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Method of preparing poly(ADP-ribose) polymerases inhibitors

A compound and alkyl technology, applied in the field of preparing compounds that inhibit polymerase, can solve the problem of no PARP inhibitor

Active Publication Date: 2007-08-29
PFIZER INC +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

There are currently no PARP inhibitors on the market

Method used

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  • Method of preparing poly(ADP-ribose) polymerases inhibitors
  • Method of preparing poly(ADP-ribose) polymerases inhibitors
  • Method of preparing poly(ADP-ribose) polymerases inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0082] Example 1. Synthesis of 4-trimethylsilylethynyl-benzaldehyde (2)

[0083]

[0084] 4-Bromobenzaldehyde (1) (185g, 1.0mol) was dissolved in THF (1L), then copper(I) iodide (7.6g, 0.04mol), dichlorobis(triphenylphosphine)palladium was added (II) (14.02 g, 0.02 mol) and triethylamine (151.5 g, 1.5 mol). Ethynyltrimethylsilane (109.1 g, 1.11 mol) was added from the addition funnel as a solution in THF (0.2 L). The reaction was stirred at 30°C for 30 minutes, then at 25°C for 20 hours. Analysis by HPLC indicated the reaction was complete. THF was removed and the residue was treated with hexanes (1.8 L). The solids were removed by filtration, and the filter cake was washed with hexane (0.3 L). The combined hexane solutions were washed with water (2 x 0.5 L). Remove hexane in rotovap. The residue was dissolved in EtOH (0.5 L) at 50 °C. The solution was then cooled slowly to 16°C and stirred for 30 minutes. The product started to crystallize. The mixture was furth...

Embodiment 2

[0085] Example 2. Synthesis of methyl-(4-trimethylsilylethynyl-benzyl)-amine (3)

[0086]

[0087]Methylamine (8M / MeOH, 135ml) and methylamine hydrochloride (44.0g, 0.65mol) were dissolved in methanol (900ml). Add aldehyde 2 (44.0 g, 0.22 mol) and stir at room temperature for 30 minutes. Sodium cyno borohydride (17.42 g, 0.28 mol) was then added. After the addition was complete, hydrochloric acid in methanol was added to adjust the pH to 5 while maintaining the temperature at ~30°C. The reaction was stirred for 2 hours. The pH of the reaction mixture was maintained at 4-6 by addition of hydrochloric acid / MeOH solution. The reaction solvent was removed. The residue was mixed with water (400ml) and brine (50ml). The mixture was extracted with dichloromethane (2 x 300ml). The combined organic solutions were concentrated to dryness to give the crude product (40.6 g, ~85% yield), which was used in the next step without further purification. 1 H NMR (300MHz, CDCI3) δ0.25...

Embodiment 3

[0088] Example 3. Synthesis of methyl-(4-trimethylsilylethynyl-benzyl)-methyl carbamate (4)

[0089]

[0090] Amine 3 (90.0 g, -0.41 mol) was dissolved in dichloromethane (810 ml). Triethylamine (66.6 g, 0.66 mol) was added and the solution was cooled to 5°C. Then methyl chloroformate (47.0 g, 0.50 mol) / dichloromethane (100 ml) was added slowly, and the reaction temperature was kept at 10°C-14°C. After the addition was complete, the reaction solution was stirred at room temperature for 12 hours. Water (540ml) was added. The aqueous phase is separated. The organic phase was concentrated to dryness to afford crude 4. The crude product was used in the next step without further purification. 1 H NMR (300MHz, CDCl 3 )δ 0.279(s, 9H), 2.86(d, br, 3H), 3.774(s, 3H), 4.484(s, br, 2H), 7.190(s, br, 2H), 7.46(d, 2H, J = 8.10Hz).

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PUM

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Abstract

The invention relates to a new and convergent route to small molecule inhibitors of poly(ADP-ribose) polymerase, such as 8-fluoro-2{4-[(methylamino)methyl]phenyl}-1,3,4,5-tetrahydro-6H-azepino [5,4,3-cd]indol-6-one, via a key Sonogashira coupling reaction and a Cul-promoted indole formation.

Description

[0001] This application claims priority to US Provisional Application Serial No. 60 / 612,457, filed September 22, 2004, which is hereby incorporated by reference in its entirety. technical field [0002] The invention mainly relates to a method for preparing a compound inhibiting poly(ADP-ribose) polymerase, thereby delaying DNA chain damage repair. The methods of the invention are particularly useful for the preparation of compounds that can be used to potentiate anticancer therapy. Background technique [0003] Compound 8-fluoro-2{4-[(methylamino)methyl]phenyl}-1,3,4,5-tetrahydro-6H-azepine (azepino) [5, 4,3-cd]indol-6-one [0004] [0005] is a small molecule inhibitor of poly(ADP-ribose) polymerase (PARP). 8-fluoro-2{4-[(methylamino)methyl]phenyl}-1,3,4, 5-Tetrahydro-6H-azazelo[5,4,3-cd]indol-6-one and its salts, the entire contents of the above disclosure are hereby incorporated by reference. Named "Polymorphic Forms of the Phosphate Salt of 8-Fluoro-2-{4-[(methyl...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/06C07D223/00C07D209/00
CPCC07D487/06A61K31/4353
Inventor C·马N·纳亚尔N·S·斯坦科维奇
Owner PFIZER INC
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