# US 10,478,435 B2 · Use of CRAC channel inhibitors for the treatment of stroke and traumatic brain injury

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- Number: US 10,478,435 B2
- Document ID: US10478435B2
- Status: Granted
- Kind: B2
- Application number: 15/751,098
- Filed: 2016-08-05
- Published: 2018-08-23
- Granted: 2019-11-19
- Earliest claimed: 2015-08-07
- Assignees: Calcimedica, Inc.; The United States Government as represented by the Department of Veterans Affairs
- Applicants: CalciMedica, Inc.; The United States Government as Represented by the Department of Veterans Affairs
- Inventors: Kenneth Stauderman; Michael Dunn; Sudarshan Hebbar; Midori Yenari; Rachid Kacimi
- Web page: https://patentgrep.com/patent/US10478435B2

## CPC

- A61K 31/497: containing further heterocyclic rings
- A61K 31/415: 1,2-Diazoles
- A61K 31/422: not condensed and containing further heterocyclic rings
- A61K 31/425: Thiazoles
- A61K 31/427: not condensed and containing further heterocyclic rings
- A61K 31/44: Non condensed pyridines; Hydrogenated derivatives thereof
- A61K 31/496: Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 7/00: Drugs for disorders of the blood or the extracellular fluid
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 25/00: Drugs for disorders of the nervous system
- 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

Described herein are methods of treatment of stroke and traumatic brain injury comprising administration of a CRAC channel inhibitor.

## Claims

### Claim 1

A method for treating stroke or traumatic brain injury in an individual in need thereof comprising administering to the individual a therapeutically effective amount of a compound having the structure of Formula (II):
wherein:
R′1 is
L2 is —NH—C(═O)—, or —C(═O)NH—;
X is CR3 or N;
Y is independently selected from CR9 or N;
R2 is C1-C6alkyl, C3-C8cycloalkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C2-C8heterocycloalkyl, C1-C4alkyleneC2-C8heterocycloalkyl, aryl, heteroaryl, fused aryl or fused heteroaryl; wherein C1-C6alkyl, C3-C8cycloalkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C2-C8heterocycloalkyl, C1-C4alkyleneC2-C8heterocycloalkyl, aryl, heteroaryl, fused aryl or fused heteroaryl is optionally substituted with at least one R3;
R3 is independently selected from H, F, D, Cl, Br, I, —CN, —NO2, —OH, —CF3, —OCF3, —OR5, C1-C6alkyl, C3-C8cycloalkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C2-C5heterocycloalkyl, optionally substituted aryl, optionally substituted O-aryl, optionally substituted heteroaryl,
n is an integer selected from 0-2;
R9 is independently selected from H, D, halogen, C1-C6alkyl, C1-C6haloalkyl, —OR5, —OCF3, C1-C6 carbonylalkyl, or —CF3; or two R9 attached to the same carbon atom form an oxetane ring;
R10 is selected from halogen, C1-C6alkyl, C1-C6haloalkyl, —OR5, —OCF3, C1-C6 carbonylalkyl, or —CF3;
R5 is independently selected from H, C1-C6alkyl, C1-C6haloalkyl, C3-C8cycloalkyl, phenyl, and benzyl;
or a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

The method of claim 1 wherein X is CH.

### Claim 3 (depends on 1)

The method of claim 1 wherein R′1 is
and Y is CH.

### Claim 4 (depends on 3)

The method of claim 3 wherein R2 is phenyl substituted with at least one R3.

### Claim 5 (depends on 4)

The method of claim 4 wherein at least one R3 is selected from Cl, Br, F, I, CF3, C1-C6alkyl, or OC1-C6alkyl.

### Claim 6 (depends on 5)

The method of claim 5 wherein at least one R3 is selected from Cl, F, and CH3.

### Claim 7 (depends on 3)

The method of claim 3 wherein R2 is phenyl substituted with at least one F.

### Claim 8 (depends on 7)

The method of claim 7 wherein at least one R9 is a halogen.

### Claim 9 (depends on 1)

The method of claim 1 wherein R′1 is
and n is 0.

### Claim 10 (depends on 9)

The method of claim 9 wherein R10 is a halogen or C1-C6alkyl.

### Claim 11 (depends on 10)

The method of claim 10 wherein R10 is Cl.

### Claim 12 (depends on 10)

The method of claim 10 wherein R10 is —CH3.

### Claim 13 (depends on 10)

The method of claim 10 wherein R10 is —CH2CH3.

### Claim 14 (depends on 1)

The method of claim 1 wherein R2 is phenyl substituted with two R3, wherein one R3 is F and one R3 is CH3.

### Claim 15 (depends on 1)

The method of claim 1 wherein R2 is phenyl substituted with two R3, wherein each R3 is F.

### Claim 16 (depends on 1)

The method of claim 1 wherein R2 is phenyl substituted with three R3, wherein each R3 is F.

### Claim 17 (depends on 1)

The method of claim 1 wherein R2 is heteroaryl substituted with at least one R3.

### Claim 18 (depends on 17)

The method of claim 17 wherein heteroaryl is pyridyl.

### Claim 19 (depends on 17)

The method of claim 17 wherein R2 is heteroaryl substituted with at least one R3 selected from Cl, Br, F, I, CF3, C1-C6alkyl, or OC1-C6alkyl.

### Claim 20 (depends on 1)

The method of claim 1 wherein L2 is —NH—C(═O)—.