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US 8,653,142 B2Granted
Styrenyl derivative compounds for treating ophthalmic diseases and disorders
AssigneeAcucela Inc.
InventorsIan Leslie Scott, Vladimir Aleksandrovich Kuksa, Mark W. Orme, Ryo Kubota
Life of this patent
Estimating the term…
Abstract
The present invention relates generally to compositions and methods for treating neurodegenerative diseases and disorders, particularly ophthalmic diseases and disorders. Provided herein are styrenyl derivative compounds, including but not limited to stilbene derivative compounds, and compositions comprising these compounds, that are useful for treating and preventing ophthalmic diseases and disorders, including age-related macular degeneration (AMD) and Stargardt's Disease.
Claims25
A method for treating an ophthalmic disease or disorder resulting at least in part from lipofuscin pigment accumulation in an eye of a subject, comprising administering to the subject a pharmaceutical composition comprising a compound having a structure of Formula (E):
- as an isolated E or Z geometric isomer or a mixture of E and Z geometric isomers, as a tautomer or a mixture of tautomers, as a stereoisomer, or as a pharmaceutically acceptable salt, hydrate, solvate, or N-oxide thereof, wherein:
- R1 and R2 are each the same or different and independently hydrogen;
- R3, R4, R5 and R6 are each the same or different and independently hydrogen, halogen, —OR12, alkyl or fluoroalkyl;
- R7 and R8 are each the same or different and independently hydrogen;
- each R12 is independently selected from hydrogen or alkyl;
- R14 and R15 are each the same or different and independently hydrogen, halogen, alkyl, fluoroalkyl, —OR12, or —NR18R19;
- or R14 and R15 form an oxo;
- R16 and R17 are each the same or different and independently hydrogen, halogen, alkyl, fluoroalkyl, —OR12, or —NR18R19;
- or R16 and R17 form an oxo;
- each R18 and R19 are each the same or different and independently hydrogen or alkyl;
- t is 0, 1, 2, or 3;
- and
- each R20 is the same or different and independently alkyl, —OR12, —SR12, alkenyl, alkynyl, halogen, fluoroalkyl, aryl or aralkyl, or two adjacent R20, together with the two carbon atoms to which they are attached, form a fused phenyl ring.
10 more elements
A method for treating an ophthalmic disease or disorder resulting at least in part from lipofuscin pigment accumulation in an eye of a subject, comprising administering to the subject a pharmaceutical composition comprising a compound having a structure of Formula (G):
- as an isolated E or Z geometric isomer or a mixture of E and Z geometric isomers, as a tautomer or a mixture of tautomers, as a stereoisomer, or as a pharmaceutically acceptable salt, hydrate, solvate, or N-oxide thereof, wherein:
- R1 and R2 are hydrogen;
- R3, R4, R5 and R6 are each the same or different and independently hydrogen, halogen, —OR12, alkyl or fluoroalkyl;
- R7 and R8 are each the same or different and independently hydrogen or alkyl;
- R9 is hydrogen or —C(═O)R13;
- R10 is hydrogen;
- each R12 is independently selected from hydrogen or alkyl;
- R13 is alkyl;
- R14 and R15 are each the same or different and independently hydrogen, halogen, alkyl, fluoroalkyl, —OR12, or —NR18R19;
- or R14 and R15 together form an oxo;
- R16 and R17 are each the same or different and independently hydrogen, halogen, alkyl, fluoroalkyl, or —OR12;
- or R16 and R17 together form an oxo;
- each R18 and R19 is independently selected from hydrogen or alkyl;
- p is 0, 1, 2, 3, 4, or 5;
- and
- each R21 is the same or different and independently alkyl, —OR12, halogen, or fluoroalkyl.
13 more elements
A method for treating an ophthalmic disease or disorder resulting at least in part from lipofuscin pigment accumulation in an eye of a subject, comprising administering to the subject a pharmaceutical composition comprising a compound having a structure of Formula (A):
- as an isolated E or Z geometric isomer or a mixture of E and Z geometric isomers, as a tautomer or a mixture of tautomers, as a stereoisomer or as a pharmaceutically acceptable salt, hydrate, solvate, or N-oxide thereof, wherein:
- R1 and R2 are each the same or different and independently hydrogen or alkyl;
- R3, R4, R5 and R6 are each the same or different and independently hydrogen, halogen, —OR12, alkyl or fluoroalkyl;
- R7 and R8 are hydrogen;
- R9 and R10 are hydrogen;
- R11 is alkyl;
- each R12 is independently selected from hydrogen or alkyl;
- Z is W—Y, wherein
- W is —C(R14)(R15)—;
- Y is —C(R16)(R17)—;
- R14 and R15 are each the same or different and independently hydrogen, halogen, alkyl, fluoroalkyl, —OR12, or —NR18R19;
- or R14 and R15 together form an oxo;
- R16 and R17 are each the same or different and independently hydrogen, halogen, alkyl, fluoroalkyl, —OR12, or —NR18R19;
- or R16 and R17 together form an oxo;
- or
- optionally, R14 and R16 together form a direct bond to provide a double bond connecting W and Y;
- or optionally, R14 and R16 together form a direct bond, and R15 and R17 together form a direct bond to provide a triple bond connecting W and Y;
- and
- each R18 and R19 is independently selected from hydrogen or alkyl.
16 more elements
A method for treating an ophthalmic disease or disorder resulting at least in part from lipofuscin pigment accumulation in an eye of a subject, comprising administering to the subject a pharmaceutical composition comprising a compound selected from:
- (E)-3-(3-(2,6-dimethylstyryl)phenyl)propan-1-amine;
- (Z)-3-(3-(2,6-dimethylstyryl)phenyl)propan-1-amine;
- (E)-3-(3-(2-methylstyryl)phenyl)propan-1-amine;
- (Z)-3-(3-(2-methylstyryl)phenyl)propan-1-amine;
- (E)-3-(3-(2,6-dimethylstyryl)-2-methylphenyl)propan-1-amine;
- (Z)-3-(3-(2,6-dimethylstyryl)-2-methylphenyl)propan-1-amine;
- (E/Z)-3-(3-(2-ethyl-6-methylstyryl)phenyl)propan-1-amine;
- (E/Z)-3-(3-(2,5-dimethylstyryl)phenyl)propan-1-amine;
- (E/Z)-3-(3-(2,4-dimethylstyryl)phenyl)propan-1-amine;
- (E)-3-(3-(2,4,6-trimethylstyryl)phenyl)propan-1-amine;
- (E/Z)-3-(3-(2-ethylstyryl)phenyl)propan-1-amine;
- (E/Z)-3-(3-(2-ethynylstyryl)phenyl)propan-1-amine;
- (E/Z)-3-(3-(3,4-dimethylstyryl)phenyl)propan-1-amine;
- (E/Z)-3-(3-(2-isopropylstyryl)phenyl)propan-1-amine;
- (E/Z)-4-(3-(3,5-dimethylstyryl)phenyl)propan-1-amine;
- (E/Z)-4-(3-(2-methoxystyryl)phenyl)propan-1-amine;
- (E)-3-(3-(2,6-dichlorostyryl)phenyl)propan-1-amine;
- (E/Z)-3-(3-(2,3-dimethylstyryl)phenyl)propan-1-amine;
- (E)-3-(3-(2,6-dimethylstyryl)-4-fluorophenyl)propan-1-amine;
- (E/Z)-3-(3-(2-(trifluoromethyl)styryl)phenyl)propan-1-amine;
- (E)-3-(3-(2,6-dimethoxystyryl)phenyl)propan-1-amine;
- (E)-3-(3-(2,6-bis(trifluoromethyl)styryl)phenyl)propan-1-amine;
- (E)-3-amino-1-(3-(2,6-dichlorostyryl)phenyl)propan-1-ol;
- (E)-3-amino-1-(3-(2-chloro-6-methylstyryl)phenyl)propan-1-ol;
- (E)-2-(3-(3-aminopropyl)styryl)phenol;
- (E)-3-(5-(2,6-dichlorostyryl)-2-methoxyphenyl)propan-1-amine;
- (R,E)-1-amino-3-(3-(2,6-dichlorostyryl)phenyl)propan-2-ol;
- (S,E)-1-amino-3-(3-(2,6-dichlorostyryl)phenyl)propan-2-ol;
- (E/Z)-(3-(3-(2,6-diethoxystyryl)phenyl)propan-1-amine;
- (E)-3-(3-(2-ethoxystyryl)phenyl)propan-1-amine;
- (E/Z)-3-(3-(2-isopropoxystyryl)phenyl)propan-1-amine;
- (E)-3-amino-1-(3-(2,6-dichlorostyryl)phenyl)propan-1-one;
- (E)-1-amino-3-(3-(2,6-dichlorostyryl)phenyl)propan-2-one;
- (R,E)-3-amino-1-(3-(2,6-dichlorostyryl)phenyl)propan-1-ol;
- (S,E)-3-amino-1-(3-(2,6-dichlorostyryl)phenyl)propan-1-ol;
- (S,E)-3-(3-(2,6-dichlorostyryl)phenyl)-2-fluoropropan-1-amine;
- (E)-3-(3-(2,6-dichlorostyryl)phenyl)-2,2-difluoropropan-1-amine;
- (Z)-3-(3-(2-(2-methoxyethoxy)styryl)phenyl)-propan-1-amine;
- (E)-3-(3-(3-methoxystyryl)phenyl)propan-1-amine;
- (Z)-3-(3-(4-chlorostyryl)phenyl)propan-1-amine;
- (E)-3-(3-(2-(biphenyl-2-yl)vinyl)phenyl)propan-1-amine;
- (E)-3-(3-(3-chlorostyryl)phenyl)propan-1-amine;
- (E)-3-(3-(2-butoxystyryl)phenyl)propan-1-amine;
- (E)-3-(3-(4-methoxystyryl)phenyl)propan-1-amine;
- (Z)-3-(3-(2-Propoxystyryl)phenyl)propan-1-amine;
- (E)-3-(5-(2-Chloro-6-(methylthio)styryl)-2-methoxyphenyl)propan-1-amine;
- (E)-3-(3-(2-(1-methoxynaphthalen-2-yl)vinyl)phenyl)propan-1-amine;
- (Z)-3-(3-(2-(naphthalen-1-yl)vinyl)phenyl)propan-1-amine;
- (Z)-3-(3-(2-(3-methoxynaphthalen-2-yl)vinyl)phenyl)propan-1-amine;
- (E/Z)-3-(3-(2-(2-methoxynaphthalen-1-yl)vinyl)phenyl)propan-1-amine;
- (E)-3-(3-(2-(2,6,6-trimethylcyclohex-1-enyl)vinyl)phenyl)propan-1-amine;
- (E)-3-amino-1-(3-(2-(2,6,6-trimethylcyclohex-1-enyl)vinyl)phenyl)propan-1-ol;
- (S,E)-3-amino-1-(3-(2-(2,6,6-trimethylcyclohex-1-enyl)vinyl)phenyl)propan-1-ol;
- (R,E)-3-Amino-1-(3-(2-(2,6,6-trimethylcyclohex-1-enyl)vinyl)phenyl)propan-1-ol;
- (E)-2-methyl-3-(3-(2-(2,6,6-trimethylcyclohex-1-enyl)vinyl)phenyl)propan-1-amine;
- (E)-3-(3-(2-(2,6,6-trimethylcyclohex-1-enyl)vinyl)phenyl)butan-1-amine;
- (E)-3-(2-methyl-5-(2-(2,6,6-trimethylcyclohex-1-enyl)vinyl)phenyl)propan-1-amine;
- (E/Z)-4-amino-2-(3-(2-(2,6,6-trimethylcyclohex-1-enyl)vinyl)phenyl)butan-2-ol;
- (E)-3-fluoro-3-(3-(2-(2,6,6-trimethylcyclohex-1-enyl)vinyl)phenyl)propan-1-amine;
- (E)-4-amino-1,1,1-trifluoro-2-(3-(2-(2,6,6-trimethylcyclohex-1-enyl)vinyl)phenyl)butan-2-ol;
- (E)-3-amino-2,2-dimethyl-1-(3-(2-(2,6,6-trimethylcyclohex-1-enyl)vinyl)phenyl)propan-1-ol;
- (E)-3-amino-2-methyl-1-(3-(2-(2,6,6-trimethylcyclohex-1-enyl)vinyl)phenyl)propan-1-ol;
- (E)-1-(3-(2-(2,6,6-trimethylcyclohex-1-enyl)vinyl)phenyl)propane-1,3-diamine;
- (E)-4,4,4-trifluoro-3-(3-(2-(2,6,6-trimethylcyclohex-1-enyl)vinyl)phenyl)butan-1-amine;
- (E)-3-methoxy-3-(3-(2-(2,6,6-trimethylcyclohex-1-enyl)vinyl)phenyl)propan-1-amine;
- (E)-4-(3-(2-(2,6,6-trimethylcyclohex-1-enyl)vinyl)phenyl)butan-2-amine;
- (E)-1-amino-3-(3-(2-(2,6,6-trimethylcyclohex-1-enyl)vinyl)phenyl)propan-2-ol;
- (E)-2-(3-(3-(2-(2,6,6-trimethylcyclohex-1-enyl)vinyl)phenyl)propylamino)ethanol;
- (E)-3-methoxy-N-methyl-3-(3-(2-(2,6,6-trimethylcyclohex-1-enyl)vinyl)phenyl)propan-1-amine;
- (E)-3-amino-1-(3-(2-(2,6,6-trimethylcyclohex-1-enyl)vinyl)phenyl)propan-1-one;
- (E)-3-amino-2,2-dimethyl-1-(3-(2-(2,6,6-trimethylcyclohex-1-enyl)vinyl)phenyl)propan-1-one;
- (E)-3-amino-2-methyl-1-(3-(2-(2,6,6-trimethylcyclohex-1-enyl)vinyl)phenyl)propan-1-one;
- (E)-3-amino-2-fluoro-1-(3-(2-(2,6,6-trimethylcyclohex-1-enyl)vinyl)phenyl)propan-1-one;
- (E)-2-(3-(2-(2,6,6-trimethylcyclohex-1-enyl)vinyl)phenoxy)ethanamine;
- (E)-2-amino-N-(3-(2-(2,6,6-trimethylcyclohex-1-enyl)vinyl)phenyl)acetamide;
- (E)-3-(3-(pent-1-enyl)phenyl)propan-1-amine;
- (E)-3-(3-(hept-1-enyl)phenyl)propan-1-amine;
- (E)-3-(3-(non-4-en-5-yl)phenyl)propan-1-amine;
- (E)-4-(3-(3-aminopropyl)phenyl)-2-methylbut-3-en-2-ol;
- (E)-4-(3-(3-aminopropyl)styryl)heptan-4-ol;
- (E)-1-(3-(3-aminopropyl)phenyl)hex-1-en-3-ol;
- (E)-1-(3-(3-aminopropyl)phenyl)-3-ethylpent-1-en-3-ol;
- (E)-3-(3-(3-aminopropyl)phenyl)prop-2-en-1-ol;
- (E)-3-(3-(3-methoxyprop-1-enyl)phenyl)propan-1-amine;
- (Z)-3-amino-1-(3-(2,6-dimethylstyryl)phenyl)propan-1-one oxime;
- (Z)-3-amino-1-(3-((E)-2-(2,6,6-trimethylcyclohex-1-enyl)vinyl)phenyl)propan-1-one oxime;
- (Z)-3-(3-(2,6-dimethylstyryl)phenyl)-3-hydrazonopropan-1-amine;
- (Z)-3-hydrazono-3-(3-((E)-2-(2,6,6-trimethylcyclohex-1-enyl)vinyl)phenyl)propan-1-amine;
- (E)-1-(3-(3-aminopropyl)phenyl)-3-methylhex-1-en-3-ol;
- and
- (E)-1-(3-(3-aminopropyl)phenyl)-3-ethylhex-1-en-3-ol.
88 more elements
Dependencies are inferred from the claim text.