# US 9,750,724 B2 · Use of an aromatase inhibitor for the treatment of hypogonadism and related diseases

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- Number: US 9,750,724 B2
- Document ID: US9750724B2
- Status: Granted
- Kind: B2
- Application number: 15/050,394
- Filed: 2016-02-22
- Published: 2016-08-25
- Granted: 2017-09-05
- Earliest claimed: 2011-09-08
- Assignees: Mereo BioPharma 2 Limited
- Applicants: Mereo BioPharma 2 Limited
- Inventors: Ann Taylor; Lloyd B. Klickstein
- Web page: https://patentgrep.com/patent/US9750724B2

## CPC

- A61K 31/4196: 1,2,4-Triazoles
- A61K 9/4833: {Encapsulating processes; Filling of capsules (mechanical aspects A61J3/07)}
- A61K 9/485: {Inorganic compounds}
- A61K 9/4858: {Organic compounds}
- A61K 9/4866: {Organic macromolecular compounds}
- A61P 1/14: Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
- A61P 3/04: Anorexiants; Antiobesity agents
- A61P 3/06: Antihyperlipidemics
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 5/00: Drugs for disorders of the endocrine system
- A61P 5/24: of the sex hormones
- A61P 5/26: Androgens
- A61P 5/50: for increasing or potentiating the activity of insulin
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 15/00: Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives
- A61P 15/08: for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
- A61P 15/10: for impotence
- A61P 17/14: for baldness or alopecia
- A61P 19/08: for bone diseases, e.g. rachitism, Paget's disease
- A61P 19/10: for osteoporosis
- A61P 21/06: Anabolic agents (androgens A61P5/26)
- A61P 25/24: Antidepressants
- 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 35/00: Antineoplastic agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- 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

## Abstract

The aromatase inhibitor 4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrile increases testosterone levels and treats hypogonadism and related diseases. A particular dosing regimen is disclosed as well as pharmaceutical compositions comprising said of 4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrile, optionally in combination with other active ingredients and kits comprising the pharmaceutical compositions.

## Claims

### Claim 1

A method for the treatment of a male patient with serum total testosterone levels below 400 ng/dl and in need of increased testosterone levels comprising administering to said patient an effective amount of the compound 4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrile, wherein the effective amount of the compound is from about 0.0005 mg to about 5.0 mg per dose, and wherein the compound is administered according to a dosing regimen having a dosing periodicity selected from about one dose once weekly to about one dose once every month.

### Claim 2 (depends on 1)

The method of claim 1 wherein said male patient has primary testicular failure.

### Claim 3 (depends on 1)

The method of claim 1 wherein said male patient has secondary testicular failure with suppression of gonadotropins.

### Claim 4 (depends on 2)

The method of claim 2, wherein said testicular failure is due to endogenous defects, trauma, infection, chemotherapy, or radiation therapy.

### Claim 5 (depends on 1)

The method of claim 1, wherein the testosterone level is increased by at least 10% in comparison to the testosterone level prior to administration of the compound.

### Claim 6 (depends on 1)

The method of claim 1, wherein the testosterone level is normalized.

### Claim 7 (depends on 1)

The method of claim 1, wherein the patient is in need of the prevention or treatment of one or more disorders selected from the group consisting of decreased libido, decreased spontaneous erections, erectile dysfunction, decreased fertility, loss of body hair, reduced shaving, lack of energy, fatigue, impaired cognition, depression, changes in mood, low bone mineral density, increased risk of fractures, decreased muscle mass, decreased muscle strength, increased abdominal fat mass and limited body performance capacity.

### Claim 8 (depends on 1)

The method of claim 1, wherein the patient is in need of one or more of increased muscle mass and strength, a normalized body composition, a decrease in abdominal fat mass, an improved sexual function and desire, increased fertility and increased bone mineral density.

### Claim 9 (depends on 1)

The method of claim 1, wherein the effective amount of 4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrile is from about 0.01 mg to about 1.0 mg per dose.

### Claim 10 (depends on 1)

The method of claim 1, wherein the effective amount of 4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrile further comprising the administration of a loading dose of 0.3 mg.

### Claim 11 (depends on 1)

The method of claim 1, wherein the effective amount of 4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrile is orally administered to the patient.

### Claim 12 (depends on 11)

The method of claim 11, wherein the effective amount of 4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrile is about 0.1 mg per dose administered about once weekly.

### Claim 13 (depends on 1)

The method of claim 1, wherein 4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrile is administered according to a dosing regimen having a dosing periodicity selected from about one dose once weekly, about one dose once every 10 days, about one dose once biweekly, about one dose once every 3 weeks, about one dose once every 4 weeks, and about one dose once monthly.

### Claim 14 (depends on 13)

The method of claim 13, wherein 4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrile is administered according to a dosing regimen having a dosing periodicity of about one dose once biweekly.

### Claim 15 (depends on 13)

The method of claim 13, wherein 4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrile is administered according to a dosing regimen having a dosing periodicity of about one dose once monthly.

### Claim 16 (depends on 1)

The method of claim 1, wherein 4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrile, when administered to the patient, shows an apparent elimination half-life chosen from one or more of at least about 14 days, at least about 20 days, at least about 25 days and at least about 30 days.

### Claim 17 (depends on 1)

The method of claim 1, wherein when administering a single dose of 4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrile, said dose results in an increased effective blood concentration of testosterone over a period of time from 3 to 30 days.

### Claim 18 (depends on 17)

The method of claim 17, wherein the serum concentration of testosterone is increased by at least 10% over the serum testosterone concentration prior to administration of the compound.

### Claim 19 (depends on 18)

The method of claim 18, wherein serum estradiol is reduced by at least about 30%.

### Claim 20 (depends on 19)

The method of claim 19, wherein the serum estradiol is reduced by 30-50%.

### Claim 21 (depends on 20)

The method of claim 20, wherein the serum estradiol is not suppressed.