Looking for breakthrough ideas for innovation challenges? Try Patsnap Eureka!

Heterocyclic compounds and methods of use

A compound and heterocycle technology, applied in the fields of drug combination, organic chemistry, pharmaceutical formulation, etc., can solve the problems of cytotoxicity, weak binding, etc.

Active Publication Date: 2014-01-01
GENENTECH INC +2
View PDF8 Cites 0 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

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

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Heterocyclic compounds and methods of use
  • Heterocyclic compounds and methods of use
  • Heterocyclic compounds and methods of use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0284] Synthesis of 2-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)thiazole-4-carboxylic acid (1):

[0285]

[0286] step 1 : Preparation of tert-butyl 8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (1A).

[0287]

[0288] To 2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-8-carboxylic acid (6.8g, 24.5mmol) and benzo[d]thiazol-2-amine (5.52g , 36.8 mmol) in DCM (80 mL), EDCI (9.4 g, 49.04 mmol) and DMAP (6 g, 49 mmol) were added. The mixture was stirred overnight at room temperature. The reaction mixture was diluted with DCM (400 mL), washed with 5% aqueous HCl, water, brine, washed with Na 2 SO 4 Drying and concentration under reduced pressure afforded 8.5 g of the desired product 8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinoline-2(1H)-tert-butylcarboxylate Esters (1A): 1 H NMR (300MHz, CDCl 3 )δppm 7.83 (1H, m), 7.48 (1H, d), 7.34 (4H, m), 7.19 (1H, t), 4.91 (2H, m), 3.67 (2H, t), 2.92 (2H, t) ,...

Embodiment 2

[0298] 2-(8-(Benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-(3-phenoxypropyl) Synthesis of thiazole-4-carboxylic acid (2):

[0299]

[0300] step 1 : Preparation of ethyl 3-bromo-6-chloro-2-oxohexanoate (2A).

[0301]

[0302] Bromine (0.85 mL, 16.5 mmol) was added to carbon tetrachloride (30 mL) containing ethyl 6-chloro-2-oxohexanoate (2.9 g, 15 mmol), and stirred at room temperature for 1 hour. The reaction mixture was diluted with EtOAc, washed with Na2 S 2 o 3 solution, water, brine, washed with MgSO 4 Dry, filter and concentrate under reduced pressure. The crude material was purified by column chromatography on silica gel eluting with a gradient of 0 to 10% EtOAc in hexanes to afford the desired product ethyl 3-bromo-6-chloro-2-oxohexanoate (2A) in 95% yield %. 1 H NMR (300MHz, DMSO-d 6 ) δ ppm 5.25 (1H, dd), 4.29 (2H, q), 3.71 (2H, t), 2.16 (1H, m), 1.91 (1H, m), 1.29 (3H, t).

[0303] step 2 : 2-(8-(Benzo[d]thiazol-2-ylcarbamoyl)-3,...

Embodiment 3

[0312] 2-(8-(Benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-(3-(pyridin-4-yl Synthesis of thio)propyl)thiazole-4-carboxylic acid (3):

[0313]

[0314] The title compound 2-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-(3-(pyridine- 4-ylthio)propyl)thiazole-4-carboxylic acid (3) was prepared by the following procedure: The title compound was prepared by substituting pyridine-4-thiol for phenol in step 4 of Example 2. After precipitation of the desired product, the solid was purified by HPLC (pre-preparative reverse phase HPLC performed with an automated Gilson HPLC system using a SymmetryPrep Shield RP18 pre-preparative column, 250mmx21.20mm i.d., 10um, flow rate 25mL / min; λ = 214, 245nm; flow Phase A, H with 0.1% TFA 2 O; mobile phase B, CH 3 CN; linear gradient 0-90% of B in 40 minutes) to provide 2-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinoline-2 (1H)-yl)-5-(3-(pyridin-4-ylthio)propyl)thiazole-4-carboxylic acid (...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

No PUM Login to View More

Abstract

In one aspect, the present invention provides for a compound of Formula I in which the variable X1a, X1b, X1c, X1d, Q, A, R1, B, L, E, and the subscripts m and n have the meanings as described 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 / 139,492, 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 a biological process essential to 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 by which potentially dangerous cells, such as cells carrying cancerous defects, are removed. 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 protein family is characterized by structural homeodomains BH1, BH2, BH3 and BH4. Depending on...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
Patent Type & Authority Patents(China)
IPC IPC(8): C07D417/14A61K31/4725
CPCC07D495/04C07D417/14C07D473/00C07D513/04C07D513/06C07D487/04C07D471/06A61P35/00A61P35/02A61P7/00A61P7/02A61P9/00A61P9/10A61K31/4725C07D473/02
Inventor 乔纳森·B·贝尔金·西恩·布伊彼得·科尔曼彼得·扎博塔尔达内特·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L·A·哈斯沃尔德A·M·佩特洛斯A·J·索尔斯Z·陶L·王X·王库尔特·德赛
Owner GENENTECH INC
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Patsnap Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Patsnap Eureka Blog
Learn More
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic, Popular Technical Reports.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap|About US| Contact US: help@patsnap.com