Application of 5-HT6 receptor antagonists for the alleviation of cognitive deficits of down syndrome

• US 10,478,436 B2
• Filed: 04/08/2015
• Issued: 11/19/2019
• Est. Priority Date: 10/03/2011
• Status: Active Grant

• Current Assignee: University of Utah Research Foundation (State of Utah)
• Original Assignee: University of Utah Research Foundation (State of Utah)
• Inventors: Korenberg, Julie Ruth, Wilcox, Karen Sue, West, Peter Jeffrey, Kesner, Raymond Pierre
• Primary Examiner(s): Pihonak, Sarah
• Application Number:
  US14/681,312
• Publication Number:
  US 20150209353A1
• Time in Patent Office: 1,686 Days
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/404 Indoles, e.g. pindolol
• CPC Class Codes: A61K 31/4045 Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
• CPC Class Codes: A61K 31/454 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
• CPC Class Codes: A61K 31/4745 condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48
• CPC Class Codes: A61K 31/495 having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazinesA61K31/48 takes precedence ; with three nitrogen atoms A61K31/53
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 31/4985 Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
• CPC Class Codes: A61K 31/505 Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: C07D 209/14 Radicals substituted by nitrogen atoms, not forming part of a nitro radical
• CPC Class Codes: C07D 239/50 Three nitrogen atoms
• CPC Class Codes: C07D 295/096 with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/10 linked by a carbon chain containing aromatic rings
• CPC Class Codes: C07D 487/04 Ortho-condensed systems

Abstract

Methods for treating Down syndrome and improving cognitive function of a patient with an intellectual disability are disclosed. 5-hydroxytryptamine sub-receptor six (5-HT₆) receptor antagonists are provided for improving the cognition of a Down syndrome patient.

Claims

1. A method of improving cognitive function in a subject with Down syndrome, comprising administering to the subject a 5-HT₆ receptor antagonist in an amount sufficient for a therapeutic effect by binding to a 5-HT₆ receptor, wherein the subject has chronic cognitive impairment caused by a genetic anomaly, wherein the 5-HT₆ receptor antagonist is an effective amount of a compound having a structure according to Formula I:

2. The method of claim 1, wherein the route of administration of the 5-HT₆ antagonist is selected from at least one of the following:

intravenous, intraperitoneal, subcutaneous, parenteral, intramuscular, oral, topical, transmucosal, intraventricular, or intrathecal administration.

3. The method of claim 1, wherein the subject suffers from a comorbid disorder associated with Down syndrome comprising Autism spectrum disorders, attention deficit hyperactivity disorder, obsessive compulsive disorder, and disorders involving speech and language.

7. The method of claim 1, wherein the 5-HT₆ antagonist is administered in combination with another therapeutic agent.

8. The method of claim 7, wherein the 5-HT₆ antagonist is administered in combination with a cholinesterase inhibitor or an acetylcholine receptor agonist.

9. The method of claim 1, wherein the subject is administered a pharmaceutical composition comprising a 5-HT₆ receptor antagonist or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

14. The method of claim 1, where the 5-HT₆ receptor antagonist is chosen from:

a 5-HT₆ receptor inverse agonist, a 5-HT₆ receptor competitive antagonist, or a 5-HT₆ receptor inhibitor.

15. The method of claim 14, wherein the 5-HT₆ receptor antagonist is a 5-HT₆ receptor competitive antagonist.

16. The method of claim 1, wherein the 5-HT₆ receptor antagonist directly binds to the 5-HT₆ receptor.

18. The method of claim 7, wherein the 5-HT₆ antagonist is administered in combination with a cholinesterase inhibitor.

19. The method of claim 18, wherein the cholinesterase inhibitor is selected from at least one of:

physostigmine, galantamine, pyridostigmine, or neostigmine.

20. The method of claim 7, wherein the 5-HT₆ antagonist is administered in combination with an acetylcholine receptor agonist.

4. A method of improving cognitive function in a subject with Down syndrome, comprising administering to the subject a 5-HT₆ receptor antagonist in an amount sufficient for a therapeutic effect by binding to a 5-HT₆ receptor, wherein:

(i) the 5-HT₆ receptor antagonist is a small molecule 5-HT₆ receptor antagonist;

(ii) the small molecule 5-HT₆ receptor antagonist has a molecular weight of less than 800 Daltons; and

(iii) the subject has chronic cognitive impairment caused by a genetic anomaly,

wherein the 5-HT₆ antagonist is an effective amount of compound 7, having the chemical formula;

5. The method of claim 4, wherein the 5-HT₆ antagonist is administered in combination with another therapeutic agent.

6. The method of claim 5, wherein the 5-HT₆ antagonist is administered in combination with a cholinesterase inhibitor or an acetylcholine receptor agonist.

17. The method of claim 4, wherein the subject is administered a pharmaceutical composition comprising a 5-HT₆ receptor antagonist or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

10. A method of improving cognitive function in a subject with Down syndrome, comprising administering to the subject a 5-HT₆ receptor antagonist in an amount sufficient for a therapeutic effect by binding to a 5-HT₆ receptor, wherein the subject has chronic cognitive impairment caused by a genetic anomaly, wherein the 5-HT₆ receptor antagonist is an effective amount of a compound having a structure according to Formula II:

11. The method of claim 10, wherein the 5-HT₆ antagonist is administered in combination with another therapeutic agent.

12. The method of claim 11, wherein the 5-HT₆ antagonist is administered in combination with a cholinesterase inhibitor or an acetylcholine receptor agonist.

13. The method of claim 10, wherein the subject is administered a pharmaceutical composition comprising a 5-HT₆ receptor antagonist or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.