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Derivatives of sulindac, use thereof and preparation thereof

A compound, CH3S technology, applied in the amide derivatives of sulindac, the preparation of the disclosed compounds, the treatment and prevention of precancerous conditions and cancers in mammals, can solve the problems of undescribed and undescribed anticancer activities

Inactive Publication Date: 2009-02-11
SOUTHERN RES INST & IP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, no anticancer activity has been described and modifications to improve anticancer efficacy (potency) have not been described

Method used

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  • Derivatives of sulindac, use thereof and preparation thereof
  • Derivatives of sulindac, use thereof and preparation thereof
  • Derivatives of sulindac, use thereof and preparation thereof

Examples

Experimental program
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Effect test

example 1

[0065] N-[2-(Dimethylamino)ethyl]-5-fluoro-2-methyl-1-[[4-(methylsulfinyl)phenyl]methylene]-1H-indene-3 - Acetamide (1):

[0066] Use CHCl 3 / MeOH+0.2% NH 4 OH (9:1) to purify the crude product by column chromatography. The product was obtained as a yellow solid in 98% yield. ESI-MS m / z: 427[M+H] + . 1 H NMR (CDCl 3 ): δ 7.74-7.65 (2H, m, 2′-H, 3′-H), 7.17 (1H, dd, J=5.2Hz, 8.4Hz, 7-H), 6.88 (1H, dd, J=2.4 Hz, 8.9Hz, 4-H), 6.59 (1H, ddd, J = 2.4Hz, 9.0Hz, 11.0Hz, 6-H), 6.19 (1H, br s, -NHCH 2 CH 2 N(CH 3 ) 2), 3.28 (2H, dd, J = 5.7Hz, 11, 2Hz, -NHCH 2 CH 2 N(CH 3 ) 2 ), 3.51 (2H, s, 3-CH 2 ), 2.81 (3H, s, 4'-CH 3 ), 2.33 (2H, t, J=6.0Hz, -NHCH 2 CH 2 N(CH 3 ) 2 ), 2.13 (6H, s, N (CH 3 ) 2 , 2.12 (3H, s, 2-CH 3 ). Experimental values ​​for CHN: C, 67.99; H, 6.45; N, 6.60. C 24 h 27 FN 2 o 2 Calculated for S: C, 67.59; H, 6.38; N, 6.57.

example 2

[0068] 5-fluoro-2-methyl-N-[(1-methyl-2-pyrrolidinyl)methyl]-1-[[4-(methylsulfinyl)phenyl]methylene]-1H -Indene-3-acetamide (2):

[0069] Use CHCl 3 / MeOH+0.2%NH 4 OH (8:1) to purify the crude product by column chromatography. Yellow solid, 91% yield. ESI-MS m / z: 467[M+H] + . 1 H NMR (DMSO-d 6 ): δ 8.10 (1H, t, J=4.2Hz, -NHCH 2 CH 2 ), 7.79 (1H, d, J=8.4Hz, 3′-H), 7.71 (1H, d, J=8.2Hz, 2′-H), 7.36 (1H, s, 8-H), 6.71 (1H , dd, J=5.4Hz, 8.5Hz, 7-H), 3.41 (2H, s, 1-CH 2 ), 3.12-3.06 (2H, m, -NHCH 2 CH 2 ), 2.88-2.79 (1H, m, 2"-H), 2.82 (3H, s, 4'-CH 3 ), 2.18 (3H, s, 2-CH 3 ), 2.12 (3H, s, N-CH 3 ), 2.00-1.91 (3H, m, 3"-H a , 5"-CH 2 ), 1.91-1.68 (2H, m, 3"-H b ), 1.68-1.50 (2H, m, -NHCH 2 CH b , 4"H b ), 1.40-1.07 (2H, m, -NHCH 2 CH a , 4"-H a ). Experimental values ​​for CHN: C, 67.62; H, 6.48; N, 6.22. C 27 h 31 FN 2 o 2 S 0.8H 2 Calculated for O: C, 67.40; H, 6.83; N, 5.82.

example 3

[0071] 5-fluoro-2-methyl-1-[[4-(methylsulfinyl)phenyl]methylene]-N-[2-(1-piperazinyl)ethyl]-1H-indene- 3-Acetamide (3):

[0072] The crude product was subjected to column chromatography using CHCl 3 / MeOH+0.2% NH 4 OH (4:1) and purified by prep TLC using CHCl 3 / MeOH+0.2% NH 4 OH (5:1) for further purification. Yellow solid, 58% yield. ESI-MS m / z: 468[M+H] + . 1 H NMR (DMSO-d 6 ): δ 7.97 (1H, t, J=4.2Hz, -NHCH 2 CH 2 ), 7.80 (2H, d, J=8.4Hz, 3′-H, 5′-H), 7.72 (2H, d, J=8.2Hz, 2′-H, 6′-H), 7.35 (1H, s, 8-H), 7.15 (1H, dd, J = 5.3Hz, 8.4Hz, 7'-H), 7.10 (1H, dd, J = 2.4Hz, 9.3Hz, 4-H), 6.71 (1H, ddd, J=2.4Hz, 9.6Hz, 11.8Hz, 6-H), 3.43 (2H, s, 1-CH 2 ), 3.16 (2H, dd, J = 5.94Hz, 11.9Hz, -NHCH 2 CH 2 ), 2.66 (4H, t, J=4.7Hz, 3"-H and 5"-H), 2.51-2.30 (6H, m, -NHCH 2 CH 2 , 2"-H and 6"-H), 2.18 (3H, s, 2-CH 3 ). Experimental values ​​for CHN: C, 63.53; H, 6.46; N, 8.53. C 26 h 30 FN 3 o 2 S 1.3H 2 Calculated for O: C, 63.60; H, 6.69; N, 8.55.

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Abstract

Derivatives of sulindac are provided along with-pharmaceutical compositions containing them and use for precancerous conditions and treating cancer. Derivatives of sulindac are also suitable for treating chronic inflammatory conditions. A method for preparing the derivatives is also provided.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to USSN 60 / 755,847, filed January 4, 2006, the entire disclosure of which is incorporated herein by reference. technical field [0003] The present invention relates to certain sulindac derivatives and in particular to amide derivatives of sulindac. The invention also relates to pharmaceutical compositions comprising the disclosed sulindac derivatives, and a method of using said compounds for the treatment and prevention of precancerous conditions and cancers in mammals. The present invention also relates to a method of preparing the disclosed compounds. Background technique [0004] Despite significant advances in cancer treatment, it remains a major health concern. Cancer is reported to be the leading cause of death in the United States, where one in four Americans may be diagnosed with the disease. [0005] By way of example only, known chemotherapy drugs include carmustine, doxo...

Claims

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Application Information

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IPC IPC(8): A61K31/74
CPCC07D211/12C07C323/62C07D213/38C07D307/58C07D295/108C07D307/52C07D207/06C07D233/61C07D295/13C07C317/44C07D233/64C07D307/42C07D207/09C07C2102/08C07D213/40C07C2602/08A61P35/00C07C317/32C07C321/28A61K31/10
Inventor 加里·普拉扎罗伯特·雷诺兹
Owner SOUTHERN RES INST & IP
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