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Prodrugs of methyl hydrogen fumarate, pharmaceutical compositions thereof, and methods of use

A kind of compound, the technology of di-ester, is applied in the prodrug of methyl hydrogen fumarate, its pharmaceutical composition, and its use field, can solve problems such as poor water solubility

Inactive Publication Date: 2011-07-13
XENOPORT
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition, DMF exhibits poor water solubility

Method used

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  • Prodrugs of methyl hydrogen fumarate, pharmaceutical compositions thereof, and methods of use
  • Prodrugs of methyl hydrogen fumarate, pharmaceutical compositions thereof, and methods of use
  • Prodrugs of methyl hydrogen fumarate, pharmaceutical compositions thereof, and methods of use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0480] (N,N-Diethylcarbamoyl)methylmethyl(2E)but-2-ene-1,4-dioate (1)

[0481]

[0482] According to General Procedure A, methyl hydrogen fumarate (MHF) (0.39 g, 3.00 mmol) dissolved in NMP was mixed with 2-chloro-N,N-diethylacetamide (0.44 g, 3.00 mmol) at about 55 °C ) in CsHCO 3 (0.69 g, 3.60 mmol) gave 0.37 g ( 51% yield) of the title compound (1). M.p.: 53-56°C. 1 H NMR (CDCl 3 , 400MHz): δ6.99-6.90(m, 2H), 4.83(s, 2H), 3.80(s, 3H), 3.39(q, J=7.2Hz, 2H), 3.26(q, J=7.2Hz, 2H), 1.24(t, J=7.2Hz, 3H), 1.14(t, J=7.2Hz, 3H). MS(ESI): m / z 244.13(M+H) + .

Embodiment 2

[0484] Methyl[N-benzylcarbamoyl]methyl(2E)but-2-ene-1,4-dioate (2)

[0485]

[0486] According to General Procedure A, methyl hydrogen fumarate (MHF) (0.50 g, 3.85 mmol) dissolved in NMP was mixed with N-benzylchloroacetamide (0.84 g, 4.61 mmol) in CsHCO at about 55 °C. 3 Reaction in the presence of (0.89 g, 4.61 mmol) afforded 0.56 g (53% yield) of the title compound (2) as a white solid after purification by mass-directed preparative HPLC and lyophilization. 1 H NMR (CDCl 3 , 400MHz): δ7.36-7.26(m, 5H), 6.94-6.88(m, 2H), 6.19(br s, 1H), 4.73(s, 2H), 4.51(d, J=5.6Hz, 2H) , 3.81(s, 3H). MS(ESI): m / z 278.04(M+H) + .

Embodiment 3

[0488] Methyl 2-morpholin-4-yl-2-oxoethyl(2E)but-2-ene-1,4-dioate (3)

[0489]

[0490] According to General Procedure A, methyl hydrogen fumarate (MHF) (0.50 g, 3.84 mmol) dissolved in NMP was mixed with 4-(chloroacetyl)morpholine (0.75 g, 4.61 mmol) in CsHCO at about 55 °C. 3 Reaction in the presence of (0.89 g, 4.61 mmol) afforded 0.34 g (35% yield) of the title compound (3) as a white solid after purification by mass-directed preparative HPLC and lyophilization. M.p.: 124-126°C; 1 H NMR (CDCl 3 , 400MHz): δ6.97-6.91(m, 2H), 4.84(s, 2H), 3.82(s, 3H), 3.72-3.70(m, 4H), 3.64-3.62(m, 2H), 3.46-3.41 (m, 2H). MS(ESI): m / z 258.04(M+H) + .

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Abstract

Prodrugs of methyl hydrogen fumarate, pharmaceutical compositions comprising the prodrugs of methyl hydrogen fumarate, and methods of using the prodrugs of methyl hydrogen fumarate and the pharmaceutical compositions thereof for treating diseases such as psoriasis, asthma, multiple sclerosis, inflammatory bowel disease, and arthritis are disclosed.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to U.S. Provisional Application 61 / 090,163, filed August 19, 2008, entitled "Prodrugs of Methyl Hydrogen Fumarate, Pharmaceutical Compositions Thereof, and Methods of Use," which is hereby incorporated by reference in its entirety Apply. technical field [0003] The application discloses a prodrug of methyl hydrogen fumarate, a pharmaceutical composition comprising the methyl hydrogen fumarate prodrug, and a prodrug of methyl hydrogen fumarate and a pharmaceutical composition thereof for the treatment of diseases such as Usage in diseases of psoriasis, asthma, multiple sclerosis, inflammatory bowel disease, and arthritis. Background technique [0004] Esters of fumaric acid (FAE) are approved in Germany for the treatment of psoriasis, are being evaluated in the United States for the treatment of psoriasis and multiple sclerosis, and have been proposed for the treatment of various immun...

Claims

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Application Information

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IPC IPC(8): A61P17/06A61P9/10A61P19/02A61K31/16C07C69/60C07C69/96
CPCC07D295/185C07D263/20C07D207/16C07D295/18C07C235/06C07C69/96C07C271/64C07C235/10C07D285/12C07C259/06C07C69/78C07C2101/14C07C69/75C07C275/50C07C69/60C07C235/08C07C235/12C07C2601/14A61P1/00A61P1/04A61P11/00A61P11/06A61P17/00A61P17/06A61P19/00A61P19/02A61P25/00A61P25/16A61P25/28A61P29/00A61P9/00A61P9/10
Inventor A·冈加克赫德卡X·戴N·泽朗古尔P·A·沃斯克
Owner XENOPORT
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