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Compounds and methods of use

A kind of compound and fusion technology, applied in the direction of drug combination, organic chemistry, pharmaceutical formulation, etc., can solve problems such as weak binding and cytotoxicity

Active Publication Date: 2014-04-02
GENENTECH INC +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] Abbott Laboratories has developed a class of BH3-only small molecule mimics, ABT-737 and ABT-263, which interact with Bcl-2, Bcl-w and Bcl-x L Binds strongly to a subset of anti-apoptotic Bcl-2 proteins but only weakly to Mcl-1 and A1, and exhibits mechanism-based cytotoxicity

Method used

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  • Compounds and methods of use
  • Compounds and methods of use
  • Compounds and methods of use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0236] 2-(1-(Benzo[d]thiazol-2-ylcarbamoyl)-1,2,3,4-tetrahydroquinolin-7-yl)-5-(4-methoxyphenyl) Synthesis of thiazole-4-carboxylic acid (1):

[0237]

[0238] step 1 : Preparation of 3-(4-bromophenyl)propanoic acid (1A).

[0239]

[0240] 2,2-Dimethyl-[1,3]dioxane-4,6-dione (120g, 0.84mol) and 4-bromo-benzaldehyde (153.4g, 0.84mol) in 300mL TEA and dissolved in acetic acid. The reaction mixture was refluxed overnight. At this point, the reaction mixture was diluted with water (4 L) and acidified with 6M HCl (1 L) until pH=2. The precipitated solid was filtered off, washed with dilute HCl, then dissolved in 5% NaHCO 3 dissolved in the solution. The aqueous brine was washed with ether (4 x 500 mL), filtered and acidified with dilute HCl. It was then filtered and dried in vacuo to afford 100 g (67%) of the desired product 3-(4-bromophenyl)propanoic acid (1A): 1 H NMR (DMSO-d6, 400 MHz), δ 2.5 (m, 2H), 2.8 (m, 2H), 7.2 (m, 2H), 7.5 (m, 2H), 12.2 (s, 1H).

[0241] ...

Embodiment 2

[0282] Synthesis of N-(thiazol-2-yl)-1H-imidazole-1-carboxamide (2).

[0283]

[0284] The title compound N-(thiazol-2-yl)-1H-imidazole-1-carboxamide (2) was prepared by: N-(thiazol-2-yl)-1H-imidazole-1-carboxamide (2) according to Prepared in a similar manner as described in Example 1, except that 2-aminothiazole was used in place of 2-aminobenzothiazole in step 13 of Example 1. LC / MS (APCI): m / z 195.0 (M+H).

Embodiment 3

[0286] Synthesis of N-(5-methylthiazol-2-yl)-1H-imidazole-1-carboxamide (3).

[0287]

[0288] The title compound N-(5-methylthiazol-2-yl)-1H-imidazole-1-carboxamide (3) was prepared by: N-(5-methylthiazol-2-yl)-1H-imidazole- 1-Carboxamide (3) was prepared in a similar manner as described in Example 1, except that 2-amino-5-methylthiazole was used in place of 2-aminobenzothiazole in step 13 of Example 1. LC / MS (APCI): m / z 209.2 (M+H).

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Abstract

In one aspect, the present invention provides for a compound of Formula I in which in Formula I, the variables X1, X2a, X2b, X2c, R1, B, L, E, A and the subscript n are as defined herein. In another aspect, the present invention provides for pharmaceutical compositions comprising compounds of Formula I as well as methods for using compounds of Formula I for the treatment of diseases and conditions (e.g., cancer, thrombocythemia, etc) characterized by the expression or over-expression of Bcl-2 anti-apoptotic proteins, e.g., of anti-apoptotic Bcl-xL proteins.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of US Provisional Application No. 61 / 139,479, filed December 19, 2008, the contents of which are hereby incorporated by reference in their entirety. Background of the invention [0003] Apoptosis is now recognized as an essential biological process for tissue homeostasis in all living species. In mammals in particular, it has been shown to regulate early embryonic development. Later in life, cell death is the default mechanism for removing potentially dangerous cells, such as cells carrying cancerous defects. Several apoptotic pathways have been revealed, and one of the most important involves the Bcl-2 family of proteins, which are key regulators of the mitochondrial (also called "intrinsic") pathway of apoptosis. See Danial, N.N. and Korsmeyer, S.J. Cell (2004) 116, 205-219. This family of proteins is characterized by structural homology domains BH1, BH2, BH3 and BH4. Depending o...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K31/535
CPCC07D487/04C07D417/14C07D417/12A61P17/14A61P31/18A61P35/00A61P35/02A61P37/06A61P37/08A61P7/00A61P7/02A61P9/00A61P9/10C07D215/16C07D277/62
Inventor 乔纳森·B·贝尔金·西恩·布伊彼得·科尔曼达内特·A·达德利韦恩·J·费尔布罗瑟约翰·A·弗莱加尔纪劳姆·L·莱塞尼查迪·杜巴库乔治·尼克拉科普罗斯卡尔·史蒂文·拉伊布拉德·E·斯利布斯布赖恩·J·史密斯K·G·沃特森S·W·艾尔摩尔A·M·佩特洛斯A·J·索尔斯彼得·扎博塔尔
Owner GENENTECH INC
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