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US 2003/0149250 A1Published application
Stilbene derivatives and their use for binding and imaging amyloid plaques
AssigneeThe Trustees of the University of Pennsylvania
InventorsHank F. Kung, Mei-Ping Kung, Zhi-Ping Zhuang
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Abstract
This invention relates to a method of imaging amyloid deposits and to labeled compounds, and methods of making labeled compounds useful in imaging amyloid deposits. This invention also relates to compounds, and methods of making compounds for inhibiting the aggregation of amyloid proteins to form amyloid deposits, and a method of delivering a therapeutic agent to amyloid deposits.
Claims39
A compound of general Formula I:
- 25
- or a pharmaceutically acceptable salt thereof, wherein:
- R5 is hydrogen or C1-4 alkyl;
- R1, R2 and R3, in each instance, is independently selected from the group consisting of hydrogen, halogen, C1-4 alkyl, cyano, carboxy(C1-5)alkyl, trifluoromethyl, nitro, methylamino, dimethylamino, halo(C1-4)alkyl, and formyl;
- R4 is selected from the group consisting of:
- a. C1-4 alkylthio,
- b. halo(C1-4)alkoxy,
- c. carboxy(C1-5)alkyl,
- d. hydroxy,
- e. C1-4 alkoxy,
- f. NR6R7, wherein
- R6 and R7 are hydrogen, fluoro(C1-4)alkyl or C1-4 alkyl,
- g. phenyl(C1-4)alkyl,
- h. C6-10 aryl,
- i. heteroaryl,
- j. heterocycle,
- k. heterocycle(C1-4)alkyl, and
- l. C3-6 cycloalkyl,
- wherein said phenyl(C1-4)alkyl, C6-10 aryl, heteroaryl, heterocycle, heterocycle(C1-4)alkyl or C3-6 cycloalkyl is substituted with one of the following:
- C1-4 alkylthio, C1-4 alkyl sulfonyl, methoxy, hydroxy, dimethylamino or methylamino;
- and,
- X′ is 125I, 123I, 131I, 18F, 18Fluoro(C1-4)alkyl, [18Fluoro(C1-4)alkyl]amino, [18Fluoro(C1-4)alkyl]alkylamino, 76Br, 77Br or Sn(alkyl)3.
19 more elements
A compound of general Formula II:
- 26
- or a pharmaceutically acceptable salt thereof, wherein:
- Z is O, S or NRa, wherein
- Ra is C1-4 alkyl;
- R9, R10 and R11, in each instance, is independently selected from the group consisting of hydrogen, halogen, C1-4 alkyl, cyano, carboxy(C1-5)alkyl, trifluoromethyl, nitro, methylamino, dimethylamino, halo(C1-4)alkyl, and formyl;
- R12 is selected from the group consisting of:
- a. C1-4 alkylthio,
- b. halo(C1-4)alkoxy,
- c. carboxy(C1-5)alkyl,
- d. hydroxy,
- e. C1-4 alkoxy,
- f. NR13R14, wherein
- R13 and R14 are hydrogen, fluoro(C1-4)alkyl or C1-4 alkyl,
- g. phenyl(C1-4)alkyl,
- h. C6-10 aryl,
- i. heteroaryl,
- j. heterocycle,
- k. heterocycle(C1-4)alkyl, and
- l. C3-6 cycloalkyl,
- wherein said phenyl(C1-4)alkyl, C6-10 aryl, heteroaryl, heterocycle, heterocycle(C1-4)alkyl or C3-6 cycloalkyl is substituted with one of the following:
- C1-4 alkylthio, C1-4 alkyl sulfonyl, methoxy, hydroxy, dimethylamino or methylamino;
- and,
- X′ is 125I, 123I, 131I, 18F, 18Fluoro(C1-4)alkyl, [18Fluoro(C1-4)alkyl]amino, [18Fluoro(C1-4)alkyl]alkylamino, 76Br, 77Br or Sn(alkyl)3.
20 more elements
A compound of general Formula III:
- 27
- or a pharmaceutically acceptable salt thereof, wherein:
- R28 is hydrogen or C1-4 alkyl,
- n is equal to a number from zero to four,
- Z is O, S or —CR15═CR16—, wherein
- R15, R16, R17, R18, R19, R20, R21, R22, R23, R24 and R25 are independently selected from the group consisting of:
- a. hydrogen
- b. C1-4 alkylthio,
- c. hydroxy,
- d. C1-4 alkoxy,
- e. NR26R27, wherein
- R26 and R27 are hydrogen or C1-4 alkyl,
- f. phenyl(C1-4)alkyl,
- g. C6-10 aryl,
- h. heteroaryl,
- i. heterocycle,
- j. heterocycle(C1-4)alkyl, and
- k. C3-6 cycloalkyl,
- wherein said phenyl(C1-4)alkyl, C6-10 aryl, heteroaryl, heterocycle, heterocycle(C1-4)alkyl or C3-6 cycloalkyl is substituted with one of the following:
- C1-4 alkylthio, C1-4 alkyl, methoxy, hydroxy, dimethylamino or methylamino;
- provided that one or more of R15, R16, R17, R18, R19, R20, R21, R22, R23, R24 and R25 is other than hydrogen;
- and,
- RP is hydrogen or a sulfur protecting group, such as methoxymethyl, methoxyethoxymethyl, p-methoxybenzyl or benzyl.
20 more elements
A compound containing a radioisotope complex and having the Formula:
- 28
- wherein:
- R28 is hydrogen or C1-4 alkyl,
- n is equal to a number from zero to four,
- Z is O, S or —CR15═CR16—, wherein
- R15, R16, R17, R18, R19, R20, R21, R22, R23, R24 and R25 are independently selected from the group consisting of:
- a. hydrogen
- b. C1-4 alkylthio,
- c. hydroxy,
- d. C1-4 alkoxy,
- e. NR26R27, wherein
- R26 and R27 are hydrogen or C1-4 alkyl,
- f. phenyl(C1-4)alkyl,
- g. C6-10 aryl,
- h. heteroaryl,
- i. heterocycle,
- j. heterocycle(C1-4)alkyl, and
- k. C3-6 cycloalkyl,
- wherein said phenyl(C1-4)alkyl, C6-10 aryl, heteroaryl, heterocycle, heterocycle(C1-4)alkyl or C3-6 cycloalkyl is substituted with one of the following:
- C1-4 alkylthio, C1-4 alkyl, methoxy, hydroxy, dimethylamino or methylamino;
- with the provisos that,
- a) one or more of R15, R16, R17, R18, R19, R21, R22, R24 and R25 is other than hydrogen;
- and
- b) one of R20 and R23 is selected from the group consisting of:
- a. hydrogen,
- b. phenyl(C1-4)alkyl,
- c. C6-10 aryl,
- d. heteroaryl,
- e. heterocycle,
- f. heterocycle(C1-4)alkyl, and
- g. C3-6 cycloalkyl,
- wherein said phenyl(C1-4)alkyl, C6-10 aryl, heteroaryl, heterocycle, heterocycle(C1-4)alkyl or C3-6 cycloalkyl is substituted with one of the following:
- C1-4 alkylthio, C1-4 alkyl sulfonyl, methoxy, hydroxy, dimethylamino or methylamino;
- the other of R20 and R23 represents an unsubstituted position.
31 more elements
A compound of general Formula IV:
- 29
- or a pharmaceutically acceptable salt thereof, wherein:
- n is equal to a number between zero and four,
- R29, R30, R31, R32, R33, R34 and R35 are independently selected from the group consisting of:
- a. hydrogen,
- b. C1-4 alkylthio,
- c. C1-4 alkylsulfonyl,
- d. hydroxy,
- e. C1-4 alkoxy,
- f. NR6R7, wherein
- R6 and R7 are hydrogen or C1-4 alkyl,
- g. phenyl(C1-4)alkyl,
- h. C6-10 aryl,
- i. heteroaryl,
- j. heterocycle,
- k. heterocycle(C1-4)alkyl, and
- l. C3-6 cycloalkyl,
- wherein said phenyl(C1-4)alkyl, C6-10 aryl, heteroaryl, heterocycle, heterocycle(C1-4)alkyl or C3-6 cycloalkyl is substituted with one of the following:
- C1-4 alkylthio, C1-4 alkyl sulfonyl, methoxy, hydroxy, dimethylamino or methylamino;
- provided that one of R29 through R35 is monoalkylaminophenyl or dialkylaminophenyl;
- and
- RP is hydrogen or a sulfur protecting group, such as methoxymethyl, methoxyethoxymethyl, p-methoxybenzyl or benzyl.
19 more elements
A compound containing a radioisotope complex and having the Formula:
- 30
- wherein:
- n is equal to a number between zero and four,
- R29, R30, R31, R32, R33, R34 and R35 are independently selected from the group consisting of:
- a. hydrogen,
- b. C1-4 alkylthio,
- c. C1-4 alkylsulfonyl,
- d. hydroxy,
- e. C1-4 alkoxy,
- f. NR6R7, wherein
- R6 and R7 are hydrogen or C1-4 alkyl,
- g. phenyl(C1-4)alkyl,
- h. C6-10 aryl,
- i. heteroaryl,
- j. heterocycle,
- k. heterocycle(C1-4)alkyl, and
- l. C3-6 cycloalkyl,
- wherein said phenyl(C1-4)alkyl, C6-10 aryl, heteroaryl, heterocycle, heterocycle(C1-4)alkyl or C3-6 cycloalkyl is substituted with one of the following:
- C1-4 alkylthio, C1-4 alkyl sulfonyl, methoxy, hydroxy, dimethylamino or methylamino;
- with the provisos that,
- a) one of R33 through R35 is monoalkylaminophenyl or dialkylaminophenyl;
- and
- b) one of R29 and R32 is selected from the group consisting of:
- a. hydrogen
- b. phenyl(C1-4)alkyl,
- c. C6-10 aryl,
- d. heteroaryl,
- e. heterocycle,
- f. heterocycle(C1-4)alkyl, and
- g. C3-6 cycloalkyl,
- wherein said phenyl(C1-4)alkyl, C6-10 aryl, heteroaryl, heterocycle, heterocycle(C1-4)alkyl or C3-6 cycloalkyl is substituted with one of the following:
- C1-4 alkylthio, C1-4 alkyl sulfonyl, methoxy, hydroxy, dimethylamino or methylamino, the other of R29 and R32 represents an unsubstituted position.
29 more elements
A compound of general Formula V:
- 31
- or a pharmaceutically acceptable salt thereof, wherein:
- R is selected from the group consisting of:
- a. C1-4 alkylthio,
- b. halo(C1-4)alkoxy,
- c. carboxy(C1-5)alkyl,
- d. hydroxy,
- e. C1-4 alkoxy,
- f. NR36R37, wherein
- R36 and R37 are hydrogen, fluoro(C1-4)alkyl or C1-4 alkyl,
- g. phenyl(C1-4)alkyl,
- h. C6-10 aryl,
- i. heteroaryl,
- j. heterocycle,
- k. heterocycle(C1-4)alkyl,
- l. C3-6 cycloalkyl,
- wherein said phenyl(C1-4)alkyl, C6-10 aryl, heteroaryl, heterocycle, heterocycle(C1-4)alkyl or C3-6 cycloalkyl is substituted with one of the following:
- C1-4 alkylthio, C1-4 alkyl sulfonyl, methoxy, hydroxy, dimethylamino or methylamino, and
- m. alkyl;
- and
- RP is hydrogen or a sulfur protecting group.
18 more elements
Dependencies are inferred from the claim text.