# US 10,478,436 B2 · Application of 5-HT6 receptor antagonists for the alleviation of cognitive deficits of down syndrome

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- Number: US 10,478,436 B2
- Document ID: US10478436B2
- Status: Granted
- Kind: B2
- Application number: 14/681,312
- Filed: 2015-04-08
- Published: 2015-07-30
- Granted: 2019-11-19
- Earliest claimed: 2011-10-03
- Assignees: University of Utah Research Foundation
- Applicants: The University of Utah Research Foundation
- Inventors: Julie Ruth Korenberg; Karen Sue Wilcox; Peter Jeffrey West; Raymond Pierre Kesner
- Web page: https://patentgrep.com/patent/US10478436B2

## CPC

- A61K 31/505: Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K 31/404: Indoles, e.g. pindolol
- A61K 31/4045: Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
- A61K 31/454: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
- 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)
- A61K 31/495: having six-membered rings with two {or more} nitrogen atoms as the only ring heteroatoms, e.g. piperazine {or tetrazines}(A61K31/48 takes precedence {; with three nitrogen atoms A61K31/53})
- A61K 31/496: Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
- A61K 31/4985: Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
- A61K 31/506: not condensed and containing further heterocyclic rings
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 25/00: Drugs for disorders of the nervous system
- 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
- C07D 209/14: Radicals substituted by nitrogen atoms, not forming part of a nitro radical
- C07D 239/50: Three nitrogen atoms
- 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
- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- C07D 401/10: linked by a carbon chain containing aromatic rings
- C07D 487/04: Ortho-condensed systems
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## 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

### Claim 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:
wherein, for compounds having a structure according to Formula I:
RA is selected from —H, —NH2, —NH(alkyl), —N(alkyl)2, —NH(aryl), —N(aryl)2, —N(aryl)(alkyl), —NH-heterocycle, or —NH-heterocycloalkyl, where, in the case of —N(alkyl)2 or —N(aryl)2, the alkyl groups or the aryl groups can be identical or different;
RB is selected from —H, —NH2, —NH(alkyl), —N(alkyl)2, —NH(aryl), —N(aryl)2, —N(aryl)(alkyl), —NH-heterocycle, or —NH-heterocycloalkyl, where, in the case of —N(alkyl)2 or —N(aryl)2, the alkyl groups or the aryl groups can be identical or different;
RC is selected from —H, —OH, —O(alkyl), —O(aryl), -halogen, -alkyl, or haloalkyl;
RD is selected from —H, -alkyl, -halogen, -haloalkyl, or -aryl;
RE is selected from —H, -halogen, —OH, —O(alkyl), —NH2, —NH(alkyl), or —N(alkyl)2, where, in the case of —N(alkyl)2, the alkyl groups can be identical alkyl chains or can be of different length alkyl chains;
RF is —H, —NH2, —NH(alkyl), —N(alkyl)2, —NH(aryl), —N(aryl)2, —N(aryl)(alkyl), —NH-heterocycle, or —NH-heterocycloalkyl, where, in the case of a dialkyl or diaryl nitrogen the alkyl groups or the aryl groups can be identical or different;
X and Y are independently —N— or —C(H)—; and
Z is selected from —CH2—, —CHX—, —CX2—, —CH(alkyl)-, —CH(aryl)-, —C(aryl)(alkyl)-, —C(alkyl)2-, —C(aryl)2-, —O—, —S—, —S(═O)—, or —S(═O)2—, where X is a halogen and where, in the case of —C(alkyl)2- or —C(aryl)2-, the alkyl groups or aryl groups can be identical or different;
and pharmaceutically acceptable hydrates, solvates, tautomers, salts, and complexes thereof.

### Claim 2 (depends on 1)

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.

### Claim 3 (depends on 1)

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.

### Claim 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:
or pharmaceutically acceptable hydrates, solvates, tautomers, salts, and complexes thereof.

### Claim 5 (depends on 4)

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

### Claim 6 (depends on 5)

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

### Claim 7 (depends on 1)

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

### Claim 8 (depends on 7)

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

### Claim 9 (depends on 1)

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.

### Claim 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:
wherein, for compounds having a structure according to Formula II:
RZ is selected from —H, —OH, —O(alkyl), —O(aryl)-O—S-phenyl, —O—S(═O) -phenyl, —O—S(═O)2-phenyl, —O—S-alkyl, —O—S(═O)-alkyl, —O—S(═O)2-alkyl, —O—S-haloalkyl, —O—S(═O)-haloalkyl, —O—S(═O)2-haloalkyl, —O—S-2,6-dihalophenyl, —O—S(═O)-2,6-dihalophenyl, or —OS(═O)2-2,6-dihalophenyl;
RY is selected from —H, -halogen, —NH2, —NH(alkyl), —N(alkyl)2, —NH(aryl), —N(aryl)2, —N(aryl)(alkyl), —NH-heterocycle, or —NH-heterocycloalkyl, where, in the case of —N(alkyl)2 or —N(aryl)2, the alkyl groups or the aryl groups can independently be identical or different;
RW is selected from —H, —OH, —O(alkyl), —O(aryl), -halogen, -alkyl, or haloalkyl;
RV is selected from —H, -2-ethyl-NH(alkyl), -2-ethyl-N(alkyl)2, -2-ethyl-NH(aryl), -2-ethyl-NH(arylalkyl), -2-ethyl-NH(benzyl), -2-ethyl-NH(alkoxybenzyl), -2-ethyl-NH(haloalkoxybenzyl), -2-ethyl-NH(m-haloalkoxybenzyl), -2-ethyl-N(aryl)2, -2-ethyl-N(alkyl)(aryl), -3-propyl-NH(alkyl), -3-propyl-N(alkyl)2, -3-propyl-NH(aryl), -3-propyl-N(aryl)2, -3-propyl-N(aryl)(alkyl), —NH-heterocycle, or —NH-heterocycloalkyl, where, in the case of a dialkyl or diaryl nitrogen, the alkyl groups or the aryl groups can be identical or different;
Z′ is selected from —H, —CH2—, —CHX—, —CX2—, —CH(alkyl)-, —CH(aryl)-, —C(aryl)(alkyl)-, —C(alkyl)2-, —C(aryl)2-, —O—, —S—, —S(═O)—, or —S(═O)2—, where X is a halogen and where, in the case of —C(alkyl)2- or —C(aryl)2-, the alkyl groups or the aryl groups can be identical or different; and
RX is optionally present, and if present is selected from —H, —OH, —O(alkyl), —O(aryl), -halogen, -alkyl, -haloalkyl, or -aryl;
and pharmaceutically acceptable hydrates, solvates, tautomers, salts, and complexes thereof.

### Claim 11 (depends on 10)

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

### Claim 12 (depends on 11)

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

### Claim 13 (depends on 10)

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.

### Claim 14 (depends on 1)

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.

### Claim 15 (depends on 14)

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

### Claim 16 (depends on 1)

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

### Claim 17 (depends on 4)

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.

### Claim 18 (depends on 7)

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

### Claim 19 (depends on 18)

The method of claim 18, wherein the cholinesterase inhibitor is selected from at least one of: physostigmine, galantamine, pyridostigmine, or neostigmine.

### Claim 20 (depends on 7)

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