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Modulators of the glucocorticoid receptor and method

a technology of glucocorticoid receptor and modulator, which is applied in the direction of drug composition, immunological disorders, metabolism disorders, etc., can solve the problem of limited systemic use of the receptor

Inactive Publication Date: 2005-08-04
VACCARO WAYNE +9
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Particularly concerning GR, although glucocorticoids are potent anti-inflammatory agents, their systemic use is limited by side effects.

Method used

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  • Modulators of the glucocorticoid receptor and method
  • Modulators of the glucocorticoid receptor and method
  • Modulators of the glucocorticoid receptor and method

Examples

Experimental program
Comparison scheme
Effect test

preparation 1

2-Amino-4-[1-(4-fluoro)naphthyl]thiazole 1a

[0381]

Step 1

[0382] To a solution of 4′-fluoro-1′-acetonaphthone (28.69 mmol, 5.4 g) in 1,4-dioxane (18.0 mL) at 0° C. was added bromine (35.13 mmol, 5.61 g). After 3 hours at room temperature the reaction mixture was concentrated in vacuo to give 7.66 g (Y: δ 100%) of the product of step 1.

Step 2

[0383] To a solution of the product of step 1 (28.69 mmol, 7.66 g) in ethyl alcohol (20 mL) at room temperature was added thiourea (36.13 mmol, 2.75 g). After 1 hour at room temperature a precipitate formed. To the reaction mixture was added water (100 mL) and the solid was collected by vacuum filtration. The solid was then washed with water (3×100 mL) and dichloromethane (3×100 mL). The solid was then dried in vacuo to give 5.5 g (Y: 75%) of the title compound 1a. MS (E+) m / z: 245 (MH+).

[0384] In a similar manner the following compounds were prepared from the corresponding ketone.

PreparationStructure1b1c1d1e1f1g1h1i1j1k1l1m1n1o1p1q1r1s1t1u...

preparation 2

2-Amino-4-[1-(4-fluoro)naphthyl]imidazole 2a

[0385]

Step 1

[0386] To a solution of the product of preparation 1a, step 1 (18.73 mmol, 5.0 g) in DMF (15 mL) at room temperature was added 1-acetylguanidine (57.43 mmol, 5.80 g). After 5 hours at room temperature, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (3×100 mL). The organic phases were concentrated in vacuo and the residue chromatographed on silica gel (eluted with 5% methanol in dichloromethane) to give 2.0 g (Y: 39%) of the product of step 1. MS (E+) m / z: 270 (MH+).

Step 2

[0387] To a solution of the product of step 1 (7.43 mmol, 2.0 g) in methanol (17 mL) was added water (8.5 mL) and 12 N HCl (12.0 mL). After 1 hour at reflux the reaction mixture was concentrated in vacuo to approximately 15 mL. The resulting solution was then purified and neutralized by cation exchange SPE to give 1.66 g (Y: 99%) of the title compound 2a. MS (E+) m / z: 228 (MH+).

[0388] In a similar manner the followi...

preparation 3

2-Amino-4-(1-naphthyl)oxazole 3a

[0389]

Step 1

[0390] To a solution of 1-acetonaphthone (29.38 mmol, 5.0 g) in glacial acetic acid (10.0 mL) at RT was added bromine (30.06 mmol, 4.80 g) in glacial acetic acid (5.0 mL). After 5 minutes the reaction mixture was poured onto crushed ice and extracted with dichloromethane to give 7.31 g (Y: 100%) of the product of step 1. MS (E+) m / z: 250 (MH+).

Step 2

[0391] To a solution of the product of step 1 (5.50 mmol, 1.37 g) in ethyl alcohol (10 mL) was added urea (27.50 mmol, 1.65 g). After 2 hours at reflux the reaction mixture was concentrated in vacuo and the residue chromatographed on silica gel (eluted with 30% ethyl acetate in hexane) to give 100 mg (Y: 9%) of the title compound 3a. MS (E+) m / z: 211 (MH+).

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Abstract

Novel non-steroidal compounds are provided which are glucocorticoid receptor modulators which are useful in treating diseases requiring glucocorticoid receptor agonist or antagonist therapy such as obesity, diabetes, inflammatory and immune disorders, and have the structure where Z is CONR1R2 or CH2NR1R2 and where R, Ra, Rb, Rc, Rd, Z, A and B are defined herein.

Description

[0001] This application claims priority from U.S. Provisional Application 60 / 396,877 filed Jul. 18, 2002 which is incorporated herein by reference.[0002] The present invention relates to new non-steroidal compounds which are glucocorticoid receptor (GR) modulators (that is agonists and antagonists) and thus are useful in treating diseases requiring glucocorticoid receptor agonist or antagonist therapy such as obesity, diabetes and inflammatory or immune associated diseases, and to a method for using such compounds to treat these and related diseases. BACKGROUND OF THE INVENTION [0003] The nuclear hormone receptor (NHR) family of transcription factors bind low molecular weight ligands and either stimulate or repress transcription (The Nuclear Receptor Facts Book, V. Laudet and H. Gronemeyer, Academic Press, p 345, 2002). NHRs stimulate transcription by binding to DNA and inducing transcription of specific genes. NHRs may also stimulate transcription by not binding to DNA itself, rath...

Claims

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Application Information

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IPC IPC(8): A61K31/403A61K31/415A61K31/425A61K31/473A61K31/495A61K45/06C07D207/34C07D209/48C07D213/40C07D213/75C07D213/82C07D215/38C07D217/22C07D231/16C07D233/88C07D235/10C07D235/14C07D235/30C07D239/42C07D239/94C07D241/20C07D261/12C07D261/14C07D263/48C07D277/46C07D277/64C07D285/06C07D307/58C07D317/58C07D333/20C07D333/34C07D401/04C07D405/04C07D417/04C07D417/10C07D417/12C07D471/04C07D471/08C07D487/04C07D495/04
CPCA61K31/403A61K31/473A61K45/06C07D207/34C07D209/48C07D213/40C07D213/75C07D213/82C07D215/38C07D217/22C07D231/16C07D233/88C07D235/14C07D235/30C07D239/42C07D239/94C07D241/20C07D261/12C07D261/14C07D263/48C07D277/46C07D277/64C07D285/06C07D307/58C07D317/58C07D333/20C07D333/34C07D401/04C07D405/04C07D417/04C07D417/10C07D417/12C07D471/04C07D471/08C07D487/04C07D495/04A61P1/00A61P1/02A61P1/04A61P1/16A61P1/18A61P11/00A61P11/02A61P11/06A61P11/16A61P13/12A61P17/00A61P17/02A61P17/06A61P17/14A61P19/00A61P19/02A61P19/06A61P19/08A61P21/04A61P25/00A61P27/02A61P27/14A61P29/00A61P3/00A61P3/04A61P31/04A61P35/00A61P35/02A61P37/00A61P37/02A61P37/06A61P37/08A61P43/00A61P5/00A61P7/00A61P7/06A61P9/10A61P3/10A61K2300/00
Inventor VACCARO, WAYNEYANG, BINGWEIKIM, SOONG-HOONHUYNH, TRAMTORTOLANI, DAVIDLEAVITT, KENNETHLI, WENYINGDOWEYKO, ARTHURCHEN, XIAO-TAODOWEYKO, LIDIA
Owner VACCARO WAYNE
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