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Macrocyclic compounds and methods of making and using the same

A technology of compounds and oxides, applied in the field of peristaltic accelerators and a family of macrocyclic compounds

Inactive Publication Date: 2007-04-18
RIB-X PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, these methods of making macrolide derivatives have had only limited success

Method used

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  • Macrocyclic compounds and methods of making and using the same
  • Macrocyclic compounds and methods of making and using the same
  • Macrocyclic compounds and methods of making and using the same

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0603] Example 1 - Synthesis of Compounds 101-280

[0604] Schemes 100 and 101 below describe the synthesis of compounds 101-280. 3'-N-desmethylazithromycin 2 is selectively generated by demethylation of azithromycin 1. Amine 2 was selectively alkylated with tosylate 11, 12, 13 to generate alkynes 3, 4, 5, respectively. As shown in Scheme 101, alkynes 3, 4 or 5 and azides 14a-14gm selectively provide triazoles 101-280 in the presence of cuprous iodide.

[0605] Scheme 100: Synthesis of alkynes 3, 4 and 5.

[0606]

[0607] Synthesis of 3'-N-desmethylazithromycin 2

[0608] Azithromycin 1 (0.80 g, 1.02 mmol) and sodium acetate (0.712 g, 8.06 mmol) were dissolved in 80% aqueous methanol (25 mL). The solution was heated to 50°C, then iodine (0.272 g, 1.07 mmol) was added in three portions over three minutes. The pH of the reaction was maintained between 8-9 by adding 1N sodium hydroxide (1 ml) at intervals of 10-45. The solution became a colorless liquid within 45 minute...

Embodiment 2

[0641] Example 2 - Synthesis of Compounds 301-357

[0642] Below; Schemes 103 and 104 are the synthesis of compounds 301-357. 3'-N-desmethylerythromycin A20 is selectively generated by demethylation of erythromycin A. Likewise, demethyl clarithromycin produces 3'-N-desmethyl clarithromycin21. Selective N-alkylation of amines 20 and 21 with propargyl bromide or with tosylate 11 or 12 yielded alkynes 23, 24, 25, 26, 27, or 28, respectively. As shown in Scheme 2, alkynes 23-28 and azides 14a-14eb selectively provide triazoles 301-357 in the presence of cuprous iodide.

[0643]

[0644] Synthesis of 3'-N-desmethylerythromycin A20

[0645] Compound 20 was prepared from erythromycin using the method described in U.S. Patent No. 3,725,385.

[0646] Synthesis of 3'-N-desmethyl clarithromycin 21

[0647] In clarithromycin (1.00 g, 1.3 mmol) and NaOAc·H 2 O (0.885 g, 6.5 mmol) was added to the mixture of MeOH-H 2 O (20ml, 4:1), the mixture was heated to 55-60°C. Iodine (0.330...

Embodiment 3

[0668] Example 3 - Synthesis of Compounds 401-417

[0669] Compounds 401-417 shown in Table 4 were derived from telithromycin by a method similar to Tables 2 and 3 above. Telithromycin, like azithromycin, erythromycin and clarithromycin as described above, is selectively demethylated and then alkylated with tosylate. As a result, alkynes were added to the corresponding triazoles via the same copper cycloaddition catalysis [3+2] as described above for azide 14.

[0670] Synthesis of 3'-N-desmethyltelithromycin 30

[0671] To a solution of telithromycin 29 (3.0 g, 3.60 mmol) in anhydrous acetonitrile was added N-iodosuccinimide (NIS) (0.98 g, 4.32 mmol) in two portions with argon at 0 °C Air for 30 minutes. The mixture was warmed to room temperature and stirred overnight. Join CH 2 CL 2 (250 ml) and 5% Na 2 S 2 o 3 (80 mL) until the two layers were separated. Organic layer with 5% Na 2 S 2 o 3 (1 x 80 mL) extracted with NH 4 CL (1×80 ml) diluted with Na 2 SO 4 dr...

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Abstract

The present invention provides macrocyclic compounds useful as therapeutic agents. More particularly, these compounds are useful as anti-infective, anti-proliferative, anti-inflammatory, and prokinetic agents.

Description

[0001] related application [0002] This application claims priority to U.S. Patent Application No. 60 / 548,280, filed February 27, 2004, and U.S. Patent Application No. 60 / 575,949, filed June 1, 2004, both of which published The contents of are hereby incorporated by reference in their entirety. field of invention [0003] This application relates to anti-infective drugs, anti-proliferative drugs, anti-inflammatory drugs, and motility promoters. More specifically, the present invention relates to a family of macrocyclic compounds that are useful as such agents. technical background [0004] Since the discovery of penicillin in the 1920s and streptomycin in the 1940s, many compounds have been discovered or designed as antibiotic drugs. It was once believed that through the use of such drugs, infectious diseases could be completely controlled and eradicated. However, this belief has been shaken by the continuous evolution of cell lines or microorganisms that are resistant t...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H17/00C07H17/08A61K31/7048A61K31/7052A61P31/04
Inventor 杰伊·J·法默阿肖克·包哈塔查杰陈毅乔尔·A·戈德伯格约瑟夫·A·伊波利托佐欧坦·F·凯尤楼荣亮阿德格博伊加·K·欧耶利尔爱德华·C·舍瑞尔乔伊斯·A·萨特克利夫王德平吴育生杜严明
Owner RIB-X PHARMA
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