Androgen receptor modulator compounds and methods

a technology of androgen receptors and modulators, applied in the field of nonsteroidal compounds, can solve the problems of modulators of steroid receptors and homeostatic imbalances in patients

Inactive Publication Date: 2007-07-19
LIGAND PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The effectiveness of known modulators of steroid receptors is often tempered by their undesired side-effect profile, particularly during long-term administration.
Similarly, the progesterone antagonist, mifepristone (RU486), if administered for chronic indications, such as uterine fibroids, endometriosis and certain hormone-dependent cancers, could lead to homeostatic imbalances in a patient due to its inherent cross-reactivity as a GR antagonist.

Method used

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  • Androgen receptor modulator compounds and methods
  • Androgen receptor modulator compounds and methods
  • Androgen receptor modulator compounds and methods

Examples

Experimental program
Comparison scheme
Effect test

example 1

1,2,3,6-Tetrahydro-1-methyl-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one (Compound 101, Structure 6 of Scheme I, where R1═H, R=trifluoromethyl, R6═H, Rx═H)

[0154] General Method 1: Cyclization of an α-chloroacetyl chloride to 2-amino-5-nitrophenol. To a solution of 2-amino-5-nitrophenol (1.0 equiv), NaHCO3 (2.4 equiv) in 4-methyl-2-pentanone (0.6 mL / mmol) and water (0.6 mL / mmol) was added an α-chloroacetyl chloride derivative (1.15equiv) via syringe pump over 45 min at 0° C. The reaction mixture was allowed to warm to room temperature and then refluxed overnight. The crude reaction mixture was allowed to cool to room temperature, filtered and washed with water (3×1.2 mL / mmol) to afford the desired product as a tan solid.

[0155] 7-Nitro-2H-1,4-benzoxazin-3(4H)-one (Structure 2 of Scheme I, where R6═H). This compound was prepared by General Method 1 from 2-amino-5-nitrophenol (6.0 g, 39 mmol), NaHCO3 (7.8 g, 93 mmol), and chloroacetyl chloride (3.58 mL, 45 mmol) to afford ...

example 2

1,2,3,6-Tetrahydro-1,6-dimethyl-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one (Compound 102, Structure 7 of Scheme I, where R1═H, R2=trifluoromethyl, R6═H, Rx═H)

[0164] General Method 6: N-Methylation of a pyridone (compounds of Structure 6) to form a compound of Structure 7. To an oven dried rb flask containing a pyridone of Structure 6 (1.0 equiv) in THF (5 mL / mmol) was added portionwise sodium hydride (60% dispersion in mineral oil, 1.2 equiv) under N2. After 30 min, iodomethane (1.2 equiv) was added and the mixture was allowed to stir under N2 an additional 8-10 hrs. The reaction mixture was then diluted with pH 7 phosphate buffer (50 mL / mmol), extracted with CH2Cl2 (3×30 mL) and washed with brine (50 mL / mmol). The organic solution was dried (MgSO4) and concentrated under reduced pressure. Purification by flash chromatography (silica gel, 20:1, CH2Cl2:MeOH) afforded the desired product as a fluorescent-yellow solid.

[0165] 1,2,3,6-Tetrahydro-1,6-dimethyl-9-(trifluorom...

example 3

1-Ethyl-1,2,3,6-tetrahydro-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one (Compound 103, Structure 6 of Scheme I, where R1═H, R2=trifluoromethyl, R6═H, Rx═CH3)

[0166] 4-Ethyl-3,4-dihydro-7-nitro-2H-1,4-benzoxazine (Structure 4 of Scheme I, where R6═H, Rx═CH3). This compound was prepared by General Method 3 (EXAMPLE 1) from 3,4-dihydro-7-nitro-2H-1,4-benzoxazine (EXAMPLE 1) (1.15 g, 6.39 mmol), acetaldehyde (3.59 mL, 64.2 mmol) and NaBH3CN (1.95 g, 31 mmol) to afford 984 mg (74%) of 4-ethyl-3,4-dihydro-7-nitro-2H-1,4-benzoxazine, a yellow solid. Data for 4-ethyl-3,4-dihydro-7-nitro-2H-1,4-benzoxazine: Rf0.85 (11.5:1 CH2Cl2:MeOH); 1H NMR (400 MHz, CDCl3) δ 7.81 (dd, 1H, J=9.6,2.6), 7.66 (d, 1H, J=2.7), 6.29 (d, 1H, J=9.2), 4.23 (t, 2H, J=4.7), 3.47 (t, 2H, J=4.7), 3.45 (q, 2H, J=7.2), 1.22 (t, 3H, J=7.0).

[0167] 7-Amino-4-ethyl-3,4-dihydro-2H-1,4-benzoxazine (Structure 5 of Scheme I, where R6═H, Rx═CH). This compound was prepared by General Method 4 (EXAMPLE 1) from 4-ethyl-...

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Abstract

Compounds, pharmaceutical compositions, and methods for modulating processes mediated by steroid receptors. In particular, preparation and methods of use of non-steroidal compounds and compositions that are agonists, partial agonists, and antagonists for the androgen receptor (AR) are described. Further, described are the methods of making and use of critical intermediates including a stereoselective synthetic route to intermediates for the AR modulators.

Description

[0001] This application is a continuation of U.S. application Ser. No. 10 / 238,363, filed Sep. 9, 2002, which is a divisional of U.S. application Ser. No. 09 / 648,684, filed Aug. 25, 2000, now U.S. Pat. No. 6,462,038, which claims the benefit of U.S. Provisional Application Ser. No. 60 / 160,988, filed Aug. 27, 1999. The entire disclosure of each of these applications is hereby incorporated by reference herein.FIELD OF THE INVENTION [0002] This invention relates to non-steroidal compounds that are modulators (i.e. agonists and antagonists) of androgen receptors, and to methods for the making and use of such compounds. BACKGROUND OF THE INVENTION [0003] Intracellular receptors (IRs) form a class of structurally-related genetic regulators scientists have named “ligand dependent transcription factors.” R. M. Evans, Science, 240:889 (1988). Steroid receptors are a recognized subset of the IRs, including the progesterone receptor (PR), androgen receptor (AR), estrogen receptor (ER), glucocor...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/538A61K31/498A61K31/4985A61K31/5383A61K31/542A61P5/00A61P5/24A61P5/26A61P5/28A61P7/00A61P7/06A61P13/08A61P15/08A61P15/10A61P15/16A61P17/10A61P17/14A61P19/10A61P35/00C07D471/04C07D498/04C07D498/14C07D513/04
CPCC07D471/04C07D513/04C07D498/14C07D498/04A61P13/08A61P15/08A61P15/10A61P15/16A61P17/10A61P17/14A61P19/10A61P35/00A61P5/00A61P5/24A61P5/26A61P5/28A61P7/00A61P7/06
Inventor HIGUCHI, ROBERTARIENTI, KRISTENMANI, NEELAKANDHAPIO, BARBARAZHI, LINCHEN, PENGHUICAFERRO, THOMAS
Owner LIGAND PHARMA INC
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