# US 11,110,104 B2 · Glutamine antagonists for the treatment of cognitive deficits and psychiatric disorders

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- Number: US 11,110,104 B2
- Document ID: US11110104B2
- Status: Granted
- Kind: B2
- Application number: 15/884,974
- Filed: 2018-01-31
- Published: 2018-07-12
- Granted: 2021-09-07
- Earliest claimed: 2015-07-31
- Assignees: The Johns Hopkins University; Icahn School of Medicine at Mount Sinai
- Applicants: The Johns Hopkins University; Icahn School of Medicine At Mount Sinai
- Inventors: Barbara Slusher; David Volsky; Mike Nedelcovych; Kristen Hollinger; Atsushi Kamiya
- Web page: https://patentgrep.com/patent/US11110104B2

## CPC

- A61K 31/655: Azo (—N=N—), diazo (=N2), azoxy (>N—O—N< or N(=O)—N<), azido (—N3) or diazoamino (—N=N—N<) compounds
- A61K 31/198: Alpha-amino acids, e.g. alanine or edetic acid [EDTA] (betaine A61K31/205; proline A61K31/401; tryptophan A61K31/405; histidine A61K31/4172; peptides not degraded to individual amino acids A61K38/00)
- A61K 31/223: of alpha-aminoacids
- A61K 31/42: Oxazoles
- 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
- 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

## Abstract

The disclosure provides compounds having formula (I): and the pharmaceutically acceptable salts thereof, wherein R1, R2, R2′, and X are as defined as set forth in the specification, for use in treating cognitive deficits and/or psychiatric disorders, such as those associated with neurological or neurodegenerative disorders, psychiatric or mood disorders, and HIV-associated neurocognitive disorders (HAND). Compounds having formula (I) are prodrugs that release glutamine analogs, e.g., 6-diazo-5-oxo-L-norleucine (DON).

## Claims

### Claim 1

A method for treating a subject having a cognitive deficit, the method comprising administering to the subject a compound having formula (II):
or a pharmaceutically acceptable salt thereof;
wherein:
R1 is selected from the group consisting of H and C1-6 alkyl;
R3 and R4 are independently selected from the group consisting of H, C1-C6 alkyl, substituted C1-C6 alkyl, aryl, and substituted aryl; and
R10 is C1-6 alkyl,
in an amount effective to treat the cognitive deficit.

### Claim 2 (depends on 1)

The method of claim 1, wherein R1 is selected from the group consisting of methyl, ethyl, and isopropyl.

### Claim 3 (depends on 1)

The method of claim 1, wherein R3 is H and R4 is selected from the group consisting of methyl and phenyl.

### Claim 4 (depends on 1)

The method of claim 1, wherein R10 is selected from the group consisting of isopropyl and tert-butyl.

### Claim 5 (depends on 1)

The method of claim 1, wherein the compound having formula (II) is selected from the group consisting of:

### Claim 6 (depends on 5)

The method of claim 5, wherein the compound having formula (I) is selected from the group consisting of:

### Claim 7 (depends on 1)

The method of claim 1, wherein the cognitive deficit is characterized by impairment of the mental processes of perception, learning, memory, judgment, and/or reasoning.

### Claim 8 (depends on 1)

The method of claim 1, wherein the cognitive deficit is due to a viral infection.

### Claim 9 (depends on 8)

The method of claim 8, wherein the cognitive deficit is due to the human immunodeficiency virus (HIV).

### Claim 10 (depends on 9)

The method of claim 9, wherein the virus is latent.

### Claim 11 (depends on 1)

The method of claim 1, wherein the cognitive deficit is selected from the group consisting of asymptomatic neurocognitive impairment (ANI) and mild neurocognitive disorder (MND).

### Claim 12 (depends on 1)

The method of claim 1, wherein the cognitive deficit is associated with a neurodegenerative disorder.

### Claim 13 (depends on 1)

The method of claim 1, wherein the cognitive deficit is associated with multiple sclerosis.