Pharmaceutical compounds and use of same in cancer and tauopathies

Patent metadata

Field	Value
Publication number	US-9642843-B2
Application number	US-201414770850-A
Country	US
Kind code	B2
Filing date	Feb 27, 2014
Priority date	Feb 27, 2013
Publication date	May 9, 2017
Grant date	May 9, 2017

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. 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.

3. 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.

4. A compound having a structure selected from the group consisting of

or a compound having a structure

or a salt thereof.

5. A compound having a structure of formula (V):

wherein
Ar is pyridinyl, thiazolyl, pyrazinyl, or pyridinonyl;
R 1 , R 2 , R 3 , and R 8 are each selected from the group consisting of hydrogen, fluoro, chloro, methoxy, ethoxy, methyl, ethyl, propyl, isopropyl, trifluromethyl, SO 2 Me, NO 2 , trifluromethoxy, CN, ethoxy, propoxy, and isopropoxy, with the proviso that at least one of R 1 , R 2 , R 3 , and R 8 is not hydrogen;
R 7 is selected from ethyl, allyl, benzyl, methoxy, ethoxy, C 3-6 cycloalkyl, and (CH 2 ) 1-3 CO 2 R, and
R is a C 1-3 alkyl;
or a salt thereof.

6. A compound having the structure selected from the group consisting of

or a salt thereof.

Assignees

• Univ Michigan Regents

Inventors

• Gestwicki Jason E

Classifications

• C07D277/64

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

• C07D417/14

  containing three or more hetero rings · CPC title

• A61K31/428

  condensed with carbocyclic rings · CPC title

• A61K38/05

  Dipeptides · CPC title