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US 2008/0166299 A1Published application
Acetylene Derivatives And Their Use For Binding And Imaging Amyloid Plaques
AssigneeThe Trustees of the University of Pennsylvania
InventorsHank F. Kung, Mei Ping Kung
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Abstract
The invention relates to radiolabeled compounds and their use in methods of imaging amyloid deposits, as well as to methods of their manufacture. The invention also relates to compounds for inhibiting the aggregation of amyloid proteins that form amyloid deposits, methods for delivering therapeutic agents to amyloid deposits, as well as methods of making compounds that inhibit the aggregation of amyloid proteins.
Claims50
A compound of Formula I,
- or a pharmaceutically acceptable salt or prodrug thereof, wherein:
- A1 and A2 are independently CH or N;
- R1 and R2 are each independently:
- a. NR′R″, wherein R′ and R″ are independently hydrogen, C1-4 alkyl, hydroxy(C1-4)alkyl or halo(C1-4)alkyl,
- b. hydroxy,
- c. C1-4 alkoxy,
- d. hydroxy(C1-4)alkyl,
- e. halogen,
- f. cyano,
- g. hydrogen,
- h. nitro,
- i. (C1-C4)alkyl,
- j. halo(C1-C4)alkyl,
- k. formyl,
- l. —O—CO(C1-4 alkyl),
- m. —COO(C1-4 alkyl),
- n. —NHCO(C1-4 alkyl), or
- o. radiohalogen;
- R3 is fragment i, ii or iii, wherein:
- fragment i is:
- wherein n is an integer from 1 to 10;
- m is an integer from 0 to 5;
- y is an integer from 0 to 5;
- R5 is hydrogen, C1-4 alkyl, or hydroxy(C1-4)alkyl;
- Ra, Rb, Rc, Rd, Re, Rf, Rg and Rh are each independently hydrogen, halogen, hydroxy, C1-4 alkoxy, C1-4 alkyl, or hydroxy(C1-4)alkyl;
- and
- Z is:
- a) X, wherein X is hydrogen, hydroxy, halogen, radiohalogen, C1-4 alkoxy, hydroxy(C1-4)alkyl, halo(C1-4)alkyl, radiohalo(C1-4)alkyl or NRxRy, wherein Rx and Ry are independently hydrogen, C1-4 alkyl, hydroxy(C1-4)alkyl, radiohalo(C1-4)alkyl or halo(C1-4)alkyl;
- b) one of the following groups, each of which contains X as a substituent:
- benzoyloxy, phenyl(C1-4)alkyl, aryloxy or C6-10 aryl;
- or
- c) Zc, having the following structure:
- wherein p is an integer from 1 to 4, Q is O or NR5 and G is —C═C—(RG)X or —C≡C—X, wherein RG is hydrogen or C1-4 alkyl, and Rn and Ro are independently hydrogen, hydroxyl or C1-4 alkyl;
- fragment ii is:
- wherein y′ is an integer from 0 to 5;
- and fragment iii is:
- wherein e is 0 or 1;
- R4 is hydrogen, halogen, hydroxy, radiohalogen, C1-4 alkyl, C1-4 alkoxy, hydroxy(C1-4)alkyl or NR′ R″;
- provided that,
- X is or contains F or 18F, but if X is not or does not contain F or 18F, then R4 is F, 18F, 123I, 125I, 131I, 76Br, 77Br or Br.
37 more elements
The compound of 20, wherein:
- Z is:
- X, wherein X is hydrogen, halogen, radiohalogen, C1-4 alkoxy, hydroxy or NR′R″;
- or
- Zc, having the following structure:
1 more element
A compound Formula II, having the structure:
- or a pharmaceutically acceptable salt or prodrug thereof, wherein:
- A1 and A2 are independently CH or N;
- R21 and R22 are each independently:
- a. NR′R″, wherein R′ and R″ are independently hydrogen, C1-4 alkyl, hydroxy(C1-4)alkyl or halo(C1-4)alkyl;
- b. hydroxy,
- c. C1-4 alkoxy,
- d. hydroxy(C1-4)alkyl,
- e. halogen,
- f. cyano,
- g. hydrogen,
- h. nitro,
- i. (C1-C4)alkyl,
- j. halo(C1-C4)alkyl,
- k. formyl,
- l. —NHCO(C1-4 alkyl), or
- m. radiohalogen;
- R24 is hydrogen, hydroxy, halogen, radiohalogen, C1-4 alkyl, C1-4 alkoxy, hydroxy(C1-4)alkyl or NR′R″;
- R23 is fragment i, ii, iii or iv, wherein:
- fragment i is:
- wherein n is an integer from 1 to 10;
- m is an integer from 0 to 5;
- y is an integer from 1 to 5;
- R5 is hydrogen, C1-4 alkyl, or hydroxy(C1-4)alkyl;
- Ra, Rb, Rc, Rd, Re, Rf, Rg and Rh are each independently hydrogen, halogen, hydroxy, C1-4 alkoxy, C1-4 alkyl or hydroxy(C1-4)alkyl;
- and Z′ is:
- a) —Ch;
- b) one of the following groups, each of which contains a —Ch directly bound to the aromatic ring:
- benzoyloxy, phenyl(C1-4)alkyl, aryloxy or C6-10 aryl;
- or
- c) Z′c, having the following structure:
- wherein p is an integer from 1 to 4, Q is O or NR5, G is —C═C—(RG)Ch or —C—C—Ch, wherein RG is hydrogen or C1-4 alkyl;
- and Rn and Ro are independently hydrogen, hydroxy or C1-4 alkyl;
- fragment ii is:
- wherein y′ is an integer from 0 to 5;
- fragment iii is:
- wherein e is 0 or 1;
- and fragment iv is:
- wherein q is an integer from 1 to 10;
- or R23 and R24 taken together form —Ch,
- wherein —Ch is a tetradentate chelating ligand capable of complexing with a metal to form a metal chelate.
37 more elements
Dependencies are inferred from the claim text.