# US 7,410,977 B2 · Fluorinated 4-azasteroids as androgen receptor modulators

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- Number: US 7,410,977 B2
- Document ID: US7410977B2
- Status: Granted
- Kind: B2
- Application number: 11/578,755
- Filed: 2005-04-22
- Published: 2007-10-18
- Granted: 2008-08-12
- Earliest claimed: 2005-04-22
- Assignees: Merck & Co., Inc.
- Inventors: Robert S. Meissner; James J. Perkins
- Web page: https://patentgrep.com/patent/US7410977B2

## CPC

- C07J 73/005: {by nitrogen as hetero atom}
- A61P 1/02: Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
- A61P 3/02: Nutrients, e.g. vitamins, minerals
- A61P 3/04: Anorexiants; Antiobesity agents
- A61P 3/06: Antihyperlipidemics
- A61P 5/26: Androgens
- A61P 5/30: Oestrogens
- A61P 7/06: Antianaemics
- 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 11/00: Drugs for disorders of the respiratory system
- A61P 15/10: for impotence
- A61P 15/12: for climacteric disorders
- A61P 19/00: Drugs for skeletal disorders
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 19/08: for bone diseases, e.g. rachitism, Paget's disease
- A61P 19/10: for osteoporosis
- A61P 21/00: Drugs for disorders of the muscular or neuromuscular system
- A61P 21/04: for myasthenia gravis
- 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 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/18: for HIV
- A61P 35/00: Antineoplastic agents
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07J: STEROIDS (seco-steroids C07C)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Compounds of structural formula I are modulators of the androgen receptor (AR) in a tissue selective manner. These compounds are useful in the enhancement of weakened muscle tone and the treatment of conditions caused by androgen deficiency or which can be ameliorated by androgen administration, including osteoporosis, osteopenia, glucocorticoid-induced osteoporosis, periodontal disease, bone fracture, bone damage following bone reconstructive surgery, sarcopenia, frailty, aging skin, male hypogonadism, postmenopausal symptoms in women, atherosclerosis, hypercholesterolemia, hyperlipidemia, obesity, aplastic anemia and other hematopoietic disorders, inflammatory arthritis and joint repair, HIV-wasting, prostate cancer, benign prostatic hyperplasia (BPH), cancer cachexia, Alzheimer's disease, muscular dystrophies, cognitive decline, sexual dysfunction, sleep apnea, depression, premature ovarian failure, and autoimmune disease, alone or in combination with other active agents.

## Claims

### Claim 1

A compound of structural formula I:
a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:
X and Y are each independently chosen from hydrogen, halogen, hydroxy, and C1-3 alkyl, wherein said alkyl is optionally substituted with one to seven fluorine atoms, provided that when X is methyl than Y is other than methyl; or
X and Y, together with the carbon atom to which they are attached, can optionally form a C3-6cycloalkyl group; and
Z is chosen from hydrogen, carbonyl(C1-3 alkyl), hydroxy, C1-4 alkoxy, halogen, hydroxymethyl, (C0-6 alkyl)2amino, and C1-3 alkyl, wherein said alkoxy and alkyl are each optionally substituted with one to seven fluorine atoms; and provided that when X is hydrogen, Y is other than hydrogen.

### Claim 2 (depends on 1)

The compound of claim 1, wherein X is methyl and Y is selected from hydrogen and C1-3 alkyl; or X and Y, together with the carbon atom to which they are attached, can optionally form a cyclopropyl group.

### Claim 3 (depends on 2)

The compound of claim 2, wherein Z is chosen from hydrogen, and halogen.

### Claim 4 (depends on 1)

The compound of claim 1, selected from:
N-[1(R)-(3H-imidazo[4,5-b]pyridin-2-yl)ethyl]-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;
N-[1(S)-(3H-imidazo[4,5-b]pyridin-2-yl)ethyl]-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;
N-[1-(3H-imidazo[4,5-b]pyridin-2-yl)cyclopropyl]-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;
N-[1(R)-(3H-imidazo[4,5-b]-(5-bromopyridin)-2-yl)ethyl]-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide; and
pharmaceutically acceptable salts and stereoisomers thereof.

### Claim 5 (depends on 1, 2, 3, 4)

A pharmaceutical composition comprising a compound of any one of claims 1-4 or a pharmaceutically acceptable salt or stereoisomer thereof and a pharmaceutically acceptable carrier.

### Claim 6 (depends on 1, 2, 3, 4)

A process for making a pharmaceutical composition comprising combining a compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt or stereoisomer thereof and a pharmaceutically acceptable carrier.