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Substituted isoindoline-1,3-dione derivative

A technology of deuterium substitution and compound, which is applied in the direction of metabolic diseases, drug combination, and resistance to vector-borne diseases, etc., and can solve problems such as decreased metabolic clearance rate

Active Publication Date: 2012-07-11
CONCERT PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

For some compounds, deuteration causes decreased metabolic clearance in the body

Method used

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  • Substituted isoindoline-1,3-dione derivative
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  • Substituted isoindoline-1,3-dione derivative

Examples

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preparation example Construction

[0107] Scheme 2 describes the preparation of aldehyde 10, a useful starting material for Scheme 1. As generally described by Li, Juren et al. Hecheng Huaxue (1993), 1(4), 333-40, treatment of appropriately deuterated diol 13 with appropriately deuterated bromoethane 14 under phase transfer conditions yields phenol 15 . Reimer-Tiemann reaction of phenol 15 with chloroform yields aldehyde 16. Deuterated reagents and solvents can be used in this step to maximize the level of isotope incorporation. Alternatively, tetrabutylammonium bromide conditions can be used to convert 15 to 16 as generally described by Li, Ying-chun et al., Yingyong Huagong (2004), 33(1), 26-27. Treatment of 16 with appropriately deuterated dimethyl sulfate 17 yields the desired intermediate 10 according to the general method of Kiehlmann, E. et al., Organic Preparations and Procedures International (1982), 14(5), 337-42.

[0108] For example, commercially available dimethyl sulfate-d6 can be used as reage...

Embodiment 1

[0158] Example 1: (S)-N-(2-(1-d-2-(methylsulfonyl)-1-(3-(ethoxy-d 5 )-4-(methoxy-d 3 )Synthesis of phenyl)ethyl)-1,3-dioxoisoindolin-4-yl)acetamide (compound 113a).

[0159] Scheme 4: Preparation of compound 113a.

[0160]

[0161] Step 1: 3-Hydroxy-4-(methoxy-d 3 )-ethyl benzoate (23).

[0162] Commercially available ester 22 (10 g, 55 mmol) was mixed with CD in DMF 3 I (99 atomic % D, Cambridge Isotopes; 8.1 g, 55 mol) and K 2 CO 3 (7.59g) were combined and stirred at room temperature over the weekend. LCMS showed 3 peaks with masses consistent with the starting material (20%), the desired mono-alkylated product 23 (55%) and the di-alkylated by-product (23%). The reaction was filtered through a pad of Celite, washed with EtOAc, and the filtrate was concentrated to almost dryness. The residue was dissolved in CH 2 Cl 2 (300mL), and the solution was washed with water (5x50mL), brine, dried (Na 2 SO 4 ) and concentrate. The crude product was purified by...

Embodiment 2

[0175] Example 2: (S)-N-(2-(2-(-(methylsulfonyl)-1-(3-(ethoxy-d 5 )-4-(methoxy-d 3 )Synthesis of phenyl)ethyl)-1,3-dioxoisoindolin-4-yl)acetamide (compound 107a).

[0176] Scheme 5: Preparation of compound 107a.

[0177]

[0178]

[0179] Step 1: 3-Hydroxy-4-(methoxy-d 3 )-benzaldehyde (27).

[0180] Commercially available 3,4-dihydroxy-benzaldehyde 26 (10 g, 80 mmol) was dissolved in DMF (50 mL). Join K 2 CO 3 (10 g), and the solution was cooled in an ice-water bath. Add CD slowly 3 I (99 atomic % D, Cambridge Isotopes; 12.4 g, 84 mmol), and the reaction was stirred overnight at room temperature. The reaction was diluted with EtOAc (200 mL) and filtered through a pad of celite. The filtrate was concentrated to give a dark oil. EtOAc (150 mL) and water (50 mL) were added, and the layers were separated. The aqueous phase was adjusted to pH 6 by slow addition of 1N HCl, and the mixture was extracted with EtOAc (2x100 mL). dry (Na 2 SO 4 ) combined or...

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Abstract

The invention relates to a novel substituted isoindoline-1,3-dione derivative and the pharmaceutically acceptable salts thereof. More particularly, the invention relates to a novel substituted isoindoline-1,3-dione derivative used as an analogue of apremilast. The invention further provides a composition containing the compound disclosed by the invention and a carrier, and the application of the disclosed compound and composition in a method for beneficially treating diseases and conditions by administering apremilast.

Description

Background technique [0001] Many existing drugs suffer from poor absorption, distribution, metabolism and / or excretion (ADME) properties, which prevent their wider use or limit their use in specific indications. Poor ADME properties are also the main reason why drug candidates fail in clinical trials. Although formulation techniques and prodrug strategies can in some cases be used to enhance certain ADME properties, these approaches often fail to address fundamental ADME problems that exist for many drugs and drug candidates. One such problem is rapid metabolism that causes many drugs that are otherwise very effective in treating disease to be cleared too quickly from the body. A possible solution for rapid drug clearance is frequent or high dose dosing to achieve sufficiently high drug plasma levels. However, this introduces many potential treatment problems, such as poor patient compliance with the dosing regimen, higher doses leading to more severe side effects and increa...

Claims

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Application Information

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IPC IPC(8): C07D209/48A61K31/4035A61P17/06A61P17/00A61P19/02A61P37/06A61P1/02A61P25/00A61P31/04A61P29/00A61P9/00A61P33/06A61P17/04A61P27/02A61P9/04A61P3/00A61P35/00A61P19/08A61P1/06A61P1/04A61P25/28A61P37/02A61P17/16A61P11/00A61P11/06
CPCC07D209/48Y02A50/30
Inventor J·F·刘
Owner CONCERT PHARMA INC
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