Pharmaceutical compounds and use of same in cancer and tauopathies

Patent metadata

Field	Value
Publication number	US-9808448-B2
Application number	US-201715484445-A
Country	US
Kind code	B2
Filing date	Apr 11, 2017
Priority date	Feb 27, 2013
Publication date	Nov 7, 2017
Grant date	Nov 7, 2017

Abstract

Disclosed are compounds of formula (l)-(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 method of treating a subject suffering from cancer comprising administering to the subject a compound or salt thereof in an amount effective to treat the cancer, wherein the compound or salt thereof has a structure of Formula (I) or (III):

R 1 , R 2 , and R 3 are each selected from the group consisting of hydrogen, fluoro, chloro, methoxy, and trifluoromethyl,

R 4 and R 5 are each selected from the group consisting of 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;
(2) when each of R 1 , R 2 , R 3 , R 4 , and R 5 is hydrogen R 6 is CH 2 Ar; and
(3) when the compound has a structure of Formula (III) and R 7 is ethyl, at least one of R 4 and R 5 is other than hydrogen.

2. The method of claim 1 , wherein the cancer is a melanoma, hepatoma, glioma, neurobalstoma, sarcoma, carcinoma of the lung, carcinoma of the colon, carcinoma of the breast, carcinoma of the bladder, carcinoma of the ovary, carcinoma of the testes, carcinoma of the prostate, carcinoma of the cervix, carcinoma of the pancreas, carcinoma of the stomach, carcinoma of the small intestine, leukemia, lymphoma, myeloma, or a liquid tumor.

3. The method of claim 1 , wherein the cancer is myeloma or breast cancer.

4. A method of inhibiting tau protein aggregate formation in a cell comprising contacting the cell with a compound or salt thereof in an amount effective to inhibit tau protein aggregate formation,
wherein the compound or salt thereof has a structure of Formula (I) or (III):

R 1 , R 2 , and R 3 are each selected from the group consisting of hydrogen, fluoro, chloro, methoxy, and trifluoromethyl,
R 4 and R 5 are each selected from the group consisting of 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;
(2) when each of R 1 , R 2 , R 3 , R 4 , and R 5 is hydrogen R 6 is CH 2 Ar; and
(3) when the compound has a structure of Formula (III) and R 7 is ethyl, at least one of R 4 and R 5 is other than hydrogen.

5. The method of claim 4 , wherein the contacting comprises administering to a patient suffering from a tauopathy, and the tauopathy is selected from Alzheimer's disease, Pick's disease, Progressive Supranuclear Palsy (PSP), fronto-temporal dementia (FTD), parkinsonism linked to chromosome 17 (FTDP-I 7), disinhibition-dementia-parkinsonism-amyotrophy complex (DDPAC), pallido-ponto-nigral degeneration (PPND), Guam-ALS syndrome, pallido-nigro-luysian degeneration (PNLD), Huntington's disease, Kennedy disease, dentatorubropallidoluysian atrophy, Spinocerebellar ataxia, Machado-Joseph disease, cortico-basal degeneration (CBD), amyotrophic lateral sclerosis (ALS), and traumatic brain injury.

6. A method of inhibiting tau protein aggregate formation in a cell or a method of inhibiting a cancer cell comprising contacting the cell with a compound having a structure of formula (IV) to inhibit tau protein aggregate formation or to inhibit the cancer cell:

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

7. The method of claim 6 , wherein the contacting comprises administering to a subject and the subject suffers from a tauopathy selected from the group consisting of Alzheimer's disease, Pick's disease, Progressive Supranuclear Palsy (PSP), fronto-temporal dementia (FTD), parkinsonism linked to chromosome 17 (FTDP-I 7), disinhibition-dementia-parkinsonism-amyotrophy complex (DDPAC), pallido-ponto-nigral degeneration (PPND), Guam-ALS syndrome, pallido-nigro-luysian degeneration (PNLD), Huntington's disease, Kennedy disease, dentatorubropallidoluysian atrophy, Spinocerebellar ataxia, Machado-Joseph disease, cortico-basal degeneration (CBD), amyotrophic lateral sclerosis (ALS), and traumatic brain injury.

8. The method of claim 6 , wherein the compound is

or a salt thereof.

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

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

11. The method of claim 1 , wherein at least one of R 1 , R 2 , and R 3 is trifluoromethyl.

12. The method of claim 1 , wherein Ar is phenyl.

13. The method of claim 1 , wherein Ar is phenyl substituted with up to four substituents selected from the group consisting of fluoro, chloro, and CH 2 NH(CO)Oalkyl.

14. The method of claim 1 , wherein R 4 and R 5 are each hydrogen.

15. The method of claim 1 , wherein one of R 4 and R 5 is hydrogen and the other is chloro or fluoro.

16. The method of claim 1 , 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.

17. The method of claim 1 , wherein the compound or salt thereof is selected from the group consisting of

18. A method of inhibiting tau protein aggregate formation in a cell or a method of inhibiting a cancer cell comprising contacting the cell with a compound or salt thereof selected from the group consisting of

Assignees

• Univ Michigan Regents
• Univ South Florida
• Univ Michigan

Inventors

• Gestwicki Jason E
• Dickey Chad

Classifications

• C07D277/64

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

• C07D417/14

  containing three or more hetero rings · CPC title

• A61K31/428

  condensed with carbocyclic rings · CPC title

• 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