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Boronate ester compounds and pharmaceutical compositions thereof

a technology of ester compounds and boroxines, which is applied in the field of boronate ester compounds, can solve the problems of limited pharmaceutical utility of boronic acid compounds, difficult to obtain analytically pure boronic acid compounds, and difficult to achieve alkylboronic acid and their boroxines

Inactive Publication Date: 2009-12-31
TAKEDA PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Unfortunately, boronic acid compounds are relatively difficult to obtain in analytically pure form.
Also, alkylboronic acids and their boroxines are often air-sensitive.
These difficulties limit the pharmaceutical utility of boronic acid compounds, complicating the characterization of pharmaceutical agents comprising boronic acid compounds and limiting their shelf-life.

Method used

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  • Boronate ester compounds and pharmaceutical compositions thereof
  • Boronate ester compounds and pharmaceutical compositions thereof
  • Boronate ester compounds and pharmaceutical compositions thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1

Synthesis of 4-(R,S)-(carboxymethyl)-2-((R)-1-(2-(2,5-dichlorobenzamido)acetamido)-3-methylbutyl)-6-oxo-1,3,2-dioxaborinane-4-carboxylic Acid (I-1)

[0474]

Step 1: 2,5-[(dichlorobenzoyl)amino]acetic Acid

[0475]To a mixture of NaOH (12 g, 300 mmol) and glycine (18 g, 239 mmol) in water (120 mL) was added dropwise over 45 min a solution of 2,5-dichlorobenzoyl chloride (10 g, 48 mmol) in THF (15 mL) keeping the internal temperature below about 25° C. After 1 h, the mixture was acidified with 2.0 M HCl (125 mL) keeping the internal temperature below about 5° C. The resulting precipitate was collected by vacuum filtration. The crude product was recrystallized from water to give 2,5-[(dichlorobenzoyl)amino]acetic acid as a white, crystalline solid (6.1 g, 52%). mp 173.3° C. 1H NMR (300 MHz, DMSO-d6, δ): 12.72 (bs, 1H), 8.89 (t, J=6.0 Hz, 1H), 7.54 (m, 2H), 7.48 (m, 1H), 3.93 (d, J=6.0 Hz). 13C NMR (75 MHz, DMSO-d6, δ): 41.6, 129.3, 129.6, 131.4, 132.2, 138.2, 171.4, 165.9. MS (m / z): [M+H] cal...

example 1a

Alternate Synthesis of 4-(RS)-(carboxymethyl)-2-((R)-1-(2-(2,5-dichlorobenzamido)acetamido)-3-methylbutyl)-6-oxo-1,3,2-dioxaborinane-4-carboxylic Acid (I-1) Form 2

[0490]A 50-L glass reactor equipped with mechanical stirrer, dropping funnel, temperature indicator, and heating / cooling control unit (under nitrogen) was charged with 1.2 micron filtered EtOAc (18.9 kg) and anhydrous citric acid (0.561 kg, 2.9 mol). The mixture was heated to 71° C. and a solution resulted. N,N′,N″-{boroxin-2,4,6-triyltris[[(1R)-3-methylbutane-1,1-diyl]imino(2-oxoethane-2,1-diyl)]}tris(2,5-dichlorobenzamide) (1.109 kg, 3.1 mol) dissolved in EtOAc (4.0 kg) was clarified using an in-line filter (1.2 micron), and the solution was added to the reaction mixture under stirring (193 rpm) over a period of 20 min while maintaining a temperature of 73° C. to 75° C. The stirring was reduced to 96 rpm and the mixture was cooled as follows: (1) The mixture was kept at 73° C. 75° C. for 25 min; (2) The mixture was stepw...

example 2

Synthesis of 2,5-dichloro-N-(2-{[(1R)-3-methyl-1-(4-oxo-1,3,2-dioxaborolan-2-yl)butyl]amino}-2-oxoethyl)benzamide (I-2)

[0493]To a solution of glycolic acid (0.041 g, 0.54 mmol) in EtOAc (2.0 mL) with an internal temperature of about 60° C. was added a solution of N,N′,N″-{boroxin-2,4,6-triyltris[[(1R)-3-methylbutane-1,1-diyl]imino(2-oxoethane-2,1-diyl)]}tris(2,5-dichlorobenzamide) (0.199 g, 0.19 mmol) in EtOAc (1.0 mL). The solution was cooled uncontrolled until the internal temperature was about 25° C. and the solvent was removed by evaporation to yield 2,5-dichloro-N-(2-{[(1R)-3-methyl-1-(4-oxo-1,3,2-dioxaborolan-2-yl)butyl]amino}-2-oxoethyl)benzamide as a white solid (0.215 g, 95%). MS (m / z) in CH3CN: [M+Et3N+H] calculated for C22H35BCl2N3O5, 502.2; found, 502.0. MS (m / z) in CH3CN: [M−H] calculated for C16H18BCl2N2O5, 399.1; found, 399.0.

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Abstract

The present invention provides novel compounds useful as proteasome inhibitors. The invention also provides pharmaceutical compositions comprising the compounds of the invention and methods of using the compositions in the treatment of various diseases.

Description

PRIORITY[0001]This application claims priority from U.S. Provisional Patent Application Ser. No. 61 / 132,244, filed Jun. 17, 2008, and U.S. Provisional Patent Application Ser. No. 61 / 211,499, filed Mar. 31, 2009; both which are hereby incorporated by reference in their entirety.FIELD OF THE INVENTION[0002]The present invention relates to boronate ester compounds useful as proteasome inhibitors. The invention also provides pharmaceutical compositions comprising the compounds of the invention, and methods of using the compositions in the treatment of various diseases.BACKGROUND OF THE INVENTION[0003]Boronic acid and boronate ester compounds display a variety of pharmaceutically useful biological activities. Shenvi et al., U.S. Pat. No. 4,499,082 (1985), discloses that peptide boronic acids are inhibitors of certain proteolytic enzymes. Kettner and Shenvi, U.S. Pat. No. 5,187,157 (1993), U.S. Pat. No. 5,242,904 (1993), and U.S. Pat. No. 5,250,720 (1993), describe a class of peptide boro...

Claims

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Application Information

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IPC IPC(8): A61K31/69C07F5/04A61P35/00
CPCC07F5/025C07K5/06139C07K5/06191C07F5/04A61K31/198A61K31/454A61K31/69C07C233/83A61K9/0019A61K9/19A61K47/183C07F5/02A61K38/00A61K2300/00A61P1/00A61P1/04A61P1/16A61P11/00A61P11/06A61P17/00A61P17/02A61P17/06A61P19/02A61P25/00A61P25/04A61P25/14A61P25/16A61P25/28A61P27/02A61P29/00A61P31/00A61P31/18A61P35/00A61P35/02A61P35/04A61P37/02A61P37/06A61P43/00A61P7/06A61P9/00A61P9/10C07F5/05
Inventor ELLIOTT, ERIC L.FERDOUS, ABU J.KAUFMAN, MICHAEL J.KOMAR, SONJA A.MAZAIK, DEBRA L.MCCUBBIN, QUENTIN J.NGUYENPALANIAPPAN, VAITHIANATHANSKWIERCZYNSKI, RAYMOND D.TRUONG, NOBEL T.VARGA, CSANAD M.ZAWANEH, PETER N.
Owner TAKEDA PHARMA CO LTD
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