Targeted Modulators for Neurodegenerative Care

Introduction

This serotonin modulation technology offers an innovative treatment method for managing hallucinations in patients with neurodegenerative diseases. By targeting the 5-HT2A serotonin receptor with specific diaryl and arylheteroaryl urea derivatives, the technology provides a new pathway to control and reduce the distressing hallucinations often associated with conditions like Parkinson’s and Alzheimer’s disease. For pharmaceutical and biotechnology companies, this invention represents a significant advancement in the field of neurodegenerative care, providing a targeted approach that can improve patients’ quality of life and support ongoing therapeutic efforts.

The Challenge: Managing Hallucinations in Neurodegenerative Diseases

Hallucinations are a common and distressing symptom for many individuals with neurodegenerative disorders, greatly impacting their mental health and daily living. Current treatments for these symptoms are limited and often come with unwanted side effects, making them unsuitable for long-term use. The lack of effective options for managing hallucinations associated with neurodegenerative diseases leaves both patients and caregivers facing significant challenges in symptom management. As the global prevalence of neurodegenerative conditions rises, there is an urgent need for safe, effective treatments that can address these symptoms without compromising patient well-being.

Serotonin Modulation for Improved Neuropsychiatric Care

This technology addresses these challenges by providing targeted modulation of the 5-HT2A serotonin receptor, a key receptor linked to hallucinations in neurodegenerative disorders. By modulating this receptor with selective urea derivatives, the technology offers a controlled and effective approach to managing hallucinations without the common side effects of traditional antipsychotic drugs. This targeted approach not only reduces the frequency and severity of hallucinations but also supports the broader therapeutic goal of improving patient mental health and quality of life. The technology’s precision makes it a valuable asset for developing treatments that prioritize patient safety and effectiveness.

Key Benefits for Pharmaceuticals and Neuroscience

For pharmaceutical companies and neuroscientists, this technology offers a novel approach to treating neuropsychiatric symptoms in patients with neurodegenerative diseases. It enables the development of specialized medications that improve symptom management while reducing side effects, giving patients a more sustainable treatment option. Healthcare providers can use this approach to support better outcomes for individuals suffering from conditions such as Parkinson’s and Alzheimer’s, helping them manage symptoms in a way that enhances overall quality of life.

Invest in the Future of Neurodegenerative Treatment

Licensing this serotonin modulation technology positions your company as a leader in neurodegenerative care innovation. By offering a treatment that effectively targets hallucinations without compromising safety, your business can meet the rising demand for advanced neuropsychiatric solutions. This technology is an invaluable asset for companies focused on advancing mental health care and providing specialized treatments for neurodegenerative diseases, driving forward compassionate and effective solutions for complex conditions.

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Abstract
Claims

The present invention relates to certain pyrazole derivatives of Formula (I) and pharmaceutical compositions thereof that modulate the activity of the 5-HT2A serotonin receptor and their uses for the treatment and prophylaxis of visual hallucinations associated with Lewy Body dementia.

1. A method for the treatment of visual hallucinations, in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a 5-HT_2Ainverse agonist.

2. The method of claim 1, wherein the 5-HT_2Ainverse agonist is selected from nelotanserin, pimavanserin, pruvanserin, eplivanserin, volinanserin, glemanserin, ketanserin, ritanserin, clozapine, and a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof.

3. The method of claim 2, wherein the 5-HT_2Ainverse agonist is nelotanserin or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof.

4. The method of claim 3, wherein the nelotanserin or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof is selected from the group consisting of Form I of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea, Form II of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea and a combination thereof.

5. The method of claim 3, wherein the therapeutically effective amount of nelotanserin or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof is from about 10 mg to about 160 mg.

6. The method of claim 3, wherein the therapeutically effective amount of nelotanserin or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof is about 10 mg, about 20 mg, about 40 mg, about 80 mg, or about 160 mg.

7. The method of claim 3, wherein the therapeutically effective amount of nelotanserin is about 10 mg, about 20 mg, about 40 mg, about 80 mg, or about 160 mg.

8. The method of claim 3, wherein the therapeutically effective amount of nelotanserin is about 10 mg.

9. The method of claim 3, wherein the therapeutically effective amount of nelotanserin is about 20 mg.

10. The method of claim 3, wherein the therapeutically effective amount of nelotanserin is about 40 mg.

11. The method of claim 3, wherein the therapeutically effective amount of nelotanserin is about 80 mg.

12. The method of claim 3, wherein the therapeutically effective amount of nelotanserin is about 160 mg.

13. The method of claim 1, wherein the therapeutically effective amount of the 5-HT_2Ainverse agonist is administered once a day, twice a day, three times a day, or four times a day.

14. The method of claim 1, wherein the 5-HT_2Ainverse agonist is in a pharmaceutical composition configured for immediate release, for extended release, for delayed release, or any combination thereof.

15. The method of claim 1, wherein the 5-HT_2Ainverse agonist is in a pharmaceutical composition, and wherein the pharmaceutical composition is formulated for oral administration.

16. The method of claim 1, wherein the therapeutically effective amount of the 5-HT_2Ainverse agonist is administered about one to about four times per day, once daily in the morning, once daily about 1 hour prior to the subject’s bedtime, or twice daily.

17. The method of claim 1, wherein the subject is a human.

18. The method of claim 17, wherein the human is an adult with a diagnosis of a condition selected from Lewy Body Dementia, probable Dementia with Lewy bodies, Dementia with Lewy bodies, Parkinson’s disease dementia, Parkinson’s disease, multiple system atrophy, Alzheimer’s disease, vascular dementia, dementia, mild cognitive impairment, Parkinson’s disease psychosis, Alzheimer’s disease psychosis, a sleep disturbance, insomnia, delusions, agitation, Alzheimer’s agitation, aggression, REM sleep behavior disorder, schizophrenia, and any combination thereof.

19. The method of claim 17, wherein the human has a concurrent diagnosis of visual hallucinations, and a condition selected from Lewy Body Dementia, probable Dementia with Lewy bodies, Dementia with Lewy bodies, Parkinson’s disease dementia, Parkinson’s disease, multiple system atrophy, Alzheimer’s disease, vascular dementia, dementia, mild cognitive impairment, Parkinson’s disease psychosis, Alzheimer’s disease psychosis, a sleep disturbance, insomnia, delusions, agitation, Alzheimer’s agitation, aggression, REM sleep behavior disorder, schizophrenia, and any combination thereof.

20. The method of claim 17, wherein the human has a diagnosis of probable Dementia with Lewy Bodies.

21. The method of claim 20, wherein the diagnosis of probable Dementia with Lewy bodies is defined by the presence of dementia and at least one of:

at least two Core Criteria selected from visual hallucinations, cognitive fluctuations, and Parkinsonism, and any combination thereof; and

one Core Criteria selected from visual hallucinations, cognitive fluctuations, and Parkinsonism, and any combination thereof; and at least one Suggestive Criteria selected from REM Sleep Behavior Disorder, Severe Neuroleptic Sensitivity, Low Dopamine Transporter Uptake on DaT SPECT Imaging Scan; and any combination thereof.

22. The method of claim 17, wherein the human has a diagnosis of Dementia with Lewy Bodies.

23. The method of claim 17, wherein the human has a Mini Mental State Examination score of greater than, or equal to, about 18.

24. The method of claim 17, wherein the human is an adult with a diagnosis of visual hallucinations associated with Dementia with Lewy Bodies.

25. The method of claim 17, wherein the human is an adult aged 50-85 inclusive.

26. The method of claim 17, wherein the human has experienced persistent visual hallucinations.

27. The method of claim 26, wherein the presence of persistent hallucinations is defined by a score of four or greater on the hallucinations component of the Neuropsychiatric Inventory (NPI Item B) at screening

28. The method of claim 17, wherein the human has experienced visual hallucinations on at least five days in a week.

29. The method of claim 1, wherein the subject is concurrently receiving a therapeutically effective amount of at least one additional therapeutic agent selected from the group consisting of melatonin, quetiapine, clonazepam, levodopa, carbidopa, an antiparkinsonian drug, an acetylcholinesterase inhibitor, NMDA receptor antagonist, and a combination thereof.

30. The method of claim 29, wherein the antiparkinsonian drug is selected from an MAO-B inhibitor, a COMT inhibitor, a dopamine agonist and any combination thereof.

Title

Diaryl and arylheteroaryl urea derivatives as modulators of the 5-ht2a serotonin receptor useful for the prophylaxis and treatment of hallucinations associated with a neurodegenerative disease

Inventor(s)

Lawrence Tim FRIEDHOFF, Shankar Ramaswamy, Yandong Wen

Assignee(s)

Axovant Sciences GmbH

Patent #

20210177804

Patent Date

June 17, 2021