Novel Substituted Benzothiazole Compounds for Treating Huntington’s Disease

Important Compound Classes

Title

Heteroaryl Compounds for Treating Huntington’s Disease

Patent Publication Number

WO 2020/005877 A1

Publication Date

January 2, 2020

Priority Application

US 62/690,540

Priority Date

June 27, 2018

Inventors

Zhang, N.; Babu, S.; Barraza, S. J.; Bhattacharyya, A.; Chen, G.; Karp, G. M.; Kassick, A. J.; Mazzotti, A. R.; Moon, Y.; Narasimhan, J.; Sydorenko, N.; Turpoff, A.; Woll, M. G.; Yan, W.

Assignee Company

PTC Therapeutics, Inc., USA

Disease Area

Huntington’s disease

Biological Target

Huntington protein

Summary

Huntington’s disease (HD) is a progressive, autosomal dominant neurodegenerative disorder of the brain, having symptoms characterized by involuntary movements, cognitive impairment, and mental deterioration. Death, typically caused by pneumonia or coronary artery disease, usually occurs 13–15 years after the onset of symptoms. The prevalence of HD is between 3 and 7 individuals per 100 000 in populations of western European descent. In North America, an estimated 30 000 people have HD, while an additional 200 000 people are at risk of inheriting the disease from an affected parent. The disease is caused by an expansion of uninterrupted trinucleotide CAG repeats in the “mutant” huntingtin (Htt) gene, leading to production of HTT (Htt protein) with an expanded polyglutamine (polyQ) stretch, also known as a “CAG repeat” sequence. There are no current small molecule therapies targeting the underlying cause of the disease, leaving a high unmet need for medications that can be used for treating or ameliorating HD.

The present application describes a series of novel substituted benzothiazole compounds of Formula (I) or Formula (II), useful for treating or ameliorating Huntington’s disease. Further, the application discloses compounds, their preparation, use, pharmaceutical composition, and treatment.

Definitions

W₁, W₂ and W₃ = C-R_a, or N;

R_a = H, CN, halogen, OH, C_1–6alkyl, halo-C_1–6alkyl, C_1–6alkylcarbonyl, C_1–6alkoxy, halo-C_1–6alkoxy, C_1–6alkoxy-C_1–6alkyl, C_1–6alkoxy-carbonyl, amino, C_1–6alkyl-amino, (C_1–6alkyl)₂-amino, and hydroxyl-C_1–4alkyl;

X = N-R_b, O or a bond;

R_b = H and C_1–6alkyl;

R₁ = C_3–10cycloalkyl and heterocyclyl;

wherein heterocyclyl is a saturated or partially unsaturated 3–7 membered monocyclic, 6–10 membered bicyclic or 13–16 membered polycyclic ring system having 1, 2, or 3 heteroatom ring members independently selected from N, O or S; and

wherein C_3–10cycloalkyl and heterocyclyl is optionally substituted with one, two, three or four R₃ substituents and optionally, with one additional R₄ substituent, or

wherein C_3–10cycloalkyl and heterocyclyl is optionally substituted with one, two, three, four, or five R₃ substituents; and

R₂ = phenyl or heteroaryl;

wherein heteroaryl is a 3–7 membered monocyclic, 6–10 membered bicyclic ring system having 1,2,3,or 4 heteroatom ring members independently selected from N, O, or S;

wherein phenyl and heteroaryl is optionally substituted with one, two, or three R₅ substituents and optionally, with one additional R₆ substituent, or,

wherein phenyl and heteroaryl is optionally substituted with one, two, three, or four R₅ substituent.

Key Structures

Biological Assay

The endogenous Huntington protein assay was performed. The compounds described in this application were tested, and their IC₅₀ (μM) values are shown in the following table.

Biological Data

The table below shows representative compounds that were tested. The biological data obtained from testing representative examples are listed in the following table. For IC₅₀: (*) means between >3.0 and ≤9.0 μM; (**) means between >1.0 and ≤3.0 μM; (***) means between >0.5 and ≤1.0 μM; (****) means between >0.1 and ≤0.5 μM; (*****) means ≤0.1 μM.

Claims

Total claims: 17

Compound claims: 7

Pharmaceutical composition claims: 2

Method of treatment claims: 2

Use of compound claims: 6

Recent Review Articles

• 1.Moldovean S. N.; Chis V.. ACS Chem. Neurosci. 2020, 11, 105.
• 2.Kumar A.; Kumar V.; Singh K.; Kumar S.; Kim Y.; Lee Y.; Kim J.. Brain Sci. 2020, 10, 43.
• 3.Lebouc M.; Richard Q.; Garret M.; Baufreton J.. Neurobiol. Dis. 2020, 145, 105076.
• 4.Karagas N. E.; Rocha N. P.; Stimming E. F.. J. Huntington's Dis. 2020, 9, 107.
• 5.Stahl C. M.; Feigin A.. Neurol. Clin. 2020, 38, 367.
• 6.Taran A. S.; Shuvalova L. D.; Lagarkova M. A.; Alieva I. B.. Cells 2020, 9, 1514.

The author declares no competing financial interest.