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Pyrimidothiophene compounds

A technology of compounds and oxides, applied in 24] The present invention relates to the field of using a class of substituted thieno[2, substituted bicyclic thieno[2

Inactive Publication Date: 2006-10-04
VERNALIS (R&D) LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, this still leads to inhibition of HSP function and degradation of many HSP90 chaperone proteins (Marcu et al., 2000a)

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0134] 2-Amino-4-phenyl-thieno[2,3-d]pyrimidine-6-carboxylic acid ethyl ester

[0135]

[0136] step 1

[0137] 2-Amino-4-chloro-thieno[2,3-d]pyrimidine-6-carboxylic acid ethyl ester

[0138]

[0139] To a mixture of 2-amino-4,6-dichloro-5-formyl-pyridine (1 eq) and potassium carbonate (1 eq) in acetonitrile was added ethyl 2-mercaptoacetate (0.95 eq) with stirring at ambient temperature ) and the mixture was stirred at ambient temperature for 3 hours, then heated at 80 °C for 1 hour. After cooling the mixture was concentrated to dryness under vacuum. Column chromatography on silica, eluting with ethyl acetate and hexanes, gave a sample of Example 1 as a yellow powder.

[0140] LC-MS retention time: 2.371 minutes, [M+H] + 258.0

[0141] Step 2 (Suzuki reaction):

[0142] 2-Amino-4-phenyl-thieno[2,3-d]pyrimidine-6-carboxylic acid ethyl ester

[0143]

[0144] Nitrogen was passed into the solution of 1,4-dioxane and water (3.5:1) of the sample (1 equivalent) of s...

Embodiment 2

[0148] 2-Amino 4-(4-trifluoromethyl-phenyl)-thieno[2,3-d]pyrimidine-6-carboxylic acid ethyl ester

[0149]

[0150] Prepared according to Example 1.

[0151] LC-MS retention time: 2.768 minutes, [M+H] + 368.1

[0152] 1 H NMR (400MHz, d6-DMSO): δ = 1.07 (3H, t, J = 7.1Hz), 4.09 (2H, q, J = 7.1Hz), 7.25 (2H, br s), 7.68 (1H, s) , 7.76 (2H, d, J = 8.0 Hz), 7.85 (2H, d, J = 8.0 Hz).

[0153] This compound has activity 'B' using the fluorescence polarization assay described below.

[0154] The compounds in Table 1 below were synthesized and tested using the fluorescence polarization analysis described below. Suzuki reaction was carried out according to step 2 of Example 1. The reductive amination reaction was carried out as in Example 33 below:

Embodiment 33

[0154] The compounds in Table 1 below were synthesized and tested using the fluorescence polarization analysis described below. Suzuki reaction was carried out according to step 2 of Example 1. The reductive amination reaction was carried out as in Example 33 below:

[0155] 2-Amino-4-(4-piperidin-1-ylmethyl-phenyl)-thieno[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (Example 33 of Table 1)

[0156]

[0157] To a suspension of ethyl 2-amino-4-(4-formyl-phenyl)-thieno[2,3-d]pyrimidine-6-carboxylate (1 eq) in methanol was added pyrrolidine (5 eq) . The reaction mixture was heated to reflux for 3.5 hours and then cooled to room temperature. Sodium borohydride (3 equiv) was added and stirred for 10 minutes. The mixture was concentrated in vacuo then partitioned between ethyl acetate and water. The phases were separated and the organic layer was washed with brine, dried and evaporated to a yellow oil. The crude product was purified by preparative HPLC.

[0158] LC-MS re...

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Abstract

Compounds of formula (1) are inhibitors of HSP90 activity in vitro or in vivo, and of use in the treatment of cancer: wherein R2 is a group of formula -(Ar<1>)m-(Alk<1>)P-(Z)r-(Alk2)S-Q wherein Ar<1> is an optionally substituted aryl or heteroaryl radical, Alk' and Alk 2 are optionally substituted divalent C1-C3 alkylene or C2-C3 alkenylene radicals, m, p, r and s are independently 0 or 1, Z is -0-, -S-, -(C=O)-, -(C=S)-, -S02-, -C(=O)O-, -C(=O) NR - , -C(=S)NR -, -S02NR -, -NR C(=O)_, -NR S02- or-NR -wherein R is hydrogen or C1-C6 alkyl, and Q is hydrogen or an optionally substituted carbocyclic or heterocyclic radical; R3 is hydrogen, an optional substituent, or an optionally substituted (C1-C6)alkyl, aryl or heteroaryl radical; and R4 is a carboxylic ester, carboxamide or sulfonamide group.

Description

[0001] The present invention relates to a substituted bicyclic thieno[2,3-d]pyrimidine (hereinafter referred to as 'pyrimidothiophene') compound having HSP90 inhibitory activity, and to the use of this compound in medicine to treat Responsive diseases such as cancer, and to pharmaceutical compositions containing such compositions. Background of the invention [0002] Molecular chaperones maintain protein folding and conformation and are critical for regulating the balance of protein synthesis and degradation. They have been shown to be important in the regulation of many important cellular functions such as cell proliferation and apoptosis (Jolly and Morimoto, 2000; Smith et al., 1998; Smith, 2001). [0003] heat shock protein (HSP) [0004] Exposure of cells to a number of environmental stresses, including heat shock, alcohols, heavy metals, and oxidative stress, causes cells to accumulate chaperones, which are commonly referred to as heat shock ...

Claims

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Application Information

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IPC IPC(8): C07D495/04A61K31/00A61P35/00
Inventor B·W·迪莫克M·J·德赖斯代尔C·弗罗蒙特A·乔丹X·巴里－阿朗索
Owner VERNALIS (R&D) LTD
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