Reverse-turn mimetics and method relating thereto

A technology of alkyl and compound, which is applied in the field of back-turning mimic structure and its related compound library, which can solve the problems of easy deformation and difficult biological application

Inactive Publication Date: 2006-07-05
JW PHARMA CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, such cyclized peptides are generally still very deformable and di

Method used

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  • Reverse-turn mimetics and method relating thereto

Examples

Experimental program
Comparison scheme
Effect test

preparation Embodiment 1

[0790] (N-Fmoc-N'-R 3 -Preparation of -hydrazino)-acetic acid

[0791] (1) Preparation of N-Fmoc-N'-methylhydrazine

[0792]

[0793] A 2L two-neck round bottom flask was fitted with a glass stopper and calcium tube. Add methylhydrazine sulfate (20g, 139mmol, wherein R 3is methyl) in THF (300 mL), and DiBoc (33 g, 153 mmol) in THF was added. Over 2 hours, saturated aqueous sodium bicarbonate (500 mL) was added dropwise from an addition funnel with vigorous stirring. After 6 hours, a THF solution of Fmoc-Cl (39 g, 153 mmol) was added slowly. The resulting suspension was stirred at 0°C for 6 hours. The mixture was extracted with ethyl acetate (EA, 500 mL), and the organic layer was retained. The solution was dried over sodium sulfate and evaporated in vacuo. Proceed to the next step without purification.

[0794] Fit a 1L two-neck round bottom flask with a glass stopper and calcium tube. A solution of the product from the previous step in MeOH (300 mL) was...

preparation Embodiment 2

[0803] (N-Moc-N'-R 7 -Preparation of -hydrazino)-acetic acid

[0804] (1) Preparation of (N'-methoxycarbonyl-hydrazine) ethyl acetate

[0805]

[0806] MOC-NH-NH 2 (50 g, 0.55 mol) was dissolved in DMF (300 ml), then ethyl bromoacetate (68 ml, 0.555 mol) and potassium carbonate (77 g, 0.555 mol) were added to the reaction vessel. The mixture was heated to 50°C for 5 hours. After the reaction was complete, the mixture was filtered and diluted with EtOAc, then washed with brine (3 times). The crude product was purified by column (eluent: Hex / EtOAc=4 / 1) to obtain 72 g of colorless oil.

[0807] (2)[N-R 7 -N'-methoxycarbonyl-hydrazino]-ethyl acetate

[0808]

[0809] Ethyl ester (10g, 0.05mol), potassium carbonate (6.9g, 0.05mol) and R 7 - Bromine (14.1 g, 0.06 mol) was dissolved in DMF (200 ml), and the mixture was heated to 50° C. for 5 hours. After the reaction was complete, the mixture was filtered and diluted with EA, then washed with brine (3 ti...

Embodiment 1

[0814]

[0815] (1)N β -Moc-N α - Preparation of benzyl-hydrazinoglycine

[0816]

[0817] The compounds were prepared according to literature procedures. (Cheguillaume et al., Synlett 2000, 3, 331).

[0818] (2) 1-methoxycarbonyl-2,8-dibenzyl-6-methyl-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4] Preparation of triazines

[0819] Bromoacetal resin (60 mg, 0.98 mmol / g) and benzylamine in DMSO (2.5 ml, 2M) were placed in a vial fitted with a screw cap. The reaction mixture was shaken at 60°C for 12 hours using a rotary oven [Robbins Scientific]. The resin was collected by filtration and washed with DMF and then DCM to give the first fraction.

[0820] A solution of Fmoc-alanine (4 equiv, commercially available, second component fragment), HATU (PerSeptiveBiosystems, 4 equiv) and DIEA (4 equiv) in NMP (Advanced ChemTech) was added to the resin. After shaking the reaction mixture at room temperature for 4 hours, the resin was collected by filtration and washed with DMF,...

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Abstract

Conformationally constrained compounds that mimic the secondary structure of reverse-turn regions of biologically active peptides and proteins are disclosed. Such reverse-turn mimetic structures have utility over a wide range of fields, including use as diagnostic and therapeutic agents. Libraries containing the reverse-turn mimetic structures of this invention are also disclosed as well as methods for screening the same to identify biologically active members. The invention also relates to the use of such compounds for inhibiting or treating disorders modulated by Wnt-signaling pathway, such as cancer, especially colorectal cancer, restenosis associated with angioplasty, polycystic kidney disease, aberrant angiogenesis disease, rheumatoid arthritis disease, tuberous sclerosis complex, Alzheimer's disease, excess hair growth or loss, or ulcerative colitis.

Description

technical field [0001] The present invention generally relates to reverse-turn mimetic structures and libraries of compounds related thereto. The invention also relates to the use in the treatment of medical diseases, such as cancer diseases, and to pharmaceutical compositions containing this mimic. Background technique [0002] Random screening of molecules to determine their potential activity as therapeutic agents has existed for many years and has led to the discovery of a number of important drugs. While advances in molecular biology and computational chemistry have led to growing interest in what is known as "rational drug design," the technique has not proven to be as fast or reliable as originally expected. As a result, interest has shifted back to randomized drug screening in recent years. Thus, a special step has been taken based on the development of combinatorial compound libraries and new techniques for screening such libraries in searches for biologically act...

Claims

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Application Information

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IPC IPC(8): C07D471/00C07D487/00G01N33/50A61KA61K31/498A61K31/53A61K31/5513A61K45/06A61P1/04A61P9/08A61P13/12A61P29/00C07D487/02C07D487/04C07D521/00C40B30/04C40B40/04C40B50/14G01N33/15
CPCC07D487/04A61K31/5513A61K45/06C07D231/12C07D233/56C07D249/08C40B30/04C40B40/04C40B50/14A61P1/04A61P9/00A61P9/08A61P13/12A61P17/14A61P25/02A61P25/28A61P29/00A61P35/00A61P43/00A61K2300/00A61K31/498A61K31/53C07D487/02
Inventor 文圣焕郑宰旭李承灿M·埃奇M·卡恩郑光远C·恩因
Owner JW PHARMA CORP
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