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US 2004/0006050 A1Published application
Substituted phenylsulfonamide inhibitors of beta amyloid production
AssigneesWyeth, ArQule, Inc.
InventorsAnthony Frank Kreft, Derek Cecil Cole, Kevin Roger Woller, Joseph Raymond Stock, Kristina Martha Kutterer, Dennis Martin Kubrak, Charles William Mann, William Jay Moore, David Scott Casebier
Life of this patent
Estimating the term…
Abstract
Compounds of Formula I, 1 wherein R1-R8 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 described.
Claims22
A method of lowering beta amyloid levels comprising the steps of:
- a) delivering to a patient, a pharmaceutically acceptable amount of a compound of Formula J:
- 73
- wherein:
- R1 is selected from the group consisting of H, halogen, and O;
- R2 is selected from the group consisting of H, halogen, and N═N;
- R3 is selected from the group consisting of H and halogen;
- R4 is selected from the group consisting of H, halogen, amino, and N═N;
- R5 is selected from the group consisting of H, halogen, methoxy, methyl, and O;
- or
- R1 and R2;
- R2 and R3;
- R4 and R5;
- or R3 and R4 are fused to form a carbon-based, naphthalene ring with the benzene ring;
- R6 is selected from the group consisting of H, lower alkyl, lower alkenyl, 3-phenyl-2-propyn-1-yl, benzyl, substituted benzyl, CH2 cycloalkyl, CH2-2-furan, (CH2)2SCH3, and (CH2)2NHBOC;
- R7 is selected from the group consisting of H, lower alkyl, and cycloalkyl;
- R8 is selected from the group consisting of lower alkyl, substituted alkyl, cycloalkyl, phenyl, substituted phenyl, benzyl, substituted benzyl, CH2 cycloalkyl, CH2-3-indole, CH(lower alkyl)-2-furan, CH(lower alkyl)-4-methoxyphenyl, CH(lower alkyl) phenyl, and CH(OH)-4-SCH3-phenyl;
- or
- R7 and R8 are fused to form a saturated carbon-based ring;
- T is
- 74
- R9 and R10 are H;
- or
- R9 is H and R10 is selected from the group consisting of lower alkyl, lower alkenyl, CF3, methyl-substituted alkenyl, lower alkynyl, cycloalkyl, substituted phenyl, 1-naphthyl, and CH2CH2-1,3-dioxolane;
- or
- R9 and R10 are independently selected from the group consisting of lower alkyl, lower alkenyl, phenyl, 4-substituted-phenyl, and 1-naphthyl;
- wherein:
- (i) when R5 is a methoxy;
- R2 is halogen and R1, R3, and R4 are H;
- (ii) when R5 is a methyl;
- R1 is halogen and R2, R3, and R4 are H;
- (iii) when R4 is an amino;
- R3 is halogen and R1, R2, and R5 are H;
- (iv) when R2 is N═N and R1 is O;
- R2 is bound to R1 to form a heterocyclic ring;
- (v) when R4 is N═N and R5 is O;
- R4 is bound to R5 to form a heterocyclic ring;
- and
- (vi) at least one of R1, R2, R3, R4, and R5 is halogen unless R1 and R2;
- R2 and R3;
- R4 and R5;
- or R3 and R4 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 levels of beta-amyloid in the patient.
41 more elements
A method of preventing or treating Alzheimer's disease, Down's Syndrome, mild cognitive impairment and other beta amyloid-involved diseases, comprising the steps of:
- a) administering to a patient, a pharmaceutically acceptable amount of a compound, sufficient to alleviate the symptoms or progress of said disease, Formula I:
- 76
- wherein:
- R1 is selected from the group consisting of H, halogen, and O;
- R2 is selected from the group consisting of H, halogen, and N═N;
- R3 is selected from the group consisting of H and halogen;
- R4 is selected from the group consisting of H, halogen, amino, and N═N;
- R5 is selected from the group consisting of H, halogen, methoxy, methyl, and O;
- or
- R1 and R2;
- R2 and R3;
- R4 and R5;
- or R3 and R4 are fused to form a carbon-based, naphthalene ring with the benzene ring;
- R6 is selected from the group consisting of H, lower alkyl, lower alkenyl, 3-phenyl-2-propyn-1-yl, benzyl, substituted benzyl, CH2 cycloalkyl, CH2-2-furan, (CH2)2SCH3, and (CH2)2NHBOC;
- R7 is selected from the group consisting of H, lower alkyl, and cycloalkyl;
- R8 is selected from the group consisting of lower alkyl, substituted alkyl, cycloalkyl, phenyl, substituted phenyl, benzyl, substituted benzyl, CH2 cycloalkyl, CH2-3-indole, CH(lower alkyl)-2-furan, CH(lower alkyl)-4-methoxyphenyl, CH(lower alkyl) phenyl, and CH(OH)-4-SCH3-phenyl;
- or
- R7 and R8 are fused to form a saturated carbon-based ring;
- T is
- 77
- R9 and R10 are H;
- or
- R9 is H and R10 is lower alkyl, lower alkenyl, methyl-substituted alkenyl, lower alkynyl, CF3, cycloalkyl, substituted phenyl, 1-naphthyl, or CH2CH2-1,3-dioxolane;
- or
- R9 and R10 are independently selected from the group consisting of lower alkyl, lower alkenyl, phenyl, 4-substituted-phenyl, and 1-naphthyl;
- wherein:
- (i) when R5 is a methoxy;
- R2 is halogen and R1, R3, and R4 are H;
- (ii) when R5 is a methyl;
- R1 is halogen and R2, R3, and R4 are H;
- (iii) when R4 is an amino;
- R3 is halogen and R1, R2, and R5 are H;
- (iv) when R2 is N═N and R1 is O;
- R2 is bound to R1 to form a heterocyclic ring;
- (v) when R4 is N═N and R5 is O;
- R4 is bound to R5 to form a heterocyclic ring;
- and
- (vi) at least one of R1, R2, R3, R4, and R5 is halogen unless R1 and R2;
- R2 and R3;
- R4 and R5;
- or R3 and R4 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.
41 more elements
A compound of Formula Ia:
- 78
- wherein:
- R1 is selected from the group consisting of H, halogen, and O;
- R2 is selected from the group consisting of H, halogen, and N═N;
- R3 is selected from the group consisting of H and halogen;
- R4 is selected from the group consisting of H, halogen, amino, and N═N;
- R5 is selected from the group consisting of H, halogen, methoxy, methyl, and O;
- R6 is selected from the group consisting of H, lower alkyl, lower alkenyl, 3-phenyl-2-propyn-1-yl, benzyl, substituted benzyl, CH2 cycloalkyl, CH2-2-furan, (CH2)2SCH3, and (CH2)2NHBOC;
- R8 is selected from the group consisting of n-propyl, iso-propyl, iso-butyl, n-butyl, t-butyl, substituted butyl, optionally substituted hexyl, optionally substituted heptyl, cycloalkyl, CH2 cycloalkyl, CH(lower alkyl)-2-furan, CH(lower alkyl)-4-methoxyphenyl, CH(lower alkyl) phenyl, CH(OH)-4-SCH3-phenyl, and (CH2)2—S— lower alkyl;
- T is
- 79
- R9 and R10 are H;
- or
- R9 is H and R10 is selected from the group consisting of lower alkyl, lower alkenyl, CF3, methyl-substituted alkenyl, lower alkynyl, cycloalkyl, substituted phenyl, 1-naphthyl, and CH2CH2-1,3-dioxolane;
- or
- R9 and R10 are independently selected from the group consisting of lower alkyl, lower alkenyl, phenyl, 4-substituted-phenyl, and 1-naphthyl;
- wherein:
- (i) when R5 is a methoxy;
- R2 is halogen and R1, R3, and R4 are H;
- (ii) when R5 is a methyl;
- R1 is halogen and R2, R3, and R4 are H;
- (iii) when R4 is an amino;
- R3 is halogen and R1, R2, and R5 are H;
- (iv) when R2 is N═N and R1 is O;
- R2 is bound to R1 to form a heterocyclic ring;
- (v) when R4 is N═N and R5 is O;
- R4 is bound to R5 to form a heterocyclic ring;
- and
- (vi) one or more of R1 to R5 is a halogen;
- or a pharmaceutically acceptable salt, metabolite, hydrate, or prodrug thereof.
27 more elements
A compound of Formula I:
- 80
- wherein:
- R1 is selected from the group consisting of H, halogen, and O;
- R2 is selected from the group consisting of H, halogen, and N═N;
- R3 is selected from the group consisting of H and halogen;
- R4 is selected from the group consisting of H, halogen, amino, and N═N;
- R5 is selected from the group consisting of H, halogen, methoxy, methyl, and O;
- or
- R1 and R2 or R4 and R5 are fused to form a carbon-based, unsaturated ring;
- R6 is selected from the group consisting of H, lower alkyl, lower alkenyl, 3-phenyl-2-propyn-1-yl, benzyl, substituted benzyl, CH2 cycloalkyl, CH2-2-furan, (CH2)2SCH3, and (CH2)2NHBOC;
- R7 is selected from the group consisting of H, lower alkyl, and cycloalkyl;
- R8 is selected from the group consisting of benzyl and substituted benzyl;
- T is
- 81
- R9 and R10 are H;
- or
- R9 is H and R10 is selected from the group consisting of lower alkyl, lower alkenyl, CF3, methyl-substituted alkenyl, lower alkynyl, cycloalkyl, substituted phenyl, 1-naphthyl, and CH2CH2-1,3-dioxolane;
- or
- R9 and R10 are independently selected from the group consisting of lower alkyl, lower alkenyl, phenyl, 4-substituted-phenyl, and 1-naphthyl;
- wherein:
- (i) when R5 is a methoxy;
- R2 is halogen and R1, R3, and R4 are H;
- (ii) when R5 is a methyl;
- R1 is halogen and R2, R3, and R4 are H;
- (iii) when R4 is an amino;
- R3 is halogen and R1, R2, and R5 are H;
- (iv) when R2 is N═N and R1 is O;
- R2 is bound to R1 to form a heterocyclic ring;
- (v) when R4 is N═N and R5 is O;
- R4 is bound to R5 to form a heterocyclic ring;
- and
- (vi) one or more of R1 to R5 is a halogen;
- or a pharmaceutically acceptable salt, metabolite, hydrate, or prodrug thereof.
30 more elements
A compound of Formula Ib:
- 82
- wherein:
- R1 is selected from the group consisting of H, halogen, and O;
- R2 is selected from the group consisting of H, halogen, and N═N;
- R3 is selected from the group consisting of H, bromine, fluorine, and iodine;
- R4 is selected from the group consisting of H, halogen, amino, and N═N;
- R5 is selected from the group consisting of H, halogen, methoxy, methyl, and O;
- R6 is selected from the group consisting of H, lower alkyl, lower alkenyl, 3-phenyl-2-propyn-1-yl, benzyl, substituted benzyl, CH2 cycloalkyl, CH2-2-furan, (CH2)2SCH3, and (CH2)2NHBOC;
- R7 is selected from the group consisting of H, lower alkyl, and cycloalkyl;
- T is
- 83
- R9 and R10 are H;
- or
- R9 is H and R10 is selected from the group consisting of lower alkyl, lower alkenyl, CF3, methyl-substituted alkenyl, lower alkynyl, cycloalkyl, substituted phenyl,
- 1-naphthyl, and CH2CH2-1,3-dioxolane;
- or
- R9 and R10 are independently selected from the group consisting of lower alkyl, lower alkenyl, phenyl, 4-substituted-phenyl, and 1-naphthyl;
- wherein:
- (i) when R5 is a methoxy;
- R2 is halogen and R1, R3, and R4 are H;
- (ii) when R5 is a methyl;
- R1 is halogen and R2, R3, and R4 are H;
- (iii) when R4 is an amino;
- R3 is halogen and R1, R2, and R5 are H;
- (iv) when R2 or R4 is N═N;
- R1 or R5 is O and R2 or R4 is bound to R1 or R5 to form a heterocyclic ring;
- and
- (v) one or more of R1 to R5 is a halogen;
- or a pharmaceutically acceptable salt, metabolite, hydrate, or prodrug thereof.
26 more elements
A compound of Formula I:
- 84
- wherein:
- R1 is selected from the group consisting of H, halogen, and O;
- R2 is selected from the group consisting of H, halogen, and N═N;
- R3 is selected from the group consisting of H and halogen;
- R4 is selected from the group consisting of H, halogen, amino, and N═N;
- R5 is selected from the group consisting of H, halogen, methoxy, methyl, and O;
- R6 is selected from the group consisting of H, lower alkyl, lower alkenyl, 3-phenyl-2-propyn-1-yl, benzyl, substituted benzyl, CH2 cycloalkyl, CH2-2-furan, (CH2)2SCH3, and (CH2)2NHBOC;
- R7 is selected from the group consisting of lower alkyl and cycloalkyl;
- R8 is selected from the group consisting of cycloalkyl, phenyl, substituted phenyl, CH2 cycloalkyl, CH(lower alkyl)-2-furan, CH(lower alkyl)-4-methoxyphenyl, CH(lower alkyl) phenyl, and CH(OH)-4-SCH3-phenyl;
- T is
- 85
- R9 and R10 are H;
- or
- R9 is H and R10 is selected from the group consisting of lower alkyl, lower alkenyl, CF3, methyl-substituted alkenyl, lower alkynyl, cycloalkyl, substituted phenyl, 1-naphthyl, and CH2CH2-1,3-dioxolane;
- or
- R9 and R10 are independently selected from the group consisting of lower alkyl, lower alkenyl, phenyl, 4-substituted-phenyl, and 1-naphthyl;
- wherein:
- (i) when R5 is a methoxy;
- R2 is halogen and R1, R3, and R4 are H;
- (ii) when R5 is a methyl;
- R1 is halogen and R2, R3, and R4 are H;
- (iii) when R4 is an amino;
- R3 is halogen and R1, R2, and R5 are H;
- (iv) when R2 is N═N and R1 is O;
- R2 is bound to R1 to form a heterocyclic ring;
- and
- (v) when R4 is N═N and R5 is O;
- R4 is bound to R5 to form a heterocyclic ring;
- and
- (vi) one or more of R1 to R5 is a halogen;
- or a pharmaceutically acceptable salt, metabolite, hydrate, or prodrug thereof.
29 more elements
A compound of Formula I:
- 86
- wherein:
- R1 is selected from the group consisting of H, halogen, and O;
- R2 is selected from the group consisting of H, halogen, and N═N;
- R3 is selected from the group consisting of H and halogen;
- R4 is selected from the group consisting of H, halogen, amino, and N═N;
- R5 is selected from the group consisting of H, halogen, methoxy, methyl, and or
- R1 and R2;
- R2 and R3;
- R-4 and R5;
- or R3 and R4 are fused to form a carbon-based, naphthalene ring with the benzene ring;
- R6 is selected from the group consisting of H, lower alkyl, lower alkenyl, 3-phenyl-2-propyn-1-yl, benzyl, substituted benzyl, CH2 cycloalkyl, CH2-2-furan, (CH2)2SCH3, and (CH2)2NHBOC;
- R7 is selected from the group consisting of H, lower alkyl, and cycloalkyl;
- R8 is selected from the group consisting of cycloalkyl, phenyl, substituted phenyl, benzyl, substituted benzyl, CH2 cycloalkyl, CH(lower alkyl)-2-furan, CH(lower alkyl)-4-methoxyphenyl, CH(lower alkyl) phenyl, and CH(OH)-4-SCH3-phenyl;
- or
- R7 and R8 are fused to form a saturated carbon-based ring;
- T is
- 87
- wherein:
- (i) when R5 is a methoxy;
- R2 is halogen and R1, R3, and R4 are H;
- (ii) when R5 is a methyl;
- R1 is halogen and R2, R3, and R4 are H;
- (iii) when R4 is an amino;
- R3 is halogen and R1, R2, and R5 are H;
- (iv) when R2 is N═N and R1 is O;
- R2 is bound to R1 to form a heterocyclic ring;
- (v) when R4 is N═N and R5 is O;
- R4 is bound to R5 to form a heterocyclic ring;
- (vi) when each of R1, R2, R4, R5, and R6 is H, R3 is halogen, and R7 is H, then R8 is C5 to C8 alkyl or R7 and R8 are fused to form a saturated carbon-based ring;
- (vii) when each of R3, R4, R5, R6, and R7 is H and R1 and R2 are fused to form a carbon-based naphthalene ring, then R8 is selected from the group consisting of lower alkyl, cycloalkyl, phenyl, substituted phenyl, benzyl, substituted benzyl, CH2 cycloalkyl, CH(lower alkyl)-2-furan, CH(lower alkyl)-4-methoxyphenyl;
- CH(lower alkyl) phenyl, and CH(OH)-4-SCH3-phenyl;
- (viii) when each of R1, R2, R4, R5, and R6 is H and R3 is halogen, then R7 and R8 are not both CH3;
- and
- (ix) at least one of R1, R2, R3, R4, and R5 is halogen unless R1 and R2;
- R2 and R3;
- R4 and R5;
- or R3 and R4 are fused to form a carbon-based, naphthalene ring with the benzene ring;
- or a pharmaceutically acceptable salt, metabolite, hydrate, or prodrug thereof.
36 more elements
A compound of Formula I:
- 88
- wherein:
- R1 is selected from the group consisting of H, halogen, and O;
- R2 is selected from the group consisting of H, halogen, and N═N;
- R3 is selected from the group consisting of H and halogen;
- R4 is selected from the group consisting of H, halogen, amino, and N═N;
- R5 is selected from the group consisting of H, halogen, methoxy, methyl, and O;
- or
- R1 and R2;
- R2 and R3;
- R4 and R5;
- or R3 and R4 are fused to form a carbon-based, naphthalene ring with the benzene ring;
- R6 is selected from the group consisting of lower alkyl, lower alkenyl, 3-phenyl-2-propyn-1-yl, benzyl, substituted benzyl, CH2 cycloalkyl, CH2-2-furan, (CH2)2SCH3, and (CH2)2NHBOC;
- R7 and R8 are fused to form a saturated carbon-based ring;
- T is
- 89
- R9 and R10 are H;
- or
- R9 is H and R10 is selected from the group consisting of lower alkyl, lower alkenyl, CF3, methyl-substituted alkenyl, lower alkynyl, cycloalkyl, substituted phenyl, 1-naphthyl, and CH2CH2-1,3-dioxolane;
- or
- R9 and R10 are independently selected from the group consisting of lower alkyl, lower alkenyl, phenyl, 4-substituted-phenyl, and 1-naphthyl;
- wherein:
- (i) when R5 is a methoxy;
- R2 is halogen and R1, R3, and R4 are H;
- (ii) when R5 is a methyl;
- R1 is halogen and R2, R3, and R4 are H;
- (iii) when R4 is an amino;
- R3 is halogen and R1, R2, and R5 are H;
- (iv) when R2 is N═N and R1 is O;
- R2 is bound to R1 to form a heterocyclic ring;
- (v) when R4 is N═N and R5 is O;
- R4 is bound to R5 to form a heterocyclic ring;
- and
- (vi) at least one of R1, R2, R3, R4, and R5 is halogen unless R1 and R2;
- R2 and R3;
- R4 and R5;
- or R3 and R4 are fused to form a carbon-based, naphthalene ring with the benzene ring;
- or a pharmaceutically acceptable salt, metabolite, hydrate, or prodrug thereof.
35 more elements
Dependencies are inferred from the claim text.