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4-azasteroid derivatives as androgen receptor modulators

a technology of androgen receptor and derivatives, applied in the field of 4azasteroid derivatives, can solve the problems of limited use of androgens, increased risk of cardiovascular disease, and significant bone loss in men, and achieves the effects of reducing the risk of cardiovascular diseas

Inactive Publication Date: 2005-06-16
WANG JIABING +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0026] The present invention also relates to methods for the treatment of 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 hematopoie

Problems solved by technology

Despite the beneficial effects of androgens in postmenopausal women, the use of androgens has been limited because of the undesirable virilizing and metabolic action of androgens.
Therefore, non-tissue selective AR agonists may increase the risk of cardiovascular disease.
In response to hormonal deprivation, these men suffered from hot flushes, significant bone loss, weakness, and fatigue.
In postmenopausal women, estrogen deficiency leads to increased bone resorption resulting in bone loss in the vertebrae of around 5% per year, immediately following menopause.
However, inhibitors of bone resorption are not sufficient to restore bone mass for patients who have already lost a significant amount of bone.
In addition, as the rate of bone turnover differs from site to site, higher in the trabecular bone of the vertebrae than in the cortex of the long bones, the bone resorption inhibitors are less effective in increasing hip BMD and preventing hip fracture.

Method used

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  • 4-azasteroid derivatives as androgen receptor modulators
  • 4-azasteroid derivatives as androgen receptor modulators
  • 4-azasteroid derivatives as androgen receptor modulators

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0775]

Step A: 3-Oxo-4-aza-5α-androst-5-en-17(3-carboxylic acid methyl ester (1-2)

[0776] A mixture of 1-1, (J. Med. Chem., 29: 2298-2315 (1986)), (50.0 g, 157.5 mmol), EDC.HCl (33.2 g, 173.3 inmol) and DMAP (1.9 g, 15.8 mmol) in MeOH (300 mL) was stirred for 24 hr. The mixture was concentrated and diluted with water (1000 mL). After filtration, the solid was collected and dried to furnish the desired product 1-2 as a solid which was used in Step B without further purification.

[0777] MS calculated M+H: 332.2, found 332.2

Step B: 4-Methyl-3-oxo-4-aza-5α-androst-5-en-17β-carboxylic acid methyl ester (1-3)

[0778] To a suspension of 1-2 (7.0 g, 21.1 mmol) in 100 mL dry THF was added NaH (1.3 g, 32 nmnol) gradually. The reaction mixture was stirred at rt for 1 h. Me2SO4 (10 mL) was added in one portion. The mixture was stirred overnight. MeOH (30 mL) was gradually added. After stirring for 3 h, water (500 mL) was added. A solid precipitated out immediately. After filtration, the collec...

example 2

[0786]

S-Pyridin-2-yl)-4-methyl-6-methyl-3-oxo-4-aza-5α-androst-5-en-17β-carbothioate (2-1)

[0787] A mixture of 1-6 (1.9 g, 5.3 mmol), Ph3P (2.8 g, 10.6 mmol) and 2,2′-dipyridyl disulfide (2.3 g, 10.6 mmol) in toluene (30 mL) was stirred overnight. After solvent removal, the residue was purified by flash silica gel chromatography (10% EtOAc / 90% Hexanes to 100% EtOAc) to provide the desired product 2-1 as a solid.

[0788] MS calculated M+H: 439.2, found 439.3

N-Phenyl-4-methyl-6-methyl-3-oxo-4-aza-5α-androst-5-en-17β-carboxamide (2-2)

[0789] To a solution of 2-1 (0.05 g, 0.1 mmol) in CH2Cl2 (1 mL) was added aniline (0.03 g, 0.3 mmol) and AgOTf (0.3 g, 0.1 mmol). The mixture was stirred overnight. After filtration, the filtrate was concentrated and subsequently purified via reverse-phase chromatography [30% CH3CN / 70% H2O (with 0.02% HCl) to 95% CH3CN / 5% H2O (with 0.02% HCl) over 10 min] to afford the desired product 2-2.

[0790] MS calculated M+H: 421.3, found 421.3

[0791] Examples 2-8...

example 85

[0792]

N-(1H-benzimidazol-2-ylmethyl)-4-methyl-6-methyl-3-oxo-4-aza-5α-androst-5-en-17β-carboxamide (3-1)

[0793] A mixture of 1-6 (0.15 g, 0.4 mmol), RNH2 (0.26 g, 1.3 mmol), EDC (0.17 g, 0.87 mmol), HOAt (0.089 g, 0.65 mmol) and EtNiPr2 (0.28 g, 2.2 mmol) was stirred at rt overnight. It was concentrated and purified via reverse phase HPLC to afford the desired product 3-1 as a solid. MS calculated M+H: 475.652, found 475.3054

[0794] Examples 86 -130 in Table 2 were prepared in a similar manner as Compound 3-1 (Example 85 in Table 2), but using the appropriate amine to generate the final desired carboxamide.

TABLE 2MASSSPECTRUMMeasuredEXNR2R3NAME[M + 1]85N-(benzimidazol-2- ylmethyl)-4-methyl-6- methyl-3-oxo-4-aza-5α- androst-5-en-17β- carboxamide475.305486N-(2-fluoro-6- chlorophenylmethyl)-4- methyl-6-methyl-3-oxo-4- aza-5α-androst-5-en-17β- carboxamide487.087N-((R)- phenylmethylmethyl)-4- methyl-6-methyl-3-oxo-4- aza-5α-androst-5-en-17β- carboxamide449.188N-((S)- phenylmethylmethy...

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Abstract

Compounds of structural formula I are modulators of the androgen receptor (AR) in a tissue selective manner. They are useful as agonists of the androgen receptor in bone and / or muscle tissue while antagonizing the AR in the prostate of a male patient or in the uterus of a female patient. These compounds are therefore useful in 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, cancer cachexia, Alzheimer s disease, muscular dystrophies, premature ovarian failure, and autoimmune disease, alone or in combination with other active agents.

Description

FIELD OF THE INVENTION [0001] The present invention relates to 4-azasteroid derivatives, their synthesis, and their use as androgen receptor modulators. More particularly, the compounds of the present invention are tissue-selective androgen receptor modulators and are thereby useful for the treatment of conditions caused by androgen deficiency or which can be ameliorated by androgen administration, such as osteoporosis, periodontal disease, bone fracture, frailty, and sarcopenia. BACKGROUND OF THE INVENTION [0002] The androgen receptor (AR) belongs to the superfamily of steroid / thyroid hormone nuclear receptors, whose other members include the estrogen receptor (ER), the progesterone receptor (PR), the glucocorticoid receptor (GR), and the mineralocorticoid receptor (MR). The AR is expressed in numerous tissues of the body and is the receptor through which the physiological as well as the pathophysiological effects of endogenous androgen ligands, such as testosterone (T) and dihydro...

Claims

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Application Information

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IPC IPC(8): A61P1/02A61P3/04A61P3/06A61K31/56A61P5/26A61P7/06A61P9/10A61P15/10A61P15/12A61P17/00A61P19/02A61P19/08A61P19/10A61P21/00A61P21/04A61P25/28A61P31/18A61P35/00A61P37/02C07J73/00
CPCC07D221/18C07J73/005C07D403/02A61P1/02A61P15/10A61P15/12A61P17/00A61P19/02A61P19/08A61P19/10A61P21/00A61P21/04A61P25/28A61P3/04A61P31/18A61P35/00A61P3/06A61P37/02A61P5/26A61P7/06A61P9/10
Inventor WANG, JIABINGMCVEAN, CAROL A.
Owner WANG JIABING
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