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Chemokine receptor binding heterocyclic compounds with enhanced efficacy

A compound and effective dose technology, applied in the directions of active ingredients of heterocyclic compounds, medical preparations containing active ingredients, organic chemistry, etc.

Inactive Publication Date: 2006-05-24
ANORMED
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] While endogenous growth factors are pharmacologically effective, the well-known disadvantage of using proteins and peptides as drugs creates the potential need to add small molecule substrates to this list of growth factors

Method used

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  • Chemokine receptor binding heterocyclic compounds with enhanced efficacy
  • Chemokine receptor binding heterocyclic compounds with enhanced efficacy
  • Chemokine receptor binding heterocyclic compounds with enhanced efficacy

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0210]

[0211] Compound 1:

[0212] 4-(3,3"-dimethyl-3',4',5',6'-tetrahydro-2'H-cis-[2,2';6',2"]terpyridine-1' -yl)-butylamine

[0213] To a cold (-78°C) solution of N,N,N',N'-tetramethylethylenediamine (TMEDA) (4.06 mL, 26.9 mmol) in dry THF (50 mL) under Ar atmosphere, n-butyl Lithium (2.5M in hexane, 10.7 mL, 26.9 mmol). 2-Bromo-3-methylpyridine (3.0 mL, 26.9 mmol) was added dropwise, and the temperature was raised to -55° C. for 30 min. The reaction mixture turned red. It was then cooled to -78°C and dimethyl glutarate (1.65 mL, 11.2 mmol) was added. The reaction mixture was stirred at -78 °C for 1 h. Water (200mL) was added, and CH 2 Cl 2 The mixture was extracted (3 times, 200 mL). The combined organic extracts were washed with saturated brine (200 mL), and passed through MgSO 4 Dry, filter and concentrate. The crude product was purified by flash chromatography on silica gel (1:1 EtOAc:hexanes) to afford 1.5 g (48%) of 1,5-bis-(3-methyl-pyridin-2-yl) as a w...

Embodiment 2

[0221]

[0222] Compound 2:

[0223] [3-aminomethyl-4-meso-(3,3"-dimethyl-3',4',5',6'-tetrahydro-2'H-cis-[2,2'; 6',2"]terpyridine-1'-ylmethyl)-phenyl]-methanol

[0224] At 0°C, to a solution of 3-picolinecarbaldehyde (43.27g, 357mmol) in MeOH (179mL) was added NH 4OAc (151.14 g, 197 mmol). 1,3-Acetonedicarboxylic acid (26.10 g, 178.6 mmol) was then slowly added to the reaction over 15 min. After a large number of bubbles were eliminated, the solution was warmed to room temperature for 1 h while stirring. The solvent was removed under reduced pressure and CH was added 2 Cl 2 (500mL). The solution is saturated with Na 2 CO 3 Aqueous solution (350 mL) was washed and separated. Aqueous phase with CH 2 Cl 2 (2×400mL) extraction, the combined organic components were dissolved in Na 2 SO 4 Dried and concentrated under reduced pressure, purified by flash chromatography on a silica gel plug (2:0.5:97.5 MeOH / NH 4 OH / CH 2 Cl 2 ), resulting in yellow meso-3,3"-dimethyl-...

Embodiment 3

[0234]

[0235] Compound 3: (1-[4-((2′S,6′R)-3,3″-dimethyl-3′,4′,5′,6′-tetrahydro-2′H-[2 ,2'; 6',2"]terpyridin-1'-yl)butyl]-3-(1H-imidazol-2-yl)-urea

[0236] CH 2 Cl 2 (10 mL) the solution was stirred for 5 h, then the solvent was removed. The residue was dissolved in DMF (6 mL), and 4-((2'S,6'R)-3,3"-dimethyl-3',4',5',6'-tetrahydro-2' was added H-[2,2';6',2"]terpyridin-1'-yl)-butylamine (0.130 g, 0.384 mmol) and DIPEA (0.293 g, 2.27 mmol). The mixture was heated at 75 °C for 16 h, then cooled to room temperature. Add saturated NaHCO 3 aqueous solution (20 mL), and the mixture was distilled with CH 2 Cl 2 (3 x 30 mL) extraction. The combined extracts were treated with Na 2 SO 4 dry. After filtration, the solvent was evaporated under vacuum, and the residue was purified by flash chromatography on a silica gel column (100:5:2 CH 2 Cl 2 / CH 3 OH / NH 4 OH), with CH2Cl 2 / hexane precipitation and evaporation in vacuo to give a pale yellow solid (0.115 g, 67%). 1...

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Abstract

The present invention discloses compounds that interact with the CXCR4 receptor. These compounds are useful in the treatment of, for example, HIV infection and inflammatory conditions such as rheumatoid arthritis, as well as asthma or cancer, and are effective in methods that increase the number of progenitor and stem cells, as well as in methods that increase the number of white blood cells.

Description

[0001] Cross-applied related applications [0002] The priority texts from which this application is claimed are: U.S. Provisional Patent Application Nos. 60 / 505,230, filed September 22, 2003, and U.S. Provisional Patent Application Nos. 60 / 464,858, filed April 22, 2003, both of which are incorporated in this application is quoted. technical field [0003] The present invention generally relates to novel compounds, pharmaceutical compositions and their uses. More particularly, the present invention relates to novel heterocyclic compounds that bind to chemokine receptors, including CXCR4 and CCR5, and exhibit protection against infection of target cells by human immunodeficiency virus (HIV), as well as promoting progenitor and and / or increase the number of stem cells, stimulate the production of white blood cells and / or affect the regeneration of heart tissue. Background technique [0004] Scientists have identified more than 40 human chemokines that function, at least in p...

Claims

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Application Information

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IPC IPC(8): A61K31/40A61K31/445A61K31/495A61K31/54A61K31/55C07D223/02C07D227/00C07D401/04
Inventor G·J·布里杰E·J·麦基切恩R·斯基勒D·斯古尔斯I·贝尔德A·凯勒C·哈维格Y·朱G·陈K·斯库平斯卡M·梅茨
Owner ANORMED
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