# US 12,005,065 B2 · Corticotropin releasing factor receptor antagonists

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- Number: US 12,005,065 B2
- Document ID: US12005065B2
- Status: Granted
- Kind: B2
- Application number: 18/307,718
- Filed: 2023-04-26
- Published: 2023-12-28
- Granted: 2024-06-11
- Earliest claimed: 2017-08-14
- Assignees: Spruce Biosciences, Inc.
- Applicants: Spruce Biosciences, Inc.
- Inventors: Alexis Howerton; Hal Gerber; Michael Huang
- Web page: https://patentgrep.com/patent/US12005065B2

## CPC

- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61K 9/14: Particulate form, e.g. powders, {Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles (microspheres A61K9/16; microcapsules A61K9/50; nanocapsules, nanoparticles of the matrix type A61K9/51)}
- A61K 9/48: Preparations in capsules, e.g. of gelatin, of chocolate {(A61K9/0004 takes precedence; bite capsules A61K9/0056)}
- A61K 9/4825: {Proteins, e.g. gelatin (gelatin capsule shells with substantial amounts of other macromolecular substances A61K9/4816)}
- A61K 31/573: substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
- A61P 5/00: Drugs for disorders of the endocrine system
- A61P 5/24: of the sex hormones
- A61P 5/38: of the suprarenal hormones
- C07D 487/04: Ortho-condensed systems
- A61K 2300/00: Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
- 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

The present invention provides novel pharmaceutical compositions comprising -(4-Chloro-2-(morpholin-4-yl)thiazol-5-yl)-7-(1-ethylpropyl)-2,5-dimethylpyrazolo(1,5-a)pyrimidine and methods of using the same for the treatment of Congenital adrenal hyperplasia (CAH).

## Claims

### Claim 1

A method for treating congenital adrenal hyperplasia (CAH) in a human, comprising:
administering to said human a therapeutically-effective amount of a CRF1 receptor antagonist or a pharmaceutically acceptable salt thereof,
wherein said human has received or has been previously determined to receive a first dose of a glucocorticoid, and
administering to said human a second dose of a glucocorticoid, wherein said second dose of a glucocorticoid is reduced compared to said first dose of a glucocorticoid,
wherein an androstenedione (A4) level in said subject is reduced from baseline, or
wherein an adrenocorticotropic hormone (ACTH) level in said subject is reduced from baseline, or
wherein a 17-hydroxyprogesterone (17-OHP) level in said subject is reduced from baseline,
wherein said CRF1 receptor antagonist or a pharmaceutically acceptable salt thereof is administered at a dose between about 50 mg/day and about 200 mg/day, and wherein said CRF1 receptor antagonist is stable for storage for a minimum of six months.

### Claim 2 (depends on 1)

The method of claim 1, wherein said A4 level, said ACTH level, or said 17-OHP level in said human is reduced by at least 5% from baseline.

### Claim 3 (depends on 1)

The method of claim 1, wherein said A4 level, said ACTH level, or said 17-OHP level in said human is reduced by at least 10% from baseline.

### Claim 4 (depends on 1)

The method of claim 1, wherein said A4 level, said ACTH level, or said 17-OHP level in said human is reduced by at least 15% from baseline.

### Claim 5 (depends on 1)

The method of claim 1, wherein said A4 level, said ACTH level, or said 17-OHP level in said human is reduced by at least 20% from baseline.

### Claim 6 (depends on 1)

The method of claim 1, wherein said A4 level, said ACTH level, or said 17-OHP level in said human is reduced by at least 25% from baseline.

### Claim 7 (depends on 1)

The method of claim 1, wherein said A4 level, said ACTH level, or said 17-OHP level in said human is reduced from baseline and is maintained at a reduced level post 24 hours.

### Claim 8 (depends on 1)

The method of claim 1, wherein said A4 level, said ACTH level, or said 17-OHP level in said human is reduced from baseline and is maintained at a reduced level post 4 weeks.

### Claim 9 (depends on 1)

The method of claim 1, wherein said A4 level, said ACTH level, or said 17-OHP level in said human is reduced from baseline and is maintained at a reduced level post 6 weeks.

### Claim 10 (depends on 1)

The method of claim 1, wherein said administering of said first dose of said glucocorticoid is concurrently or sequentially within 2 hours of said administering of said therapeutically-effective amount of a CRF1 receptor antagonist or a pharmaceutically acceptable salt thereof.

### Claim 11 (depends on 1)

The method of claim 1, wherein said CRF1 receptor antagonist or a pharmaceutically acceptable salt thereof is Compound 1:
or a pharmaceutically acceptable salt thereof.

### Claim 12 (depends on 1)

The method of claim 1, wherein said glucocorticoid is selected from beclomethasone, betamethasone, budesonide, cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone, and triamcinolone.

### Claim 13 (depends on 1)

The method of claim 1, wherein said glucocorticoid is hydrocortisone.

### Claim 14 (depends on 1)

The method of claim 1, wherein said first dose of said glucocorticoid comprises a supraphysiologic amount of said glucocorticoid.

### Claim 15 (depends on 1)

The method of claim 1, wherein said second dose of said glucocorticoid comprises a physiologic amount of said glucocorticoid.

### Claim 16 (depends on 1)

The method of claim 1, wherein said CRF1 receptor antagonist or a pharmaceutically acceptable salt thereof is orally administered.

### Claim 17 (depends on 16)

The method of claim 16, wherein said oral administration is once a day.

### Claim 18 (depends on 16)

The method of claim 16, wherein said oral administration is twice a day.

### Claim 19 (depends on 1)

The method of claim 1, wherein said first dose is a first daily dose and said second dose is a second daily dose.

### Claim 20 (depends on 1)

The method of claim 1, wherein said second dose of said glucocorticoid is at least about 5%, at least about 10%, or at least about 20% lower than said first dose of said glucocorticoid.

### Claim 21 (depends on 1)

The method of claim 1, wherein said CRF1 receptor antagonist is stable between about 25° C. and about 40° C.