# US 11,077,108 B2 · Allosteric corticotropin-releasing factor receptor 1 (CRFR1) antagonists that decrease p-tau and improve cognition

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- Number: US 11,077,108 B2
- Document ID: US11077108B2
- Status: Granted
- Kind: B2
- Application number: 16/330,754
- Filed: 2017-09-06
- Published: 2019-10-10
- Granted: 2021-08-03
- Earliest claimed: 2016-09-07
- Assignees: The Regents of the University of California
- Applicants: The Regents of the University of California
- Inventors: Mohammad Parvez Alam; Varghese John; Barbara Jagodzinska
- Web page: https://patentgrep.com/patent/US11077108B2

## CPC

- A61K 31/506: not condensed and containing further heterocyclic rings
- A61K 9/0053: {Mouth and digestive tract, i.e. intraoral and peroral administration}
- A61K 31/505: Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/12: Antihypertensives
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 15/00: Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives
- A61P 15/06: Antiabortive agents; Labour repressants
- A61P 15/10: for impotence
- A61P 21/02: Muscle relaxants, e.g. for tetanus or cramps
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/14: for treating abnormal movements, e.g. chorea, dyskinesia
- A61P 25/16: Anti-Parkinson drugs
- A61P 25/18: Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
- A61P 25/20: Hypnotics; Sedatives
- 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
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- A61P 37/08: Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14)
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 239/34: One oxygen atom
- C07D 239/47: One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
- C07D 239/52: Two oxygen atoms
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- C07D 405/12: linked by a chain containing hetero atoms as chain links
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- 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

In various embodiments novel allosteric antagonists of the CRFR1 receptor are provided. It discovered that allosteric CRFR1 receptor antagonists are effective to modulate p-Tau levels in Alzheimer's disease (AD) models. In one illustrative embodiment, a compound that is a CRFR1 receptor antagonist is a compound according to the formula or a pharmaceutically acceptable salt, ester, amide, solvate, or prodrug thereof.

## Claims

### Claim 1

A compound that is a CRFR1 receptor antagonist, wherein said compound is a compound according to the formula
or a pharmaceutically acceptable salt, enantiomer, or solvate thereof, wherein:
X and Y are independently selected from the group consisting of Me, H, CF3, deuterated methyl, and halogen;
R1 is an unsubstituted aminoaryl or a substituted aminoaryl, wherein the substituted aminoaryl is substituted with a substituent selected from the group consisting of CH3, OCH3, halogen, CH2NH2, CN, and CR83, wherein R8 is halogen; and
R2 is an unsubstituted branched alkoxide or a substituted branched alkoxide, wherein the substituted branched alkoxide is substituted with a substituent selected from the group consisting of OCH3, CH3, and CH2OH, and wherein at least one of R1 or R2 is substituted with —OCH3.

### Claim 2 (depends on 1)

The compound of claim 1, wherein X and/or Y is CH3.

### Claim 3 (depends on 1)

The compound of claim 1, wherein R2 is
wherein:
R3 is O,
R4 is selected from the group consisting of OCH3, CH3, and CH2OH; and
R5 is selected from the group consisting of CH3 and OCH3.

### Claim 4 (depends on 3)

The compound of claim 3, wherein R2 is selected from the group consisting of

### Claim 5 (depends on 1)

The compound of claim 1, wherein R1 is
wherein
R10 is NH;
R11 is selected from the group consisting of H, CH3, OCH3, halogen, CH2NH2, CN, and CR83 where R8 is halogen;
R12 is selected from the group consisting of H, CH3, or halogen; and
R13 is selected from the group consisting of CH3, halogen, and CR93 where R9 is halogen.

### Claim 6 (depends on 5)

The compound of claim 5, wherein R1 is selected from the group consisting of

### Claim 7 (depends on 1)

The compound of claim 1, wherein said compound is selected from the group consisting of
or a pharmaceutically acceptable salt, enantiomer, or solvate thereof.

### Claim 8 (depends on 1)

A pharmaceutical formulation comprising the compound of claim 1, and a pharmaceutically acceptable carrier or excipient.

### Claim 9 (depends on 1)

The compound of claim 1, wherein R1 is the substituted aminoaryl.

### Claim 10 (depends on 1)

The compound of claim 1, wherein R2 is the substituted branched alkoxide.

### Claim 11 (depends on 1)

The compound of claim 1, wherein said compound is
or a pharmaceutically acceptable salt or solvate thereof.

### Claim 12 (depends on 11)

A pharmaceutical formulation comprising the compound of claim 11, and a pharmaceutically acceptable carrier or excipient.

### Claim 13 (depends on 1)

The compound of claim 1, wherein said compound is an enantiomer of
or a pharmaceutically acceptable salt or solvate thereof.

### Claim 14 (depends on 13)

A pharmaceutical formulation comprising the compound of claim 13, and a pharmaceutically acceptable carrier or excipient.