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17-heterocyclic-4-azasteroid derivatives as androgen receptor modulators

一种杂环基、杂环烷基的技术，应用在17-杂环-4-氮杂甾类衍生物领域，能够解决降低等问题

Inactive Publication Date: 2006-10-18
MERCK & CO INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The survey found that women who received a combination of estrogen (1.25mg) and methyltestosterone (2.50mg) maintained a stable level of performance on the Building Memory task, but women who received estrogen (1.25mg ) women showed reduced performance

Method used

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

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0933] Step A: N,O-(Dimethylhydroxy)-4-methyl-3-oxo-4-aza-5α-androst-1-ene- 17β-formamide (1-2)

[0934] at 0°C to 1-1 (36.5g, 110.12mmol) in CH 2 Cl 2 (500mL) solution was added Et 3 N (74.0 mL, 528.6 mmol). Isobutyl chloroformate (21.4 mL, 165.2 mmol) was added dropwise, after 15 minutes the cooling bath was removed and the reaction was stirred for 45 minutes. The reaction was then cooled to 0 °C and Et was added 3 N (55.2 mL, 396.4 mmol) and N,O-dimethylhydroxylamine hydrochloride (32.2 g, 330.4 mmol). The reaction was warmed to room temperature and stirred for 12 hours. The reaction was quenched by dropwise addition of 1N NaOH solution (100 mL) and washed with CH 2 Cl 2 (900 mL) extraction. The organic layer was washed with brine, dried (MgSO 4 ) and then concentrated. Dissolve the residue in a minimum amount of CH 2 Cl 2 in combination with Et 2 O grinding. The solid was collected and washed with Et 2 O washed and dried under high vacuum to give a whit...

Embodiment 32

[0956] Step A: 17β-[2-(1-Methyl-1H-imidazole-5-amido)-1,3-thiazol-4-yl]-4-methanol Base-4-aza-5α-androst-1-en-3-one (2-2)

[0957] to room temperature 1-30 (0.100g, 0.26mmol) in 1:1 pyridine:CH 2 Cl 2 (5 mL) was added 1-methyl-1H-imidazole-5-carbonylchloride (0.075 g, 0.52 mmol) and DMAP (0.005 g, 0.03 mmol) and the reaction was stirred for 14 hours. The reaction was concentrated and the residue was purified by silica gel chromatography (0-100% EtOAc in hexanes) to give a white solid 2-2 .

[0958] MS calcd M+H: 494, found 494.

[0959] Examples 33-50 in Table 2 were prepared in a manner similar to Example 32, except that the appropriate acid chloride, alkyl chloroformate, or sulfonyl chloride was used to generate the amides, carbamates, sulfamates as described.

[0960] Table 2

[0961]

[0962]

[0963]

[0964]

[0965]

[0966] Flowchart 3

[0967]

Embodiment 51

[0969] Step A: 17β-[2-(ureido)-1,3-thiazol-4-yl]-4-methyl-4-aza-5α-androst- 1-en-3-one (3-2)

[0970] to room temperature 1-30 (2.100g, 5.5mmol) in CH 2 Cl 2 (50 mL) was added N,N-carbonyldiimidazole (1.06 g, 6.5 mmol) and the reaction was stirred for 3 hours. Ammonia (13.6 mL, 27.2 mmol, 2M in MeOH) was added dropwise and the reaction was stirred for 18 hours. The reaction was concentrated and the residue was purified by silica gel chromatography (0-100% EtOAc in hexanes) to give a white solid 3-2 .

[0971] MS calcd M+H: 429, found 429.

[0972] Examples 52-60 in Table 3 were prepared in a similar manner to Example 51 except using the appropriate amine to yield the desired urea.

[0973] table 3

[0974]

[0975]

[0976]

[0977]

[0978] Flowchart 4

[0979]

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PUM

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Abstract

Compounds of formula I are modulators of the androgen receptor (AR) in a tissue-selective manner. These compounds are used alone or in combination with other active agents for the enhancement of attenuated muscle tone and for the treatment of conditions caused by androgen deficiency or ameliorated by the administration of androgens, including osteoporosis, osteopenia, glucocorticoid-induced bone osteoporosis, periodontal disease, fractures, bone damage after bone reconstruction surgery, sarcopenia, fragility, skin aging, male hypogonadism, postmenopausal symptoms in women, arteriosclerosis, hypercholesterolemia, hyperlipidemia, Obesity, aplastic anemia and other hematopoietic disorders, inflammatory arthritis and joint repair, HIV-wasting, prostate cancer, benign prostatic hyperplasia (BPH), abdominal fat, metabolic syndrome, type II diabetes, cancer Cachexia, Alzheimer's disease, muscular dystrophy, cognitive decline, sexual dysfunction, sleep apnea, depression, premature ovarian failure, and autoimmune diseases.

Description

field of invention [0001] The present invention relates to 17-heterocyclic-4-azasteroid derivatives, their synthesis, and their use as androgen receptor modulators. More specifically, the compounds of the present invention are tissue selective androgen receptor modulators (SARMs) and are thus useful in the treatment of conditions caused by androgen deficiency or which can be improved by administration of androgens, such as osteoporosis, dental Peripheral disease, fractures, frailty and sarcopenia. In addition, the SARMs of the present invention can be used to treat psychiatric disorders associated with low testosterone, such as depression, sexual dysfunction, and cognitive decline. SARMs that act as antagonists in specific tissues are also useful in conditions where elevated androgen status or activity causes symptoms, such as benign prostatic hyperplasia and sleep apnea. Background of the invention [0002] The androgen receptor (AR) belongs to the very large family of st...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/473C07D221/18C07D401/04C07D413/04C07D417/04
CPCA61P1/02A61P3/04A61P3/06A61P5/26A61P7/00A61P7/06A61P9/10A61P13/08A61P15/00A61P15/10A61P17/16A61P19/00A61P19/02A61P19/10A61P21/00A61P21/04A61P25/00A61P25/28A61P29/00A61P31/18A61P35/00A61P37/06C07D401/04C07D417/04C07D417/14C07J73/005
Inventor M·L·考夫曼R·S·梅斯纳H·J·米切尔
Owner MERCK & CO INC
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