Amino-5,5-diphenylimidazolone derivatives for the inhibition of β-secretase
The present invention provides a compound of formula I and the use thereof for the therapeutic treatment, prevention or amelioration of a disease or disorder characterized by elevated β-amyloid deposits or β-amyloid levels in a patient.
1. A compound of formula I
wherein W is CO;
X is N, NO or CR 10 ;
Y is N, NO or CR 11 ;
Z is N, NO or CR 19 with the proviso that no more than two of X, Y or Z may be N or NO;
R 1 and R 2 are each independently H, COR 20 , CO 2 R 21 or an optionally substituted C 1 -C 4 alkyl group;
R 3 is H, OR 12 or a C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl or aryl(C 1 -C 6 )alkyl group each optionally substituted;
R 4 and R 5 are each independently H, halogen, NO 2 , CN, OR 13 , NR 14 R 15 or a C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or C 3 -C 8 cycloalkyl group each optionally substituted or when attached to adjacent carbon atoms R 4 and R 5 may be taken together with the atoms to which they are attached to form an optionally substituted 5- to 7-membered ring optionally containing one or two heteroatoms selected from O, N or S;
R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 19 are each independently H, halogen, NO 2 , CN, OR 16 , NR 17 R 18 or a C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or C 3 -C 8 cycloalkyl group each optionally substituted;
n is 0 or 1;
is a single bond when n is 0 or a double bond when n is 1;
R 12 , R 13 , R 16 , R 20 and R 21 are each independently H or a C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl or aryl group each optionally substituted; and
R 14 , R 15 , R 17 and R 18 are each independently H or C 1 -C 4 alkyl; or
a tautomer thereof, a stereoisomer thereof or a pharmaceutically acceptable salt thereof.
2. The compound according to claim 1 wherein R 3 is methyl.
3. The compound according to claim 1 wherein R 1 and R 2 are H and R 3 is C 1 -C 4 alkyl.
4. The compound according to claim 1 wherein n is 1.
5. The compound according to claim 1 having the structure Ia
wherein, R 5 is OR 13 or optionally substituted C 1 -C 6 alkyl.
6. The compound according to claim 1 having the structure Ib
7. The compound according to claim 6 wherein R 3 is methyl.
8. The compound according to claim 7 wherein Y is CR 11 and R 1 and R 2 are H.
9. The compound according to claim 1 selected from the group consisting of:
2-amino-5-(4-fluoro-3-pyrimidin-5-ylphenyl)-5-(4-methoxy-3-methylphenyl)-3-methyl-3,5-dihydro-4H-imidazol-4-one;
(5S)-2-amino-5-[3-(2-fluoropyridin-3-yl)phenyl]-5-(4-methoxy-3-methylphenyl)-3-methyl-3,5-dihydro-4H-imidazol-4-one;
2-amino-5-(4-methoxy-3-methylphenyl)-3-methyl-5-(3-pyrimidin-5-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;
(5S)-2-amino-5-(4-methoxy-3-methylphenyl)-3-methyl-5-(3-pyrimidin-5-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;
(5R)-2-amino-5-(4-fluoro-3-pyrimidin-5-ylphenyl)-3-methyl-5-[4-(trifluoromethoxy)phenyl]-3,5-dihydro-4H-imidazol-4-one;
4-[2-amino-4-(4-methoxy-3-methylphenyl)-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl]-2-pyridin-3-ylbenzonitrile;
2-amino-5-(4-methoxy-3-methylphenyl)-3-methyl-5-(4-methyl-3-pyridin-3-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;
2-amino-5-[4-methoxy-3-(trifluoromethyl)phenyl]-3-methyl-5-(3-pyridin-3-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;
2-amino-3-ethyl-5-(4-methoxy-3-methylphenyl)-5-(3-pyridin-3-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;
2-amino-5-(4-methoxy-3-methylphenyl)-3-methyl-5-(3-pyrazin-2-ylphenyl)-3,5-dihydro -4H-imidazol-4-one;
2-amino-3-methyl-5-(3-pyrimidin-2-ylphenyl)-5-[4-(trifluoromethoxy)phenyl]- 3,5-dihydro -4H-imidazol-4-one;
2-amino-5-(4-hydroxy-3-methylphenyl)-3-methyl-5-(3-pyridin-3-ylphenyl)-3,5-dihydro-4H -imidazol-4-one;
2-amino-5-[4-methoxy-3-(trifluoromethyl)phenyl]-3-methyl-5-(3-pyrazin-2-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;
(5R)-2-amino-5-(4-methoxy-3-methylphenyl)-3-methyl-5-(3-pyrimidin-5-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;
2-amino-5-(4-methoxy-3-methylphenyl)-3-methyl-5-(3-pyridin-3-ylphenyl)-3,5-dihydro -4H-imidazol-4-one;
2-amino-5-(3,4-diethoxyphenyl)-3-methyl-5-(3-pyridin-3-ylphenyl)-3,5-dihydro-4H -imidazol-4-one;
2-amino-5-(3,4-dimethoxyphenyl)-3-methyl-5-(3-pyridin-3-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;
2-amino-5-(3-cyclopentyl-4-methoxyphenyl)-3-methyl-5-(3-pyridin-3-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;
2-amino-5-(4-methoxy-3-propoxyphenyl)-3-methyl-5-(3-pyridin-3-ylphenyl)-3,5-dihydro -4H-imidazol-4-one;
2-amino-5-(3-butoxy-4-methoxyphenyl)-3-methyl-5-(3-pyridin-3-ylphenyl)-3,5-dihydro -4H-imidazol-4-one;
2-amino-5-(3-isopropoxy-4-methoxyphenyl)-3-methyl-5-(3-pyridin-3-ylphenyl)- 3,5-dihydro-4H-imidazol-4-one;
2-amino-5-(1,3-benzodioxol-5-yl)-3-methyl-5-(3-pyridin-3-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;
2-amino-5-(2,3-dihydro-1-benzofuran-5-yl)-3-methyl-5-(3-pyridin-3-ylphenyl)-3,5-dihydro -4H-imidazol-4-one;
2-amino-5-[3-(cyclopentyloxy)-4-methoxyphenyl]-3-methyl-5-(3-pyridin-3-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;
5-[2-amino-1-methyl-5-oxo-4-(3-pyridin-3-ylphenyl)-4,5-dihydro-1H-imidazol-4-yl]-2-methoxybenzonitrile;
2-amino-5-(3-fluoro-4-methoxyphenyl)-3-methyl-5-(3-pyridin-3-ylphenyl)-3,5-dihydro-4H- imidazol-4-one;
2-amino-5-(2,3-dihydro-1,4-benzodioxin-6-yl)-3-methyl-5-(3-pyridin-3-ylphenyl)-3,5- dihydro-4H-imidazol-4-one;
2-amino-5-(3-chloro-4-methoxyphenyl)-3-methyl-5-(3-pyridin-3-ylphenyl)-3,5-dihydro-4H- imidazol-4-one;
2-amino-3-methyl-5-(3-pyridin-3-ylphenyl)-5-(3,4,5-trimethoxyphenyl)-3,5-dihydro-4H- imidazol-4-one;
2-amino-5-(4-methoxy-3-methylphenyl)-3-methyl-5-(3-pyridin-4-ylphenyl)-3,5-dihydro- 4H-imidazol-4-one;
2-amino-5-(3-ethoxy-4-methoxyphenyl)-3-methyl-5-(3-pyridin-3-ylphenyl)-3,5-dihydro- 4H-imidazol-4-one;
2-amino-3-methyl-5-(3-pyridin-3-ylphenyl)-5-[4-(trifluoromethoxy)phenyl]- 3,5-dihydro-4H- imidazol-4-one;
2-amino-3-methyl-5-(3-pyridin-3-ylphenyl)-5-[(4-trifluoromethoxy-3- trifluoromethyl)phenyl]-3,5-dihydro-4H-imidazol-4-one;
2-amino-5-(3,4-diethoxyphenyl)-5-(4-fluoro-3-pyridin-3-ylphenyl)-3-methyl- 3,5-dihydro- 4H-imidazol-4-one;
2-amino-5-(3-chloro-4-trifluoromethoxyphenyl)-5-(4-fluoro-3-pyridin-3-ylphenyl)-3-methyl- 3,5-dihydro-4H-imidazol-4-one;
a tautomer thereof; a stereoisomer thereof; and
a pharmaceutically acceptable salt thereof.
10. A method for the treatment of Alzheimer's disease in a patient which comprises providing said patient with a therapeutically effective amount of a compound of formula I
wherein W is CO;
X is N, NO or CR 10;
Y is N, NO or CR 11;
Z is N, NO or CR 19 with the proviso that no more than two of X, Y or Z may be N or NO;
R 1 and R 2 are each independently H, COR 20 , CO 2 R 21 or an optionally substituted C 1 -C 4 alkyl group;
R 3 is H, OR 12 or a C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl or aryl(C 1 -C 6 )alkyl group each optionally substituted;
R 4 and R 5 are each independently H, halogen, NO 2 , CN, OR 13 , NR 14 R 15 or a C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or C 3 -C 8 cycloalkyl group each optionally substituted or when attached to adjacent carbon atoms R 4 and R 5 may be taken together with the atoms to which they are attached to form an optionally substituted 5- to 7-membered ring optionally containing one or two heteroatoms selected from O, N or S;
R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 19 are each independently H, halogen, NO 2 , CN, OR 16 , NR 17 R 18 or a C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or C 3 -C 8 cycloalkyl group each optionally substituted;
n is 0 or 1;
is a single bond when n is 0 or a double bond when n is 1;
R 12 , R 13 , R 16 , R 20 and R 21 are each independently H or a C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl or aryl group each optionally substituted; and
R 14 , R 15 , R 17 and R 18 are each independently H or C 1 -C 4 alkyl; or a tautomer thereof, a stereoisomer thereof or a pharmaceutically acceptable salt thereof.
11. The method according to claim 10 having a formula I compound wherein the structure is
wherein R 5 is OR 13 or optionally substituted C 1 -C 6 alkyl.
12. The method according to claim 10 having a formula I compound wherein the structure is
13. A pharmaceutical composition which comprises a pharmaceutically acceptable carrier and an effective amount of a compound of formula I
wherein W is CO;
X is N, NO or CR 10 ;
Y is N, NO or CR 11 ;
Z is N, NO or CR 19 with the proviso that no more than two of X, Y or Z may be N or NO;
R 1 and R 2 are each independently H, COR 20 , CO 2 R 21 or an optionally substituted C 1 -C 4 alkyl group;
R 3 is H, OR 12 or a C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl or aryl(C 1 -C 6 )alkyl group each optionally substituted;
R 4 and R 5 are each independently H, halogen, NO 2 , CN, OR 13 , NR 14 R 15 or a C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or C 3 -C 8 cycloalkyl group each optionally substituted or when attached to adjacent carbon atoms R 4 and R 5 may be taken together with the atoms to which they are attached to form an optionally substituted 5- to 7-membered ring optionally containing one or two heteroatoms selected from O, N or S; R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 19 are each independently H, halogen, NO 2 , CN, OR 16 , NR 17 R 18 or a C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or C 3 -C 8 cycloalkyl group each optionally substituted;
n is 0 or 1;
is a single bond when n is 0 or a double bond when n is 1;
R 12 , R 13 , R 16 , R 20 and R 21 are each independently H or a C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl or aryl group each optionally substituted; and
R 14 , R 15 , R 17 and R 18 are each independently H or C 1 -C 4 alkyl; or a tautomer thereof, a stereoisomer thereof or a pharmaceutically acceptable salt thereof.
14. The composition according to claim 13 having a formula I compound wherein the structure is Ia
wherein, R 5 is OR 13 or optionally substituted C 1 -C 6 alkyl.
15. The composition according to claim 13 having a formula I compound wherein the structure is Ib
16. The composition according to claim 15 wherein R 1 and R 2 are H; R 3 is methyl; and Y is CR 11 .
17. The composition according to claim 13 having a formula I compound selected from the group consisting of:
2-amino-5-(4-fluoro-3-pyrimidin-5-ylphenyl)-5-(4-methoxy-3-methylphenyl)-3-methyl-3,5- dihydro-4H-imidazol-4-one;
(5S)-2-amino-5-[3-(2-fluoropyridin-3-yl)phenyl]-5-(4-methoxy-3-methylphenyl)-3-methyl-3,5-dihydro-4H-imidazol-4-one;
2-amino-5-(4-methoxy-3-methylphenyl)-3-methyl-5-(3-pyrimidin-5-ylphenyl)-3,5-dihydro-4H -imidazol-4-one;
(5S)-2-amino-5-(4-methoxy-3-methylphenyl)-3-methyl-5-(3-pyrimidin-5-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;
(5R)-2-amino-5-(4-fluoro-3-pyrimidin-5-ylphenyl)-3-methyl-5-[4-(trifluoromethoxy)phenyl]-3,5-dihydro-4H-imidazol-4-one;
4-[2-amino-4-(4-methoxy-3-methylphenyl)-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl]-2-pyridin-3-ylbenzonitrile;
2-amino-5-(4-methoxy-3-methylphenyl)-3-methyl-5-(4-methyl-3-pyridin-3-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;
2-amino-5-[4-methoxy-3-(trifluoromethyl)phenyl]-3-methyl-5-(3-pyridin-3-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;
2-amino-3-ethyl-5-(4-methoxy-3-methylphenyl)-5-(3-pyridin-3-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;
2-amino-5-(4-methoxy-3-methylphenyl)-3-methyl-5-(3-pyrazin-2-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;
2-amino-3-methyl-5-(3-pyrimidin-2-ylphenyl)-5-[4-(trifluoromethoxy)phenyl]-3,5-dihydro-4H-im dazol-4-one;
2-amino-5-(4-hydroxy-3-methylphenyl)-3-methyl-5-(3-pyridin-3-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;
2-amino-5-[4-methoxy-3-(trifluoromethyl)phenyl]-3-methyl-5-(3-pyrazin-2-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;
(5R)-2-amino-5-(4-methoxy-3-methylphenyl)-3-methyl-5-(3-pyrimidin-5-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;
2-amino-5-(4-methoxy-3-methylphenyl)-3-methyl-5-(3-pyridin-3-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;
2-amino-5-(3,4-diethoxyphenyl)-3-methyl-5-(3-pyridin-3-ylphenyl)-3,5-dihydro-4H-midazol-4-one;
2-amino-5-(3,4-dimethoxyphenyl)-3-methyl-5-(3-pyridin-3-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;
2-amino-5-(3-cyclopentyl-4-methoxyphenyl)-3-methyl-5-(3-pyridin-3-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;
2-amino-5-(4-methoxy-3-propoxyphenyl)-3-methyl-5-(3-pyridin-3-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;
2-amino-5-(3-butoxy-4-methoxyphenyl)-3-methyl-5-(3-pyridin-3-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;
2-amino-5-(3-isopropoxy-4-methoxyphenyl)-3-methyl-5-(3-pyridin-3-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;
2-amino-5-(1,3-benzodioxol-5-yl)-3-methyl-5-(3-pyridin-3-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;
2-amino-5-(2,3-dihydro-1-benzofuran-5-yl)-3-methyl-5-(3-pyridin-3-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;
2-amino-5-[3-(cyclopentyloxy)-4-methoxyphenyl]-3-methyl-5-(3-pyridin-3-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;
5-[2-amino-1-methyl-5-oxo-4-(3-pyridin-3-ylphenyl)-4,5-dihydro-1H-imidazol-4-yl]-2-methoxybenzonitrile;
2-amino-5-(3-fluoro-4-methoxyphenyl)-3-methyl-5-(3-pyridin-3-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;
2-amino-5-(2,3-dihydro-1,4-benzodioxin-6-yl)-3-methyl-5-(3-pyridin-3-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;
2-amino-5-(3-chloro-4-methoxyphenyl)-3-methyl-5-(3-pyridin-3-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;
2-amino-3-methyl-5-(3-pyridin-3-ylphenyl)-5-(3,4,5-trimethoxyphenyl)-3,5-dihydro-4H-imidazol-4-one;
2-amino-5-(4-methoxy-3-methylphenyl)-3-methyl-5-(3-pyridin-4-ylphenyl)-3,5-dihydro-4H -imidazol-4-one;
2-amino-5-(3-ethoxy-4-methoxyphenyl)-3-methyl-5-(3-pyridin-3-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;
2-amino-3-methyl-5-(3-pyridin-3-ylphenyl)-5-[4-(trifluoromethoxy)phenyl]-3,5-dihydro-4H-imidazol-4-one;
2-amino-3-methyl-5-(3-pyridin-3-ylphenyl)-5-[(4-trifluoromethoxy-3-trifluoromethyl)phenyl]-3,5-dihydro-4H-imidazol-4-one;
2-amino-5-(3,4-diethoxyphenyl)-5-(4-fluoro-3-pyridin-3-ylphenyl)-3-methyl-3,5-dihydro-4H -imidazol-4-one;
2-amino-5-(3-chloro-4-trifluoromethoxyphenyl)-5-(4-fluoro-3-pyridin-3-ylphenyl)-3-methyl-3,5-dihydro-4H-imidazol-4-one;
a tautomer thereof; a stereoisomer thereof; and
a pharmaceutically acceptable salt thereof.
18. A process for the preparation of a compound of formula I
wherein W is CO;
X is N, NO or CR 10 ;
Y is N, NO or CR 11 ;
Z is N, NO or CR 19 with the proviso that no more than two of X, Y or Z may be N or NO;
R 1 and R 2 are each independently H, COR 20 , CO 2 R 21 or an optionally substituted C 1 -C 4 alkyl group;
R 3 is H, OR 12 or a C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl or aryl(C 1 -C 6 )alkyl group each optionally substituted;
R 4 and R 5 are each independently H, halogen, NO 2 , CN, OR 13 , NR 14 R 15 or a C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or C 3 -C 8 cycloalkyl group each optionally substituted or when attached to adjacent carbon atoms R 4 and R 5 may be taken together with the atoms to which they are attached to form an optionally substituted 5- to 7-membered ring optionally containing one or two heteroatoms selected from O, N or S;
R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 19 are each independently H, halogen, NO 2 , CN, OR 16 , NR 17 R 18 or a C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or C 3 -C 8 cycloalkyl group each optionally substituted;
n is 0 or 1;
is a single bond when n is 0 or a double bond when n is 1;
R 12 , R 13 , R 16 , R 20 and R 21 are each independently H or a C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl or aryl group each optionally substituted; and
R 14 , R 15 , R 17 and R 18 are each independently H or C 1 -C 4 alkyl
which process comprises reacting a compound of formula II
wherein Ha is Cl or Br and W, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are as described for formula I hereinabove with a compound of formula III
wherein Q is B(OH) 2 , Sn(n.Bu) 3 or Sn(CH 3 ) 3 and X, Y, Z, R 8 , R 9 and n are as described for formula I hereinabove in the presence of a palladium catalyst optionally in the presence of a solvent.