubstituted or is substituted one or more
times in the by halogen, aryl, C.sub.1-4 alkyl, halogenated
C.sub.1-4 alkyl, hydroxy, C.sub.1-4-alkoxy, halogenated C.sub.1-4
alkoxy, cyano, trifluoromethyl, nitro, oxo, amino,
C.sub.1-4-alkylamino, di-C.sub.1-4-alkylamino, carboxy,
alkoxycarbonyl, or combinations thereof (e.g., piperidinyl-ethyl
and pyrrolinyl-methyl), or [0029] carbocycle which is nonaromatic,
monocyclic or bicyclic, group having 5 to 14 carbon atoms, which is
unsubstituted or is substituted one or more times in the by
halogen, C.sub.1-4 alkyl, halogenated C.sub.1-4 alkyl, hydroxy,
C.sub.1-4-alkoxy, halogenated C.sub.1-4 alkoxy, nitro,
methylenedioxy, ethylenedioxy, amino, C.sub.1-4 alkylamino,
di-C.sub.1-4-alkylamino, C.sub.1-4-hydroxyalkyl,
C.sub.1-4-hydroxyalkoxy, carboxy, cyano, hydroxamic acid,
carboxamide, C.sub.2-4-acyl, C.sub.2-4-alkoxycarbonyl,
C.sub.1-4-alkylthio, C.sub.1-4-alkylsulphinyl,
C.sub.1-4-alkylsulphonyl, phenoxy, or combinations thereof; [0030]
and [0031] pharmaceutically acceptable salts thereof, [0032] with
the provisos that: [0033] (a) when R.sup.1 is methyl, then R.sup.2
is not arylalkyl, heteroarylalkyl,
2-(1,2,3,4-tetrahydro)quinolinyl-methyl, methyl or 2-butyl; [0034]
(b) when R.sup.1 is cyclopropyl, R.sup.2 is not 4-methylbenzyl;
[0035] (c) when R.sup.1 is ethyl, then R.sup.2 is not ethyl,
3-aminobenzyl, 2-thienylmethyl, 3-thienylmethyl, or
2-pyridylmethyl; [0036] (d) when R.sup.1 is cyclopropyl, then
R.sup.2 is not cyclopropylmethyl; [0037] (e) when R.sup.1 is H,
then R.sup.2 is not methyl, ethyl, benzyl, 4-methylbenzyl, or
substituted tetrahydrofuranyl; [0038] (f) when R.sup.1 is
methoxyethyl, then R.sup.2 is not benzyl, 3-dimethylaminobenzyl, or
3-thienylmethyl; [0039] (g) when R.sup.1 is iso-butyl, then R.sup.2
is not benzyl; and [0040] (h) when R.sup.1 is n-butyl, then R.sup.2
is not n-butyl.
[0041] According to a further aspect of the invention there is
provided a genus according to formula I wherein when R.sup.1 is
methyl, R.sup.2 is not arylalkyl, heteroarylalkyl,
2-(1,2,3,4-tetrahydro)quinolinyl-methyl or C.sub.1-5-alkyl.
[0042] According to a further aspect of the invention there is
provided a genus according to formula I wherein when R.sup.1 is
methyl, R.sup.2 is not arylalkyl, heteroarylalkyl,
heterocycle-alkyl or C.sub.1-5-alkyl.
[0043] According to a further aspect of the invention there is
provided a genus according to formula I wherein when R.sup.1 is
cyclopropyl, R.sup.2 is not arylalkyl.
[0044] According to a further aspect of the invention there is
provided a genus according to formula I wherein when R.sup.1 is
ethyl, R.sup.2 is not arylalkyl, heteroarylalkyl, or
C.sub.1-3-alkyl.
[0045] According to a further aspect of the invention there is
provided a genus according to formula I wherein when R.sup.1 is
cyclopropyl, R.sup.2 is not cycloalkylalkyl.
[0046] According to a further aspect of the invention there is
provided a genus according to formula I wherein when R.sup.1 is H,
R.sup.2 is not arylalkyl, heterocycle or C.sub.1-3-alkyl.
[0047] According to a further aspect of the invention there is
provided a genus according to formula I wherein when R.sup.1 is
methoxyethyl, R.sup.1 is not arylalkyl or heteroarylalkyl.
[0048] According to a further aspect of the invention there is
provided a genus according to formula I wherein when R.sup.1 is a
butyl group, R.sup.2 is not arylalkyl or C.sub.1-5-alkyl.
[0049] According to a preferred aspect of the invention there is
provided a genus of novel compounds according to formula II
##STR00004##
[0050] wherein [0051] R.sup.1' is methyl, ethyl, or cyclopropyl;
and [0052] R.sup.2' is cycloalkyl having 3 to 12 carbon atoms,
which is unsubstituted or substituted one or more times by halogen,
C.sub.1-4 alkyl, halogenated C.sub.1-4 alkyl, C.sub.1-4 alkoxy,
cyano or combinations thereof, [0053] aryl having 6 to 14 carbon
atoms, which is unsubstituted or substituted one or more times by
halogen, C.sub.1-4 alkyl, halogenated C.sub.1-4 alkyl, hydroxy,
C.sub.1-4-alkoxy, halogenated C.sub.1-4 alkoxy, nitro,
methylenedioxy, ethylenedioxy, amino, C.sub.1-4 alkylamino,
di-C.sub.1-4-alkylamino, C.sub.1-4-hydroxyalkyl,
C.sub.1-4-hydroxyalkoxy, carboxy, cyano, hydroxamic acid,
carboxamide, C.sub.2-4-acyl, C.sub.2-4-alkoxycarbonyl,
C.sub.1-4-alkylthio, C.sub.1-4-alkylsulphinyl,
C.sub.1-4-alkylsulphonyl, phenoxy, or combinations thereof, [0054]
heteroaryl having 5 to 10 ring atoms in which at least 1 ring atom
is a heteroatom, which is unsubstituted or substituted one or more
times by halogen, aryl, C.sub.1-4 alkyl, halogenated C.sub.1-4
alkyl, hydroxy, C.sub.1-4-alkoxy, halogenated C.sub.1-4 alkoxy,
cyano, trifluoromethyl, nitro, oxo, amino, C.sub.1-4-alkylamino,
di-C.sub.1-4-alkylamino, carboxy, alkoxycarbonyl, hydroxamic acid,
carboxamide, C.sub.1-4-alkylthio, C.sub.1-4-alkylsulphinyl,
C.sub.1-4-alkylsulphonyl, or combinations thereof, [0055]
heterocycle having 5 to 10 ring atoms in which at least 1 ring atom
is a heteroatom, which is unsubstituted or is substituted one or
more times in the by halogen, aryl, C.sub.1-4 alkyl, halogenated
C.sub.1-4 alkyl, hydroxy, C.sub.1-4-alkoxy, halogenated C.sub.1-4
alkoxy, cyano, trifluoromethyl, nitro, oxo, amino,
C.sub.1-4-alkylamino, di-C.sub.1-4-alkylamino, carboxy,
alkoxycarbonyl, or combinations thereof (e.g., piperidinyl,
imidazolinyl, imidazolidinyl, pyrrolinyl, pyrrolidinyl,
morpholinyl, piperazinyl, and indolinyl), or [0056] carbocycle
which is nonaromatic, monocyclic or bicyclic, group having 5 to 14
carbon atoms, which is unsubstituted or is substituted one or more
times in the by halogen, C.sub.1-4 alkyl, halogenated C.sub.1-4
alkyl, hydroxy, C.sub.1-4-alkoxy, halogenated C.sub.1-4 alkoxy,
nitro, methylenedioxy, ethylenedioxy, amino, C.sub.1-4 alkylamino,
di-C.sub.1-4-alkylamino, C.sub.1-4-hydroxyalkyl,
C.sub.1-4-hydroxyalkoxy, carboxy, cyano, hydroxamic acid,
carboxamide, C.sub.2-4-acyl, C.sub.2-4-alkoxycarbonyl,
C.sub.1-4-alkylthio, C.sub.1-4-alkylsulphinyl,
C.sub.1-4-alkylsulphonyl, phenoxy, or combinations thereof; [0057]
and [0058] pharmaceutically acceptable salts thereof.
[0059] According to a further aspect of the invention there is
provided a genus of novel compounds according to the Formula
III:
##STR00005##
wherein [0060] R.sup.1'' is H, [0061] alkyl having 1 to 5 carbon
atoms, [0062] alkyl having 1 to 5 carbon atoms which is substituted
one or more times by halogen, hydroxy, oxo, cyano or combinations
thereof, [0063] cycloalkyl having 3 to 6 carbon atoms, [0064]
cycloalkyl having 3 to 6 carbon atoms, which is substituted one or
more times by halogen, alkyl, oxo or combinations thereof, [0065]
cycloalkylalkyl having 4 to 7 C atoms, [0066] cycloalkylalkyl
having 4 to 7 C atoms, which is substituted one or more times by
C.sub.1-4 alkyl, halogen, halogenated C.sub.1-4 alkyl, or
combinations thereof, [0067] R.sup.2'' is alkyl having 1 to 12
carbon atoms, [0068] alkyl having 1 to 12 carbon atoms which is
substituted one or more times by halogen, hydroxy, oxo, cyano or
combinations thereof, [0069] alkyl ether having 3 to 12 carbon
atoms, [0070] cycloalkyl having 3 to 12 carbon atoms, [0071]
cycloalkyl having 3 to 12 carbon atoms which is substituted one or
more times by halogen, C.sub.1-4 alkyl, oxo or combinations
thereof, [0072] cycloalkylalkyl having 4 to 12 C atoms, [0073]
cycloalkylalkyl having 4 to 12 C atoms, which is substituted one or
more times by C.sub.1-4 alkyl, halogen, halogenated C.sub.1-4
alkyl, or combinations thereof, [0074] aryl having 6 to 10 carbon
atoms, [0075] aryl having 6 to 10 carbon atoms which is substituted
one or more times by halogen, C.sub.1-4 alkyl, halogenated
C.sub.1-4 alkyl, hydroxy, C.sub.1-4-alkoxy, nitro, methylenedioxy,
ethylenedioxy, amino, C.sub.1-4 alkylamino,
di-C.sub.1-4-alkylamino, C.sub.1-4-hydroxyalkyl,
C.sub.1-4-hydroxyalkoxy, carboxy, cyano, C.sub.2-4, acyl,
C.sub.2-4-alkoxycarbonyl, C.sub.1-4-alkylthio,
C.sub.1-4-alkylsulphinyl, C.sub.1-4-alkylsulphonyl, phenoxy, or
combinations thereof, [0076] arylalkyl having 7 to 16 carbon atoms,
[0077] arylalkyl having 7 to 16 carbon atoms which is substituted
one or more times by halogen, C.sub.1-4 alkyl, halogenated
C.sub.1-4 alkyl, hydroxy, C.sub.1-4-alkoxy, nitro methylenedioxy,
ethylenedioxy, amino, C.sub.1-4 alkylamino, di-C.sub.1-alkylamino,
C.sub.1-4-hydroxyalkyl, C.sub.1-4-hydroxyalkoxy, carboxy, cyano,
C.sub.2-4, acyl, C.sub.2-4-alkoxycarbonyl, C.sub.1-4-alkylthio,
C.sub.1-4-alkylsulphinyl, C.sub.1-4-alkylsulphonyl, phenoxy, or
combinations thereof, [0078] heteroaryl having 5 to 10 ring atoms
in which at least 1 ring atom is a heteroatom, [0079] substituted
heteroaryl having 5 to 10 ring atoms, in which at least 1 ring atom
is a heteroatom, which is substituted one or more times by halogen,
aryl, C.sub.1-4-alkyl, C.sub.1-4-alkoxy, cyano, trifluoromethyl,
nitro, oxo, amino, C.sub.1-4-alkylamino, di-C.sub.1-4-alkylamino or
combinations thereof, [0080] heteroarylalkyl having 5 to 10 ring
atoms in which at least 1 ring atom is a heteroatom, or [0081]
substituted heteroarylalkyl having 5 to 10 ring atoms in which at
least 1 ring atom is a heteroatom and which is substituted one or
more times in the heteroaryl portion by halogen, aryl,
C.sub.1-4-alkyl, C.sub.1-4-alkoxy, cyano, trifluoromethyl, nitro,
oxo, amino, C.sub.1-4-alkylamino, di-C.sub.1-4-alkylamino or
combinations thereof and/or substituted in the alkyl portion by
halogen, oxo, cyano, or combinations thereof; [0082] and [0083]
pharmaceutically acceptable salts thereof, [0084] with the provisos
that [0085] (a) when R.sup.1'' is methyl, then R.sup.2'' is not
arylalkyl, heteroarylalkyl, methyl or 2-butyl, [0086] (b) when
R.sup.1'' is cyclopropyl, R.sup.2'' is not 4-methylbenzyl, [0087]
(c) when R.sup.1'' is ethyl, then R.sup.2'' is not ethyl, and
[0088] (d) when R.sup.1'' is cyclopropyl, then R.sup.2'' is not
cyclopropylmethyl.
[0089] In accordance with a further aspect of the invention, there
is provided a genus of formula III in which R.sup.1'' and R.sup.2''
are in accordance with the following subformulas:
[0090] IIIa R.sup.1'' is cyclopropyl; and [0091] R.sup.2'' is
cycloalkyl.
[0092] IIIb R.sup.1'' is methyl; and [0093] R.sup.2'' is
cycloalkyl.
[0094] IIIc R.sup.1'' is methyl, ethyl, cyclopropyl; and [0095]
R.sup.2'' is phenyl or substituted phenyl.
[0096] IIId R.sup.1'' is methyl, ethyl, cyclopropyl; and [0097]
R.sup.2'' is heteroaryl or substituted heteroaryl.
[0098] The compounds of the present invention are effective in
inhibiting, or modulating the activity of PDE4 in animals, e.g.,
mammals, especially humans. These compounds exhibit neurological
activity, especially where such activity affects cognition,
including long term memory. These compounds will also be effective
in treating diseases where decreased cAMP levels are involved. This
includes but is not limited to inflammatory diseases. These
compounds may also function as antidepressants, or be useful in
treating cognitive and negative symptoms of schizophrenia.
[0099] In accordance with the method aspect of the invention, there
is provided a method of treating a patient (e.g., a mammal such as
a human) suffering from a disease state (e.g., memory impairment,
inflammatory diseases, depression, etc.) involving decreased cAMP
levels and/or increased intracellular PDE4 levels, comprising
administering to the patient a compound according to formula
I.sup.a:
##STR00006##
wherein, [0100] R.sup.1a is H, [0101] alkyl having 1 to 5 carbon
atoms, which is unsubstituted or substituted one or more times by
halogen, hydroxy, or combinations thereof, and wherein a
--CH.sub.2-- group can be optionally replaced by --O--, --S--, or
--NH--, [0102] cycloalkyl having 3 to 6 carbon atoms, or [0103]
cycloalkylalkyl having 4 to 7 C atoms; [0104] R.sup.2a is alkyl
having 1 to 12 carbon atoms, which is unsubstituted or substituted
one or more times by halogen, hydroxy, cyano or combinations
thereof, wherein one or more --CH.sub.2-- groups is each
independently optionally replaced by --O--, --S--, or --NH--, and
wherein optionally one or more --CH.sub.2C.sub.2-- groups is
replaced in each case by --CH.dbd.CH-- or --C.ident.C-- [0105]
alkyl ether having 3 to 12 carbon atoms, [0106] cycloalkyl having 3
to 12 carbon atoms, which is unsubstituted or substituted one or
more times by halogen, C.sub.1-4 alkyl, halogenated C.sub.1-4
alkyl, C.sub.1-4 alkoxy, cyano or combinations thereof, [0107]
cycloalkylalkyl having 4 to 12 C atoms, which is unsubstituted or
substituted one or more times by C.sub.1-4 alkyl, halogenated
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, cyano, halogen, or combinations
thereof, [0108] aryl having 6 to 14 carbon atoms, which is
unsubstituted or substituted one or more times by halogen,
C.sub.1-4 alkyl, halogenated C.sub.1-4 alkyl, hydroxy,
C.sub.1-4-alkoxy, halogenated C.sub.1-4 alkoxy, nitro,
methylenedioxy, ethylenedioxy, amino, C.sub.1-4 alkylamino,
di-C.sub.1-4-alkylamino, C.sub.1-4-hydroxyalkyl,
C.sub.1-4-hydroxyalkoxy, carboxy, cyano, hydroxamic acid,
carboxamide, C.sub.2-4-acyl, C.sub.2-4-alkoxycarbonyl,
C.sub.1-4-alkylthio, C.sub.1-4-alkylsulphinyl,
C.sub.1-4-alkylsulphonyl, phenoxy, or combinations thereof,
arylalkyl having 7 to 16 carbon atoms, which is unsubstituted or
substituted one or more times by halogen, C.sub.1-4 alkyl,
halogenated C.sub.1-4 alkyl, hydroxy, C.sub.1-4-alkoxy, halogenated
C.sub.1-4 alkoxy, nitro, methylenedioxy, ethylenedioxy, amino,
C.sub.1-4 alkylamino, di-C.sub.14-alkylamino,
C.sub.1-4-hydroxyakyl, C.sub.1-4-hydroxyalkoxy, carboxy, cyano,
hydroxamic acid, carboxamide, C.sub.2-4-acyl,
C.sub.2-4-alkoxycarbonyl, C.sub.1-4-alkylthio,
C.sub.1-4-alkylsulphinyl, C.sub.1-4-alkylsulphonyl, phenoxy, or
combinations thereof, [0109] heteroaryl having 5 to 10 ring atoms
in which at least 1 ring atom is a heteroatom, which is
unsubstituted or substituted one or more times by halogen, aryl,
C.sub.1-4 alkyl, halogenated C.sub.1-4 alkyl, hydroxy,
C.sub.1-4-alkoxy, halogenated C.sub.1-4 alkoxy, cyano,
trifluoromethyl, nitro, oxo, amino, C.sub.1-4-alkylamino,
di-C.sub.1-4-alkylamino, carboxy, alkoxycarbonyl, hydroxamic acid,
carboxamide, C.sub.1-4-alkylthio, C.sub.1-4-alkylsulphinyl,
C.sub.1-4-alkylsulphonyl, or combinations thereof, [0110]
heteroarylalkyl wherein the heteroaryl portion has 5 to 10 ring
atoms in which at least 1 ring atom is a heteroatom and the alkyl
portion has 1 to 3 carbon atoms, the heteroaryl portion is
unsubstituted or is substituted one or more times in by halogen,
aryl, C.sub.1-4 alkyl, halogenated C.sub.1-4 alkyl, hydroxy,
C.sub.1-4-alkoxy, halogenated C.sub.1-4-alkoxy, cyano,
trifluoromethyl, nitro, oxo, amino, C.sub.1-4-alkylamino,
di-C.sub.1-4-alkylamino, carboxy, alkoxycarbonyl, hydroxamic acid,
carboxamide, C.sub.1-4-alkylthio, C.sub.1-4-alkylsulphinyl,
C.sub.1-4-alkylsulphonyl, or combinations thereof, [0111]
heterocycle having 5 to 10 ring atoms in which at least 1 ring atom
is a heteroatom, which is unsubstituted or is substituted one or
more times in by halogen, aryl, C.sub.1-4 alkyl, halogenated
C.sub.1-4 alkyl, hydroxy, C.sub.1-4-alkoxy, halogenated C.sub.1-4
alkoxy, cyano, trifluoromethyl, nitro, oxo, amino,
C.sub.1-4-alkylamino, di-C.sub.1-4-alkylamino, carboxy,
alkoxycarbonyl, or combinations thereof (e.g., piperidinyl,
imidazolinyl, imidazolidinyl, pyrrolinyl, pyrrolidinyl,
morpholinyl, piperazinyl, and indolinyl), [0112] heterocycle-alkyl
wherein the heterocycle portion has 5 to 10 ring atoms in which at
least 1 ring atom is a heteroatom and the alkyl portion has 1 to 3
carbon atoms, the heterocycle portion is nonarmoatic and is
unsubstituted or is substituted one or more times in the by
halogen, aryl, C.sub.1-4 alkyl, halogenated C.sub.1-4 alkyl,
hydroxy, C.sub.1-4-alkoxy, halogenated C.sub.1-4 alkoxy, cyano,
trifluoromethyl, nitro, oxo, amino, C.sub.1-4-alkylamino,
di-C.sub.14-alkylamino, carboxy, alkoxycarbonyl, or combinations
thereof (e.g., piperidinyl-ethyl and pyrrolinyl-methyl), or [0113]
carbocycle which is nonaromatic, monocyclic or bicyclic, group
having 5 to 14 carbon atoms, which is unsubstituted or is
substituted one or more times in the by halogen, C.sub.1-4 alkyl,
halogenated C.sub.1-4 alkyl, hydroxy, C.sub.1-4-alkoxy, halogenated
C.sub.1-4 alkoxy, nitro, methylenedioxy, ethylenedioxy, amino,
C.sub.1-4 alkylamino, di-C.sub.1-4-alkylamino,
C.sub.1-4-hydroxyalkyl, C.sub.1-4-hydroxyalkoxy, carboxy, cyano,
hydroxamic acid, carboxamide, C.sub.2-4-acyl,
C.sub.2-4-alkoxycarbonyl, C.sub.1-4-alkylthio,
C.sub.1-4-alkylsulphinyl, C.sub.1-4-alkylsulphonyl, phenoxy, or
combinations thereof; [0114] and [0115] pharmaceutically acceptable
salts thereof, [0116] with the provisos that: [0117] (a) when
R.sup.1a is methyl, then R.sup.2a is not arylalkyl,
heteroarylalkyl, 2-(1,2,3,4-tetrahydro)quinolinyl-methyl, methyl or
2-butyl; [0118] (b) when R.sup.1a is cyclopropyl, R.sup.2a is not
4-methylbenzyl; [0119] (c) when R.sup.1a is ethyl, then R.sup.2a is
not ethyl, 3-aminobenzyl, 2-thienylmethyl, 3-thienylmethyl, or
2-pyridylmethyl; [0120] (d) when R.sup.1a is cyclopropyl, then
R.sup.2a is not cyclopropylmethyl; [0121] (e) when R.sup.1a is H,
then R.sup.2a is not methyl, ethyl, benzyl, 4-methylbenzyl, or
substituted tetrahydrofuranyl; [0122] (f) when R.sup.1a is
methoxyethyl then lea is not benzyl, 3-dimethylaminobenzyl, or
3-thienylmethyl; [0123] (g) when R.sup.1a is iso-butyl, then
R.sup.2a is not benzyl; and [0124] (h) when R.sup.1a is n-butyl,
then R.sup.2a is not n-butyl.
[0125] In accordance with the method aspect of the invention, there
is provided a method of treating a patient (e.g., a mammal such as
a human) suffering from a disease state (e.g., memory impairment)
involving decreased cAMP levels and/or increased intracellular PDE4
levels, comprising administering to the patient a compound
according to formula I.sup.b:
##STR00007##
wherein, [0126] R.sup.1b is H, [0127] alkyl having 1 to 5 carbon
atoms, which is unsubstituted or substituted one or more times by
halogen, hydroxy, or combinations thereof, and wherein a
--CH.sub.2-- group can be optionally replaced by --O--, --S--, or
--NH--, [0128] cycloalkyl having 3 to 6 carbon atoms, or [0129]
cycloalkylalkyl having 4 to 7 C atoms; [0130] R.sup.2b is alkyl
having 1 to 12 carbon atoms, which is unsubstituted or substituted
one or more times by halogen, hydroxy, cyano or combinations
thereof, wherein one or more --CH.sub.2-- groups is each
independently optionally replaced by --O--, --S--, or --NH--, and
wherein optionally one or more --CH.sub.2CH.sub.2-- groups is
replaced in each case by --CH.dbd.CH-- or --C.ident.C-- [0131]
alkyl ether having 3 to 12 carbon atoms, [0132] cycloalkyl having 3
to 12 carbon atoms, which is unsubstituted or substituted one or
more times by halogen, C.sub.1-4 alkyl, halogenated C.sub.1-4
alkyl, C.sub.1-4 alkoxy, cyano or combinations thereof, [0133]
cycloalkylalkyl having 4 to 12 C atoms, which is unsubstituted or
substituted one or more times by C.sub.1-4 alkyl, halogenated
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, cyano, halogen, or combinations
thereof, [0134] aryl having 6 to 14 carbon atoms, which is
unsubstituted or substituted one or more times by halogen,
C.sub.1-4 alkyl, halogenated C.sub.1-4 alkyl, hydroxy,
C.sub.1-4-alkoxy, halogenated C.sub.1-4 alkoxy, nitro,
methylenedioxy, ethylenedioxy, amino, C.sub.1-4 alkylamino,
di-C.sub.1-4-alkylamino, C.sub.1-4-hydroxyalkyl,
C.sub.1-4-hydroxyalkoxy carboxy, cyano, hydroxamic acid,
carboxamide, C.sub.2-4-acyl, C.sub.2-4-alkoxycarbonyl,
C.sub.1-4-alkylthio, C.sub.1-4-alkylsulphinyl,
C.sub.1-4-alkylsulphonyl phenoxy, or combinations thereof, [0135]
arylalkyl having 7 to 16 carbon atoms, which is unsubstituted or
substituted one or more times by halogen, C.sub.1-4 alkyl,
halogenated C.sub.1-4 alkyl, hydroxy, C.sub.1-4-alkoxy, halogenated
C.sub.1-4 alkoxy, nitro, methylenedioxy, ethylenedioxy, amino,
C.sub.1-4 alkylamino, di-C.sub.1-4-alkylamino,
C.sub.1-4-hydroxyalkyl, C.sub.1-4-hydroxyalkoxy, carboxy, cyano,
hydroxamic acid, carboxamide, C.sub.2-4-acyl,
C.sub.2-4-alkoxycarbonyl, C.sub.1-4-alkylthio,
C.sub.1-4-alkylsulphinyl, C.sub.1-4-alkylsulphonyl, phenoxy, or
combinations thereof, [0136] heteroaryl having 5 to 10 ring atoms
in which at least 1 ring atom is a heteroatom, which is
unsubstituted or substituted one or more times by halogen, aryl,
C.sub.1-4 alkyl, halogenated C.sub.1-4 alkyl, hydroxy,
C.sub.1-4-alkoxy, halogenated C.sub.1-4 alkoxy, cyano,
trifluoromethyl, nitro, oxo, amino, C.sub.1-4alkylamino,
di-C.sub.1-4-alkylamino, carboxy, alkoxycarbonyl, hydroxamic acid,
carboxamide, C.sub.1-4-alkylthio C.sub.1-4-alkylsulphinyl,
C.sub.1-4-alkylsulphonyl, or combinations thereof, [0137]
heteroarylalkyl wherein the heteroaryl portion has 5 to 10 ring
atoms in which at least 1 ring atom is a heteroatom and the alkyl
portion has 1 to 3 carbon atoms, the heteroaryl portion is
unsubstituted or is substituted one or more times in by halogen,
aryl, C.sub.1-4 alkyl, halogenated C.sub.1-4 alkyl, hydroxy,
C.sub.1-4-alkoxy, halogenated C.sub.1-4 alkoxy, cyano,
trifluoromethyl, nitro, oxo, amino, C.sub.1-4-alkylamino,
di-C.sub.1-4-alkylamino, carboxy, alkoxycarbonyl, hydroxamic acid,
carboxamide, C.sub.1-4-alkylthio, C.sub.1-4-alkylsulphinyl,
C.sub.1-4-alkylsulphonyl, or combinations thereof, [0138]
heterocycle having 5 to 10 ring atoms in which at least 1 ring atom
is a heteroatom, which is unsubstituted or is substituted one or
more times in the by halogen, aryl, C.sub.1-4 alkyl, halogenated
C.sub.1-4 alkyl, hydroxy, C.sub.1-4alkoxy, halogenated C.sub.1-4
alkoxy, cyano, trifluormethyl, nitro, oxo, amino,
C.sub.1-4-alkylamino, di-C.sub.1-4-alkylamino, carboxy,
alkoxycarbonyl, or combinations thereof (e.g., piperidinyl,
imidazolinyl, imidazolidinyl, pyrrolinyl, pyrrolidinyl,
morpholinyl, piperazinyl, and indolinyl), [0139] heterocycle-alkyl
wherein the heterocycle portion has 5 to 10 ring atoms in which at
least 1 ring atom is a heteroatom and the alkyl portion has 1 to 3
carbon atoms, the heterocycle portion is nonarmoatic and is
unsubstituted or is substituted one or more times in the by
halogen, aryl, C.sub.1-4 alkyl, halogenated C.sub.1-4 alkyl,
hydroxy, C.sub.1-4-alkoxy, halogenated C.sub.1-4 alkoxy, cyano,
trifluoromethyl, nitro, oxo, amino, C.sub.1-4-alkylamino,
di-C.sub.1-4-alkylamino, carboxy, alkoxycarbonyl, or combinations
thereof (e.g., piperidinyl-ethyl and pyrrolinyl-methyl), or [0140]
carbocycle which is nonaromatic, monocyclic or bicyclic, group
having 5 to 14 carbon atoms, which is unsubstituted or is
substituted one or more times in the by halogen, C.sub.1-4 alkyl,
halogenated C.sub.1-4 alkyl, hydroxy, C.sub.1-4-alkoxy, halogenated
C.sub.1-4 alkoxy, nitro, methylenedioxy, ethylenedioxy, amino,
C.sub.1-4 alkylamino, di-C.sub.1-4-alkylamino,
C.sub.1-4-hydroxyalkyl, C.sub.1-4-hydroxyalkoxy, carboxy, cyano,
hydroxamic acid, carboxamide, C.sub.2-4-acyl,
C.sub.2-4-alkoxycarbonyl, C.sub.1-4-alkylthio, C.sub.1-4
alkylsulphinyl, C.sub.1-4-alkylsulphonyl, phenoxy, or combinations
thereof; [0141] and [0142] pharmaceutically acceptable salts
thereof, [0143] with the provisos that when R.sup.1b is methyl,
then R.sup.2b is not arylalkyl, methyl or 2-butyl; and when
R.sup.1b is H, then R.sup.2b is not benzyl.
[0144] In accordance with a further method aspect of the invention,
there is provided a method of treating a patient (e.g., a mammal
such as a human) suffering from a disease state (e.g., memory
impairment) involving decreased cAMP levels and/or increased
intracellular PDE4 levels, comprising administering to the patient
a compound according to formula I.sup.c:
##STR00008##
wherein, [0145] R.sup.1c is H, [0146] alkyl having 1 to 5 carbon
atoms, which is unsubstituted or substituted one or more times by
halogen, hydroxy, or combinations thereof, and wherein a
--CH.sub.2-- group can be optionally replaced by --O--, --S--, or
--NH--, [0147] cycloalkyl having 3 to 6 carbon atoms, or [0148]
cycloalkylalkyl having 4 to 7 C atoms; [0149] R.sup.2c is alkyl
having 1 to 12 carbon atoms, which is unsubstituted or substituted
one or more times by halogen, hydroxy, cyano or combinations
thereof, wherein one or more --CH.sub.2-- groups is each
independently optionally replaced by --O--, --S--, or --NH--, and
wherein optionally one or more --CH.sub.2CH.sub.2-- groups is
replaced in each case by --CH.dbd.CH-- or --C.ident.C-- [0150]
alkyl ether having 3 to 12 carbon atoms, [0151] cycloalkyl having 3
to 12 carbon atoms, which is unsubstituted or substituted one or
more times by halogen, C.sub.1-4 alkyl, halogenated C.sub.1-4
alkyl, C.sub.1-4 alkoxy, cyano or combinations thereof, [0152]
cycloalkylalkyl having 4 to 12 C atoms, which is unsubstituted or
substituted one or more times by C.sub.1-4 alkyl, halogenated
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, cyano, halogen, or combinations
thereof, [0153] aryl having 6 to 14 carbon atoms, which is
unsubstituted or substituted one or more times by halogen,
C.sub.1-4 alkyl, halogenated C.sub.1-4 alkyl, hydroxy,
C.sub.1-4-alkoxy, halogenated C.sub.1-4 alkoxy, nitro,
methylenedioxy, ethylenedioxy, amino, C.sub.1-4 alkylamino,
di-C.sub.1-4-alkylamino, C.sub.1-4-hydroxyalkyl,
C.sub.1-4-hydroxyalkoxy, carboxy, cyano, hydroxamic acid,
carboxamide, C.sub.2-24-acyl, C.sub.2-4-alkoxycarbonyl,
C.sub.1-4-alkylthio, C.sub.1-4-alkylsulphinyl,
C.sub.1-4-alkylsulphonyl, phenoxy, or combinations thereof, [0154]
arylalkyl having 7 to 16 carbon atoms, which is unsubstituted or
substituted one or more times by halogen, C.sub.1-4 alkyl,
halogenated C.sub.1-4 alkyl, hydroxy, C.sub.1-4-alkoxy, halogenated
C.sub.1-4 alkoxy, nitro, methylenedioxy, ethylenedioxy, amino,
C.sub.1-4 alkylamino, di-C.sub.1-4-alkylamino,
C.sub.1-4-hydroxyalkyl, C.sub.1-4-hydroxyalkoxy, carboxy, cyano,
hydroxamic acid, carboxamide, C.sub.2-4-acyl,
C.sub.2-4-alkoxycarbonyl, C.sub.1-4alkylthio,
C.sub.1-4-alkylsulphinyl, C.sub.1-4alkylsulphonyl, phenoxy, or
combinations thereof, [0155] heteroaryl having 5 to 10 ring atoms
in which at least 1 ring atom is a heteroatom, which is
unsubstituted or substituted one or more times by halogen, aryl,
C.sub.1-4 alkyl halogenated C.sub.1-4 alkyl, hydroxy,
C.sub.1-4-alkoxy, halogenated C.sub.1-4 alkoxy, cyano,
trifluoromethyl, nitro, oxo, amino, C.sub.1-4-alkylamino,
di-C.sub.1-4-alkylamino, carboxy, alkoxycarbonyl, hydroxamic acid,
carboxamide, C.sub.1-4-alkylthio, C.sub.1-4-alkylsulphinyl,
C.sub.1-4-alkylsulphonyl, or combinations thereof, [0156]
heteroarylalkyl wherein the heteroaryl portion has 5 to 10 ring
atoms in which at least 1 ring atom is a heteroatom and the alkyl
portion has 1 to 3 carbon atoms, the heteroaryl portion is
unsubstituted or is substituted one or more times in by halogen,
aryl, C.sub.1-4 alkyl, halogenated C.sub.1-4 alkyl, hydroxy,
C.sub.1-4-alkoxy, halogenated C.sub.1-4 alkoxy, cyano,
trifluoromethyl, nitro, oxo, amino, C.sub.1-4-alkylamino,
di-C.sub.1-4-alkylamino, carboxy, alkoxycarbonyl, hydroxamic acid,
carboxamide, C.sub.1-4-alkylthio, C.sub.1-4-alkylsulphinyl,
C.sub.1-4-alkylsulphonyl, or combinations thereof, [0157]
heterocycle having 5 to 10 ring atoms in which at least 1 ring atom
is a heteroatom, which is unsubstituted or is substituted one or
more times in the by halogen, aryl, C.sub.1-4 alkyl, halogenated
C.sub.1-4 alkyl, hydroxy, C.sub.1-4-alkoxy, halogenated C.sub.1-4
alkoxy, cyano, trifluoromethyl, nitro, oxo, amino,
C.sub.1-4-alkylamino, di-C.sub.1-4-alkylamino, carboxy,
alkoxycarbonyl, or combinations thereof (e.g., piperidinyl,
imidazolinyl, imidazolidinyl, pyrrolinyl, pyrrolidinyl,
morpholinyl, piperazinyl, and indolinyl), [0158] heterocycle-alkyl
wherein the heterocycle portion has 5 to 10 ring atoms in which at
least 1 ring atom is a heteroatom and the alkyl portion has 1 to 3
carbon atoms, the heterocycle portion is nonaromatic and is
unsubstituted or is substituted one or more times in the by
halogen, aryl, C.sub.1-4 alkyl, halogenated C.sub.1-4 alkyl,
hydroxy, C.sub.1-4-alkoxy, halogenated C.sub.1-4 alkoxy, cyano,
trifluoromethyl, nitro, oxo, amino, C.sub.1-4-alkylamino,
di-C.sub.1-4-alkylamino, carboxy, alkoxycarbonyl, or combinations
thereof (e.g., piperidinyl-ethyl and pyrrolinyl-methyl), or [0159]
carbocycle which is nonaromatic, monocyclic or bicyclic, group
having 5 to 14 carbon atoms, which is unsubstituted or is
substituted one or more times in the by halogen, di-C.sub.1-4
alkyl, halogenated C.sub.1-4 alkyl, hydroxy, C.sub.1-4-alkoxy,
halogenated C.sub.1-4 alkoxy, nitro, methylenedioxy, ethylenedioxy,
amino, C.sub.1-4 alkylamino, di-C.sub.1-4-alkylamino,
C.sub.1-4-hydroxyalkyl, C.sub.1-4-hydroxyalkoxy, carboxy, cyano,
hydroxamic acid, carboxamide, C.sub.2-4-acyl,
C.sub.2-4-alkoxycarbonyl, C.sub.1-4-alkylthio, C.sub.1-4
alkylsulphinyl, C.sub.1-4-alkylsulphonyl, phenoxy, or combinations
thereof; [0160] and [0161] pharmaceutically acceptable salts
thereof, [0162] with the proviso that said compound is not
6-methylamino-9-(2-fluorobenzyl-2-trifluoromethylpurine.
[0163] In accordance with a further method aspect of the invention,
there is provided a method of treating a patient (e.g., a mammal
such as a human) suffering from a disease state (e.g., memory
impairment) involving decreased cAMP levels and/or increased
intracellular PDE4 levels, comprising administering to the patient
a compound according to formula II
##STR00009##
wherein [0164] R.sup.1' is methyl, ethyl or cyclopropyl; and [0165]
R.sup.2' is cycloalkyl having 3 to 12 carbon atoms, which is
unsubstituted or substituted one or more times by halogen,
C.sub.1-4 alkyl, halogenated C.sub.1-4 alkyl C.sub.1-4 alkoxy,
cyano or combinations thereof, [0166] aryl having 6 to 14 carbon
atoms, which is unsubstituted or substituted one or more times by
halogen, C.sub.1-4 alkyl, halogenated 1-4 alkyl, hydroxy,
C.sub.1-4-alkoxy, halogenated C.sub.1-4-alkoxy, nitro,
methylenedioxy, ethylenedioxy, amino, C.sub.1-4 alkylamino,
di-C.sub.1-4-alkylamino, C.sub.1-4-hydroxyalkyl,
C.sub.1-4-hydroxyalkoxy, carboxy, cyano, hydroxamic acid,
carboxamide, C.sub.2-4-acyl, C.sub.2-4-alkoxycarbonyl,
C.sub.1-4-alkylthio, C.sub.1-4-alkylsulphinyl,
C.sub.1-4alkylsulphonyl, phenoxy, or combinations thereof, [0167]
heteroaryl having 5 to 10 ring atoms in which at least 1 ring atom
is a heteroatom, which is unsubstituted or substituted one or more
times by halogen, aryl C.sub.1-4 alkyl, halogenated C.sub.1-4
alkyl, hydroxy, C.sub.1-4-alkoxy, halogenated C.sub.1-4 alkoxy,
cyano, trifluoromethyl, nitro, oxo, amino, C.sub.1-4-alkylamino,
di-C.sub.1-4-alkylamino, carboxy, alkoxycarbonyl, hydroxamic acid,
carboxamide, C.sub.1-4-alkylthio, C.sub.1-4-alkylsulphinyl,
C.sub.1-4-alkylsulphonyl, or combinations thereof, [0168]
heterocycle having 5 to 10 ring atoms in which at least 1 ring atom
is a heteroatom, which is unsubstituted or is substituted one or
more times in the by halogen, aryl, C.sub.1-4 alkyl, halogenated
C.sub.1-4 alkyl, hydroxy, C.sub.1-4-alkoxy, halogenated C.sub.1-4
alkoxy, cyano, trifluoromethyl, nitro, oxo, amino,
C.sub.1-4-alkylamino, di-C.sub.1-4-alkylamino, carboxy,
alkoxycarbonyl, or combinations thereof (e.g., piperidinyl,
imidazolinyl, imidazolidinyl, pyrrolinyl, pyrrolidinyl,
morpholinyl, piperazinyl, and indolinyl), or [0169] carbocycle
which is nonaromatic, monocyclic or bicyclic, group having 5 to 14
carbon atoms, which is unsubstituted or is substituted one or more
times in the by halogen, C.sub.1-4 alkyl, halogenated C.sub.1-4
alkyl, hydroxy, C.sub.1-4-alkoxy, halogenated C.sub.1-4 alkoxy,
nitro, methylenedioxy, ethylenedioxy, amino, C.sub.1-4 alkylamino,
di-C.sub.1-4-alkylamino, C.sub.1-4-hydroxyalkyl,
C.sub.1-4-hydroxyalkoxy, carboxy, cyano, hydroxamic acid,
carboxamide, C.sub.2-4-acyl, C.sub.2-4-alkoxycarbonyl,
C.sub.1-4-alkylthio, C.sub.1-4-alkylsulphinyl,
C.sub.1-4-alkylsulphonyl, phenoxy, or combinations thereof; [0170]
and [0171] pharmaceutically acceptable salts thereof.
[0172] In accordance with a further method aspect of the invention,
there is provided a method of treating a patient (e.g., a mammal
such as a human) suffering from a disease state (e.g., memory
impairment) involving decreased cAMP levels and/or increased
intracellular PDE4 levels, comprising administering to the patient
a compound according to formula III.sup.a:
##STR00010##
wherein, [0173] R.sup.1''' is H, [0174] alkyl having 1 to 5 carbon
atoms, which is unsubstituted or is substituted one or more times
by halogen, hydroxy, oxo, cyano or combinations thereof, [0175]
cycloalkyl having 3 to 6 carbon atoms, which is unsubstituted or is
substituted one or more times by halogen, alkyl, oxo or
combinations thereof, or [0176] cycloalkylalkyl having 4 to 7 C
atoms, which is unsubstituted or is substituted one or more times
by C.sub.1-4 alkyl, halogen, halogenated C.sub.1-4 alkyl, or
combinations thereof; and [0177] R.sup.2''' is alkyl having 1 to 12
carbon atoms, which is unsubstituted or which is substituted one or
more times by halogen, hydroxy, oxo, cyano or combinations thereof,
[0178] alkyl ether having 3 to 12 carbon atoms, [0179] cycloalkyl
having 3 to 12 carbon atoms, which is unsubstituted or which is
substituted one or more times by halogen, C.sub.1-4 alkyl, oxo or
combinations thereof, [0180] cycloalkylalkyl having 4 to 12 C
atoms, which is unsubstituted or is substituted one or more times
by C.sub.1-4 alkyl, halogen, halogenated C.sub.1-4 alkyl, or
combinations thereof, [0181] aryl having 6 to 10 carbon atoms,
which is unsubstituted or is substituted one or more times by
halogen, C.sub.1-4 alkyl, halogenated C.sub.1-4 alkyl, hydroxy,
C.sub.1-4-alkoxy, nitro, methylenedioxy, ethylenedioxy, amino,
C.sub.1-4 alkylamino, di-C.sub.1-4-alkylamino,
C.sub.1-4-hydroxyalkyl, C.sub.1-4-hydoxyalkoxy, carboxy, cyano,
C.sub.2-4-acyl, C.sub.2-4-alkoxycarbonyl, C.sub.1-4-alkylthio
C.sub.1-4-alkylsulphinyl, C.sub.1-4alkylsulphonyl, phenoxy, or
combinations thereof, [0182] arylalkyl having 7 to 16 carbon atoms,
which is unsubstituted or is substituted one or more times by
halogen, C.sub.1-4 alkyl, halogenated C.sub.1-4 alkyl, hydroxy,
C.sub.1-4-alkoxy, nitro, methylenedioxy, ethylenedioxy, amino,
C.sub.1-4 alkylamino, di-C.sub.1-4-alkylamino,
C.sub.1-4-hydroxyalkyl, C.sub.1-4-hydroxyalkoxy, carboxy, cyano,
C.sub.2-4-acyl, C.sub.2-4alkoxycarbonyl, C.sub.1-4-alkylthio,
C.sub.1-4alkylsulphinyl, C.sub.1-4-alkylsulphonyl, phenoxy, or
combinations thereof, [0183] heteroaryl having 5 to 10 ring atoms
in which at least 1 ring atom is a heteroatom, substituted
heteroaryl having 5 to 10 ring atoms, in which at least 1 ring atom
is a heteroatom, which is substituted one or more times by halogen,
aryl C.sub.1-4-alkyl, C.sub.1-4-alkoxy, cyano, trifluoromethyl,
nitro, oxo, amino, C.sub.1-4-alkylamino, di-C.sub.1-4-alkylamino or
combinations thereof, or [0184] heteroarylalkyl having 5 to 10 ring
atoms in which at least 1 ring atom is a heteroatom, which is
unsubstituted or is substituted one or more times in the heteroaryl
portion by halogen, aryl, C.sub.1-4-alkyl, C.sub.1-4-alkoxy, cyano,
trifluoromethyl, nitro, oxo, amino, C.sub.1-4-alkylamino,
di-C.sub.1-4-alkylamino or combinations thereof and/or substituted
in the alkyl portion by halogen, oxo, cyano, or combinations
thereof; and [0185] pharmaceutically acceptable salts thereof,
[0186] with the proviso that [0187] (a) when R.sup.1''' is methyl,
then R.sup.2''' is not arylalkyl, heteroarylalkyl, methyl or
2-butyl. [0188] In formula III.sup.a, R.sup.1''' is preferably
methyl, ethyl or cyclopropyl.
[0189] Assays for determining PDE inhibiting activity as well as
selectivity of PDE 4 inhibiting activity and selectivity of
inhibiting PDE 4 isoenzymes are known within the art. See, e.g.,
U.S. Pat. No. 6,136,821, the disclosure of which is incorporated
herein by reference.
[0190] Halogen herein refers to F, Cl, Br, and I. Preferred
halogens are F and Cl.
[0191] Alkyl, as a group or substituent per se or as part of a
group or substituent (e.g., alkylamino, trialkylsilyloxy,
aminoalkyl, hydroxyalkyl), means a straight-chain or branched-chain
aliphatic hydrocarbon radical having 1 to 12 carbon atoms,
preferably 1 to 8 carbon atoms, especially 1 to 4 carbon atoms.
[0192] Alkyl radicals for R.sup.1 have up to 5 carbon atoms,
preferably 1 to 4 carbon atoms, especially 1 to 3 carbon atoms.
Suitable alkyl groups for R.sup.1 include methyl, ethyl, propyl,
isopropyl, butyl, isopropyl and pentyl. Other examples of suitable
alkyl groups for R.sup.1 include 1-, 2- or 3-methylbutyl, 1,1-,
1,2- or 2,2-dimethylpropyl and 1-ethylpropyl.
[0193] Alkyl radicals for R.sup.2 have up to 12 carbon atoms,
preferably 3 to 8 carbon atoms, especially 3 to 6 carbon atoms.
Suitable alkyl groups for R.sup.2 include those listed above for
R.sup.1 as well as hexyl, heptyl, octyl, nonyl, decyl, undecyl,
dodecyl, 1-, 2-, 3- or 4-methylpentyl, tert-butyl, 1,1-, 1,2-,
1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl 1- or 2-ethylbutyl,
ethylmethylpropyl, trimethylpropyl, methylhexyl, dimethylpentyl,
ethylpentyl, ethylmethylbutyl, dimethylbutyl, and the like.
[0194] Substituted alkyl groups are alkyl groups as described above
which are substituted in one or more positions by, for example,
halogens, oxo, hydroxy, C.sub.1-4-alkoxy, halogenated
C.sub.1-4-alkoxy, and/or cyano. Halogens are preferred
substituents, especially F and Cl.
[0195] Alkoxy groups means alkyl-O-- groups in which the alkyl
portion is in accordance with the previous discussion. Suitable
alkoxy groups are methoxy, ethoxy, propoxy and butoxy, pentoxy,
hexoxy, heptoxy, octoxy and trifluoromethoxy. Preferred alkoxy
groups are methoxy and ethoxy. Similarly, alkoxycarbonyl means
alkyl --O--CO-- in which the alkyl portion is in accordance with
the previous discussion. Examples include methoxycarbonyl,
ethoxycarbonyl, propoxycarbonyl, and tert-butoxycarbonyl.
[0196] Alkenyl refers to straight-chain or branched-chain aliphatic
radicals containing 2 to 12 carbon atoms in which one or more
--CH.sub.2--CH.sub.2-- structures are each replaced by
--CH.dbd.CH--. Suitable alkenyl groups are ethenyl, 1-propenyl,
2-methylethenyl, 1-butene, 2-butene, 1-pentenyl, and
2-pentenyl.
[0197] Alkynyl refers to straight-chain or branched-chain aliphatic
radicals containing 2 to 12 carbon atoms in which one or more
--CH.sub.2--CH.sub.2-- structures are each replaced by
--C.ident.C--. Suitable alkynyl groups are ethynyl, propynyl,
1-butynyl, and 2-butynyl.
[0198] Cycloalkyl means a monocyclic, bicyclic or tricyclic
nonaromatic saturated hydrocarbon radical. Cycloalkyl radicals for
R.sup.1 have 3 to 6 carbon atoms, preferably 3 to 5 carbon atoms,
especially 3 carbon atoms. Suitable cycloalkyl groups for R.sup.1
include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
Cycloalkyl radicals for R.sup.2 have 3 to 12 carbon atoms,
preferably 3 to 10 carbon atoms, especially 4 to 8 carbon atoms.
Suitable cycloakyl groups for R.sup.2 include those listed above
for R.sup.1 as well as cycloheptyl, cyclooctyl, cyclononyl,
norbornyl, 1-decalin, adamant-1-yl, and adamant-2-yl. Other
suitable cycloalkyl groups for R.sup.2 include spiro[2,4]heptyl,
spiro[2.5]octyl, bicylo[5.1.0]octyl, bicyclo[2.2.0]hexyl,
spiro[3.3]heptyl, and bicyclo[4.2.0]octyl.
[0199] The cycloalkyl group can be substituted. For example, it can
be substituted by halogens, C.sub.1-4-alkyls, C.sub.1-4-halogenated
alkyls, C.sub.1-4-alkoxy and/or cyano.
[0200] Cycloalkylalkyl refers to cycloalkyl-alkyl radicals in which
the cycloalkyl and alkyl portions are in accordance with previous
discussions. Suitable examples include cyclopropylmethyl and
cyclopentylmethyl.
[0201] Alkyl ethers refer to C.sub.3 to C.sub.1-4 alkoxyalkyl
radicals. Suitable alkyl ether groups include methoxyethyl,
ethoxyethyl, and methoxypropyl.
[0202] Aryl, as a group or substituent per se or as part of a group
or substituent, refers to an aromatic carbocyclic radical
containing 6 to 14 carbon atoms, preferably 6 to 12 carbon atoms,
especially 6 to 10 carbon atoms, Suitable aryl groups include
phenyl, naphthyl and biphenyl. Substituted aryl groups include the
above-described aryl groups which are substituted one or more times
by, for example, by halogen, C.sub.1-4-alkyl, C.sub.1-4-halogenated
alkyl, hydroxy, C.sub.1-4-alkoxy, C.sub.1-4-halogenated alkoxy,
nitro, methylenedioxy, ethylenedioxy, amino, C.sub.1-4-alkylamino,
di-C.sub.1-4-alkylamino, C.sub.1-4-hydroxyalkyl,
C.sub.1-4-hydroxyalkoxy, carboxy, cyano, C.sub.2-4-acyl,
C.sub.2-4-alkoxycarbonyl, C.sub.1-4-alkylthio,
C.sub.1-4-alkylsulphinyl, C.sub.1-4-alkylsulphonyl and phenoxy.
[0203] Arylalkyl refers to an aryl-alkyl-radical in which the aryl
and alkyl portions are in accordance with the previous
descriptions. Preferably, the aryl portion has 6 to 10 carbon atoms
and the alkyl portion, which is straight-chained or branched, has 1
to 6 carbon atoms, preferably 1 to 3 carbon atoms. The aryl portion
can be substituted by the substituents described above for aryl
groups and the alkyl portion can be substituted by oxo, halogens,
cyano or combinations thereof. Suitable examples include benzyl,
1-phenethyl, 2-phenethyl, phenpropyl, fluorobenzyl, chlorobenzyl,
methoxybenzyl, methylbenzyl and cyanobenzyl.
[0204] Heteroaryl refers to an aromatic heterocyclic group having
one or two rings and a total number of 5 to 10 ring atoms wherein
at least one of the ring atoms is a heteroatom. Preferably, the
heteroaryl group contains 1 to 3, especially 1 or 2, hetero-ring
atoms which are selected from N, O and S. Suitable heteroaryl
groups include furyl, thienyl, pyrrolyl pyrazolyl, imidazolyl,
triazolyl, tetrazolyl, isoxazolyl, oxazolyl, thiazolyl,
isothiazolyl, oxadiazolyl, oxatriazolyl, thiadiazolyl, pyridyl,
pyridazinyl pyridinyl, benzofuranyl, isobenzofuranyl,
thionaphthenyl, isothionaphthenyl, indolyl, isoindolyl, indazolyl,
benzisoxazolyl, benzoxazolyl, benzthiazolyl, benzisothiazolyl,
purinyl, benzopyranyl, quinolinyl, isoquinolinyl, cinnolinyl,
quinazolinyl, naphthyridinyl, and benzoxazinyl, e.g., 2-thienyl,
3-thienyl, 2-, 3- or 4-pyridyl, 2-, 3-, 4-, 5-, 6-, 7- or
8-quinolinyl, and 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolinyl.
[0205] Substituted heteroaryl refers to the heteroaryl groups
described above which are substituted in one or more places by, for
example, halogen, hydroxyl, aryl, alkyl, alkoxy, carboxy,
methylene, cyano, trifluoromethyl, nitro, oxo, amino, alkylamino,
and dialkylamino.
[0206] Heteroarylalkyl refers to a heteroaryl-alkyl-group wherein
the heteroaryl and alkyl portions are in accordance with the
previous discussions. Suitable examples are pyridylmethyl,
thienylmethyl, pyrimidinylmethyl, pyrazinylmethyl, and
isoquinolinylmethyl.
[0207] Heterocycles are non-aromatic cyclic groups containing at
least one hetero-ring atom, preferably selected from N, S and O,
for example, 3-tetrahydrofuranyl, piperidinyl, imidazolinyl,
imidazolidinyl, pyrrolinyl, pyrrolidinyl, morpholinyl, piperazinyl,
and indolinyl.
[0208] Heterocycle-alkyl refers to a heterocycle-alkyl-group
wherein the heterocyclic and alkyl portions are in accordance with
the previous discussions. Suitable examples are piperidinyl-ethyl
and pyrrolinyl-methyl.
[0209] Carbocycles are non-aromatic monocyclic or bicyclic
structures containing 5 to 14 carbon atoms, preferably 6 to 10
carbon atoms. Suitable examples are cyclopentenyl, cyclohexenyl,
cyclohexadienyl, tetrahydronaphthenyl and indan-2-yl.
[0210] Acyl refers to alkanoyl radicals having 1 to 6 carbon atoms
in which the alkyl portion can be substituted by halogen, alkyl,
aryl and/or alkoxy, or aroyl radicals having 7 to 15 carbon atoms
in which the aryl portion can be substituted by, for example,
halogen, alkyl and/or alkoxy. Suitable acyl groups include formyl,
acetyl, propionyl, butanoyl and benzoyl.
[0211] Substituted radicals preferably have 1 to 3 substituents,
especially 1 to 2 substituents.
[0212] R.sup.1 is preferably H, alkyl such as methyl, ethyl and
isopropyl, substituted alkyl, such as HOCH.sub.2CH.sub.2--,
cycloalkyl such as cyclopropyl, cyclobutyl, and cyclopentyl,
cycloalkylalkyl such as cyclopropylmethyl. In particular, R.sup.1
is preferably methyl, ethyl or cycloalkyl such as cyclopropyl,
cyclobutyl, or cyclopentyl, especially methyl, ethyl and
cyclopropyl.
[0213] R.sup.2 is preferably cycloalkyl, aryl, heteroaryl,
carbocycle or heterocycle. In particular, R.sup.2 is preferably
cycloalkyl such as cyclopentyl, cyclohexyl, cycloheptyl and
norbornyl, aryl which is unsubstituted or substituted one or more
times by, e.g., halogen, methoxy, nitro, cyano, amino or
combinations thereof, heteroaryl such as pyridinyl, pyrimidinyl,
thienyl, and furanyl which is unsubstituted or substituted by, for
example, methoxy and/or methylthio, carbocycle such as substituted
or unsubstituted 2-indanyl, or heterocycle such as substituted or
unsubstituted piperidinyl, pyrrolydinyl, and tetrahydrofuranyl.
[0214] In addition, preferred PDE4 inhibitors, in accordance with
the invention, are compounds described by subformulas Ia-Il which
correspond to formula I, but exhibit the following preferred
groups: [0215] Ia R.sup.1 is alkyl having 1 to 5 C atoms which is
unsubstituted or substituted by hydroxy, cycloalkylalkyl having 4
to 6 carbon atoms, or is cycloalkyl having 3-5 C atoms; and [0216]
R.sup.2 is alkyl having 3 to 8 C atoms, alkyl ether having 3 to 8
carbon atoms, cycloalkyl having 3 to 9 carbon atoms,
cycloalkylalkyl having 4 to 10 carbon atoms, aryl having 6 to 10
carbon atoms, heterocycle having 5 to 10 ring atoms, heterocycle
having 5 to 10 ring atoms, heterocycle-alkyl having 5 to 10 ring
atoms, carbocycle having 5 to 12 carbon atoms, or heteroaryl,
heteroarylalkyl or arylalkyl having 7 to 12 C atoms, wherein the
heteroaryl or aryl portion is unsubstituted or substituted one more
times by halogens, alkyl, CN, alkoxy, nitro, alkoxy, or the
combinations thereof and the alkyl portion is unsubstituted or
substituted by halogen thereof. [0217] Ib R.sup.1 is cyclopropyl;
and [0218] R.sup.2 is benzyl, phenethyl, or phenpropyl, which in
each case is substituted 1 to 3 times by halogens, C.sub.1-4 alkyl
C.sub.1-4 alkoxy or combinations thereof. [0219] Ic R.sup.1 is
cyclopropyl; and [0220] R.sup.2 is alkyl having 3 to 8 C atoms or
arylalkyl having 7 to 12 C atoms wherein the aryl portion is
substituted one more time by halogens, alkyl, CN, alkoxy, nitro, or
combinations thereof. [0221] Id R.sup.1 is cyclopropyl; and [0222]
R.sup.2 is benzyl, 2-methylbenzyl, 3-methylbenzyl, 2-chlorobenzyl,
3-chlorobenzyl, 4-chlorobenzyl, 2-fluorobenzyl, 3-fluorobenzyl,
4-fluorobenzyl, 3-methoxybenzyl, 4-cyanobenzyl,
2-trifluoromethylbenzyl, 3-trifluoromethylbenzyl,
4-trifluoromethylbenzyl 3,5-di(trifluoromethyl)benzyl,
2,4-difluorobenzyl, 3,4-difluorobenzyl, 3,5-difluorobenzyl,
2,6-difluorobenzyl, 2,3-difluorobenzyl, 2-chloro-4-fluorobenzyl,
3-chloro-4-chlorobenzyl, 2-chloro-phenethyl, 2-fluoro-phenethyl,
2-methyl-phenethyl, 3-chlorophenethyl, 3-methylphenethyl,
3-methylphenethyl, 3-methoxyphenethyl, 4-chlorophenethyl,
4-methylphenethyl, 4-methoxyphenethyl, 2-methoxy-phenpropyl,
4-chloro-phenpropyl, 4-methoxy-phenpropyl. [0223] Ie R.sup.1 is
cyclopropyl; and [0224] R.sup.2 is heteroarylalkyl which is
unsubstituted or substituted 1 to 3 halogen, C.sub.1-4-alkyl,
C.sub.1-4-alkoxy or combinations thereof. [0225] If R.sup.1 is
cyclopropyl; and [0226] R.sup.2 is 2-pyridylmethyl,
3-pyridylmethyl, 4-pyridylmethyl, 2-thienylmethyl 3-thienylmethyl,
2-furylmethyl or 3-furylmethyl. [0227] Ig R.sup.1 is methyl, ethyl,
or cyclopropyl; and [0228] R.sup.2 is cycloalkyl. [0229] Ih R.sup.1
is methyl, ethyl, or cyclopropyl; and [0230] R.sup.2 is cyclobutyl,
cyclopentyl, cyclohexyl, cycloheptyl or norbornyl. [0231] Ii
R.sup.1 is methyl, ethyl, or cyclopropyl; and [0232] R.sup.2 is
aryl (e.g. phenyl) or substituted aryl (e.g., substituted phenyl).
[0233] Ij R.sup.1 is methyl, ethyl, or cyclopropyl; and [0234]
R.sup.2 is carbocycle (e.g., 2-indanyl). [0235] Ik R.sup.1 is
methyl, ethyl, or cyclopropyl; and [0236] R.sup.2 is heterocycle
(e.g., piperidinyl). [0237] Il R.sup.1 is methyl, ethyl, or
cyclopropyl; and [0238] R.sup.2 is heteroaryl or substituted
heteroaryl (e.g., substituted or unsubstituted pyrimdinyl, pyridyl,
thienyl, and furanyl.
[0239] Preferred aspects include pharmaceutical compositions
comprising a compound of this invention and a pharmaceutically
acceptable carrier and, optionally, another active agent as
discussed below; a method of inhibiting a PDE4 enzyme, especially
an isoenzyme, e.g., as determined by a conventional assay or one
described herein, either in vitro or in vivo (in an animal, e.g.,
in an animal model, or in a mammal or in a human); a method of
treating neurological syndrome, e.g., loss of memory, especially
long-term memory, cognitive impairment or decline, memory
impairment, etc.; a method of treating a disease state modulated by
PDE4 activity, in a mammal, e.g., a human, e.g., those mentioned
herein.
[0240] The compounds of the present invention may be prepared
conventionally. Some of the processes which can be used are
described below. All starting materials are known or can be
conventionally prepared from known starting materials.
[0241] 2-Substituted hypoxanthines are produced by standard methods
in the art, such as by neat reaction between
4-amino-5-imidazolecarboxamide and 2,2,2-trifluoroacetamide (E.
Richter et al, J. Am. Chem. Soc. 1960, 82, 3144-3146; or A.
Giner-Sorala, et al, J. Am. Chem. Soc. 1958, 80, 5744-5752; or A.
Parkin, et al, J. Heterocycl. Chem. 1982, 19, 33-40).
6-Halo-2-trifluoromethylpurine may be prepared by methods common in
the art (see J.-J. Bourguignon, et al., J. Med. Chem. 1997, 40,
1768-1770; and H. Bader, et al., U.S. Pat. No. 4,405,781, 1983)
such as by reaction with a halogenating reagent such as with
SOCl.sub.2, or POCl.sub.3, or PCl.sub.5. These reactions can be run
neat or with a polar aprotic solvent such as dichloromethane,
dichloroethane, or N,N-dimethylformamide. Reaction of a
6-halopurine (e.g. 6-chloro-2-trifluoromethylpurine) with either an
alkyl halide, cycloalkyl halide, cycloalkylalkyl halide, heteroaryl
halide or arylalkyl halide in a polar aprotic solvent such as
N,N-dimethylforamide, dimethylsulfoxide, or dimethoxyethane in the
presence of a base (e.g. K.sub.2CO.sub.3, Na.sub.2CO.sub.3, NaH)
provides a mixture of 9- and 7-substituted 6-halopurines.
##STR00011##
The use of a phase transfer catalyst, for example, 18-crown-6 or
tetrabutylammonium chloride, with increased reaction temperature,
e.g., 60.degree. C. to 150.degree. C., can be used to enhance
reaction rates or reaction yields, Alternatively, reaction of a
6-halopurine under Mitsunobu conditions with an alkyl alcohol,
cycloalkyl alcohol, arylalkyl alcohol, heteroaryl alcohol, or
cycloalkylalkyl alcohol provides a mixture of 9- and 7-substituted
6-halopurines. The 9- and 7-isomers produced by the reactions
described above are readily separated by chromatography. Such
9-substituted-6-halopurines undergo reaction with amines (e.g.
ammonia, alkylamines, cycloalkylamines, or cycloalkylalkylamines)
to provide adenine derivatives of formulas I-III.
[0242] Alternatively, 6-halo-2-substituted purines readily undergo
reaction with amines (e.g. ammonia, alkylamines, cycloalkylamines,
or cycloalkylalkylamines) in the presence of polar protic solvents
(e.g. methanol, ethanol, propanol etc.) to yield 6-N-substituted
adenine analogs. Reaction with either an alkyl halide, cycloalkyl
halide, cycloalkylalkyl halide, heteroaryl halide or arylalkyl
halide in a polar aprotic solvent such as N,N-dimethylformamide,
dimethylsulfoxide, or dimethoxyethane, and in the presence of a
base (e.g. K.sub.2CO.sub.3, Na.sub.2CO.sub.3, NaH) provides adenine
derivatives of formulas I-III. The use of a phase transfer
catalyst, for example, 18-crown-6 or tetrabutylammonium chloride,
with
##STR00012##
increased reaction temperature, e.g., 60.degree. C. to 150.degree.
C., can be used to enhance reaction rates or reaction yields.
Alternatively, reaction of 6-N-substituted adenines under Mitsunobu
conditions with an alkyl alcohol, cycloalkyl alcohol, arylalkyl
alcohol, heteroaryl alcohol, or cycloalkylalkyl alcohol provides
9-substituted 6-N-substituted adenines of formulas I-III.
[0243] 6-N-Substituted-9-aryl and 9-heteroaryl-adenines may be
synthesized by methods common to the art, such as by reaction of a
4,6-dichloro-5-aminopyridine with an appropriately substituted
aniline or heteroarylamine as described by J. L. Kelley et. al., J.
Med. Chem., 1997, 40, 3207 to produce 4-arylamino or
4-heteroarylamino-6-chloropyrimidines. Cyclization by treating with
triethylorthoformate in the presence of an acid catalyst (e.g.
ethylsulfonic acid) provides 6-choro-9-aryl- or
9-heteroaryl-purines, which can be derivatized at the 6-N-position
as described above to provide adenine derivatives of formulas
I-III.
##STR00013##
Alternatively, 6-NV-substituted adenines may undergo a coupling
reaction with arylboronic acids or heteroarylboronic acids in the
presence of a base (e.g. triethylamine, pyridine,
N-methylmorpholine),
##STR00014##
a copper catalyst (e.g.) Cu(OAc).sub.2), and a polar aprotic
solvent (e.g. dichloromethane, 1,4-dioxane, THF, DMF, CH.sub.3CN)
in a modified manner as described previously for the N-arylation of
imidazole and pyrazole (see, P. Y. S. Lam et. al. Tetrahedron Lett.
1998, 39, 2941-2944) to generate 9-aryl- or 9-heteroaryl-adenines
of formulas I-III. Thus, preferably, the use of triethylamine,
rather than pyridine, as a base, and warming to 50-60.degree. C. in
CH.sub.3CN, rather than stirring at room temperature in
CH.sub.2CH.sub.2, provides the novel compounds.
[0244] Alternatively, certain halogenated aryl and heteroaryl
substrates can undergo aromatic nucleophilic substitution reaction
with 6-(substituted)amino-2-trifluoromethylpurine in a polar
aprotic solvent (e.g., DMF or DMSO) using a base (e.g., cesium
carbonate) to provide target 9-al or 9-heteroarylpurines.
[0245] Many of these synthetic procedures are described more fully
in the examples below.
[0246] One of ordinary skill in the art will recognize that some of
the compounds of Formulas I-III can exist in different geometrical
isomeric forms. In addition, some of the compounds of the present
invention possess one or more asymmetric carbon atoms and are thus
capable of existing in the form of optical isomers, as well as in
the form of racemic or nonracemic mixtures thereof, and in the form
of diastereomers and diastereomeric mixtures inter alia. All of
these compounds, including cis isomers, trans isomers, diastereomic
mixtures, racemates, nonracemic mixtures of enantiomers, and
substantially pure and pure enantiomers, are within the scope of
the present invention. Substantially pure enantiomers contain no
more than 5% w/w of the corresponding opposite enantiomer,
preferably no more than 2%, most preferably no more than 1%.
[0247] The optical isomers can be obtained by resolution of the
racemic mixtures according to conventional processes, for example,
by the formation of diastereoisomeric salts using an optically
active acid or base or formation of covalent diastereomers.
Examples of appropriate acids are tartaric, diacetyltartaric,
dibenzoyltataric, ditoluoyltartaric and camphorsulfonic acid.
Mixtures of diastereoisomers can be separated into their individual
diastereomers on the basis of their physical and/or chemical
differences by methods known to those skilled in the art, for
example, by chromatography or fractional crystallization. The
optically active bases or acids are then liberated from the
separated diastereomeric salts. A different process for separation
of optical isomers involves the use of chiral chromatography (e.g.,
chiral HPLC columns), with or without conventional derivation,
optimally chosen to maximize the separation of the enantiomers.
Suitable chiral HPLC columns are manufactured by Diacel, e.g.,
Chiracel OD and Chiracel OJ among many others, all routinely
selectable. Enzymatic separations, with or without derivitization,
are also useful. The optically active compounds of Formulae I-III
can likewise be obtained by chiral syntheses utilizing optically
active starting materials.
[0248] The present invention also relates to useful forms of the
compounds as disclosed herein, such as pharmaceutically acceptable
salts and prodrugs of all the compounds of the present invention.
Pharmaceutically acceptable salts include those obtained by
reacting the main compound, functioning as a base, with an
inorganic or organic acid to form a salt, for example, salts of
hydrochloric acid, sulfuric acid, phosphoric acid, methane sulfonic
acid, camphor sulfonic acid, oxalic acid, maleic acid, succinic
acid and citric acid. Pharmaceutically acceptable salts also
include those in which the main compound functions as an acid and
is reacted with an appropriate base to form, e.g., sodium,
potassium, calcium, mangnesium, ammonium, and choline salts. Those
skilled in the art will further recognize that acid addition salts
of the claimed compounds may be prepared by reaction of the
compounds with the appropriate inorganic or organic acid via any of
a number of known methods. Alternatively, alkali and alkaline earth
metal salts are prepared by reacting the compounds of the invention
with the appropriate base via a variety of known methods.
[0249] The following are further examples of acid salts that can be
obtained by reaction with inorganic or organic acids: acetates,
adipates, alginates, citrates, aspartates, benzoates,
benzenesulfonates, bisulfates, butyrates, camphorates,
digluconates, cyclopentanepropionates, dodecylsulfates,
ethanesulfonates, glucoheptanoates, glycerophosphates,
hemisulfates, heptanoates, hexanoates, fumarates, hydrobromides,
hydroiodides, 2-hydroxy-ethanesulfonates, lactates, maleates,
methanesulfonates, nicotinates, 2-naphthalenesulfonates, oxalates,
palmoates, pectinates, persulfates, 3-phenylpropionates, picrates,
pivalates, propionates, succinates, tartrates, thiocyanates,
tosylates, mesylates and undecanoates.
[0250] Preferably, the salts formed are pharmaceutically acceptable
for administration to mammals. However, pharmaceutically
unacceptable salts of the compounds are suitable as intermediates,
for example, for isolating the compound as a salt and then
converting the salt back to the free base compound by treatment
with an alkaline reagent. The free base can then, if desired, be
converted to a pharmaceutically acceptable acid addition salt.
[0251] The compounds of the invention can be administered alone or
as an active ingredient of a formulation. Thus, the present
invention also includes pharmaceutical compositions of compounds of
Formula I containing, for example, one or more pharmaceutically
acceptable carriers.
[0252] Numerous standard references are available that describe
procedures for preparing various formulations suitable for
administering the compounds according to the invention. Examples of
potential formulations and preparations are contained, for example,
in the Handbook of Pharmaceutical Excipients, American
Pharmaceutical Association (current edition); Pharmaceutical Dosage
Forms: Tablets (Lieberman, Lachman and Schwartz, editors) current
edition, published by Marcel Deer, Inc., as well as Remington's
Pharmaceutical Sciences (Arthur Osol, editor), 1553-1593 (current
edition).
[0253] In view of their high degree of PDE4 inhibition, the
compounds of the present invention can be administered to anyone
requiring or desiring PDE4 inhibition, and/or enhancement of
cognition. Administration may be accomplished according to patient
needs, for example, orally, nasally, parenterally (subcutaneously,
intravenously, intramuscularly, intrasternally and by infusion), by
inhalation rectally, vaginally, topically, locally, transdermally,
and by ocular administration.
[0254] Various solid oral dosage forms can be used for
administering compounds of the invention including such solid forms
as tablets, gelcaps, capsules, caplets, granules, lozenges and bulk
powders. The compounds of the present invention can be administered
alone or combined with various pharmaceutically acceptable
carriers, diluents (such as sucrose, mannitol, lactose, starches)
and excipients known in the art, including but not limited to
suspending agents, solubilizers, buffering agents, binders,
disintegrants, preservatives, colorants, flavorants, lubricants and
the like. Time release capsules, tablets and gels are also
advantageous in administering the compounds of the present
invention.
[0255] Various liquid oral dosage forms can also be used for
administering compounds of the invention, including aqueous and
non-aqueous solutions, emulsions, suspensions, syrups, and elixirs.
Such dosage forms can also contain suitable inert diluents known in
the art such as water and suitable excipients known in the art such
as preservatives, wetting agents, sweeteners, flavorants, as well
as agents for emulsifying and/or suspending the compounds of the
invention. The compounds of the present invention may be injected,
for example, intravenously, in the form of an isotonic sterile
solution. Other preparations are also possible.
[0256] Suppositories for rectal administration of the compounds of
the present invention can be prepared by mixing the compound with a
suitable excipient such as cocoa butter, salicylates and
polyethylene glycols. Formulations for vaginal administration can
be in the form of a pessary, tampon, cream, gel, paste, foam, or
spray formula containing, in addition to the active ingredient,
such suitable carriers as are known in the art.
[0257] For topical administration the pharmaceutical composition
can be in the form of creams, ointments, liniments, lotions,
emulsions, suspensions, gels, solutions, pastes, powders, sprays,
and drops suitable for administration to the ski, eye, ear or nose.
Topical administration may also involve transdermal administration
via means such as transdermal patches.
[0258] Aerosol formulations suitable for administering via
inhalation also can be made. For example, for treatment of
disorders of the respiratory tract, the compounds according to the
invention can be administered by inhalation in the form of a powder
(e.g., micronized) or in the form of atomized solutions or
suspensions. The aerosol formulation can be placed into a
pressurized acceptable propellant.
[0259] The compounds can be administered as the sole active agent
or in combination with other pharmaceutical agents such as other
agents used in the treatment of cognitive impairment and/or in the
treatment of psychosis, e.g., other PDE4 inhibitors, calcium
channel blockers, chloinergic drugs, adenosine receptor modulators,
amphakines NMDA-R modulators, mGluR modulators, and cholinesterase
inhibitors (e.g., donepezil, rivastigimine, and glanthanamine). In
such combinations, each active ingredient can be administered
either in accordance with their usual dosage range or a dose below
its usual dosage range.
[0260] The present invention further includes methods of treatment
that involve inhibition of PDE4 enzymes. Thus, the present
invention includes methods of selective inhibition of PDE4 enzymes
in animals, e.g., mammals, especially humans, wherein such
inhibition has a therapeutic effect, such as where such inhibition
may relieve conditions involving neurological syndromes, such as
the loss of memory, especially long-term memory. Such methods
comprise administering to an animal in need thereof, especially a
mammal, most especially a human, an inhibitory amount of a
compound, alone or as part of a formulation, as disclosed
herein.
[0261] The condition of memory impairment is manifested by
impairment of the ability to learn new information and/or the
inability to recall previously learned information. Memory
impairment is a primary symptom of dementia and can also be a
symptom associated with such diseases as Alzheimer's disease,
schizophrenia, Parkinson's disease, Huntington's disease, Pick's
disease, Creutzfeld-Jakob disease, HIV, cardiovascular disease, and
head trauma as well as age-related cognitive decline.
[0262] Dementias are diseases that include memory loss and
additional intellectual impairment separate from memory. The
present invention includes methods for treating patients suffering
from memory impairment in all forms of dementia. Dementias are
classified according to their cause and include: neurodegenerative
dementias (e.g., Alzheimer's, Parkinson's disease, Huntington's
disease, Pick's disease), vascular (e.g., infarcts, hemorrhage,
cardiac disorders), mixed vascular and Alzheimer's, bacterial
meningitis, Creutzfeld-Jacob Disease, multiple sclerosis, traumatic
(e.g., subdural hematoma or traumatic brain injury), infectious
(e.g., HIV), genetic (down syndrome), toxic (e.g., heavy metals,
alcohol, some medications), metabolic (e.g., vitamin B12 or folate
deficiency), CNS hypoxia, Cushing's disease, psychiatric (e.g.,
depression and schizophrenia), and hydrocephalus.
[0263] The present invention includes methods for dealing with
memory loss separate from dementia, including mild cognitive
impairment (MCI) and age-related cognitive decline. The present
invention includes methods of treatment for memory impairment as a
result of disease. In another application, the invention includes
methods for dealing with memory loss resulting from the use of
general anesthetics, chemotherapy, radiation treatment,
post-surgical trauma, and therapeutic intervention.
[0264] The compounds may be used to treat psychiatric conditions
including schizophrenia, bipolar or manic depression, major
depression, and drug addiction and morphine dependence. These
compounds may enhance wakefluness. PDE4 inhibitors can be used to
raise cAMP levels and prevent neurons from undergoing apoptosis,
PDE4 inhibitors are also known to be anti-inflammatory. The
combination of anti-apoptotic and anti-inflammatory properties make
these compounds useful to treat neurodegeneration resulting from
any disease or injury, including stroke, spinal cord injury,
neurogenesis, Alzheimer's disease, multiple sclerosis,
amylolaterosclerosis (ALS), and multiple systems atrophy (MSA).
[0265] Thus, in accordance with a preferred embodiment, the present
invention includes methods of treating patients suffering from
memory impairment due to, for example, 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 and
other neurological conditions including acute neuronal diseases, as
well as HIV and cardiovascular diseases, comprising administering
an effective amount of a compound according to Formula (I) or (I')
or pharmaceutically acceptable salts thereof.
[0266] The compounds of the present invention can also be used in a
method of treating patients suffering from disease states
characterized by decreased NMDA function, such as schizophrenia.
The compounds can also be used to treat psychosis characterized by
elevated levels of PDE 4, for example, various forms of depression,
such as manic depression, major depression, and depression
associated with psychiatric and neurological disorders.
[0267] As mentioned, the compounds of the invention also exhibit
anti-inflammatory activity. As a result, the inventive compounds
are useful in the treatment of a variety of allergic and
inflammatory diseases, particularly disease states characterized by
decreased cyclic AMP levels and/or elevated phosphodiesterase 4
levels. Thus, in accordance with a further embodiment of the
invention, there is provided a method of treating allergic and
inflammatory disease states, comprising administering an effective
amount of a compound according to Formulae (I) or (I') or a
pharmaceutically acceptable salt thereof. Such disease states
include: asthma, chronic bronchitis, chronic obstructive pulmonary
disease (COPD), atopic dermatitis, urticaria, allergic rhinitis,
allergic conjunctivitis, vernal conjunctivitis, esoniophilic
granuloma, psoriasis, inflammatory arthritis, rheumatoid arthritis,
septic shock, ulcerative colitis, Crohn's disease, reperfusion
injury of the myocardium and brain, chronic glomerulonephlitis,
endotoxic shock, adult respiratory distress syndrome, cystic
fibrosis, arterial restenosis, artherosclerosis, keratosis,
rheumatoid spondylitis, osteoarthritis, pyresis, diabetes mellitus,
pneumoconiosis, chronic obstructive airways disease, chronic
obstructive pulmonary disease, toxic and allergic contact eczema,
atopic eczema, seborrheic eczema, lichen simplex, sunburn, pruritis
in the anogenital area, alopecia great hypertrophic scars, discoid
lupus erythematosus, systemic lupus erythematosus, follicular and
wide-area pyodermias, endogenous and exogenous acne, acne rosacea,
Beghet's disease, anaphylactoid purpura nephritis, inflammatory
bowel disease, leukemia, multiple sclerosis, gastrointestinal
diseases, autoimmune diseases and the like.
[0268] PDE4 inhibitors for treating asthma, chronic bronchitis,
psoriasis, allergic rhinitis, and other inflammatory diseases, and
for inhibiting tumor necrosis factor are known within the art. See,
e.g., WO 98/58901, JP11-18957, JP10-072415, WO 93/25517, WO
94/14742, U.S. Pat. No. 5,814,651, and U.S. Pat. No. 5,935,9778
These references also describe assays for determining PDE4
inhibition activity, and methods for synthesizing such compounds.
The entire disclosures of these documents are hereby incorporated
by reference.
[0269] PDE4 inhibitors may be used to prevent or ameliorate
osteoporosis, as an antibiotic, for treatment of cardiovascular
disease by mobilizing cholesterol from atherosclerotic lesions, to
treat rheumatoid arthritis (RA), for long-term inhibition of
mesenchymal-cell proliferation after transplantation, for treatment
of urinary obstruction secondary to benign prostatic hyperplasia,
for suppression of chemotaxis and reduction of invasion of colon
cancer cells, for treatment of B cell chronic lymphocytic leukemia
(B-CLL), for inhibition of uterine contractions, to attenuate
pulmonary vascular ischemia-reperfusion injury (IRI), for corneal
hydration, for inhibition of IL-2R expression and thereby
abolishing HIV-1 DNA nuclear import into memory T cells, for
augmentation of glucose-induced insulin secretion, in both the
prevention and treatment of colitis, and to inhibit mast cell
degranulation.
[0270] The compounds of the present invention can be administered
as the sole active agent or in combination with other
pharmaceutical agents such as other agents used in the treatment of
cognitive impairment and/or in the treatment of psychosis, e.g.,
other PDE4 inhibitors, calcium channel blockers, chloinergic drugs,
adenosine receptor modulators, amphakines NMDA-R modulators, mGluR
modulators, and cholinesterase inhibitors (e.g., donepezil,
rivastigimine, and glanthanamine). In such combinations, each
active ingredient can be administered either in accordance with
their usual dosage range or a dose below their usual dosage
range.
[0271] The dosages of the compounds of the present invention depend
upon a variety of factors including the particular syndrome to be
treated, the severity of the symptoms, the route of administration,
the frequency of the dosage interval, the particular compound
utilized, the efficacy, toxicology profile, pharmacokinetic profile
of the compound, and the presence of any deleterious side-effects,
among other considerations.
[0272] The compounds of the invention are typically administered at
dosage levels and in a mammal customary for PDE4 inhibitors such as
those known compounds mentioned above. For example, the compounds
can be administered, in single or multiple doses, by oral
administration at a dosage level of, for example, 0.01-100
mg/kg/day, preferably 0.1-70 mg/kg/day, especially 0.5-10
mg/kg/day. Unit dosage forms can contain, for example, 0.1-50 mg of
active compound. For intravenous administration, the compounds can
be administered; in single or multiple dosages, at a dosage level
of, for example, 0.001-50 mg/kg/day, preferably 0.001-10 mg/kg/day,
especially 0.01-1 mg/kg/day. Unit dosage forms can contain, for
example, 0.1-10 mg of active compound.
[0273] In carrying out the procedures of the present invention it
is of course to be understood that reference to particular buffers,
media, reagents, cells, culture conditions and the like are not
intended to be limiting, but are to be read so as to include all
related materials that one of ordinary skill in the art would
recognize as being of interest or value in the particular context
in which that discussion is presented. For example, it is often
possible to substitute one buffer system or culture medium for
another and still achieve similar, if not identical, results. Those
of skill in the art will have sufficient knowledge of such systems
and methodologies so as to be able, without undue experimentation,
to make such substitutions as will optimally serve their purposes
in using the methods and procedures disclosed herein.
[0274] The present invention will now be further described by way
of the following non-limiting examples. It applying the disclosure
of these examples, it should be kept clearly in mind that other and
different embodiments of the methods disclosed according to the
present invention will no doubt suggest themselves to those of
skill in the relevant art.
[0275] In the foregoing and in the following examples, all
temperatures are set forth uncorrected in degrees Celsius; and,
unless otherwise indicated, all parts and percentages are by
weight.
[0276] The entire disclosures of all applications, patents and
publications, cited above and below, are hereby incorporated by
reference.
EXAMPLE 1
1,9-Dihydro-2-trifluoromethyl-6H-purin-6-one (Kelly, J. L.; Linn,
J. A.; Selway, J. W. T., J. Med. Chem., 1989, 32, 1757-1763.)
[0277] A 1 L round-bottom flask (tree neck) containing 340 g of
trifluoroacetamide was heated in an oil bath at 110.degree. C.,
After the trifluoroacetamide melted, 50 g of
5-aminoimidazole-4-carboxamide-HCl was added. The mixture was
warmed to reflux (bath temp 160 to 165.degree. C.) for 4 hours,
cooled to room temperature, and the rocky solid was triturated with
1 L of ether. The ether was decanted off and the remaining solid
was warmed until melted and 200 mL of ether was introduced by a
dropping-funnel through a water-cooled condenser. The mixture was
cooled to room temperature and an additional 200 mL of ether was
added with stirring. The solid was removed by filtration,
triturated with 3.times.500 mL of ether, washed with 200 mL of
H.sub.2O, and filtered to provide 89 g of crude product. The
product was treated with 3 L of MeOH and 9 g of activated carbon,
warmed to reflux for 20 minutes, filtered through a pad of celite,
and concentrated to a volume of 2.5 L. The material was warmed to
dissolve all the precipitate that formed and then cooled slowly to
room temperature. The crystalline material was isolated by
filtration and dried in vacuo to provide 41 g of the desired
hypoxanthine as a white solid. .sup.1H NMR (DMSO-d.sub.6) .delta.
8.34 (s, 1H) 7.18 (bs, 2H). MS (ES+), 205.0 (100%, M+H).
EXAMPLE 2
6-Chloro-2-trifluoromethylpurine
[0278] A mixture of 15 g (73 mmol) of 2-trifluoromethylhypoxanthine
and 300 mL of CHCl.sub.3 was warmed to reflux and treated with a
solution of 26.7 mL (366 mmol) SOCl.sub.2 and 28.3 mL (366 mmol)
DWF. The reaction was maintained at reflux for 1.5 h, cooled to
room temperature, and poured into 1.2 L of ice-water. The organic
layer was separated and washed with 2.times.300 mL of H.sub.2O. The
pH of the combined aqueous phases was adjusted to 7 with saturated
NaHCO.sub.3 aid extracted with 3.times.1.2 L of ether. The combined
ether and chloroform extracts were dried (MgSO.sub.4) and
concentrated to dryness to give 7.4 g of crude product, .sup.1H NMR
(DMSO-d.sub.6) .delta. 14.45 (bs, 1H), 8.95 (s, 1H). MS (ES+)
222.96 (100%, M+H).
EXAMPLE 3
6-Chloro-9-(2-fluorobenzyl)-2-trifluoromethylpurine
[0279] A mixture of 5 g (22.5 mmol) of 6-chloro-2
tfifluoromethylpurine, 4.05 g (29.4 mmol) of anhydrous
K.sub.2CO.sub.3, 56 mL of dry DMF, and 3.55 mL (29.4 mmol) of
2-fluorobenzyl bromide was stirred at room temperature for 16 h.
The reaction mixture was poured into 50 mL of ice-water and the pH
of the solution was adjusted to 5 or 6 with acetic acid. The
mixture was extracted with 3.times.300 mL of ether and the combined
organic fractions were washed with 3.times.350 mL of H.sub.2O, 300
mL of brine, dried (Na.sub.2SO.sub.4), and concentrated in vacuo to
provide a yellow oil. Purification by chromatography over silica
gel using a gradient elution going from 20% EtOAc in hexanes to 50%
EtOAc in hexanes provided 3.5 g (47% yield) of the desired 9-isomer
(first to elute) and 1.97 g (27% yield) of the 7-isomer. .sup.1H
NMR (CDCl.sub.3) .delta. 8.33 (s, 1H), 7.50-7.47 (m, 1H), 7.40-7.38
(m, 1H), 7.20-7.11 (m, 2H) 5.56 (s, 2H).
EXAMPLE 4
6-Cyclopropylamino-9-(2-fluorobenzyl-2-trifluoromethylpurine
[0280] A mixture of 100 mg (0.30 mmol) of
6-chloro-9-(2-fluorobenzyl)-2-trifluoromethylpurine, 1 mL (14 mmol)
of aminocyclopropane, and 5 mL of EtOH were stirred at room
temperature for 16 hours. The reaction mixture was concentrated in
vacuo and the residue was dissolved in CH.sub.2Cl.sub.2, washed
with 2.times.5 mL H.sub.2O, 5 mL brine, dried Na.sub.2SO.sub.4),
and concentrated. Chromatography over silica gel using 33% EtOAc in
hexanes as eluant provided 102 mg (97% yield) of the desired
product. M.P. 118.5-119.0.degree. C.; .sup.1H NMR (CDCl.sub.3)
.delta. 7.892 (s, 1H), 7.50-7.39 (m, 1H) 7.37-7.29 (m, 1H),
7.18-7.05 (m, 2H), 5.95 (bs, 1H), 5.44 (s, 2H), 0.94-0.91 (m, 2H),
0.65-0.64 (m, 2H).
[0281] To obtain the methansulphonate salt (mesylate salt), 4 ml of
0.1N CH.sub.3SO.sub.3H in EtOAc was added to a solution of 145 mg
(0.4 mmol)
6-cyclopropylamino-9-(2-fluorobenzyl)-2-trifluoromethylpurine in
EtOAc. Then, 1 ml of hexane was added to a warm solution and the
resultant mixture was allowed to crystallize (within a
refrigerator). The solid was collected to give 148 mg of the
mesylate salt. The salt was relatively insoluble in H.sub.2O. M.p.
167.5-169.0 C; m.p. 114-118 C for free base.
[0282] The following compounds were prepared in a similar fashion
as described above. [0283] a.
6-Methylamino-9-(2-fluorobenzyl)-2-trifluoromethylpurine [0284] b.
6-Ethylamino-9-(2-fluorobenzyl)-2-trifluoromethylpurine [0285] c.
6-Amino-9-(2-fluorobenzyl)-2-trifluoromethylpurine [0286] d.
6-N-Cyclopropylmethylamino-9-(2-fluorobenzyl)-2-trifluoromethylpurine
[0287] e.
6-[1-(2-Hydroxy)ethyl]amino-9-(2-fluorobenzyl)-2-trifluoromethy-
lpurine [0288] f.
6-Cyclopentylamino-9-(2-fluorobenzyl)-2-trifluoromethylpurine
[0289] g.
6-Cyclohexylamino-9-(2-fluorobenzyl)-2-trifluoromethylpurine [0290]
h. 6-Isopropylamino-9-(2-fluorobenzyl)-2-trifluoromethylpurine
EXAMPLE 5
6-Cyclopropylamino-2-trifluoromethylpurine
[0291] A mixture of 12 g (54 mmol) of
6-chloro-2-trifluoromethylpurine, 30 g (540 mmol) of
cyclopropylamine and 250 mL of ethanol was stirred at room
temperature for 4.5 days leaving a white solid. The mixture was
concentrated in vacuo to dryness, 215 mL of H.sub.2O was added and
the mixture was stirred for 1 hour. The product was collected by
filtration and after drying (vacuum oven, 50.degree. C. 5 hours)
8.1 g of product was obtained, 62% yield. M.P. 260.degree. C.
(dec.); .sup.1H NMR (CD.sub.3OD) .delta. 8.18 (s, 1H), 3.30 (bs,
1H), 0.904 (m, 2H), 0.67 (m, 2H).
[0292] The following compounds are prepared in a similar manner:
[0293] a. 6-Methylamino-2-trifluoromethylpurine [0294] b.
6-Cyclopentylamino-2-trifluoromethylpurine
EXAMPLE 6
6-Cyclopropylamino-9-(2-fluorobenzyl)-2-trifluoromethylpurine
[0295] To a nitrogen flushed tube with stir bar was added 25 mg
(0.13 mmol) of 2-fluorobenzyl bromide, 0.7 mL of anhydrous DMF, 18
mg (0.13 mmol) of K.sub.2CO.sub.3 and 0.5 mL (0.10 mmol) of 0.2M
6-cyclopropylamino-2-trifluoromethyladenine in anhydrous DMF. The
reaction was stirred at room temperature for 18 hours, quenched
with 2 mL of ice water and the pH was adjusted to between 5 and 6
with acetic acid. The aqueous mixture was extracted with 10 mL of
ether and the ether fraction was washed with 3 mL of H.sub.2O, 3 mL
of brine, dried (MgSO.sub.4) and concentrated to dryness in vacuo.
M.P. 118.5-119.0.degree. C.; .sup.1H NMR (CDCl.sub.3) .delta. 7.892
(s, 1H), 7.50-7.39 (m, 1H), 7.37-7.29 (m, 1H), 7.18-7.05 (m, 2H),
5.95 (bs, 1H), 5.44 (s, 2H), 0.94-0.91 (m, 2H), 0.65-0.64 (m,
2H).
[0296] The following compounds were prepared in a similar manner.
[0297] a.
6-Cyclopropylamino-9-(3-methoxybenzyl)-2-trifluoromethylpurine
[0298] b.
6-Cyclopropylamino-9-(3-chlorobenzyl)-2-trifluoromethylpurine
[0299] c.
6-Cyclopropylamino-9-(3-nitrobenzyl)-2-trifluoromethylpurine [0300]
d. 6-Cyclopropylamino-9-(4-cyanobenzyl)-2-trifluoromethylpurine
[0301] e.
6-Cyclopropylamino-9-(4-trifluoromethylbenzyl)-2-trifluoromethylpurine
[0302] f.
6-Cyclopropylamino-9-(3,4-dichlorobenzyl)-2-trifluoromethylpuri- ne
[0303] g.
6-Cyclopropylamino-9-(4-chlorobenzyl)-2-trifluoromethylpurine
[0304] h.
6-Cyclopropylamino-9-(3,4-difluorobenzyl)-2-trifluoromethylpuri- ne
[0305] i.
6-Cyclopropylamino-9-(3-pyridylmethyl)-2-trifluoromethylpurine
[0306] j.
6-Cyclopropylamino-9-[.alpha.-(2-chloroacetophenone)]-2-tfifluoromethylpu-
rine [0307] k.
6-Cyclopropylamino-9-[.alpha.-(4-methoxyacetophenone)]-2-trifluoromethylp-
urine [0308] l.
6-Cyclopropylamino-9-(3,5-difluorobenzyl)-2-trifluoromethylpurine
[0309] m. 6-Cyclopropylamino-9-ethyl-2-trifluoromethylpurine [0310]
n.
6-Cyclopropylamino-9-[(.alpha.-(4-methylacetophenone)]-2-trifluoromethylp-
urine [0311] o.
6-Cyclopropylamino-9-(3-trifluoromethylbenzyl)-2-trifluoromethylpurine
[0312] p.
6-Cyclopropylamino-9-(3,5-bistrifluoromethylbenzyl)]-2-trifluor-
omethylpurine [0313] q.
6-Cyclopropylamino-9-(4-methylsulfonylbenzyl)]-2-trifluoromethylpurine
[0314] t.
6-Cyclopropylamino-9-(4-nitrobenzyl)-2-trifluoromethylpurine [0315]
s. 6-Cyclopropylamino-9-(4-tert-butylbenzyl)-2-trifluoromethylpuri-
ne [0316] t.
6-Cyclopropylamino-9-(1-pentan-3-one)-2-trifluoromethylpurine
[0317] u.
6-Cyclopropylamino-9-[.alpha.-2-methoxyacetophenone)]-2-trifluo-
romethylpurine [0318] v.
6-Cyclopropylamino-9-[.alpha.-(4-cyanoacetophenone)]-2-trifluoromethylpur-
ine [0319] w.
6-Cyclopropylamino-9-[.alpha.-(3-chloroacetophenone)]-2-trifluoromethylpu-
rine [0320] x.
6-Cyclopropylamino-9-[.alpha.-(3-methoxyacetophenone)]-2-trifluoromethylp-
urine [0321] y.
6-Cyclopropylamino-9-[.alpha.-(4-chloroacetophenone)]-2-trifluoromethylpu-
rine [0322] z.
6-Cyclopropylamino-9-[.alpha.-(3,4-dichloroacetophenone)]-2-trifluorometh-
ylpurine [0323] aa.
6-Cyclopropylamino-9-(4-pyridylmethyl)-2-trifluoromethylpurine
[0324] bb.
6-Cyclopropylamino-9-(2-pyridylmethyl)-2-trifluoromethylpurine
[0325] cc.
6-Cyclopropylamino-9-(4-ethylbenzyl)-2-trifluoromethylpurine [0326]
dd.
6-Cyclopropylamino-9-(3,4-dimethoxybenzyl)-2-trifluoromethylpurine
[0327] ee.
6-Cyclopropylamino-9-(2,4-dichlorobenzyl)-2-trifluoromethylpurine
[0328] ff.
6-Cyclopropylamino-9-(2,3-dichlorobenzyl)-2-trifluoromethylpurine
[0329] gg.
6-Cyclopropylamino-9-(3,4-ethylenedioxybenzyl)-2-trifluoromethylpurin-
e [0330] hh.
6-Cyclopropylamino-9-(3,4-methylenedioxybenzyl)-2-trifluoromethylpurine
[0331] ii.
6-Cyclopropylamino-9-(4-isopropylbenzyl)-2-trifluoromethylpurine
[0332] jj.
6-Cyclopropylamino-9-(3-thienylmethyl)-2-trifluoromethylpurine
[0333] kk.
6-Cyclopropylamino-9-(2-thienylmethyl)-2-trifluoromethylpurine
[0334] ll.
6-Cyclopropylamino-9-(2-furylmethyl)-2-trifluoromethylpurine [0335]
mm. 6-Cyclopropylamino-9-(3-furylmethyl)-2-trifluoromethylpurine
[0336] nn.
6-Cyclopropylamino-9-[1-(2-(2-chlorophenyl)ethyl)]-2-trifluoromethylp-
urine [0337] oo.
6-Cyclopropylamino-9-[1-(2-(2-fluorophenyl)ethyl)]-2-trifluoromethylpurin-
e [0338] pp.
6-Cyclopropylamino-9-[1-(2(2-toluyl)ethyl)]-2-trifluoromethylpurine
[0339] qq.
6-Cyclopropylamino-9-[1-(2-(3-chlorophenyl)ethyl)]-2-trifluoromethylpurin-
e [0340] rr.
6-Cyclopropylamino-9-[1-(2-(3-toluoyl)ethyl)]-2-trifluoromethylpurine
[0341] ss.
6-Cyclopropylamino-9-[1-(2-(3-methoxyphenyl)ethyl)]-2-trifluoromethylpuri-
ne [0342] tt.
6-Cyclopropylamino-9-[1-(2-(4-chlorophenyl)ethyl)]-2-trifluoromethylpurin-
e [0343] uu.
6-Cyclopropylamino-9-[1-(2-(4-toluyl)ethyl)]-2-trifluoromethylpurine
[0344] vv.
6-Cyclopropylamino-9-[1-(2-(4-methoxyphenyl)ethyl)]-2-trifluoromethylpuri-
ne [0345] ww. 6-Cyclopropylamino-9-[1-(3
(2-methoxyphenyl)propyl)]-2-trifluoromethylpurine [0346] xx.
6-Cyclopropylamino-9-[1-(3-(4-chlorophenyl)propyl)]-2-trifluoromethylpuri-
ne [0347] yy.
6-Cyclopropylamino-9-[1(3-methoxyphenyl)propyl)]-2-trifluoromethylpurine
[0348] zz.
6-Cyclopropylamino-9-(3-benzyloxybenzyl)-2-trifluoromethylpurine
[0349] aaa.
6-Cyclopropylamino-9-(2,6-difluorobenzyl)-2-trifluoromethylpurine
[0350] bbb.
6-Cyclopropylamino-9-cyclopentyl-2-trifluoromethylpurine [0351]
ccc. 6-Cyclopropylamino-9-(1-propyl)-2-trifluoromethylpurine [0352]
ddd.
6-Cyclopropylamino-9-(2,3-difluorobenzyl)-2-trifluoromethylpurine
[0353] eee.
6-Cyclopropylamino-9-(4-fluorobenzyl)-2-trifluoromethylpurine
[0354] fff.
6-Cyclopropylamino-9-(2-chlorobenzyl)-2-trifluoromethylpurine
[0355] ggg.
6-Cyclopropylamino-9-(3-methylbenzyl)-2-trifluoromethylpurine
[0356] hhh.
6-Cyclopropylamino-9-(2-chloro-4-fluorobenzyl)-4-trifluoromethylpuri-
ne [0357] iii.
6-Cyclopropylamino-9-[1-(2-methoxyethyl)]-2-trifluoromethylpurine
[0358] jjj. 6-Cyclopropylamino-9-(2-butyl)-2-trifluoromethylpurine
[0359] kkk. 6-Cyclopropylamino-9-(1-butyl)-2-trifluoromethylpurine
[0360] lll.
6-Cyclopropylamino-9-(2-methylbenzyl)-2-trifluoromethylpurine
[0361] mmm.
6-Cyclopropylamino-9-(2-fluorobenzyl)-2-trifluoromethylpurine
[0362] nnn.
6-Cyclopropylamino-9-(2,4-difluorobenzyl)-2-trifluoromethylpurine
[0363] ooo.
6-Cyclopropylamino-9-(2-nitrobenzyl)-2-trifluoromethylpurine [0364]
ppp. 6-Cyclopropylamino-9-benzyl-2-trifluoromethylpurine [0365]
qqq. 6-Cyclopropylamino-9-(2-propyl)-2-trifluoromethylpurine [0366]
rrr.
6-Cyclopropylamino-9-(2-trifluoromethylbenzyl)-2-trifluoromethylpurine
[0367] sss.
6-Cyclopropylamino-9-(3-fluorobenzyl)-2-trifluoromethylpurine
[0368] ttt.
6-Cyclopropylamino-9(4-phenylbenzyl)-2-trifluoromethylpurine [0369]
uuu. 6-Cyclopropylamino-9-(2-phenylbenzyl)-2-trifluoromethylpurine
[0370] vvv. 6-Cyclopropylamino-9-cyclohexyl-2-trifluoromethylpurine
[0371] www.
6-Cyclopropylamino-9-cycloheptyl-2-trifluoromethylpurine
[0372] The following compounds can be prepared in a manner similar
to that described in Example 6 using cesium carbonate rather than
potassium carbonate: [0373] a.
6-Cyclopropylamino-9-(2,6-dichloro-4-pyridylmethyl-2-trifluoromethylpurin-
e [0374] b.
6-Cyclopropylamino-9-(4-methoxybenzyl)-2-trifluoromethylpurine
[0375] c.
6-Cyclopropylamino-9(3-nitrobenzyl)-2-trifluoromethylpurine [0376]
d. 6-Cyclopropylamino-9-(2-pyrimidyl)-2-trifluoromethylpurine
[0377] e.
6-Cyclopropylamino-9-(4-2-diethylamino)pyrimidyl)-2-trifluorome-
thylpurine [0378] f.
6-Cyclopropylamino-9-(4-(2-chloro)pyrimidyl)-2-trifluoromethylpurine
[0379] g.
6-Cyclopropylamino-9-(4-(2-methylthio)pyrimidyl)-2-trifluoromet-
hylpurine
[0380] The following compounds can be prepared in a manner similar
to that above using 6-N-methylamino-2-trifluoromethylpurine as a
starting material: [0381] a.
6-N-methylamino-9-cyclopentyl-2-trifluoromethylpurine [0382] b.
6-N-methylamino-9-cycloheptyl-2-trifluoromethylpurine
[0383] The following compound can be prepared in a manner similar
to that described above using
6-N-cyclopentylamino-2-trifluoromethylpurine as a starting
material: [0384] a.
6N-cyclopentylamino-9-methyl-2-trifluoromethylpurine.
EXAMPLE 7
6-Cyclopropylamino-9-(3-aminophenyl)-2-trifluoromethylpurine
[0385] A mixture of
6-Cyclopropylamino-9-(3-nitrophenyl)-2-trifluoromethylpurine (0.1
mmol), palladium on active carbon (0.001 mol) methanol (50 ml) and
acetic acid (3 ml) was shaken under 30 psi hydrogen. After 5 hours,
the reaction mixture was filtered through celite and the filtrate
was concentrated in vacuo. The resultant residue was dissolved in
30 ml of ethyl acetate, washed with 30 mL of aqueous 5% sodium
bicarbonate, concentrated and purified by chromatography over
SiO.sub.2 to give the amino product in quantitative yield. .sup.1H
NMR (300 MHz, CDCl.sub.3) .quadrature. 8.10 (s, 1H), 7.27 (t, J=8.1
Hz, 1H), 7.05 (s, 1H), 6.98 (d, J=8.1 Hz, 1H), 6.70 (d, J=8.1 Hz,
1H), 6.35 (b, 1H), 3.18 (b, 1H), 0.91 (m, 2H), 0.69 (m, 2H).
[0386] The following compounds can be made in a similar manner:
[0387]
6-Cyclopropylamino-9-(3-aminobenzyl)-2-trifluoro-methylpurine.
EXAMPLE 8
6-Cyclopropylamino-9-cyclopentyl-2-trifluoromethylpurine
(Pragnacharyulu, P.V.P.; Varkhedkar, V.; Curtis, M. A.; Chang, I.
F.; Abushanab, E., J. Med. Chem., 2000, 43, 469-4700).
[0388] To a solution of 20 mg (0.08 mmol)
6-cyclopropylamino-2-trifluoromethylpurine, 42 mg (0.16 mmol) of
PPh.sub.3, and 18 mg (0.21 mmol) cyclopentanol in THF under N.sub.2
atmosphere with magnetic stirring, was added 48 mg (0.23 mmol)
DIAD. The resulting mixture was stirred at room temperature for 16
hours, concentrated, taken up in 10 mL H.sub.2O and extracted with
2.times.1.5 mL of ether. The organic layer was combined and dried
over (MgSO.sub.4), concentrated in vacuo, and purified by
chromatography over silica gel using 10% MeOH in CH.sub.2Cl.sub.2
to give the desired product. .sup.1H NMR (CDCl.sub.3) 7.92 (s, 1H)
6.01 (bs, 1H), 4.98 (p, 1H), 3.18 (bs, 1H), 2.36-2.25 (m, 2H),
2.03-1.79 (m, 6H), 0.86 (dd, 2H), 0.65 (dd, 2H).
[0389] The following compounds were prepared in a similar manner:
[0390] a.
6-Cyclopropylamino-9-cyclopentylmethyl-2-trifluoromethylpurine
[0391] b.
6-Cyclopropylamino-9-cyclopentylethyl-2-trifluoromethylpurine
[0392] c.
6-Cyclopropylamino-9-cyclopentylpropyl-2-trifluoromethylpurine
[0393] d.
6-Cyclopropylamino-9-(3-(1-ethyl-pyrrolidinyl)-2-trifluoromethylpurine
[0394] e.
6-Cyclopropylamino-9-(3-(1-ethyl-piperidinyl)-trifluoromethylpu-
rine [0395] f.
6-Cyclopropylamino-9-(2-(1-ethyl-piperidinyl)-2-trifluoromethylpurine
[0396] g.
6-Cyclopropylamino-9-(piperidin-1-ylethyl)-2-trifluoromethylpur-
ine [0397] h.
6-Cyclopropylamino-9-(2-(1-methyl-piperidinyl)-2-trifluoromethylpurine
[0398] i.
6-Cyclopropylamino-9-(5-oxo-(S)-pyrrolidin-3-yl)-2-trifluoromet-
hylpurine [0399] j.
6-Cyclopropylamino-9-(5-oxo-(R)-pyrrolidin-3-yl)-2-trifluoromethylpurine
EXAMPLE 9
6-Cyclopropylamino-9-(3,4-dimethoxyphenyl)-2-trifluoromethylpurine
[0400] A mixture of 6-cyclopropylamino-2-trifluoromethyladenine (46
mg, 0.2 mmol), 3,4-dimethoxyphenyl boronic acid (44 mg, 0.24 mmol),
copper(II) acetate (36 mg, 0.2 mmol), triethylamine (1.0 mmol, 101
mg), anhydrous acetonitrile (4 ml) and molecular seives (.about.10
pellets) was stirred at 50-55.degree. C. for 18 hours. Ethyl
acetate (20 ml) was added and the solid was removed by filtration.
The filtrate was washed with 20 ml of 5% sodium bicarbonate aqueous
solution. Evaporation and chromatography over SiO.sub.2 using
hexane/ethylacetate/methanol (50:50:1) as eluant gave 7.9 mg of the
title compound (yield 10%). .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 8.10 (s, 1H), 7.39 (s, 1H), 7.13 (d, J=8.7 Hz, 2H), 6.98
(d, J=8.7 Hz, 2H), 6.35 (b, 1H), 3.93 (s, 3H), 3.90 (s, 3H), 3.18
(b, 1H), 0.91 (m, 2H), 0.69 (m, 2H)
[0401] The following compounds were prepared in a similar manner:
[0402] a.
6-Cyclopropylamino-9-(3,4-dimethoxyphenyl)-2-trifluoromethylpurine
[0403] b.
6-Cyclopropylamino-9-(3-methoxyphenyl)-2-trifluoromethylpurine
[0404] c.
6-Cyclopropylamino-9-(4-methoxyphenyl)-2-trifluoromethylpurine
[0405] d.
6-Cyclopropylamino-9-(3-nitrophenyl)-2-trifluoromethylpurine [0406]
e. 6-Cyclopropylamino-9-(2-methoxyphenyl)-2-trifluoromethylpurine
[0407] f.
6-Cyclopropylamino-9-(3-cyanophenyl)-2-trifluoromethylpurine [0408]
g. 6-Cyclopropylamino-9-(2,5-dimethoxyphenyl)-2-trifluoromethylpur-
ine [0409] h.
6-Cyclopropylamino-9-(2,4-dimethoxypyrimidyl)-2-trifluoromethylpurine
[0410] i.
6-Cyclopropylamino-9-(2-methoxy-5-pyridyl)-2-trifluoromethylpur-
ine [0411] j.
6-Cyclopropylamino-9-(4-pyridyl)-2-trifluoromethylpurine [0412] k.
6-Cyclopropylamino-9-(3-pyridyl)-2-trifluoromethylpurine [0413] l.
6-Cyclopropylamino-9-(1-tert-butoxycarbonyl-pyrrol-2-yl)-2-trifluorome-
thylpurine [0414] m.
6-Cyclopropylamino-9-(4-dimethylaminophenyl)-2-trifluoromethylpurine
[0415] n.
6-Methylamino-9-(2,4-dimethoxy-5-pyrimidyl)-2-trifluoromethylpu-
rine [0416] o.
6-Methylamino-9-(2-methoxyphenyl)-2-trifluoromethylpurine [0417] p.
6-Methylamino-9-(4-methoxyphenyl)-2-trifluorormethylpurine [0418]
q. 6-Methylamino-9-(3-acetylphenyl-2-trifluoromethylpurine [0419]
r. 6-Methylamino-9-(3-methoxyphenyl)-2-trifluoromethylpurine [0420]
s. 6-Methylamino-9-(3-nitrophenyl)-2-trifluoromethylpurine [0421]
t. 6-Cyclopropylamino-9-(3-furanyl)-2-trifluoromethylpurine [0422]
u. 6-Cyclopropylamino-9-(4-ethoxyphenyl)-2-trifluoromethylpurine
[0423] v.
6-Cyclopropylamino-9-(2-ethoxyphenyl)-2-trifluoromethylpurine
[0424] w.
6-Cyclopropylamino-9-(3,4-methylenedioxyphenyl)-2-trifluoromethylpurine
[0425] x.
6-Cyclopropylamino-9-(3-ethoxyphenyl)-2-trifluoromethylpurine
[0426] y.
6-Methylamino-9-(3,4-dimethoxyphenyl)-2-trifluoromethylpurine
[0427] z.
6-Cyclopropylamino-9-(3,5-dimethoxyphenyl)-2-trifluoromethylpur-
ine [0428] aa.
6-Cyclopropylamino-9-(2-methoxy-5-chlorophenyl)-2-trifluoromethylpurine
[0429] bb. 6-Cyclopropylamino-9-phenyl-2-trifluoromethylpurine
[0430] cc.
6-Cyclopropylamino-9-(2-fluorophenyl)-2-trifluoromethylpurine
[0431] dd.
6-Cyclopropylamino-9-(4-fluorophenyl)-2-trifluoromethylpurine
[0432] ee.
6-Cyclopropylamino-9-(4-chlorophenyl)-2-trifluoromethylpurine
[0433] ff. 6-Cyclopropylamino-9-(4-toluoyl)-2-trifluoromethylpurine
[0434] gg.
6-Cyclopropylamino-9-(4-trifluoromethylphenyl)-2-trifluoromethylpurine
[0435] hh. 6-Cyclopropylamino-9-(3-thienyl)-2-trifluoromethylpurine
[0436] ii.
6-Cyclopropylamino-9-(3-trifluoromethylphenyl)-2-trifluoromethylpurine
EXAMPLE 10
In Vitro Measurement of Type 4 Phosphodiesterase Inhibition
Activity
[0437] Human PDE4 was obtained from baculovirus-infected Sf9 cells
that expressed the recombinant enzyme. The cDNA encoding hPDE-4D6
was subcloned into a baculovirus vector. Insect cells (Sf9) were
infected with the baculovirus and cells were cultured until protein
was expressed. The baculovirus-infected cells were lysed and the
lysate was used as source of hPDE-4D6 enzyme. The enzyme was
partially purified using a DEAE ion exchange chromatography. This
procedure can be repeated using cDNA encoding other PDE-4
enzymes.
Assay:
[0438] Type 4 phosphodiesterases convert cyclic adenosine
monophosphate (cAMP) to 5'-adenosine monophosphate (5'-AMP).
Nucleotidase converts 5'-AMP to adenosine. Therefore the combined
activity of PDE4 and nucleotidase converts cAMP to adenosine.
Adenosine is readily separated from cAMP by neutral alumina
columns. Phosphodiesterase inhibitors block the conversion of cAMP
to adenosine in this assay; consequently, PDE4 inhibitors cause a
decrease in adenosine.
[0439] Cell lysates (40 ul) expressing hPDE-4D6 were combined with
50 ul of assay mix and 10 ul of inhibitors and incubated for 12 min
at room temperature. Final concentrations of assay components were:
0.4 ug enzyme, 10 mM Tris-HCl (pH 7.5), 10 mM MgCl.sub.2, 3 uM
cAMP, 0.002 U 5'-nucleotidase, and 3.times.10.sup.4 cpm of [3]cAMP
The reaction was stopped by adding 100 .mu.l of boiling 5 m HCl. An
aliquot of 75 .mu.l of reaction mixture was transferred from each
well to alumina columns Multiplate; Millipore). Labeled adenosine
was eluted into an OptiPlate by spinning at 2000 rpm for 2 min; 150
.mu.l per well of scintillation fluid was added to the OptiPlate.
The plate was sealed, shaken for about 30 min, and cpm of
[.sup.3H]adenosine was determined using a Wallac Trilux.RTM..
[0440] All test compounds are dissolved in 100% DMSO and diluted
into the assay such that the final concentration of DMSO is 0.1%
DMSO does not affect enzyme activity at this concentration.
[0441] A decrease in adenosine concentration is indicative of
inhibition of PDE activity. pIC.sub.50 values were determined by
screening 6 to 12 concentrations of compound ranging from 0.1 nM to
10,000 nM and then plotting dg concentration versus
.sup.3H-adenosine concentration. Nonlinear regression software
(Assay Explorer.RTM.) was used to estimate pIC.sub.50 values.
EXAMPLE 11
Passive Avoidance in Rats, an In Vivo Test for Learning and
Memory
[0442] The test was performed as previously described (Zhang, H-T.,
Crissman, A. M., Dorairaj, N. R., Chandler, L. J., and O'Donnell,
J. M., Neuropsychopharmacology, 2000, 23, 198-204.). The apparatus
(Model E10-16SC, Coulbourn Instruments, Allentown, Pa.) consisted
of a two-compartment chamber with an illuminated compartment
connected to a darkened compartment by a guillotine door. The floor
of the darkened compartment consisted of stainless steel rods
through which an electric foot-shock could be delivered from a
constant current source. All experimental groups were first
habituated to the apparatus the day before the start of the
experiment. During the training, the rat (Male Spraque-Dawley
(Harlan) weighing 250 to 350 g) was placed in the illuminated
compartment facing away from the closed guillotine door for 1
minute before the door was raised. Me latency for entering the
darkened compartment was recorded. After the rat entered the
darkened compartment, the door was closed and a 0.5 mA electric
shock was administered for 3 seconds. Twenty-four hours later, the
rat was administered 0.1 mg/kg MK-801 or saline, 30 minutes prior
to the injection of saline or test compound (dosed from 0.1 to 2.5
mg/kg, i.p.), which was 30 minutes before the retention test
started. The rat was again placed in the illuminated compartment
with the guillotine door open. The latency for entering the
darkened compartment was recorded for up to 180 seconds, at which
time the trial was terminated.
[0443] All data were analyzed by analyses of variance (ANOVA);
individual comparisons were made using Kewman-Keuls tests. Naive
rats required less than 30 seconds, on average, to cross from the
illuminated compartment to the darkened compartment. However, 24
hours after the electric shock exposure, most rats pretreated with
vehicle did not re-enter the darkened compartment; the average
latency was increased up to 175 seconds p<0.001). Pretreatment
with MK-801 (0.1 mg/kg) markedly reduced this latency when compared
to the vehicle (p<0.001). This amnesic effect of MK-801 is
reversed in a statistically significant manner by actual test
compounds in a dose-dependent fashion.
EXAMPLE 12
Radial Arm Maze Task in Rats, an In Vivo Test for Learning and
Memory
[0444] The test was performed as previously described (Zhang,
H.-T., Crissman, A. M., Dorairaj, N. R., Chandler, L. J., and
O'Donnell, J. M., Neuropsychopharmacology, 2000, 23, 198-204.).
Five days after initial housing, rats (male Spraque-Dawley (Harlan)
weighing 250 to 350 g) were placed in the eight-arm radial maze
(each arm was 60.times.10.times.12 cm high; the maze was elevated
70 cm above the floor) for acclimation for two days. Rats were then
placed individually in the center of the maze for 5 minutes with
food pellets placed close to the food wells, and then, the next
day, in the wells at the end of the arms; 2 sessions a day were
conducted. Next, four randomly selected arms were then baited with
one pellet of food each. The rat was restricted to the center
platform (26 cm in diameter) for 15 seconds and then allowed to
move freely throughout the maze until it collected all pellets of
food or 10 minutes passed, whichever came first. Four parameters
were recorded: 1) working memory errors, i.e., entries into baited
arms that had already been visited during the same trial; 2)
reference memory errors, i.e., entries into unbaited arms; 3) total
arm entries; and 4) the test duration (seconds), i.e., the time
spent in the collection of all the pellets in the maze. If the
working memory error was zero and the average reference memory
error was less than one in five successive trials, the rats began
the drug tests. MK-801 or saline was injected 15 minutes prior to
vehicle or test agent, which was given 45 minutes before the test.
Experiments were performed in a lighted room, which contained
several extra-maze visual cues.
[0445] All data were analyzed by analyses of variance (ANOVA);
individual comparisons were made using Kewman-Keuls tests. Compared
to control, MK-801 (0.1 mg/kg, i.p.) increased the frequencies of
both working and reference memory errors (p<0.01). This amnesic
effect of MK-801 on working memory is reversed in a statistically
significant manner by the administration of actual test compounds
in a dose-dependent fashion.
[0446] The preceding examples can be repeated with similar success
by substituting the generically or specifically described reactants
and/or operating conditions of this invention for those used in the
preceding examples.
[0447] While the invention has been illustrated with respect to the
production and of particular compounds, is apparent that variations
and modifications of the invention can be made without departing
from the spirit or scope of the invention.
* * * * *
References