Pharmaceutical compounds and use of same in cancer and tauopathies

Patent metadata

Field	Value
Publication number	US-2016000770-A1
Application number	US-201414770850-A
Country	US
Kind code	A1
Filing date	Feb 27, 2014
Priority date	Feb 27, 2013
Publication date	Jan 7, 2016
Grant date	—

Abstract

Disclosed are compounds of formula (1)-(V): where the substituents are as provided herein. Further disclosed are methods of inhibiting tau aggregation, treating or ameliorating a tauopathy or cancer by administration of such a compound. Tau is a microtubule-binding protein that accumulates in a number of neurodegenerative disorders, including frontotemporal dementia and Alzheimer's disease (AD). The presence of abnormal tau correlates with neuron loss and memory deficits in patients with AD and other neurodegenerative disorders that involve tau accumulation.

First claim

What is claimed:

1 . A compound having a structure of formula (I):

wherein
R 1 , R 2 , and R 3 are each selected from the group consisting of hydrogen, fluoro, chloro, methoxy, methyl, or trifluoromethyl,
R 4 and R 5 are each selected from hydrogen, fluoro, and chloro,
R 6 is C 1 -C 4 alkyl or CH 2 Ar;
Ar is aryl;
R 7 is ethyl, allyl, or benzyl;
X is a pharmaceutically acceptable anion, and m is 1, 2, or 3;
with the proviso that
(1) if R 6 is alkyl, R 7 is ethyl, and each of R 4 and R 5 is hydrogen, then at least one of R 1 , R 2 , and R 3 is other than hydrogen; and
(2) when each of R 1 , R 2 , R 3 , R 4 , and R 5 is hydrogen, R 6 is CH 2 Ar.

2 . The compound of claim 1 , wherein at least one of R 1 , R 2 , and R 3 is fluoro.

3 . The compound of claim 1 or 2 , wherein at least one of R 1 , R 2 , and R 3 is chloro.

4 . The compound of any one of claims 1 to 3 , wherein at least one of R 1 , R 2 , and R 3 is methyl.

5 . The compound of any one of claims 1 to 4 , wherein at least one of R 1 , R 2 , and R 3 is trifluoromethyl.

6 . The compound of any one of claims 1 to 4 , wherein at least one of R 1 , R 2 , and R 3 is methoxy.

7 . The compound of claim 1 , wherein R 1 is fluoro and each of R 2 and R 3 is hydrogen.

8 . The compound of claim 1 , wherein R 1 is chloro and each of R 2 and R 3 is hydrogen.

9 . The compound of claim 1 , wherein R 2 is chloro and each of R 1 and R 3 is hydrogen.

10 . The compound of claim 1 , wherein R 3 is chloro and each of R 1 and R 2 is hydrogen.

11 . The compound of claim 1 , wherein R 3 is trifluoromethyl and each of R 1 and R 2 is hydrogen.

12 . The compound of claim 1 , wherein R 2 is trifluoromethyl and each of R 1 and R 3 is hydrogen.

13 . The compound of claim 1 , wherein R 2 and R 3 are each fluoro or chloro and R 1 is hydrogen.

14 . The compound of claim 13 , wherein R 2 and R 3 are each fluoro.

15 . The compound of any one of claims 1 to 14 , wherein R 6 is methyl.

16 . The compound of any one of claims 1 to 14 , wherein R 6 is CH 2 Ar.

17 . The compound of claim 16 , wherein Ar is phenyl.

18 . The compound of claim 16 , wherein Ar is substituted phenyl.

19 . The compound of claim 16 , wherein phenyl is substituted with up to four substitutents selected from fluoro, chloro, and CH 2 NH(CO)Oalkyl.

20 . The compound of claim 19 , wherein the phenyl is substituted with three or four substituents selected from fluoro and chloro.

21 . The compound of claim 20 , wherein Ar is 3,4-difluorophenyl.

22 . The compound of any one of claims 1 to 21 , wherein R 4 and R 5 are each hydrogen.

23 . The compound of any one of claims 1 to 21 , wherein R 4 is chloro and R 5 is hydrogen.

24 . The compound of any one of claims 1 to 21 , wherein R 4 is hydrogen and R 5 is chloro.

25 . The compound of any one of claims 1 to 21 , wherein R 4 is fluoro and R 5 is hydrogen.

26 . The compound of any one of claims 1 to 21 , wherein R 4 is hydrogen and R 5 is fluoro.

27 . The compound of any one of claims 1 to 26 , wherein R 7 is ethyl.

28 . The compound of any one of claims 1 to 26 , wherein R 7 is benzyl.

29 . The compound of any one of claims 1 to 28 , wherein X is chloride, bromide, besylate, mesylate, sulfate, maleate, citrate, phosphate, acetate, succinate, tartrate, benzoate, alginate, fumarate, lactate, triflate, oxalate, oleate, methyl sulfate, or combinations thereof.

30 . A compound having a structure of formula (II):

wherein
R 1 , R 2 , and R 3 are each independently selected from the group consisting of hydrogen, chloro, fluoro, methoxy, and trifluoromethyl;
R 6 is CH 2 Ar or allyl;
Ar is aryl;
R 7 is ethyl, allyl, or benzyl; and
X is a pharmaceutically acceptable anion, and m is 1, 2, or 3.

31 . The compound of claim 30 , wherein R 1 is fluoro.

32 . The compound of claim 30 , wherein R 1 is chloro.

33 . The compound of claim 30 , wherein R 1 is methoxy.

34 . The compound of claim 30 , wherein R 1 is trifluoromethyl.

35 . The compound of claim 30 , wherein R 1 is hydrogen.

36 . The compound of any one of claims 30 to 35 , wherein R 2 is fluoro.

37 . The compound of any one of claims 30 to 35 , wherein R 2 is chloro.

38 . The compound of any one of claims 30 to 35 , wherein R 2 is methoxy.

39 . The compound of any one of claims 30 to 35 , wherein R 2 is trifluoromethyl.

40 . The compound of any one of claims 30 to 35 , wherein R 2 is hydrogen.

41 . The compound of any one of claims 30 to 40 , wherein R 3 is fluoro.

42 . The compound of any one of claims 30 to 40 , wherein R 3 is chloro.

43 . The compound of any one of claims 30 to 40 , wherein R 3 is methoxy.

44 . The compound of any one of claims 30 to 40 , wherein R 3 is trifluoromethyl.

45 . The compound of any one of claims 30 to 40 , wherein R 3 is hydrogen.

46 . The compound of any one of claims 30 to 45 , wherein Ar is phenyl.

47 . The compound of any one of claims 30 to 45 , wherein Ar is substituted phenyl.

48 . The compound of claim 47 , wherein Ar is phenyl substituted with up to four substituents selected from fluoro and chloro.

49 . The compound of claim 48 , wherein Ar is phenyl substituted with two substituents.

50 . The compound of claim 48 , wherein Ar is phenyl substituted with three or four fluoro.

51 . The compound of claim 48 , wherein Ar is phenyl substituted with three or four chloro.

52 . The compound of any one of claims 30 to 51 , wherein R 7 is ethyl.

53 . The compound of any one of claims 30 to 51 , wherein R 7 is benzyl.

54 . The compound of any one of claims 30 to 53 , wherein X is chloride, bromide, besylate, mesylate, sulfate, maleate, citrate, phosphate, acetate, succinate, tartrate, benzoate, alginate, fumarate, lactate, triflate, oxalate, oleate, methyl sulfate, or combinations thereof.

55 . A compound having a structure of formula (III):

wherein
R 1 , R 2 , and R 3 are each independently selected from the group consisting of hydrogen, chloro, fluoro, methoxy, and trifluoromethyl;
R 4 and R 5 are each selected from the group consisting of hydrogen, fluoro, and chloro;
R 7 is ethyl, allyl, or benzyl;

with the proviso that when R 7 is ethyl, at least one of R 4 and R 5 is other than hydrogen, or a salt thereof.

56 . The compound of claim 55

Assignees

• Univ Michigan
• Univ South Florida

Inventors

• Gestwicki Jason E
• Dickey Chad

Classifications

• A61K31/395

  having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins · CPC title

• A61K31/4439 Primary

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465) · CPC title

• A61K38/05

  Dipeptides · CPC title

• C07D417/14

  containing three or more hetero rings · CPC title

• A61K31/428

  condensed with carbocyclic rings · CPC title