Diaminediols for the treatment of Alzheimer's disease
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Abstract
The present invention relates to compounds of formula (I):
useful in treating Alzheimer'"'"'s disease and other similar diseases. These compounds include inhibitors of the beta-secretase enzyme that are useful in the treatment of Alzheimer'"'"'s disease and other diseases characterized by deposition of A beta peptide in a mammal. The compounds of the invention are useful in pharmaceutical compositions and methods of treatment to reduce A beta peptide formation.
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Citations
14 Claims
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1. A compound of the formula I:
- View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11)
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2. A compound according to claim 1 with the proviso that neither RN nor RN′
- is an alpha amino acid.
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3. A compound according to claim 2 wherein
R20 at each occurrence is H; - and
R1 is C1-C10 alkyl optionally substituted with 1, 2, or 3 groups independently selected from halogen, —
OH, ═
O, —
SH, —
C≡
N, —
CF3, —
C1-C3 alkoxy, —
S—
(C1-C3) alkyl, amino, mono- or dialkylamino, —
N(R)C(O)R′
—
, —
OC(═
O)-amino and —
OC(═
O)-mono- or dialkylamino, orC2-C6 alkenyl or C2-C6 alkynyl, each of which is optionally substituted with 1, 2, or 3 groups independently selected from halogen, —
OH, —
SH, —
C≡
N, —
CF3, C1-C3 alkoxy, amino, and mono- or dialkylamino.
- and
-
4. A compound according to claim 3 wherein
R1′ - is
—
CH2-phenyl where the phenyl ring is optionally substituted with 1, 2, 3, or 4 groups independently selected from halogen, C1-C4 alkoxy, hydroxy, —
NO2, andC1-C4 alkyl optionally substituted with 1, 2, or 3 substituents independently selected from halogen, OH, SH, NH2, NH(C1-C6 alkyl), N—
(C1-C6 alkyl)(C1-C6 alkyl), C≡
N, CF3.
- is
-
5. A compound according to claim 4 wherein
RN and RN′ - are independently —
C(═
O)—
(CRR′
)0-6R100; and
R100 represents aryl, heteroaryl, heterocyclyl, where the ring portions of each are optionally substituted with 1, 2, or 3 groups independently selected from —
OR, —
NO2, C1-C6 alkyl, halogen, —
C≡
N, —
OCF3, —
CF3, —
(CH2)0-4—
O—
P ═
O—
O)(OR)(OR′
), —
(CH2)0-4—
CO—
NR105R′
105, —
(CH2)0-4—
O—
(CH2)0-4—
CONR102R102′
, —
(CH2)0-4—
CO—
(C1-C12 alkyl), —
(CH2)0-4—
CO—
(C2-C12 alkenyl), —
(CH2)0-4—
CO—
(C2-C12 alkynyl), —
(CH2)0-4—
CO—
(CH2)0-4(C3-C7 cycloalkyl), —
(CH2)0-4—
R110, —
(CH2)0-4—
R120, —
(CH2)0-4—
R130, —
(CH2)0-4—
CO—
R110, —
(CH2)0-4—
CO—
R120, —
(CH2)0-4—
CO—
R130, —
(CH2)0-4—
CO—
R140, —
(CH2)0-4—
CO—
O—
R150, —
(CH2)0-4—
SO2—
NR105R′
105, —
(CH2)0-4—
SO—
(C1-C8 alkyl), —
(CH2)0-4—
SO2—
(C1-C12 alkyl), —
(CH2)0-4—
SO2—
(CH2)0-4—
(C3-C7 cycloalkyl), —
(CH2)0-4—
N(R150)—
CO—
O—
R150, —
(CH2)0-4—
N(R150)—
CO—
N(R150)2, —
(CH2)0-4—
N(R150)—
CS—
N(R150)2, —
(CH2)0-4—
N(R150)—
CO—
R105, —
(CH2)0-4—
NR105R′
105, —
(CH2)0-4—
R140, —
(CH2)0-4—
O—
CO—
(C1-C6 alkyl), —
(CH2)0-4—
O—
P(O)—
(O—
R110)2, —
(CH2)04—
O—
CO—
N(R150)2, —
(CH2)0-4—
O—
CS—
N(R150)2, —
(CH2)0-4—
O—
(R150), —
(CH2)0-4—
O—
R150′
—
COOH, —
(CH2)0-4—
S—
(R150), —
(CH2)0-4—
N(R150)—
SO2—
R105, —
(CH2)0-4—
C3-C7 cycloalkyl, (C2-C10)alkenyl, and (C2-C1-0)alkynyl, orR100 is C1-C10 alkyl optionally substituted with 1, 2, or 3 R115 groups.
- are independently —
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6. A compound according to claim 5 wherein
RN and RN′ - are independently —
C(═
O)-aryl or —
C(═
O)—
heteroaryl optionally substituted with 1, 2, or 3 groups independently selected from—
OR, —
NO2, C1-C6 alkyl, halogen, —
C≡
N, —
OCF3, —
CF3, —
(CH2)0-4—
CO—
NR105R′
105 and —
(CH2)0-4—
N(R150)—
SO2 —
R105, orRN and RN′
are independently —
C(═
O)—
C1-C10 alkyl optionally substituted with 1, 2, or 3 groups independently selected from halogen, —
OH, —
CO2R102, —
C1-C6 thioalkoxy, —
CO2-phenyl, —
NR105R′
105, —
SO2—
(C1-C8 alkyl), —
C(═
O)R180, R180, —
CONR105R′
105, —
SO2NR105R′
105, —
NH—
CO—
(C1-C6 alkyl), —
NH—
CO—
R110, —
NH—
CO—
R120, —
NH—
C(═
O)—
OH, —
NH—
C(═
O)—
OR, —
NH—
C(═
O)—
O-phenyl, —
O—
C(═
O)—
(C1-C6 alkyl), —
O—
C(═
O)-amino, —
O—
C(═
O)-mono- or dialkylamino, —
O—
C(═
O)-phenyl, —
O—
(C1-C6 alkyl)-CO2H, —
NH—
SO2—
(C1-C6 alkyl), C1-C6 alkoxy and C1-C6 haloalkoxy.
- are independently —
-
7. A compound according to claim 6 selected from the group consisting of:
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5-(acetylamino)-1,2,5,6-tetradeoxy-2-[({2-[methyl(methylsulfonyl)amino]-1,3-thiazol-4-yl}carbonyl)amino]-1-phenyl-D-glucitol, 5-(benzoylamino)-1,2,5,6-tetradeoxy-2-[({2-[methyl(methylsulfonyl)amino]-1,3-thiazol-4-yl}carbonyl)amino]-1-phenyl-D-glucitol, N-[(1S,2R,3R,4R)-4-(acetylamino)-1-benzyl-2,3-dihydroxyoctyl]-2-[methyl(methylsulfonyl)amino]-1,3-thiazole-4-carboxamide, N-[(1S,2R,3R,4R)-4-(benzoylamino)-1-benzyl-2,3-dihydroxyoctyl]-2-[methyl(methylsulfonyl)amino]-1,3-thiazole-4-carboxamide, 5-(acetylamino)-1,2,5,6-tetradeoxy-7-S-methyl-2-[({2-[methyl(methylsulfonyl)amino]-1,3-thiazol-4-yl}carbonyl)amino]-1-phenyl-7-thio-D-gluco-heptitol, 5-(benzoylamino)-1,2,5,6-tetradeoxy-7-S-methyl-2-[({2-[methyl(methylsulfonyl)amino]-1,3-thiazol-4-yl}carbonyl)amino]-1-phenyl-7-thio-D-gluco-heptitol, 5-(acetylamino)-1,2,5,6-tetradeoxy-7-O-methyl-2-[({2-[methyl(methylsulfonyl)amino]-1,3-thiazol-4-yl}carbonyl)amino]-1-phenyl-D-gluco-heptitol, 5-(benzoylamino)-1,2,5,6-tetradeoxy-7-O-methyl-2-[({2-[methyl(methylsulfonyl)amino]-1,3-thiazol-4-yl}carbonyl)amino]-1-phenyl-D-gluco-heptitol, 5-(acetylamino)-6-cyano-1,2,5,6-tetradeoxy-2-[({2-[methyl(methylsulfonyl)amino]-1,3-thiazol-4-yl}carbonyl)amino]-1-phenyl-D-glucitol, 5-(benzoylamino)-6-cyano-1,2,5,6-tetradeoxy-2-[({2-[methyl(methylsulfonyl)amino]-1,3-thiazol-4-yl}carbonyl)amino]-1-phenyl-D-glucitol, 5-(acetylamino)-1,2,5,6-tetradeoxy-2-[({2-[(methylsulfonyl)amino]-1,3-thiazol-4-yl}carbonyl)amino]-1-phenyl-D-glucitol, 5-(benzoylamino)-1,2,5,6-tetradeoxy-2-[({2-[(methylsulfonyl)amino]-1,3-thiazol-4-yl}carbonyl)amino]-1-phenyl-D-glucitol, N-[(1S,2R,3R,4R)-4-(acetylamino)-1-benzyl-2,3-dihydroxyoctyl]-2-[(methylsulfonyl)amino]-1,3-thiazole-4-carboxamide, N-[(1S,2R,3R,4R)-4-(benzoylamino)-1-benzyl-2,3-dihydroxyoctyl]-2-[(methylsulfonyl)amino]-1,3-thiazole-4-carboxamide, 5-(acetylamino)-1,2,5,6-tetradeoxy-7-S-methyl-2-[({2-[(methylsulfonyl)amino]-1,3-thiazol-4-yl}carbonyl)amino]-1-phenyl-7-thio-D-gluco-heptitol, 5-(benzoylamino)-1,2,5,6-tetradeoxy-7-S-methyl-2-[({2-[(methylsulfonyl)amino]-1,3-thiazol-4-yl}carbonyl)amino]-1-phenyl-7-thio-D-gluco-heptitol, 5-(acetylamino)-1,2,5,6-tetradeoxy-7-O-methyl-2-[({2-[(methylsulfonyl)amino]-1,3-thiazol-4-yl}carbonyl)amino]-1-phenyl-D-gluco-heptitol, 5-(benzoylamino)-1,2,5,6-tetradeoxy-7-O-methyl-2-[({2-[(methylsulfonyl)amino]-1,3-thiazol-4-yl}carbonyl)amino]-1-phenyl-D-gluco-heptitol, 5-(acetylamino)-6-cyano-1,2,5,6-tetradeoxy-2-[({2-[(methylsulfonyl)amino]-1,3-thiazol-4-yl}carbonyl)amino]-1-phenyl-D-glucitol, 5-(benzoylamino)-6-cyano-1,2,5,6-tetradeoxy-2-[({2-[(methylsulfonyl)amino]-1,3-thiazol-4-yl}carbonyl)amino]-1-phenyl-D-glucitol, 5-(acetylamino)-1,2,5,6-tetradeoxy-2-[({2-[methyl(methylsulfonyl)amino]-1,3-oxazol-4-yl}carbonyl)amino]-1-phenyl-D-glucitol, 5-(benzoylamino)-1,2,5,6-tetradeoxy-2-[({2-[methyl(methylsulfonyl)amino]-1,3-oxazol-4-yl}carbonyl)amino]-1-phenyl-D-glucitol, N-[(1S,2R,3R,4R)-4-(acetylamino)-1-benzyl-2,3-dihydroxyoctyl]-2-[methyl(methylsulfonyl)amino]-1,3-oxazole-4-carboxamide, N-[(1S,2R,3R,4R)-4-(benzoylamino)-1-benzyl-2,3-dihydroxyoctyl]-2-[methyl(methylsulfonyl)amino]-1,3-oxazole-4-carboxamide, 5-(acetylamino)-1,2,5,6-tetradeoxy-7-s-methyl-2-[({2-[methyl(methylsulfonyl)amino]-1,3-oxazol-4-yl}carbonyl)amino]1-1-phenyl-7-thio-D-gluco-heptitol, 5-(benzoylamino)-1,2,5,6-tetradeoxy-7-S-methyl-2-[({2-[methyl(methylsulfonyl)amino]-1,3-oxazol-4-yl}carbonyl)amino]-1-phenyl-7-thio-D-gluco-heptitol, 5-(acetylamino)-1,2,5,6-tetradeoxy-7-O-methyl-2-[({2-[methyl(methylsulfonyl)amino]-1,3-oxazol-4-yl}carbonyl)amino]-1-phenyl-D-gluco-heptitol, 5-(benzoylamino)-1,2,5,6-tetradeoxy-7-O-methyl-2-[({2-[methyl(methylsulfonyl)amino]-1,3-oxazol-4-yl}carbonyl)amino]-1-phenyl-D-gluco-heptitol, 5-(acetylamino)-6-cyano-1,2,5,6-tetradeoxy-2-[({2-[methyl(methylsulfonyl)amino]-1,3-oxazol-4-yl}carbonyl)amino]-1-phenyl-D-glucitol, 5-(benzoylamino)-6-cyano-1,2,5,6-tetradeoxy-2-[({2-[methyl(methylsulfonyl)amino]-1,3-oxazol-4-yl}carbonyl)amino]-1-phenyl-D-glucitol, 5-(acetylamino)-1,2,5,6-tetradeoxy-2-[({2-[(methylsulfonyl)amino]-1,3-oxazol-4-yl}carbonyl)amino]-1-phenyl-D-glucitol, 5-(benzoylamino)-1,2,5,6-tetradeoxy-2-[({2-[(methylsulfonyl)amino]-1,3-oxazol-4-yl}carbonyl)amino]-1-phenyl-D-glucitol, N-[(1S,2R,3R,4R)-4-(acetylamino)-1-benzyl-2,3-dihydroxyoctyl]-2-[(methylsulfonyl)amino]-1,3-oxazole -4-carboxamide, N-[(1S,2R,3R,4R)-4-(benzoylamino)-1-benzyl-2,3-dihydroxyoctyl]-2-[(methylsulfonyl)amino]-1,3-oxazole -4-carboxamide, 5-(acetylamino)-1,2,5,6-tetradeoxy-7-S-methyl-2-[({2-[(methylsulfonyl)amino]-1,3-oxazol-4-yl}carbonyl)amino]-1-phenyl-7-thio-D-gluco-heptitol, 5-(benzoylamino)-1,2,5,6-tetradeoxy-7-S-methyl-2-[({2-[(methylsulfonyl)amino]-1,3-oxazol-4-yl}carbonyl)amino]-1-phenyl-7-thio-D-gluco-heptitol, 5-(acetylamino)-1,2,5,6-tetradeoxy-7-O-methyl-2-[({2-[(methylsulfonyl)amino]-1,3-oxazol-4-yl}carbonyl)amino]-1-phenyl-D-gluco-heptitol, 5-(benzoylamino)-1,2,5,6-tetradeoxy-7-O-methyl-2-[({2-[(methylsulfonyl)amino]-1,3-oxazol-4-yl}carbonyl)amino]-1-phenyl-D-gluco-heptitol, 5-(acetylamino)-6-cyano-1,2,5,6-tetradeoxy-2-[({2-[(methylsulfonyl)amino]-1,3-oxazol-4-yl}carbonyl)amino]-1-phenyl-D-glucitol, 5-(benzoylamino)-6-cyano-1,2,5,6-tetradeoxy-2-[({2-[(methylsulfonyl)amino]-1,3-oxazol-4-yl}carbonyl)amino]-1-phenyl-D-glucitol, 5-(acetylamino)-1,2,5,6-tetradeoxy-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-1-phenyl-D-glucitol, 5-(benzoylamino)-1,2,5,6-tetradeoxy-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-1-phenyl-D-glucitol, N′
-[(1S,2R,3R,4R)-4-(acetylamino)-1-benzyl-2,3-dihydroxyoctyl]-5-methyl-N,N-dipropylisophthalamide,N′
-[(1S,2R,3R,4R)-4-(benzoylamino)-1-benzyl-2,3-dihydroxyoctyl]-5-methyl-N,N-dipropylisophthalamide,5-(acetylamino)-1,2,5,6-tetradeoxy-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-7-S-methyl -1-phenyl-7-thio-D-gluco-heptitol, 5-(benzoylamino)-1,2,5,6-tetradeoxy-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-7-S-methyl -1-phenyl-7-thio-D-gluco-heptitol, 5-(acetylamino)-1,2,5,6-tetradeoxy-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-7-O-methyl -1-phenyl-D-gluco-heptitol, 5-(benzoylamino)-1,2,5,6-tetradeoxy-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-7-O-methyl -1-phenyl-D-gluco-heptitol, 5-(acetylamino)-6-cyano-1,2,5,6-tetradeoxy-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-1-phenyl-D-glucitol, 5-(benzoylamino)-6-cyano-1,2,5,6-tetradeoxy-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino) -1-phenyl-D-glucitol, 5-(acetylamino)-2-({3-(aminocarbonyl)-5-[(dipropylamino)carbonyl]benzoyl}amino)-1,2,5,6-tetradeoxy-1-phenyl-D-glucitol, 2-({3-(aminocarbonyl)-5-[(dipropylamino)carbonyl]benzoyl}amino)-5-(benzoylamino)-1,2,5,6-tetradeoxy-1-phenyl-D-glucitol, N3-[(1S,2R,3R,4R)-4-(acetylamino)-1-benzyl-2,3-dihydroxyoctyl]-N1,N1-dipropylbenzene-1,3,5-tricarboxamide, N3-[(1S,2R,3R,4R)-4-(benzoylamino)-1-benzyl-2,3-dihydroxyoctyl]-N1,N1-dipropylbenzene-1,3,5-tricarboxamide, 5-(acetylamino)-2-({3-(aminocarbonyl)-5-[(dipropylamino)carbonyl]benzoyl}amino)-1,2,5,6-tetradeoxy-7-S-methyl-1-phenyl-7-thio-D-gluco-heptitol, 2-({3-(aminocarbonyl)-5-[(dipropylamino)carbonyl]benzoyl}amino)-5-(benzoylamino)-1,2,5,6-tetradeoxy-7-S-methyl-1-phenyl -7-thio-D-gluco-heptitol, 5-(acetylamino)-2-({3-(aminocarbonyl)-5-[(dipropylamino)carbonyl]benzoyl}amino)-1,2,5,6-tetradeoxy-7-O-methyl-1-phenyl-D-gluco-heptitol, 2-({3-(aminocarbonyl)-5-[(dipropylamino)carbonyl]benzoyl}amino)-5-(benzoylamino)-1,2,5,6-tetradeoxy-7-O-methyl-1-phenyl-D-gluco-heptitol, 5-(acetylamino)-2-({3-(aminocarbonyl)-5-[(dipropylamino)carbonyl]benzoyl}amino)-6-cyano -1,2,5,6-tetradeoxy-1-phenyl-D-glucitol, 2-({3-(aminocarbonyl)-5-[(dipropylamino)carbonyl]benzoyl}amino)-5-(benzoylamino)-6-cyano-1,2,5,6-tetradeoxy-1-phenyl-D-glucitol, 5-(acetylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-D-glucitol, 5-(benzoylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-D-glucitol, N′
-[(1S,2R,3R,4R)-4-(acetylamino)-1-(3,5-difluorobenzyl)-2,3-dihydroxyoctyl]-5-methyl-N,N-dipropylisophthalamide,N′
-[(1S,2R,3R,4R)-4-(benzoylamino)-1-(3,5-difluorobenzyl)-2,3-dihydroxyoctyl]-5-methyl-N,N-dipropylisophthalamide,5-(acetylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-7-S-methyl-7-thio-D-gluco-heptitol, 5-(benzoylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-7-S-methyl-7-thio-D-gluco-heptitol, 5-(acetylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-7-O-methyl-D-gluco-heptitol, 5-(benzoylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-7-O-methyl-D-gluco-heptitol, 5-(acetylamino)-6-cyano-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-D-glucitol, 5-(benzoylamino)-6-cyano-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-D-glucitol, 5-(acetylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-2-[({2-[methyl(methylsulfonyl)amino]-1,3-thiazol-4-yl}carbonyl)amino]-D-glucitol, 5-(benzoylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-2-[({2-[methyl(methylsulfonyl)amino]-1,3-thiazol-4-yl}carbonyl)amino]-D-glucitol, N-[(1S,2R,3R,4R)-4-(acetylamino)-1-(3,5-difluorobenzyl)-2,3-dihydroxyoctyl]-2-[methyl(methylsulfonyl)amino]-1,3-thiazole-4-carboxamide, N-[(1S,2R,3R,4R)-4-(benzoylamino)-1-(3,5-difluorobenzyl)-2,3-dihydroxyoctyl]-2-[methyl(methylsulfonyl)amino]-1,3-thiazole-4-carboxamide, 5-(acetylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-7-S-methyl-2-[({2-[methyl(methylsulfonyl)amino]-1,3-thiazol-4-yl}carbonyl)amino]-7-thio-D-gluco-heptitol, 5-(benzoylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-7-S-methyl-2-[({2-[methyl(methylsulfonyl)amino]-1,3-thiazol-4-yl}carbonyl)amino]-7-thio-D-gluco-heptitol, 5-(acetylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-7-O-methyl-2-[({2-[methyl(methylsulfonyl)amino]-1,3-thiazol-4-yl}carbonyl)amino]-D-gluco-heptitol, 5-(benzoylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-7-O-methyl-2-[({2-[methyl(methylsulfonyl)amino]-1,3-thiazol-4-yl}carbonyl)amino]-D-gluco-heptitol, 5-(acetylamino)-6-cyano-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-2-[({2-[methyl(methylsulfonyl)amino]-1,3-thiazol-4-yl}carbonyl)amino]-D-glucitol, 5-(benzoylamino)-6-cyano-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-2-[({2-[methyl(methylsulfonyl)amino]-1,3-thiazol-4-yl}carbonyl)amino]-D-glucitol, 5-(acetylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-2-[({2-[(methylsulfonyl)amino]-1,3-thiazol-4-yl}carbonyl)amino]-D-glucitol, 5-(benzoylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-2-[({2-[(methylsulfonyl)amino]-1,3-thiazol-4-yl}carbonyl)amino]-D-glucitol, N-[(1S,2R,3R,4R)-4-(acetylamino)-1-(3,5-difluorobenzyl)-2,3-dihydroxyoctyl]-2-[(methylsulfonyl)amino]-1,3-thiazole-4-carboxamide, N-[(1S,2R,3R,4R)-4-(benzoylamino)-1(3,5-difluorobenzyl)-2,3-dihydroxyoctyl]-2-[(methylsulfonyl)amino]-1,3-thiazole-4-carboxamide, 5-(acetylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-7-S-methyl-2-[({2-[(methylsulfonyl)amino]-1,3-thiazol-4-yl}carbonyl)amino]-7-thio-D-gluco-heptitol, 5-(benzoylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-7-S-methyl-2-[({2-[(methylsulfonyl)amino]-1,3-thiazol-4-yl}carbonyl)amino]-7-thio-D-gluco-heptitol, 5-(acetylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-7-O-methyl-2-[({2-[(methylsulfonyl)amino]-1,3-thiazol-4-yl}carbonyl)amino]-D-gluco-heptitol, 5-(benzoylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-7-O-methyl-2-[({2-[(methylsulfonyl)amino]-1,3-thiazol-4-yl}carbonyl)amino]-D-gluco-heptitol, 5-(acetylamino)-6-cyano-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-2-[({2-[(methylsulfonyl)amino]-1,3-thiazol-4-yl}carbonyl)amino]-D-glucitol, 5-(benzoylamino)-6-cyano-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-2-[({2-[(methylsulfonyl)amino]-1,3-thiazol-4-yl}carbonyl)amino]-D-glucitol, 5-(acetylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-2-[({2-[methyl(methylsulfonyl)amino]-1,3-oxazol-4-yl}carbonyl)amino]-D-glucitol, 5-(benzoylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-2-[({2-[methyl(methylsulfonyl)amino]-1,3-oxazol-4-yl}carbonyl)amino]-D-glucitol, N-[(1S,2R,3R,4R)-4-(acetylamino)-1-(3,5-difluorobenzyl)-2,3-dihydroxyoctyl]-2-[methyl(methylsulfonyl)amino]-1,3-oxazole-4-carboxamide, N-[(1S,2R,3R,4R)-4-(benzoylamino)-1(3,5-difluorobenzyl)-2,3-dihydroxyoctyl]-2-[methyl(methylsulfonyl)amino]-1,3-oxazole-4-carboxamide, 5-(acetylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-7-S-methyl-2-[({2-[methyl(methylsulfonyl)amino]-1,3-oxazol-4-yl}carbonyl)amino]-7-thio-D-gluco-heptitol, 5-(benzoylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-7-S-methyl-2-[({2-[methyl(methylsulfonyl)amino]-1,3-oxazol-4-yl}carbonyl)amino]-7-thio-D-gluco-heptitol, 5-(acetylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-7-O-methyl-2-[({2-[methyl(methylsulfonyl)amino]-1,3-oxazol-4-yl}carbonyl)amino]-D-gluco-heptitol, 5-(benzoylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-7-O-methyl-2-[({2-[methyl(methylsulfonyl)amino]-1,3-oxazol-4-yl}carbonyl)amino]-D-gluco-heptitol, 5-(acetylamino)-6-cyano-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-2-[({2-[methyl(methylsulfonyl)amino]-1,3-oxazol-4-yl}carbonyl)amino]-D-glucitol, 5-(benzoylamino)-6-cyano-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-2-[({2-[methyl(methylsulfonyl)amino]-1,3-oxazol-4-yl}carbonyl)amino]-D-glucitol, 5-(acetylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-2-[({2-[(methylsulfonyl)amino]-1,3-oxazol-4-yl}carbonyl)amino]-D-glucitol, 5-(benzoylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-2-[({2-[(methylsulfonyl)amino]-1,3-oxazol-4-yl}carbonyl)amino]-D-glucitol, N-[(1S,2R,3R,4R)-4-(acetylamino)-1-(3,5-difluorobenzyl)-2,3-dihydroxyoctyl]-2-[(methylsulfonyl)amino]-1,3-oxazole-4-carboxamide, N-[(1S,2R,3R,4R)-4-(benzoylamino)-1-(3,5-difluorobenzyl)-2,3-dihydroxyoctyl]-2-[(methylsulfonyl)amino]-1,3-oxazole-4-carboxamide, 5-(acetylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-7-S-methyl-2-[({2-[(methylsulfonyl)amino]-1,3-oxazol-4-yl}carbonyl)amino]-7-thio-D-gluco-heptitol, 5-(benzoylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-7-S-methyl-2-[({2-[(methylsulfonyl)amino]-1,3-oxazol-4-yl}carbonyl)amino]-7-thio-D-gluco-heptitol, 5-(acetylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-7-O-methyl-2-[({2-[(methylsulfonyl)amino]-1,3-oxazol-4-yl}carbonyl)amino]-D-gluco-heptitol, 5-(benzoylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-7-O-methyl-2-[({2-[(methylsulfonyl)amino]-1,3-oxazol-4-yl}carbonyl)amino]-D-gluco-heptitol, 5-(acetylamino)-6-cyano-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-2-[({2-[(methylsulfonyl)amino]-1,3-oxazol-4-yl}carbonyl)amino]-D-glucitol, 5-(benzoylamino)-6-cyano-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-2-[({2-[(methylsulfonyl)amino]-1,3-oxazol-4-yl}carbonyl)amino]-D-glucitol, 5-(acetylamino)-2-({3-(aminocarbonyl)-5-[(dipropylamino)carbonyl]benzoyl}amino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-D-glucitol, 2-({3-(aminocarbonyl)-5-[(dipropylamino)carbonyl]benzoyl}amino)-5-(benzoylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-D-glucitol, N3-[(1S,2R,3R,4R)-4-(acetylamino)-1-(3,5-difluorobenzyl)-2,3-dihydroxyoctyl]-N1,N1-dipropylbenzene-1,3,5-tricarboxamide, N3-[(1S,2R,3R,4R)-4(benzoylamino)-1-(3,5-difluorobenzyl)-2,3-dihydroxyoctyl]-N11N1-dipropylbenzene-1,3,5-tricarboxamide, 5-(acetylamino)-2-({3-(aminocarbonyl)-5-[(dipropylamino)carbonyl]benzoyl}amino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-7-S-methyl-7-thio-D-gluco-heptitol, 2-({3-(aminocarbonyl)-5-[(dipropylamino)carbonyl]benzoyl}amino)-5-(benzoylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-7-S-methyl-7-thio-D-gluco-heptitol, 5-(acetylamino)-2-({3-(aminocarbonyl)-5-[(dipropylamino)carbonyl]benzoyl}amino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-7-O-methyl-D-gluco-heptitol, 2-({3-(aminocarbonyl)-5-[(dipropylamino)carbonyl]benzoyl}amino)-5-(benzoylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-7-O-methyl-D-gluco-heptitol, 5-(acetylamino)-2-({3-(aminocarbonyl)-5-[(dipropylamino)carbonyl]benzoyl}amino)-6-cyano-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-D-glucitol, 2-({3-(aminocarbonyl)-5-[(dipropylamino)carbonyl]benzoyl}amino)-5-(benzoylamino)-6-cyano-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-D-glucitol, 5-(acetylamino)-1,2,5,6-tetradeoxy-1-phenyl-2-({(2R)-5-propyl-2-[(pyridin-3-ylcarbonyl)amino]octanoyl}amino)-D-glucitol, 5-(benzoylamino)-1,2,5,6-tetradeoxy-1-phenyl-2-({(2R)-5-propyl-2-[(pyridin-3-ylcarbonyl)amino]octanoyl}amino)-D-glucitol, N-[(1R)-1-({[(1S,2R,3R,4R)-4-(acetylamino)-1-benzyl-2,3-dihydroxyoctyl]amino}carbonyl)-4-propylheptyl]nicotinamide, N-[(1R)-1-({[(1S,2R,3R,4R)-4-(benzoylamino)-1-benzyl-2,3-dihydroxyoctyl]amino}carbonyl)-4-propylheptyl]nicotinamide, 5-(acetylamino)-1,2,5,6-tetradeoxy-7-S-methyl-1-phenyl-2-({(2R)-5-propyl-2-[(pyridin-3-ylcarbonyl)amino]octanoyl}amino)-7-thio-D-gluco-heptitol, 5-(benzoylamino)-1,2,5,6-tetradeoxy-7-S-methyl-1-phenyl-2-({(2R)-5-propyl-2-[(pyridin-3-ylcarbonyl)amino]octanoyl}amino)-7-thio-D-gluco-heptitol, 5-(acetylamino)-1,2,5,6-tetradeoxy-7-O-methyl-1-phenyl-2-({(2R)-5-propyl-2-[(pyridin-3-ylcarbonyl)amino]octanoyl}amino)-D-gluco-heptitol, 5-(benzoylamino)-1,2,5,6-tetradeoxy-7-O-methyl-1-phenyl-2-({(2R)-5-propyl-2-[(pyridin-3-ylcarbonyl)amino]octanoyl}amino)-D-gluco-heptitol, 5-(acetylamino)-6-cyano-1,2,5,6-tetradeoxy-1-phenyl-2-({(2R)-5-propyl-2-[(pyridin-3-ylcarbonyl)amino]octanoyl}amino)-D-glucitol, 5-(benzoylamino)-6-cyano-1,2,5,6-tetradeoxy-1-phenyl-2-({(2R)-5-propyl-2-[(pyridin-3-ylcarbonyl)amino]octanoyl}amino)-D-glucitol, 5-(acetylamino)-1,2,5,6-tetradeoxy-1-phenyl-2-({(2R)-2-[(pyridin-3-ylcarbonyl)amino]octanoyl}amino)-D-glucitol, 5-(benzoylamino)-1,2,5,6-tetradeoxy-1-phenyl-2-({(2R)-2-[(pyridin-3-ylcarbonyl)amino]octanoyl}amino)-D-glucitol, N-[(1R)-1-({[(1S,2R,3R,4R)-4-(acetylamino)-1-benzyl-2,3-dihydroxyoctyl]amino}carbonyl)heptyl]nicotinamide, N-[(1R)-1-({[(1S,2R,3R,4R)-4-(benzoylamino)-1-benzyl-2,3-dihydroxyoctyl]amino}carbonyl)heptyl]nicotinamide, 5-(acetylamino)-1,2,5,6-tetradeoxy-7-S-methyl-1-phenyl-2-({(2R)-2-[(pyridin-3-ylcarbonyl)amino]octanoyl}amino)-7-thio-D-gluco-heptitol, 5-(benzoylamino)-1,2,5,6-tetradeoxy-7-S-methyl-1-phenyl-2-({(2R)-2-[(pyridin-3-ylcarbonyl)amino]octanoyl}amino)-7-thio-D-gluco-heptitol, 5-(acetylamino)-1,2,5,6-tetradeoxy-7-O-methyl-1-phenyl-2-({(2R)-2-[(pyridin-3-ylcarbonyl)amino]octanoyl}amino)-D-gluco-heptitol, 5-(benzoylamino)-1,2,5,6-tetradeoxy-7-O-methyl-1-phenyl-2-({(2R)-2-[(pyridin-3-ylcarbonyl)amino]octanoyl}amino)-D-gluco-heptitol, 5-(acetylamino)-6-cyano-1,2,5,6-tetradeoxy-1-phenyl-2-({(2R)-2-[(pyridin-3-ylcarbonyl)amino]octanoyl}amino)-D-glucitol, 5-(benzoylamino)-6-cyano-1,2,5,6-tetradeoxy-1-phenyl-2-({(2R)-2-[(pyridin-3-ylcarbonyl)amino]octanoyl}amino)-D-glucitol, 5-(acetylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-2-({(2R)-5-propyl-2-[(pyridin-3-ylcarbonyl)amino]octanoyl}amino)-D-glucitol, 5-(benzoylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-2-({(2R)-5-propyl-2-[(pyridin-3-ylcarbonyl)amino]octanoyl}amino)-D-glucitol, N-[(1R)-1-({[(1S,2R,3R,4R)-4-(acetylamino)-1-(3,5-difluorobenzyl)-2,3-dihydroxyoctyl]amino}carbonyl)-4-propylheptyl]nicotinamide, N-[(1R)-1-({[(1S,2R,3R,4R)-4-(benzoylamino)-1-(3,5-difluorobenzyl)-2,3-dihydroxyoctyl]amino}carbonyl)-4-propylheptyl]nicotinamide, 5-(acetylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-7-S-methyl-2-({(2R)-5-propyl-2-[(pyridin-3-ylcarbonyl)amino]octanoyl}amino)-7-thio-D-gluco-heptitol, 5-(benzoylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-7-S-methyl-2-({(2R)-5-propyl-2-[(pyridin-3-ylcarbonyl)amino]octanoyl}amino)-7-thio-D-gluco-heptitol, 5-(acetylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-7-O-methyl-2-({(2R)-5-propyl-2-[(pyridin-3-ylcarbonyl)amino]octanoyl}amino)-D-gluco-heptitol, 5-(benzoylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-7-O-methyl-2-({(2R)-5-propyl-2-[(pyridin-3-ylcarbonyl)amino]octanoyl}amino)-D-gluco-heptitol, 5-(acetylamino)-6-cyano-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-2-({(2R)-5-propyl-2-[(pyridin-3-ylcarbonyl)amino]octanoyl}amino)-D-glucitol, 5-(benzoylamino)-6-cyano-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-2-({(2R)-5-propyl-2-[(pyridin-3-ylcarbonyl)amino]octanoyl}amino)-D-glucitol, 5-(acetylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-2-({(2R)-2-[(pyridin-3-ylcarbonyl)amino]octanoyl}amino)-D-glucitol, 5-(benzoylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-2-({(2R)-2-[(pyridin-3-ylcarbonyl)amino]octanoyl}amino)-D-glucitol, N-[(1R)-1-({[(1S,2R,3R,4R)-4-(acetylamino)-1-(3,5-difluorobenzyl)-2,3-dihydroxyoctyl]amino}carbonyl)heptyl]nicotinamide, N-[(1R)-1-({[(1S,2R,3R,4R)-4-(benzoylamino)-1-(3,5-difluorobenzyl)-2,3-dihydroxyoctyl]amino}carbonyl)heptyl]nicotinamide, 5-(acetylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-7-S-methyl-2-({(2R)-2-[(pyridin-3-ylcarbonyl)amino]octanoyl}amino)-7-thio-D-gluco-heptitol, 5-(benzoylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-7-S-methyl-2-({(2R)-2-[(pyridin-3-ylcarbonyl)amino]octanoyl}amino)-7-thio-D-gluco-heptitol, 5-(acetylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-7-O-methyl-2-({(2R)-2-[(pyridin-3-ylcarbonyl)amino]octanoyl}amino)-D-gluco-heptitol, 5-(benzoylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-7-O-methyl-2-({(2R)-2-[(pyridin-3-ylcarbonyl)amino]octanoyl}amino)-D-gluco-heptitol, 5-(acetylamino)-6-cyano-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-2-({(2R)-2-[(pyridin-3-ylcarbonyl)amino]octanoyl}amino)-D-glucitol, and 5-(benzoylamino)-6-cyano-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-2-({(2R)-2-[(pyridin-3-ylcarbonyl)amino]octanoyl}amino)-D-glucitol.
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8. A method for the treatment or prevention of Alzheimer'"'"'s disease, mild cognitive impairment Down'"'"'s syndrome, Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type, cerebral amyloid angiopathy, other degenerative dementias, dementias of mixed vascular and degenerative origin, dementia associated with Parkinson'"'"'s disease, dementia associated with progressive supranuclear palsy, dementia associated with cortical basal degeneration, diffuse Lewy body type of Alzheimer'"'"'s disease compriseing administration of a therapeutically effective amount of a compound or salt according to claim 1, to a patient in need thereof.
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9. A method of treatment as in claim 8, wherein the patient is a human.
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10. A method of treatment according to claim 8, wherein the disease is dementia.
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11. A method for making a compound of claim 1.
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2. A compound according to claim 1 with the proviso that neither RN nor RN′
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12. An intermediate of the formula XI:
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13. An intermediate of the formula B:
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14. The intermediate of claim 13 wherein R20 is H.
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14. The intermediate of claim 13 wherein R20 is H.
Specification
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Current AssigneePharmacia & Upjohn LLC (Pfizer Inc.)
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Original AssigneePharmacia & Upjohn LLC (Pfizer Inc.)
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InventorsSchostarez, Heinrich Josef, Chrusciel, Robert A.
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Granted Patent
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Time in Patent OfficeDays
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Field of Search
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US Class Current514/349
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CPC Class CodesA61P 25/28 for treating neurodegenerat...A61P 43/00 Drugs for specific purposes...A61P 9/10 for treating ischaemic or a...C07C 235/84 with the carbon atom of at ...C07C 255/44 at least one of the singly-...C07C 271/20 to carbon atoms of hydrocar...C07C 323/42 Y being a carbon atom of a ...C07D 213/82 in position 3C07D 263/34 with hetero atoms or with c...C07D 263/48 Nitrogen atoms not forming ...C07D 277/56 Carbon atoms having three b...