Thioflavin derivatives for use in the antemortem diagnosis of Alzheimer's disease and in vivo imaging and prevention of amyloid deposition

Patent metadata

Field	Value
Publication number	US-9833458-B2
Application number	US-201514595949-A
Country	US
Kind code	B2
Filing date	Jan 13, 2015
Priority date	Aug 24, 2000
Publication date	Dec 5, 2017
Grant date	Dec 5, 2017

Abstract

This invention relates to novel thioflavin derivatives, methods of using the derivatives in, for example, in vivo imaging of patients having neuritic plaques, pharmaceutical compositions comprising the thioflavin derivatives and method of synthesizing the compounds. The compounds find particular use in the diagnosis and treatment of patients having diseases where accumulation of neuritic plaques are prevalent. The disease states or maladies include but are not limited to Alzheimer's Disease, familial Alzheimer's Disease, Down's Syndrome and homozygotes for the apolipoprotein E4 allele.

First claim

We claim:

1. A pharmaceutical composition comprising an amyloid binding compound and a pharmaceutically acceptable carrier, wherein the amyloid binding compound is represented by the following formula or a water soluble, non-toxic salt thereof:

wherein:
Y is NR 1 R 2 ; Z is S; and R 1 is H;
wherein R 2 is selected from the group consisting of a lower alkyl group, (CH 2 ) n OR′ (wherein n=1, 2, or 3 and R′ is H or a lower alkyl group), CF 3 , CH 2 —CH 2 X, CH 2 —CH 2 —CH 2 X (wherein X=F, Cl, Br or I), R ph , and (CH 2 ) n R ph (wherein n=1, 2, 3, or 4, and R ph represents an optionally substituted phenyl group);

R 3 is selected from the group consisting of H, F, Cl, Br, I, a lower alkyl group, (CH 2 ) n OR′ (wherein n=1, 2, or 3), CF 3 , CH 2 —CH 2 X, O—CH 2 —CH 2 X, CH 2 —CH 2 —CH 2 X, O—CH 2 —CH 2 —CH 2 X (wherein X=F, Cl, Br or I), CN, (C═O)—R′, NO 2 , (C═O)N(R′) 2 , O(CO)R′, OR′, SR′, COOR′, R ph , CR′═CR′—R ph , C(R′) 2 —C(R′) 2 —R ph (wherein R′ is H or a lower alkyl group and R ph represents an optionally substituted phenyl group), a tri-alkyl tin, and a chelating group (with or without a chelated metal group) of a form W-L or V—W-L;
R 4 is selected from the group consisting of H, F, Cl, Br, I, a lower alkyl group, (CH 2 ) n OR′ (wherein n=1, 2, or 3), CF 3 , CH 2 —CH 2 X, O—CH 2 —CH 2 X, CH 2 —CH 2 —CH 2 X, O—CH 2 —CH 2 —CH 2 X (wherein X=F, Cl, Br or I), CN, (C═O)—R′, N(R′) 2 , NO 2 , (C═O)N(R′) 2 , O(CO)R′, OR′, SR′, COOR′, R ph , CR′═CR′—R ph , C(R′) 2 —C(R′) 2 —R ph (wherein R′ is H or a lower alkyl group and R ph represents an optionally substituted phenyl group), a tri-alkyl tin, and a chelating group (with or without a chelated metal group) of a form W-L or V—W-L;
R 5 is selected from the group consisting of H, F, Cl, Br, I, a lower alkyl group, (CH 2 ) n OR′ (wherein n=1, 2, or 3), CF 3 , CH 2 —CH 2 X, O—CH 2 —CH 2 X, CH 2 —CH 2 —CH 2 X, O—CH 2 —CH 2 —CH 2 X (wherein X=F, Cl, Br or I), CN, (C═O)—R′, NO 2 , (C═O)N(R′) 2 , O(CO)R′, OR′, SR′, COOR′, R ph , CR′═CR′—R ph , C(R′) 2 —C(R′) 2 —R ph (wherein R′ is H or a lower alkyl group and R ph represents an optionally substituted phenyl group), a tri-alkyl tin, and a chelating group (with or without a chelated metal group) of a form W-L or V—W-L;
R 6 is selected from the group consisting of H, F, Cl, Br, I, a lower alkyl group, (CH 2 ) n OR′ (wherein n=1, 2, or 3), CF 3 , CH 2 —CH 2 X, O—CH 2 —CH 2 X, CH 2 —CH 2 —CH 2 X, O—CH 2 —CH 2 —CH 2 X (wherein X=F, Cl, Br or I), CN, (C═O)—R′, N(R′) 2 , NO 2 , (C═O)N(R′) 2 , O(CO)R′, OR′, SR′, COOR′, R ph , CR′═CR′—R ph , C(R′) 2 —C(R′) 2 —R ph (wherein R′ is H or a lower alkyl group and R ph represents an optionally substituted phenyl group), a tri-alkyl tin, and a chelating group (with or without a chelated metal group) of a form W-L or V—W-L;
R 7 is selected from the group consisting of H, F, Cl, Br, I, a lower alkyl group, (CH 2 ) n OR′ (wherein n=1, 2, or 3), CF 3 , CH 2 —CH 2 X, O—CH 2 —CH 2 X, CH 2 —CH 2 —CH 2 X, O—CH 2 —CH 2 —CH 2 X (wherein X=F, Cl, Br or I), CN, (C═O)—R′, N(R′) 2 , NO 2 , (C═O)N(R′) 2 , O(CO)R′, OR′, SR′, COOR′, R ph , CR′═CR′—R ph , C(R′) 2 —C(R′) 2 —R ph (wherein R′ is H or a lower alkyl group and R ph represents an optionally substituted phenyl group), a tri-alkyl tin, and a chelating group (with or without a chelated metal group) of a form W-L or V—W-L;
R 8 is selected from the group consisting of H, F, Cl, Br, I, ethyl, propyl, butyl, (CH 2 ) n OR′ (wherein n=1, 2, or 3), CF 3 , CH 2 —CH 2 X, O—CH 2 —CH 2 X, CH 2 —CH 2 —CH 2 X, O—CH 2 —CH 2 —CH 2 X (wherein X=F, Cl, Br or I), CN, (C═O)—R′, N(R′) 2 , NO 2 , (C═O)N(R′) 2 , O(CO)R′, OR′, SR′, COOR′, R ph , CR′═CR′—R ph , C(R′) 2 —C(R′) 2 —R ph (wherein R′ is H or a lower alkyl group and R ph represents an optionally substituted phenyl group), a tri-alkyl tin, and a chelating group (with or without a chelated metal group) of a form W-L or V—W-L;
R 9 is selected from the group consisting of H, F, Cl, Br, I, a lower alkyl group, (CH 2 ) n OR′ (wherein n=1, 2, or 3), CF 3 , CH 2 —CH 2 X, O—CH 2 —CH 2 X, CH 2 —CH 2 —CH 2 X, O—CH 2 —CH 2 —CH 2 X (wherein X=F, Cl, Br or I), CN, (C═O)—R′, N(R′) 2 , NO 2 , (C═O)N(R′) 2 , O(CO)R′, OR′, SR′, COOR′, R ph , CR′═CR′—R ph , C(R′) 2 —C(R′) 2 —R ph (wherein R′ is H or a lower alkyl group and R ph represents an optionally substituted phenyl group), a tri-alkyl tin, and a chelating group (with or without a chelated metal group) of a form W-L or V—W-L;
R 10 is selected from the group consisting of H, F, Cl, Br, I, a lower alkyl group, (CH 2 ) n OR′ (wherein n=1, 2, or 3), CF 3 , CH 2 —CH 2 X, O—CH 2 —CH 2 X, CH 2 —CH 2 —CH 2 X, O—CH 2 —CH 2 —CH 2 X (wherein X=F, Cl, Br or I), CN, (C═O)—R′, N(R′) 2 , NO 2 , (C═O)N(R′) 2 , O(CO)R′, OR′, SR′, COOR′, R ph , CR′═CR′—R ph , C(R′) 2 —C(R′) 2 —R ph (wherein R′ is H or a lower alkyl group and R ph represents an optionally substituted phenyl group), a tri-alkyl tin, and a chelating group (with or without a chelated metal group) of a form W-L or V—W-L;
wherein in the chelating group (with or without a chelated metal group) of the form W-L or V—W-L, V is selected from the group consisting of —COO—, —CO—, —CH 2 O— and —CH 2 NH—; W is —(CH 2 ) n where n=0,1,2,3,4, or 5; and L is:

wherein M is selected from the group consisting of Tc and Re.

2. The composition of claim 1 , wherein R ph , when substituted, is substituted with one or more members selected from the group consisting of F, Cl, Br, I, a lower alkyl group, (CH 2 ) n OR′ (wherein n=1, 2, or 3), CF 3 , CH 2 —CH 2 X, O—CH 2 —CH 2 X, CH 2 —CH 2 —CH 2 X, O—CH 2 —CH 2 —CH 2 X (wherein X=F, Cl, Br or I), CN, (C═O)—R′, N(R′) 2 , NO 2 , (C═O)N(R′) 2 , O(CO)R′, OR′, SR′, COOR′ (wherein R′ is H or a lower alkyl group), a tri-alkyl tin and a chelating group (with or without a chelated metal group) of a form W-L or V—W-L, wherein V is selected from the group consisting of —COO—, —CO—, —CH 2 O— and —CH 2 NH—; W is —(CH 2 ) n where n=0, 1, 2, 3, 4, or 5; and L is:

wherein M is selected from the group consisting of Tc and Re.

3. The composition of claim 1 , wherein R 2 ═CH 3 , R 3 -R 7 ═H, R 8 ═OH and R 9 -R 10 are H.

4. The composition of claim 1 , wherein R 2 ═CH 3 and R 8 is selected from the group consisting of CN, ethyl, propyl, butyl, OH, OCH 3 and NH 2 .

5. The composition of claim 4 , wherein R 3 -R 7 and R 9 -R 10 are H.

6. The composition of claim 1 , wherein the amyloid binding compound binds to Aβ with a dissociation constant (K D ) between about 0.0001 and about 10.0 μM when measured by binding to synthetic Aβ peptide or Alzheimer's Disease brain tissue.

7. A pharmaceutical composition comprising an amyloid binding compound and a pharmaceutically acceptable carrier, wherein the amyloid binding compound is represented by the following formula or a water soluble, non-toxic salt thereof:

wherein:
Y is NR 1 R 2 ; Z is S; R 1 is H;
wherein R 2 is selected from the group consisting of a lower alkyl group, (CH 2 ) n OR′ (wherein n=1, 2, or 3 and R′ is H or a lower alkyl group), CF 3 , CH 2 —CH 2 X, CH 2 —CH 2 —CH 2 X (wherein X=F, Cl, Br or I), R ph , and (CH 2 ) n R ph (wherein n=1, 2, 3, or 4 and R ph represents an optionally substituted phenyl group);

R 3 is selected from the group consisting of H, F, Cl, Br, I, a lower alkyl group, (CH 2 ) n OR′ (wherein n=1, 2, or 3), CF 3 , CH 2 —CH 2 X, O—CH 2 —CH 2 X,

Assignees

• Univ Of Pittsburgh—Of The Commonwealth System Of Higher Education

Inventors

• Klunk William E
• Mathis Jr Chester A
• Wang Yanming

Classifications

• C07D277/64

  with only hydrocarbon or substituted hydrocarbon radicals attached in position 2 · CPC title

• A61K51/0497

  conjugates with a carrier being an organic compounds · CPC title

• C07D277/66

  with aromatic rings or ring systems directly attached in position 2 · CPC title

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title

• A61K31/428

  condensed with carbocyclic rings · CPC title