Novel 2-substituted benzimidazoles as selective androgen receptor modulators (SARMs)

A substituent, selected technology, applied in the field of application in disorders and conditions, can solve the problem of harm, etc.

Inactive Publication Date: 2009-04-15
JANSSEN PHARMA NV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Finally, aniline-sensitive patients may be harmed by metabolites of NSAIDs

Method used

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  • Novel 2-substituted benzimidazoles as selective androgen receptor modulators (SARMs)
  • Novel 2-substituted benzimidazoles as selective androgen receptor modulators (SARMs)
  • Novel 2-substituted benzimidazoles as selective androgen receptor modulators (SARMs)

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0164] 1-(5,6-dichloro-1H-benzimidazol-2-yl)-2,2,2-trifluoro-ethanol

[0165]

[0166] Into a 1-L 4-neck flask equipped with a thermocouple controller, overhead mechanical stirrer, condenser, and nitrogen inlet / outlet adapter, was charged with 4,5-dichloro-1,2-phenylenediamine (71.3 g, 0.403 mol), trifluorolactic acid (87.0 g, 0.604 mol) and 4N HCl (340 mL). The reaction mixture was heated at reflux (100° C.) for 18 h. The resulting solution was cooled to room temperature, then washed with EtOAc (1 L) and H 2 O (1L) diluted. with NaHCO 3 (500 g) the solution was worked up slowly until pH 8-9. After effervescence ceased, the phases were separated and the aqueous layer was back extracted with EtOAc (3 x 1 L). with H 2 The combined organic phases were washed with O (1 L) and brine (1 L); 4 Drying, filtering and evaporation to dryness gave a crude residue. The crude residue was subjected to flash chromatography with SiO 2 (2kg) and 10% EtOAc / CH 2 Cl 2 (2L) and 20% ...

Embodiment 2

[0168] 1-(5,6-Dichloro-1H-benzimidazol-2-yl)-2,2,2-trifluoro-ethanone

[0169]

[0170] Into a 3-L 4-neck flask equipped with a thermocouple controller, overhead mechanical stirrer, addition funnel, and nitrogen inlet / outlet adapter, was charged 1-(5,6-dichloro -1H-benzimidazol-2-yl)-2,2,2-trifluoro-ethanol (91.0g, 0.32mol), 4-methoxy-TEMPO (14.3g, 0.077mol) and KBr (4g, 0.0336 mol). The brown homogeneous solution was stirred for 15 min while cooling to -10 °C. After cooling, NaOCl (670ml) was added dropwise over a period of 1 / 2h. with EtOAc (1.5L) and H 2 O (1.5 L) diluted the reaction mixture. After effervescence ceased, the phases were separated and the aqueous layer was back extracted with EtOAc (2 L). The combined organic layers were washed with brine (2 L); 2 SO 4 Drying, filtering and evaporation to dryness gave a crude residue. The crude residue was subjected to flash chromatography with SiO 2 (1 kg) and 40% EtOAc / Hexane (24 L), and the product was dried ...

Embodiment 3

[0172] 2-(5,6-Dichloro-1H-benzimidazol-2-yl)-1,1,1-trifluoro-pent-4-en-2-ol (#1)

[0173]

[0174] 1-(5,6-Dichloro-1H-benzimidazol-2-yl)-2,2,2-trifluoro-ethanone (1.41 g; 4.99 mmol), bromopropene (0.85 mL; 10.05 mmol) and indium (1.15 g; 10.05 mmol) were suspended in THF (50 mL) and 0.01 M HCl (150 mL) and stirred vigorously over 18 hours. The layers were separated and the aqueous layer was extracted with ethyl acetate (3 x 30 mL). The combined extracts were washed with brine (50 mL) and washed with Na 2 SO 4 dry. The resulting crude brown oil was subjected to column chromatography (SiO 2 ; 20% ethyl acetate / hexanes) to afford the title compound as a tan solid.

[0175] 1 H NMR (400MHz, CD 3 CN): δ7.79(s, 2H), δ5.59(m, 1H), δ5.17(d, J=17.1Hz, 1H), δ5.07(d, J=11Hz, 1H), δ3. 13(dd, J=6.8, 14.3Hz, 1H), δ2.88(dd, J=7.2, 14.3Hz, 1H)

[0176] MS vs. C 12 h 9 Cl 2 f 3 N 2 Calculated value of O: 325.11

[0177] MS measured: 325, 327 (M+H); 323, 325 (M-1).

[0178]...

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Abstract

The present invention is directed to a novel 2-substituted benzimidazole derivatives, pharmaceutical compositions containing them and their use in the treatment of disorders and conditions modulated by the androgen receptor.

Description

field of invention [0001] The present invention relates to novel 2-substituted benzimidazole derivatives, pharmaceutical compositions containing them and their use in the treatment of disorders and conditions regulated by the androgen receptor. More particularly, the compounds of the invention are useful in the treatment of, for example, prostate cancer, benign prostatic hyperplasia (BPH), hirsutism, alopecia, anorexia nervosa, breast cancer, acne, AIDS, cachexia, andropause, osteopenia , osteoporosis, female sexual dysfunction, male sexual dysfunction, as a libido enhancer, as a male contraceptive, as a male sexual function enhancer and / or for muscle replacement in burn recovery. Background of the invention [0002] Androgens are anabolic steroid hormones of animals that control muscular and skeletal mass, reproductive system maturation, development of secondary sex characteristics and maintenance of fertility in males. In women, testosterone is converted to estrogen in mo...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D235/12C07D403/04C07D405/04C07D413/04A61K31/4184A61K31/422A61P5/00
CPCC07D403/04C07F7/1856C07D413/04C07D235/12C07D405/14C07D235/16C07D405/04A61K31/4184C07F7/1804A61P13/08A61P15/08A61P15/10A61P15/12A61P15/16A61P17/00A61P17/02A61P17/10A61P17/14A61P19/08A61P19/10A61P25/18A61P31/18A61P35/00A61P43/00A61P5/00
Inventor V·C·小阿尔福德J·C·兰特R·A·吴隋治华
Owner JANSSEN PHARMA NV
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