# US 11,306,059 B2 · Drug-induced activation of the Reelin signaling system

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- Number: US 11,306,059 B2
- Document ID: US11306059B2
- Status: Granted
- Kind: B2
- Application number: 16/758,991
- Filed: 2018-10-25
- Published: 2020-11-05
- Granted: 2022-04-19
- Earliest claimed: 2017-10-25
- Assignees: University of South Florida
- Applicants: University of South Florida
- Inventors: Edwin John Weeber; Qingyou Li; Melinda Marie Peters; Hana Marie Soueidan
- Web page: https://patentgrep.com/patent/US11306059B2

## CPC

- A61K 31/167: having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
- C07D 211/90: Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- A61K 31/166: having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
- A61K 31/4184: condensed with carbocyclic rings, e.g. benzimidazoles
- 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
- C07C 233/15: with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
- C07C 233/88: having nitrogen atoms of carboxamide groups bound to an acyclic carbon atom and to a carbon atom of a six-membered aromatic ring wherein at least one ortho-hydrogen atom has been replaced
- C07C 235/24: having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
- C07C 251/86: having doubly-bound carbon atoms of hydrazone groups bound to carbon atoms of six-membered aromatic rings
- C07D 235/18: with aryl radicals directly attached in position 2
- 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)
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS

## Abstract

Disclosed herein are compounds for activating the Reelin signaling system for the treatment of neurological disorders. Further provided are compounds and methods for activating a lipoprotein receptor, such as ApoER2 or VLDLR.

## Claims

### Claim 1

A method of treating a disease or disorder of the central nervous system is a selected from a developmental disorder, a cognitive disorder, a degenerative disorder, a neuropsychiatric disorder, or traumatic brain injury in a subject in need thereof comprising, administering to the subject an effective amount of an agonist of a lipoprotein receptor, wherein the lipoprotein receptor is selected from ApoER2 and VLDLR, thereby improving cognitive function, increasing dendritic spine density, improving associative learning, improving special learning, or improving long-term potentiation of neurons, and wherein the agonist is a compound of Formula I′:
or a pharmaceutically acceptable salt thereof,
wherein each R1 is independently hydrogen, halogen, hydroxyl, alkoxyl, or alkyl;
n is an integer from 0 to 5;
W is C, CH, CH2, or O;
Q is C, CH, CH2, N, or NH;
Z is C═O, NH or CH2;
Y is C═O, NH, or CH2, or Z and Y may together form a bicyclic ring; and
X is cycloalkyl, cycloakenyl, cycloalkynyl, heterocyclyl, aryl, or heteroaryl, and may be unsubstituted or substituted with (R2)m, wherein each R2 is independently hydrogen, halogen, hydroxyl, alkoxyl, or alkyl, and m is an integer from 0 to 5.

### Claim 2 (depends on 1)

The method of claim 1, wherein the disease or disorder of the central nervous system is the result of a Reelin deficiency.

### Claim 3 (depends on 2)

The method of claim 2, wherein the disease or disorder of the central nervous system is selected from Lissencephaly, fragile X syndrome, William's syndrome, Rett syndrome, Down's syndrome, Angelman syndrome, autism, ischemia, hypoxia, Alzheimer's disease, schizophrenia, bipolar disorder, neurodegeneration, traumatic brain injury, mental retardation, dementia, bipolar disorder, and stroke.

### Claim 4 (depends on 1)

The method of claim 1, wherein the lipoprotein receptor is ApoER2.

### Claim 5 (depends on 1)

The method of claim 1, wherein the lipoprotein receptor is VLDLR.

### Claim 6 (depends on 1)

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

### Claim 7

A method of activating a lipoprotein receptor selected from ApoER2 and VLDLR in a subject in need thereof, the method comprising administering to the subject an agonist of the lipoprotein receptor, wherein the agonist is a compound of Formula I′:
or a pharmaceutically acceptable salt thereof,
wherein each R1 is independently hydrogen, halogen, hydroxyl, alkoxyl or alkyl;
n is an integer from 0 to 5;
W is C, CH, CH2, or O;
Q is C, CH, CH2, N, or NH; Z
is C═O, NH, or CH2;
Y is C═O, NH, or CH2, or Z and Y may together firm a bicyclic ring; and
X is cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, or heteroaryl and may be unsubstituted or substituted with (R2)m, wherein each R2 is independently hydrogen, halogen, hydroxyl, alkoxyl, or alkyl, and m is an integer from 0 to 5.

### Claim 8 (depends on 7)

The method of claim 7, wherein the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.