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

A heterocyclyl, halogen technology, applied in the field of tissue-selective androgen receptor modulators, can solve problems such as reduced ability

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 study found that women who received a combination of estrogen (1.25 mg) and methyltestosterone (2.50 mg) had a stable level of ability on a memory-building task, but women who received estrogen alone (1.25 mg) showed a decrease in this ability

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

[0761] Step A: N-(3-Amino-pyridin-2-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-ene-17β-carboxamide (1-4)

[0762] at room temperature 1-1 (10.0 g, 23.6 mmol) in dichloroethane were added silver triflate (18.2 g, 70.7 mmol) and 2,3-diaminopyridine (7.7 g, 70.7 mmol). The reaction was heated to reflux and stirred for 12 hours. The reaction was cooled, diluted with MeOH, filtered and concentrated. The residue was purified by flash chromatography (0-20% MeOH in EtOAc) to give 1-4 , which is a gray solid.

[0763] MS calculated M+H: 423, found 423.

[0764] Step B: 17β-(1H-imidazo[4,5-b]pyridin-2-yl)-4-methyl-4-aza-5α-androst-1-en-3-one (1-5 )

[0765] Will 1-4 (5.0 g, 11.8 mmol) in polyphosphoric acid (30 mL) was heated to 140 °C and stirred for 14 hours. After cooling, the reaction was washed with 1:1 MeOH:CHCl 3 (500mL) diluted with cold water and NaHCO 3 Quenched by washing with saturated solution. The mixture was then washed with CH 2 Cl 2 extracted, washed with brine...

Embodiment 13

[0777] Step A: 17β-(1-methyl-imidazo[4,5-b]pyridin-2-yl)-4-methyl-4-aza-5α-androst-1-en-3-one ( 2-2)

[0778] at room temperature 1-5 (0.10 g, 0.24 mmol) in DMF was added NaH (0.019 g, 0.48 mmol) and iodomethane (0.033 mL, 0.48 mmol). The reaction was stirred at room temperature for 2 hours. The reaction uses saturated NH 4 Aqueous Cl solution was quenched with CH 2 Cl 2 Dilute and wash with brine. The organic layer was dried, filtered and concentrated. The residue was purified by flash chromatography (0-20% MeOH in EtOAc) to give 2-2 , which is a white solid.

[0779] M+H calculated by MS: 419, found 419.

[0780] Examples 14-16 in Table 2 were prepared in a manner analogous to Example 13, but utilizing an appropriate acylating or alkylating reagent.

[0781] Table 2

[0782]

[0783]

[0784] structural formula 3-6 Selective androgen receptor modulators (SARMs) were prepared according to the method shown in Scheme 3. The starting material is 17β-carboxy es...

Embodiment 17

[0793] Step A: 2α-fluoro-4-methyl-3-oxo-4-aza-5α-androstane-17β-carboxylate methyl ester (3-2)

[0794] 20 minutes introverted 3-1 (7.5 g, 21.6 mmol) in THF (100 mL) was added dropwise a 1.5M solution of LDA in THF (17.3 mL, 25.9 mmol) at -78°C and then stirred for 1 hour. Add FN(SO 2 Ph) 2 (10.2 g, 32.4 mmol) in THF (40 mL). After 30 minutes, the cooling bath was removed and the reaction was stirred for 14 hours. Join Et 2 O, the mixture was washed with water, saturated aqueous sodium bicarbonate, brine, and dried (MgSO 4 ) and then concentrated. Chromatography on silica gel (hexane-EtOAc as eluent) gave 3-2 , which is a colorless solid.

[0795] MS calculated M+H: 366, found 366.1.

[0796]Step B: 2-Fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-ene-17β-carboxylate methyl ester (3-3)

[0797] 30 minutes introverted 3-2 (30 g, 82.1 mmol) in THF (400 mL) was added dropwise a 1.5M solution of LDA in THF (71.1 mL, 107 mmol) at -78°C and then stirred for 1 hour. After this ...

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Abstract

Compounds of formula I are modulators of the androgen receptor (AR) acting in a tissue-selective manner. These compounds alone or in combination with other active agents are effective in enhancing debilitating muscle tone and treating conditions caused by androgen deficiency or ameliorated by androgen administration, including osteoporosis, osteopenia, glucocorticoid-induced bone Osteoporosis, periodontal disease, fractures, bone damage after bone reconstruction surgery, sarcopenia, frailty, aging skin, hypogonadism in men, postmenopausal syndrome in women, atherosclerosis, hypercholesterolemia, hyperlipidemia obesity, aplastic anemia and other hematopoietic disorders, inflammatory arthritis and joint repair, HIV-wasting, prostate cancer, benign prostatic hypertrophy (BPH), abdominal obesity, metabolic syndrome, type II diabetes, cancer cachexia, al 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-heterocycle-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 and are thus useful in the treatment of conditions caused by androgen deficiency or ameliorated by the administration of androgens, such as osteoporosis, periodontal disease, bone fractures, Weakness 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. By being antagonists in specific tissues, SARMs are also effective in conditions where increased androgen stress or activity triggers symptoms, such as benign prostatic hypertrophy and sleep apnea. Background of the invention [0002] The androgen receptor (AR) belongs to the superfamily of steroid / thyroid horm...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/58A61K31/473A61K31/52A61K31/585A61K45/06A61P5/26A61P5/28C07D221/18C07D401/04C07D471/04C07D473/00
CPCA61K31/473A61K31/52A61K31/58A61K31/585A61K45/06C07D401/04C07D471/04C07D473/00C07J43/003A61P1/02A61P11/00A61P13/08A61P15/00A61P15/12A61P17/00A61P19/00A61P19/02A61P19/10A61P21/00A61P25/24A61P25/28A61P29/00A61P3/04A61P31/18A61P35/00A61P3/06A61P37/02A61P43/00A61P5/26A61P5/28A61P7/00A61P9/10A61P3/10A61K2300/00
Inventor R·S·梅斯纳H·J·米切尔
Owner MERCK & CO INC
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