US2010120725A1PendingUtilityA1
Substituted Phenylsulfonamide Inhibitors of Beta Amyloid Production
Est. expiryJun 11, 2022(expired)· nominal 20-yr term from priority
Inventors:Anthony KreftDerek Cecil ColeKevin R. WollerJoseph StockKristina KuttererDennis M. KubrakCharles William MannWilliam J. MooreDavid S. Casebier
A61P 43/00C07C 2601/08A61K 31/357A61P 25/28C07C 311/40A61K 31/4245C07C 2602/42A61K 31/655C07C 311/29C07C 311/17C07C 2602/08C07C 311/18C07D 209/16C07C 311/20A61K 31/18C07D 319/06A61P 3/00A61K 31/335C07C 2601/04A61K 31/34C07C 2601/14C07C 323/49C07D 307/52
48
PatentIndex Score
0
Cited by
0
References
0
Claims
Abstract
Compounds of Formula I, wherein R 1 -R 8 are defined herein are provided, together with pharmaceutically acceptable salts, hydrates, metabolites, and/or prodrugs thereof. Uses of these compounds for inhibiting beta amyloid production and for the prevention and treatment of Alzheimer's disease and Down's syndrome are also described.
Claims
exact text as granted — not AI-modified1 . A method of preventing or treating Alzheimer's disease, Down's syndrome, mild cognitive impairment and other beta amyloid-involved diseases, comprising:
a) administering to a patient, a pharmaceutically acceptable amount of a compound, sufficient to alleviate the symptoms or progress of said disease, Formula I:
wherein:
R 1 is selected from the group consisting of H, halogen, and O;
R 2 is selected from the group consisting of H, halogen, and N═N;
R 3 is selected from the group consisting of H and halogen;
R 4 is selected from the group consisting of H, halogen, amino, and N═N;
R 5 is selected from the group consisting of H, halogen, methoxy, methyl, and O; or
R 1 and R 2 ; R 2 and R 3 ; R 4 and R 5 ; or R 3 and R 4 are fused to form a carbon-based, naphthalene ring with the benzene ring;
R 6 is selected from the group consisting of H, lower alkyl, lower alkenyl, 3-phenyl-2-propyn-1-yl, benzyl, substituted benzyl, CH 2 cycloalkyl, CH 2 -2-furan, (CH 2 ) 2 SCH 3 , and (CH 2 ) 2 NHBOC;
R 7 is selected from the group consisting of H, lower alkyl, and cycloalkyl;
R 8 is selected from the group consisting of lower alkyl, substituted alkyl, cycloalkyl, phenyl, substituted phenyl, benzyl, substituted benzyl, CH 2 cycloalkyl, CH 2 -3-indole, CH(lower alkyl)-2-furan, CH(lower alkyl)-4-methoxyphenyl, CH(lower alkyl) phenyl, and CH(OH)-4-SCH 3 -phenyl; or
R 7 and R 8 are fused to form a saturated carbon-based ring;
T is
R 9 and R 10 are H; or
R 9 is H and R 10 is lower alkyl, lower alkenyl, methyl-substituted alkenyl, lower alkynyl, CF 3 , cycloalkyl, substituted phenyl, 1-naphthyl, or CH 2 CH 2 -1,3-dioxolane; or
R 9 and R 10 are independently selected from the group consisting of lower alkyl, lower alkenyl, phenyl, 4-substituted-phenyl, and 1-naphthyl;
wherein:
when R 5 is a methoxy; R 2 is halogen and R 1 , R 3 , and R 4 are H;
(ii) when R 5 is a methyl; R 1 is halogen and R 2 , R 3 , and R 4 are H;
(iii) when R 4 is an amino; R 3 is halogen and R 1 , R 2 , and R 5 are H;
(iv) when R 2 is N═N and R 1 is O; R 2 is bound to R 1 to form a heterocyclic ring;
(v) when R 4 is N═N and R 5 is O; R 4 is bound to R 5 to form a heterocyclic ring; and
(vi) at least one of R 1 , R 2 , R 3 , R 4 , and R 5 is halogen unless R 1 and R 2 ; R 2 and R 3 ; R 4 and R 5 ; or R 3 and R 4 are fused to faun a carbon-based, naphthalene ring with the benzene ring;
or a pharmaceutically acceptable salt, metabolite, hydrate, or prodrug thereof; and
b) monitoring the patients for amelioration or stabilization of disease progress.
2 . The method according to claim 1 , wherein:
R 1 , R 2 , R 4 , R 5 , R 9 , and R 10 are H; R 3 is halogen; and R 8 is lower alkyl of S-stereochemistry at the carbon atom to which N, T, R 7 , and R 8 are attached.
3 . The method according to claim 1 , wherein said pharmaceutically acceptable salt of said compound is selected from the group consisting of salts of sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, diethanolamine, ethylene amine, salts of bases, and mixtures thereof.
4 . The method according to claim 1 , wherein said compound is delivered to said patient orally or by injection.
5 . The method according to claim 1 , wherein said compound is 2,4-difluoro-N-[(1S,2S)-1-(hydroxymethyl)-2-methylbutyl]benzenesulfonamide, 2,3-dichloro-N-[(1S,2S)-1-(hydroxymethyl)-2-methylbutyl]benzenesulfonamide, 4-bromo-N-[(1S,2R)-1-(hydroxymethyl)-2-methylbutyl]benzenesulfonamide, 4-chloro-N-[(1S,2R)-1-(hydroxymethyl)-2-methylbutyl]benzenesulfonamide, 4-chloro-N-[(1S,2S)-1-(hydroxymethyl)-2-methylbutyl]-benzenesulfonamide, 4-bromo-N-[(1S,2S)-1-(hydroxymethyl)-2-methylbutyl]-benzenesulfonamide, 3-chloro-N-[1-(hydroxymethyl)butyl]benzenesulfonamide, 4-fluoro-N-[(1S,2S)-1-(1-hydroxyethyl)-2-methylbutyl]benzenesulfonamide, N-{(1S,2S)-1-[cyclopentyl(hydroxy)methyl]-2-methylbutyl{-4-fluorobenzenesulfonamide, 4-fluoro-N-{(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]octyl}benzenesulfonamide, 4-fluoro-N-{(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]heptyl}benzenesulfonamide, 4-fluoro-N-{(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]hexyl}benzenesulfonamide, 4-fluoro-N-{(1S,2S)-1-[hydroxy(2-methylphenypmethyl]-2-methylbutyl}benzenesulfonamide, 4-fluoro-N-{(1S)-2-hydroxy-3,3-dimethyl-1-[(1S)-1-methylpropyl]butyl}benzenesulfonamide, 4-fluoro-N-{(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]-3-butenyl}benzenesulfonamide, 4-fluoro-N-{(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]-4-pentenyl}benzenesulfonamide, 4-fluoro-N-{(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]butyl}benzenesulfonamide, N-{(1S,2S)-1-[(4-chlorophenyl)(hydroxy)methyl]-2-methylbutyl}-4-fluorobenzenesulfonamide, 4-fluoro-N-{(1S)-2-hydroxy-4-methyl-1-[(1S)-1-methylpropyl]-3-pentenyl}benzenesulfonamide, 4-fluoro-N-{(1S)-2-hydroxy-3-methyl-1-[(1S)-1-methylpropyl]-3-butenyl}benzenesulfonamide, 4-fluoro-N-{(1S,2S)-1-[hydroxy(4-methoxyphenyl)methyl]-2-methylbutyl}benzenesulfonamide, N-{(1S)-4-(1,3-dioxan-2-yl)-2-hydroxy-1-[(1S)-1-methylpropyl]butyl}-4-fluorobenzenesulfonamide, 4-fluoro-N-{(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]-5-hexenyl}benzenesulfonamide, 4-fluoro-N-((1S,2S)-1-{hydroxy[4-(methylsulfanyl)phenyl]methyl}-2-methylbutyl)benzenesulfonamide, N-{(1S,2S)-1-[[4-(dimethylamino)phenyl](hydroxy)methyl]-2-methylbutyl}-4-fluorobenzenesulfonamide, 4-fluoro-N-{(1S,2S)-1-[hydroxy(1-naphthyl)methyl]-2-methylbutyl}benzenesulfonamide, 4-bromo-N-[(1S,2S)-1-(1-hydroxyethyl)-2-methylbutyl]benzenesulfonamide, 4-bromo-N-{(1S,2S)-1-[cyclopentyl(hydroxy)methyl]-2-methylbutyl}benzenesulfonamide, 4-bromo-N-{(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]heptyl}benzenesulfonamide, 4-bromo-N-{(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]hexyl}benzenesulfonamide, 4-bromo-N-{(1S)-2-hydroxy-3,3-dimethyl-1-[(1S)-1-methylpropyl]butyl}benzenesulfonamide, 4-bromo-N-{(1S)-2-hydroxy-4-methyl-1-[(1S)-1-methylpropyl]pentyl}benzenesulfonamide, 4-bromo-N-{(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]-3-butenyl}benzenesulfonamide, 4-bromo-N-{(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]-4-pentenyl}benzenesulfonamide, 4-bromo-N-{(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]butyl}benzenesulfonamide, 4-bromo-N-{(1S,2S)-1-[(4-fluorophenyl)(hydroxy)methyl]-2-methylbutyl}benzenesulfonamide, 4-bromo-N-{(1S,2S)-1-[(4-chlorophenyl)(hydroxy)methyl]-2-methylbutyl}benzenesulfonamide, 4-bromo-N-{(1S)-2-hydroxy-4-methyl-1-[(1S)-1-methylpropyl]-3-pentenyl}benzenesulfonamide, 4-bromo-N-{(1S)-2-hydroxy-3-methyl-1-[(1S)-1-methylpropyl]-3-butenyl}benzenesulfonamide, 4-bromo-N-{(1S,2S)-1-[hydroxy(4-methoxyphenyl)methyl]-2-methylbutyl}benzenesulfonamide, 4-bromo-N-{(1S,3E)-2-hydroxy-3-methyl-1-[(1S)-1-methylpropyl]-3-pentenyl}benzenesulfonamide, 4-bromo-N-{(1S)-4-(1,3-dioxan-2-yl)-2-hydroxy-1-[(1S)-1-methylpropyl]butyl}benzenesulfonamide, 4-bromo-N-{(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]-5-hexenyl}benzenesulfonamide, 4-bromo-N-{(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]-3-pentynyl}benzenesulfonamide, 4-bromo-N-((1S,2S)-1-{hydroxy[4-(methylsulfanyl)phenyl]methyl}-2-methylbutyl)benzenesulfonamide, 4-bromo-N-{(1S,2S)-1-[[4-(dimethylamino)phenyl](hydroxy)methyl]-2-methylbutyl}benzenesulfonamide, 4-chloro-N-[(1S,2S)-1-(1-hydroxyethyl)-2-methylbutyl]benzenesulfonamide, 4-chloro-N-{(1S,2S)-1-[cyclopentyl(hydroxy)methyl]-2-methylbutyl}benzenesulfonamide, 4-chloro-N-{(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]octyl}benzenesulfonamide, 4-chloro-N-{(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]heptyl}benzenesulfonamide, 4-chloro-N-{(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]hexyl}benzenesulfonamide, 4-chloro-N-{(1S)-2-hydroxy-3-methyl-1-[(1S)-1-methylpropyl]butyl}benzenesulfonamide, 4-chloro-N-{(1S,2S)-1-[hydroxy(2-methylphenyl)methyl]-2-methylbutyl}benzenesulfonamide, 4-chloro-N-{(1S)-2-hydroxy-3,3-dimethyl-1-[(1S)-1-methylpropyl]butyl}benzenesulfonamide, 4-chloro-N-{(1S)-2-hydroxy-4-methyl-1-[(1S)-1-methylpropyl]pentyl}benzenesulfonamide, 4-chloro-N-{1(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]-3-butenyl}benzenesulfonamide, 4-chloro-N-{(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]-4-pentenyl}benzenesulfonamide, 4-chloro-N-{(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]butyl}benzenesulfonamide, 4-chloro-N-{(1S,2S)-1-[(4-chlorophenyl)(hydroxy)methyl]-2-methylbutyl}benzenesulfonamide, 4-chloro-N-{(1S,2S)-1-[hydroxy(4-methoxyphenyl)methyl]-2-methylbutyl}benzenesulfonamide, 4-chloro-N-{(1S)-4-(1,3-dioxan-2-yl)-2-hydroxy-1-[(1S)-1-methylpropyl]butyl}benzenesulfonamide, 4-chloro-N-{(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]-5-hexenyl}benzenesulfonamide, 4-chloro-N-{(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]-3-pentynyl}benzenesulfonamide, 4-chloro-N-((1S,2S)-1-{hydroxy[4-(methylsulfanyl)phenyl]methyl}-2-methylbutyl)benzenesulfonamide, 4-chloro-N-{(1S,2S)-14[4-(dimethylamino)phenyl](hydroxy)methyl]-2-methylbutyl}benzenesulfonamide, 4-chloro-N-{(1S,2S)-1-[hydroxy(1-naphthyl)methyl]-2-methylbutyl}benzenesulfonamide, 3-chloro-N-[(1S,2S)-1-(1-hydroxyethyl)-2-methylbutyl]benzenesulfonamide, 3-chloro-N-{(1S,2S)-1-[cyclopentyl(hydroxy)methyl]-2-methylbutyl}benzenesulfonamide, 3-chloro-N-{(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]octyl}benzenesulfonamide, 3-chloro-N-{(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]heptyl}benzenesulfonamide, 3-chloro-N-{(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]hexyl}benzenesulfonamide, 3-chloro-N-{(1S)-2-hydroxy-3-methyl-1-[(1S)-1-methylpropyl]butyl}benzenesulfonamide, 3-chloro-N-{(1S)-2-hydroxy-3,3-dimethyl-1-[(1S)-1-methylpropyl]butyl}benzenesulfonamide, 3-chloro-N-{(1S)-2-hydroxy-4-methyl-1-[(1S)-1-methylpropyl]pentyl}benzenesulfonamide, 3-chloro-N-{(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]-3-butenyl}benzenesulfonamide, 3-chloro-N-{(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]-4-pentenyl}benzenesulfonamide, 3-chloro-N-{(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]butyl}benzenesulfonamide, 3-chloro-N-{(1S,2S)-1-[(4-chlorophenyl)(hydroxy)methyl]-2-methylbutyl}benzenesulfonamide, 3-chloro-N-{(1S)-2-hydroxy-4-methyl-1-[(1S)-1-methylpropyl]-3-pentenyl}benzenesulfonamide, 3-chloro-N-{(1S,2S)-1-[hydroxy(4-methoxyphenyl)methyl]-2-methylbutyl}benzenesulfonamide, 3-chloro-N-{(1S)-4-(1,3-dioxan-2-yl)-2-hydroxy-1-[(1S)-1-methylpropyl]butyl}benzenesulfonamide, 3-chloro-N-{(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]-5-hexenyl}benzenesulfonamide, 3-chloro-N-((1S,2S)-1-{hydroxy[4-(methylsulfanyl)phenyl]methyl}-2-methylbutyl)benzenesulfonamide, N-{(1S,2S)-1-[cyclopentyl(hydroxy)methyl]-2-methylbutyl}-2-fluorobenzenesulfonamide, 2-fluoro-N-{(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]octyl}benzenesulfonamide, 2-fluoro-N-{(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]heptyl}benzenesulfonamide, 2-fluoro-N-{(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]hexyl}benzenesulfonamide, 2-fluoro-N-{(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]-3-butenyl}benzenesulfonamide, 2-fluoro-N-{(1S,2S)-1-[(4-fluorophenyl)(hydroxy)methyl]-2-methylbutyl}benzenesulfonamide, N-{(1S,2S)-1-[(4-chlorophenyl)(hydroxy)methyl]-2-methylbutyl}-2-fluorobenzenesulfonamide, 2-fluoro-N-{(1S,2S)-1-[hydroxy(4-methoxyphenyl)methyl]-2-methylbutyl}benzenesulfonamide, N-{(1S)-4-(1,3-dioxan-2-yl)-2-hydroxy-1-[(1S)-1-methylpropyl]butyl}-2-fluorobenzenesulfonamide, 4-bromo-N-[(1S,2S)-1-(1-hydroxy-1-methylethyl)-2-methylbutyl]benzenesulfonamide, 4-bromo-N-{(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]-2-pentylheptyl}benzenesulfonamide, 4-bromo-N-{(1S)-2-butyl-2-hydroxy-1-[(1S)-1-methylpropyl]hexyl}benzenesulfonamide, 4-bromo-N-{(1S)-2-hydroxy-2-isobutyl-4-methyl-1-[(1S)-1-methylpropyl]pentyl}benzenesulfonamide, 4-bromo-N-{(1S,2S)-1-[hydroxy(diphenyl)methyl]-2-methylbutyl}benzenesulfonamide, N-{(1S)-2-allyl-2-hydroxy-1-[(1S)-1-methylpropyl]-4-pentenyl}-4-bromobenzenesulfonamide, 4-bromo-N-{(1S)-2-ethyl-2-hydroxy-1-[(1S)-1-methylpropyl]butyl}benzenesulfonamide, N-{(1S,2S)-1-[bis(4-chlorophenyl)(hydroxy)methyl]-2-methylbutyl}-4-bromobenzenesulfonamide, 4-bromo-N-{1(1S)-2-hydroxy-2-isopropenyl-3-methyl-1-[(1S)-1-methylpropyl]-3-butenyl}benzenesulfonamide, 4-bromo-N-{(1S,3E)-2-hydroxy-3-methyl-2-[(1E)-1-methyl-1-propenyl]-1-[(1S)-1-methylpropyl]-3-pentenyl benzenesulfonamide, 4-bromo-N-{(1S)-2-(3-butenyl)-2-hydroxy-1-[(1S)-1-methylpropyl]-5-hexenyl}benzenesulfonamide, 4-bromo-N-((1S,2S)-1-{hydroxy[di(1-naphthyl)]methyl}-2-methylbutyl)benzenesulfonamide, 4-chloro-N-[(1S,2S)-1-(1-hydroxy-1-methylethyl)-2-methylbutyl]benzenesulfonamide, 4-chloro-N-{(1S)-2-hexyl-2-hydroxy-1-[(1S)-1-methylpropyl]octyl}benzenesulfonamide, N-{(1S)-2-butyl-2-hydroxy-1-[(1S)-1-methylpropyl]hexyl}-4-chlorobenzenesulfonamide, 4-chloro-N-{(1S)-2-hydroxy-2-isobutyl-4-methyl-1-[(1S)-1-methylpropyl]pentyl}benzenesulfonamide, 4-chloro-N-{(1S,2S)-1-[hydroxy(diphenyl)methyl]-2-methylbutyl}benzenesulfonamide, N-{(1S)-2-allyl-2-hydroxy-1-[(1S)-1-methylpropyl]-4-pentenyl}-4-chlorobenzenesulfonamide, 4-chloro-N-{(1S)-2-ethyl-2-hydroxy-1-[(1S)-1-methylpropyl]butyl}benzenesulfonamide, 4-chloro-N-{(1S)-2-hydroxy-2-isopropenyl-3-methyl-1-[(1S)-1-methylpropyl]-3-butenyl}benzenesulfonamide, 4-chloro-N-((1S,2S)-1-{hydroxy[bis(4-methoxyphenyl)]methyl}-2-methylbutyl)benzenesulfonamide, 4-chloro-N-{(1S,3E)-2-hydroxy-3-methyl-2-[(1E)-1-methyl-1-propenyl]-1-[(1S)-1-methylpropyl]-3-pentenyl}benzenesulfonamide, N-{(1S)-2-(3-butenyl)-2-hydroxy-1-[(1S)-1-methylpropyl]-5-hexenyl}-4-chlorobenzenesulfonamide, 4-chloro-N-((1S,2S)-1-{hydroxy[di(1-naphthyl)]methyl}-2-methylbutyl)benzenesulfonamide, 4-fluoro-N-[(1S,2S)-1-(1-hydroxy-1-methylethyl)-2-methylbutyl]benzenesulfonamide, 4-fluoro-N-(1S)-2-hexyl-2-hydroxy-1-[(1S)-1-methylpropyl]octyl}benzenesulfonamide, 4-fluoro-N-{(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]-2-pentylheptyl}benzenesulfonamide, N-{(1S)-2-butyl-2-hydroxy-1-[(1S)-1-methylpropyl]hexyl}-4-fluorobenzenesulfonamide, 4-fluoro-N-{(1S)-2-hydroxy-2-isopropyl-3-methyl-1-[(1S)-1-methylpropyl]butyl}benzenesulfonamide, 4-fluoro-N-{(1S)-2-hydroxy-2-isobutyl-4-methyl-1-[(1S)-1-methylpropyl]pentyl}benzenesulfonamide, N-{(1S)-2-allyl-2-hydroxy-1-[(1S)-1-methylpropyl]-4-pentenyl}-4-fluorobenzenesulfonamide, N-{(1S)-2-ethyl-2-hydroxy-1-[(1S)-1-methylpropyl]butyl}-4-fluorobenzenesulfonamide, 4-fluoro-N-{(1S)-2-hydroxy-2-isopropenyl-3-methyl-1-[(1S)-1-methylpropyl]-3-butenyl}benzenesulfonamide, 4-fluoro-N-((1S,2S)-1-{hydroxy[bis(4-methoxyphenyl)]methyl}-2-methylbutyl)benzenesulfonamide, 4-fluoro-N-{(1S,3E)-2-hydroxy-3-methyl-2-[(1E)-1-methyl-1-propenyl]-1-[(1S)-1-methylpropyl]-3-pentenyl}benzenesulfonamide, N-{(1S)-2-(3-butenyl)-2-hydroxy-1-[(1S)-1-methylpropyl]-5-hexenyl}-4-fluorobenzenesulfonamide, N-{(1,2S)-1-[bis [4-(dimethylamino)phenyl](hydroxy)methyl]-2-methylbutyl -4-fluorobenzenesulfonamide, 4-fluoro-N-((1S,2S)-1-{hydroxy[di(1-naphthyl)]methyl}-2-methylbutyl)benzenesulfonamide, 3-chloro-N-{(1S)-2-hexyl-2-hydroxy-1-[(1S)-1-methylpropyl]octyl}benzenesulfonamide, 3-chloro-N-{(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]-2-pentylheptyl}benzenesulfonamide, N-{(1S)-2-butyl-2-hydroxy-1-[(1S)-1-methylpropyl]hexyl}-3-chlorobenzenesulfonamide, 3-chloro-N-{(1S)-2-hydroxy-2-isobutyl-4-methyl-1-[(1S)-1-methylpropyl]pentyl}benzenesulfonamide, 3-chloro-N-{(1S,2S)-1-[hydroxy(diphenyl)methyl]-2-methylbutyl}benzenesulfonamide, N-{(1S)-2-allyl-2-hydroxy-1-[(1S)-1-methylpropyl]-4-pentenyl}-3-chlorobenzenesulfonamide, 3-chloro-N-{(1S)-2-ethyl-2-hydroxy-1-[(1S)-1-methylpropyl]butyl}benzenesulfonamide, N-{(1S,2S)-1-[bis(4-chlorophenyl)(hydroxy)methyl]-2-methylbutyl}-3-chlorobenzenesulfonamide, 3-chloro-N-{(1S)-2-hydroxy-2-isopropenyl-3-methyl-1-[(1S)-1-methylpropyl]-3-butenyl}benzenesulfonamide, 3-chloro-N4 1S,2S)-1-{hydroxy[bis(4-methoxyphenyl)]methyl}-2-methylbutyl)benzenesulfonamide, 3-chloro-N-{(1S,3E)-2-hydroxy-3-methyl-2-[(1E)-1-methyl-1-propenyl]-1-[(1S)-1-methylpropyl]-3-pentenyl}benzenesulfonamide, N-{(1S)-2-(3-butenyl)-2-hydroxy-1-[(1S)-1-methylpropyl]-5-hexenyl}-3-chlorobenzenesulfonamide, 2-fluoro-N-{(1S)-2-hexyl-2-hydroxy-1-[(1S)-1-methylpropyl]octyl}benzenesulfonamide, 2-fluoro-N-{(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]-2-pentylheptyl}benzenesulfonamide, 2-fluoro-N-{(1S,2S)-1-[hydroxy(diphenyl)methyl]-2-methylbutyl}benzenesulfonamide, N-{(1S)-2-allyl-2-hydroxy-1-[(1S)-1-methylpropyl]-4-pentenyl}-2-fluorobenzenesulfonamide, N-{(1S)-2-ethyl-2-hydroxy-1-[(1S)-1-methylpropyl]butyl}-2-fluorobenzenesulfonamide, N-{(1S,2S)-1-[bis(4-fluorophenyl)(hydroxy)methyl]-2-methylbutyl}-2-fluorobenzenesulfonamide, N-{(1S,2S)-1-[bis(4-chlorophenyl)(hydroxy)methyl]-2-methylbutyl}-2-fluorobenzenesulfonamide, 2-fluoro-N-{(1S)-2-hydroxy-2-isopropenyl-3-methyl-1-[(1S)-1-methylpropyl]-3-butenyl}benzenesulfonamide, 2-fluoro-N-((1S,2S)-1-{hydroxy[bis(4-methoxyphenyl)]methyl}-2-methylbutyl)benzenesulfonamide, 2-fluoro-N-{(1S,3E)-2-hydroxy-3-methyl-2-[(1E)-1-methyl-1-propenyl]-1-[(1S)-1-methylpropyl]-3-pentenyl}benzenesulfonamide, and N-{(1S)-2-(3-butenyl)-2-hydroxy-1-[(1S)-1-methylpropyl]-5-hexenyl}-2-fluorobenzenesulfonamide, or a pharmaceutically acceptable salt.
6 . The method according to claim 1 , wherein said compound is of Formula Ia:
wherein:
R 8 is selected from the group consisting of n-propyl, iso-propyl, iso-butyl, n-butyl, and t-butyl;
wherein, one or more of R 1 to R 5 is a halogen;
or a pharmaceutically acceptable salt or prodrug thereof.
7 . The method according to claim 1 , wherein said compound is of the structure of Formula Ib:
wherein:
R 9 and R 10 are independently selected from the group consisting of lower alkyl, lower alkenyl, phenyl, 4-substituted-phenyl, and 1-naphthyl;
wherein, one or more of R 1 to R 5 is a halogen;
or a pharmaceutically acceptable salt or prodrug thereof.
8 . A method of preventing or treating a disease selected from the group consisting of amyloid angiopathy, cerebral amyloid angiopathy, systemic amyloidosis, hereditary hemorrhage with amyloidosis of the Dutch type, and inclusion body myositis, comprising:
a) administering a pharmaceutically acceptable amount of a compound of Formula I to a patient, where said amount is sufficient to alleviate the symptoms or progress of said disease, wherein said compound of Formula I is:
wherein:
R 1 is selected from the group consisting of H, halogen, and O;
R 2 is selected from the group consisting of H, halogen, and N═N;
R 3 is selected from the group consisting of H and halogen;
R 4 is selected from the group consisting of H, halogen, amino, and N═N;
R 5 is selected from the group consisting of H, halogen, methoxy, methyl, and O; or
R 1 and R 2 ; R 2 and R 3 ; R 4 and R 5 ; or R 3 and R 4 are fused to form a carbon-based, naphthalene ring with the benzene ring;
R 6 is selected from the group consisting of H, lower alkyl, lower alkenyl, 3-phenyl-2-propyn-1-yl, benzyl, substituted benzyl, CH 2 cycloalkyl, CH 2 -2-furan, (CH 2 ) 2 SCH 3 , and (CH 2 ) 2 NHBOC;
R 7 is selected from the group consisting of H, lower alkyl, and cycloalkyl;
R 8 is selected from the group consisting of lower alkyl, substituted alkyl, cycloalkyl, phenyl, substituted phenyl, benzyl, substituted benzyl, CH 2 cycloalkyl, CH 2 -3-indole, CH(lower alkyl)-2-furan, CH(lower alkyl)-4-methoxyphenyl, CH(lower alkyl) phenyl, and CH(OH)-4-SCH 3 -phenyl; or
R 7 and R 8 are fused to form a saturated carbon-based ring;
T is
R 9 and R 10 are H; or
R 9 is H and R 10 is lower alkyl, lower alkenyl, methyl-substituted alkenyl, lower alkynyl, CF 3 , cycloalkyl, substituted phenyl, 1-naphthyl, or CH 2 CH 2 -1,3-dioxolane; or
R 9 and R 10 are independently selected from the group consisting of lower alkyl, lower alkenyl, phenyl, 4-substituted-phenyl, and 1-naphthyl;
wherein:
(i) when R 5 is a methoxy; R 2 is halogen and R 1 , R 3 , and R 4 are H;
(ii) when R 5 is a methyl; R 1 is halogen and R 2 , R 3 , and R 4 are H;
when R 4 is an amino; R 3 is halogen and R 1 , R 2 , and R 5 are H;
(iv) when R 2 is N═N and R 1 is O; R 2 is bound to R 1 to form a heterocyclic ring;
(v) when R 4 is N═N and R 5 is O; R 4 is bound to R 5 to form a heterocyclic ring; and
(vi) at least one of R 1 , R 2 , R 3 , R 4 , and R 5 is halogen unless R 1 and R 2 ; R 2 and R 3 ; R 4 and R 5 ; or R 3 and R 4 are fused to form a carbon-based, naphthalene ring with the benzene ring;
or a pharmaceutically acceptable salt, metabolite, hydrate, or prodrug thereof; and
b) monitoring the patients for amelioration or stabilization of disease progress.
9 . A method of detecting an inhibitor of beta amyloid production, comprising assaying a sample from a subject treated with a compound of formula I by contacting said sample with an antibody to a compound of formula I, wherein said compound of formula I has the structure:
wherein:
R 1 is selected from the group consisting of H, halogen, and O;
R 2 is selected from the group consisting of H, halogen, and N═N;
R 3 is selected from the group consisting of H and halogen;
R 4 is selected from the group consisting of H, halogen, amino, and N═N;
R 5 is selected from the group consisting of H, halogen, methoxy, methyl, and O; or
R 1 and R 2 ; R 2 and R 3 ; R 4 and R 5 ; or R 3 and R 4 are fused to form a carbon-based, naphthalene ring with the benzene ring;
R 6 is selected from the group consisting of H, lower alkyl, lower alkenyl, 3-phenyl-2-propyn-1-yl, benzyl, substituted benzyl, CH 2 cycloalkyl, CH 2 -2-furan, (CH 2 ) 2 SCH 3 , and (CH 2 ) 2 NHBOC;
R 7 is selected from the group consisting of H, lower alkyl, and cycloalkyl;
R 8 is selected from the group consisting of lower alkyl, substituted alkyl, cycloalkyl, phenyl, substituted phenyl, benzyl, substituted benzyl, CH 2 cycloalkyl, CH 2 -3-indole, CH(lower alkyl)-2-furan, CH(lower alkyl)-4-methoxyphenyl, CH(lower alkyl) phenyl, and CH(OH)-4-SCH 3 -phenyl; or
R 7 and R 8 are fused to form a saturated carbon-based ring;
T is
R 9 and R 10 are H; or
R 9 is H and R 10 is lower alkyl, lower alkenyl, methyl-substituted alkenyl, lower alkynyl, CF 3 , cycloalkyl, substituted phenyl, 1-naphthyl, or CH 2 CH 2 -1,3-dioxolane; or
R 9 and R 10 are independently selected from the group consisting of lower alkyl, lower alkenyl, phenyl, 4-substituted-phenyl, and 1-naphthyl;
wherein:
(i) when R 5 is a methoxy; R 2 is halogen and R 1 , R 3 , and R 4 are H;
(ii) when R 5 is a methyl; R 1 is halogen and R 2 , R 3 , and R 4 are H;
when R 4 is an amino; R 3 is halogen and R 1 , R 2 , and R 5 are H;
(iv) when R 2 is N═N and R 1 is O; R 2 is bound to R 1 to form a heterocyclic ring;
(v) when R 4 is N═N and R 5 is O; R 4 is bound to R 5 to form a heterocyclic ring; and
(vi) at least one of R 1 , R 2 , R 3 , R 4 , and R 5 is halogen unless R 1 and R 2 ; R 2 and R 3 ; R 4 and R 5 ; or R 3 and R 4 are fused to form a carbon-based, naphthalene ring with the benzene ring;
or a pharmaceutically acceptable salt, metabolite, hydrate, or prodrug thereof.
10 . A method of preparing a compound of formula I:
wherein:
R 1 is selected from the group consisting of H, halogen, and O;
R 2 is selected from the group consisting of H, halogen, and N═N;
R 3 is selected from the group consisting of H and halogen;
R 4 is selected from the group consisting of H, halogen, amino, and N═N;
R 5 is selected from the group consisting of H, halogen, methoxy, methyl, and O; or
R 1 and R 2 ; R 2 and R 3 ; R 4 and R 5 ; or R 3 and R 4 are fused to form a carbon-based, naphthalene ring with the benzene ring;
R 6 is selected from the group consisting of H, lower alkyl, lower alkenyl, 3-phenyl-2-propyn-1-yl, benzyl, substituted benzyl, CH 2 cycloalkyl, CH 2 -2-furan, (CH 2 ) 2 SCH 3 , and (CH 2 ) 2 NHBOC;
R 7 is selected from the group consisting of H, lower alkyl, and cycloalkyl;
R 8 is selected from the group consisting of lower alkyl, substituted alkyl, cycloalkyl, phenyl, substituted phenyl, benzyl, substituted benzyl, CH 2 cycloalkyl, CH 2 -3-indole, CH(lower alkyl)-2-furan, CH(lower alkyl)-4-methoxyphenyl, CH(lower alkyl)phenyl, and CH(OH)-4-SCH 3 -phenyl; or
R 7 and R 8 are fused to form a saturated carbon-based ring;
T is
R 9 and R 10 are independently selected from the group consisting of lower alkyl, lower alkenyl, phenyl, 4-substituted-phenyl, and 1-naphthyl;
wherein:
when R 5 is a methoxy; R 2 is halogen and R 1 , R 3 , and R 4 are H;
(ii) when R 5 is a methyl; R 1 is halogen and R 2 , R 3 , and R 4 are H;
(iii) when R 4 is an amino; R 3 is halogen and R 1 , R 2 , and R 5 are H;
(iv) when R 2 is N═N and R 1 is O; R 2 is bound to R 1 to form a heterocyclic ring;
(v) when R 4 is N═N and R 5 is O; R 4 is bound to R 5 to form a heterocyclic ring; and
(vi) at least one of R 1 , R 2 , R 3 , R 4 , and R 5 is halogen unless R 1 and R 2 ; R 2 and R 3 ; R 4 and R 5 ; or R 3 and R 4 are fused to form a carbon-based, naphthalene ring with the benzene ring;
or a pharmaceutically acceptable salt, metabolite, hydrate, or prodrug thereof;
said method comprising reacting a 1,2-aminoalcohol of the structure:
with a sulfonyl halide of the structure:
11 . A method of preparing a compound of formula I:
wherein:
R 1 is selected from the group consisting of H, halogen, and O;
R 2 is selected from the group consisting of H, halogen, and N═N;
R 3 is selected from the group consisting of H and halogen;
R 4 is selected from the group consisting of H, halogen, amino, and N═N;
R 5 is selected from the group consisting of H, halogen, methoxy, methyl, and O; or
R 1 and R 2 ; R 2 and R 3 ; R 4 and R 5 ; or R 3 and R 4 are fused to form a carbon-based, naphthalene ring with the benzene ring;
R 6 is selected from the group consisting of H, lower alkyl, lower alkenyl, 3-phenyl-2-propyn-1-yl, benzyl, substituted benzyl, CH 2 cycloalkyl, CH 2 -2-furan, (CH 2 ) 2 SCH 3 , and (CH 2 ) 2 NHBOC;
R 7 is selected from the group consisting of H, lower alkyl, and cycloalkyl;
R 8 is selected from the group consisting of lower alkyl, substituted alkyl, cycloalkyl, phenyl, substituted phenyl, benzyl, substituted benzyl, CH 2 cycloalkyl, CH 2 -3-indole, CH(lower alkyl)-2-furan, CH(lower alkyl)-4-methoxyphenyl, CH(lower alkyl) phenyl, and CH(OH)-4-SCH 3 -phenyl; or
R 7 and R 8 are fused to form a saturated carbon-based ring;
T is
wherein:
when R 5 is a methoxy; R 2 is halogen and R 1 , R 3 , and R 4 are H;
(ii) when R 5 is a methyl; R 1 is halogen and R 2 , R 3 , and R 4 are H;
(iii) when R 4 is an amino; R 3 is halogen and R 1 , R 2 , and R 5 are H;
(iv) when R 2 is N═N and R 1 is O; R 2 is bound to R 1 to form a heterocyclic ring;
(v) when R 4 is N═N and R 5 is O; R 4 is bound to R 5 to form a heterocyclic ring; and
(vi) at least one of R 1 , R 2 , R 3 , R 4 , and R 5 is halogen unless R 1 and R 2 ; R 2 and R 3 ; R 4 and R 5 ; or R 3 and R 4 are fused to form a carbon-based, naphthalene ring with the benzene ring;
or a pharmaceutically acceptable salt, metabolite, hydrate, or prodrug thereof;
said method comprising:
(i) reacting a 1,2-aminoalcohol of the structure:
with a sulfonyl halide of the structure:
oxidizing the product of (i).
12 . A method of preparing a compound of formula I:
wherein:
R 1 is selected from the group consisting of H, halogen, and O;
R 2 is selected from the group consisting of H, halogen, and N═N;
R 3 is selected from the group consisting of H and halogen;
R 4 is selected from the group consisting of H, halogen, amino, and N═N;
R 5 is selected from the group consisting of H, halogen, methoxy, methyl, and O; or
R 1 and R 2 ; R 2 and R 3 ; R 4 and R 5 ; or R 3 and R 4 are fused to form a carbon-based, naphthalene ring with the benzene ring;
R 6 is selected from the group consisting of H, lower alkyl, lower alkenyl, 3-phenyl-2-propyn-1-yl, benzyl, substituted benzyl, CH 2 cycloalkyl, CH 2 -2-furan, (CH 2 ) 2 SCH 3 , and (CH 2 ) 2 NHBOC;
R 7 is selected from the group consisting of H, lower alkyl, and cycloalkyl;
R 8 is selected from the group consisting of lower alkyl, substituted alkyl, cycloalkyl, phenyl, substituted phenyl, benzyl, substituted benzyl, CH 2 cycloalkyl, CH 2 -3-indole, CH(lower alkyl)-2-furan, CH(lower alkyl)-4-methoxyphenyl, CH(lower alkyl)phenyl, and CH(OH)-4-SCH 3 -phenyl; or
R 7 and R 8 are fused to form a saturated carbon-based ring;
T is
R 10 is lower alkyl, lower alkenyl, methyl-substituted alkenyl, lower alkynyl, CF 3 , cycloalkyl, substituted phenyl, 1-naphthyl, or CH 2 CH 2 -1,3-dioxolane;
wherein:
(i) when R 5 is a methoxy; R 2 is halogen and R 1 , R 3 , and R 4 are H;
(ii) when R 5 is a methyl; R 1 is halogen and R 2 , R 3 , and R 4 are H;
(iii) when R 4 is an amino; R 3 is halogen and R 1 , R 2 , and R 5 are H;
(iv) when R 2 is N═N and R 1 is O; R 2 is bound to R 1 to form a heterocyclic ring;
(v) when R 4 is N═N and R 5 is O; R 4 is bound to R 5 to form a heterocyclic ring; and
(vi) at least one of R 1 , R 2 , R 3 , R 4 , and R 5 is halogen unless R 1 and R 2 ; R 2 and R 3 ; R 4 and R 5 ; or R 3 and R 4 are fused to form a carbon-based, naphthalene ring with the benzene ring;
or a pharmaceutically acceptable salt, metabolite, hydrate, or prodrug thereof;
said method comprising:
reacting a 1,2-aminoalcohol of the structure:
with a sulfonyl halide of the structure:
(ii) oxidizing the product of (i); and
(iii) reacting the product of (ii) with R 10 MgX.Join the waitlist — get patent alerts
Track US2010120725A1 — get alerts on status changes and closely related new filings.
We store only your email — no account needed. See our privacy policy.