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Derivatives of hydroxyphenyl, a method for preparing thereof and their pharmaceutical composition

A derivative and composition technology, applied in the field of hydroxyphenyl derivatives, can solve problems such as inability to recognize phosphotyrosine, loss of activated T cells, etc.

Inactive Publication Date: 2005-07-27
MOGAM BIOTECH RES INST
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

It has been observed that SH 2 The modified lck region cannot recognize phosphotyrosine, thus losing its ability to activate T cells

Method used

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  • Derivatives of hydroxyphenyl, a method for preparing thereof and their pharmaceutical composition
  • Derivatives of hydroxyphenyl, a method for preparing thereof and their pharmaceutical composition
  • Derivatives of hydroxyphenyl, a method for preparing thereof and their pharmaceutical composition

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0125] Preparation of 3-(3,4-dihydroxy-phenyl)-(R)-2-[3-trans-(3,4-dihydroxy-phenyl)-acrylamide]-propane methyl ester

[0126] (Step 1) Preparation of 3,4-dihydroxyphenyl-D-alanine methyl ester

[0127] Dissolve 2.0 g (10.14 mmol, 1 equivalent) of D-3,4-dihydroxyphenylalanine (D-DOPA) in 40 ml of methanol, and add thionyl chloride dropwise to the solution at 0° C. (7.4 ml, 101.4 mmole, 10 equivalents). The reaction mixture was stirred under nitrogen atmosphere for 18 hours and distilled under vacuum to remove excess methanol and thionyl chloride. The residue was recrystallized in methanol and ethyl acetate to provide DOPA methyl ester. The yield was 93%.

[0128] TLC (chloroform: acetone: methanol: water = 8: 8: 3: 1); Rf = 0.49

[0129] (Step 2) Preparation of 3-(3,4-dihydroxyphenyl)-(R)-2-[3-trans-(3,4-dihydroxy-phenyl)-acrylamido]-propionic acid methyl ester

[0130] In 10 ml of N,N-dimethylformamide, 2.0 g (8.07 mmole, 1 equivalent) of DOPA methyl ester obtained in...

Embodiment 2

[0134] Preparation of 3-(3,4-dihydroxy-phenyl)-(R)-2-[3-trans-(3,4-dihydroxy-phenyl)-acrylamide]-propane acid

[0135] 70 mg of 3-(3,4-dihydroxy-phenyl)-(R)-2-[3-trans-(3,4-dihydroxy-phenyl)-acrylamino]- Methyl propionate was dissolved in 50 ml of a mixed solvent containing acetone and water (4:25, v / v), and then 8 ml of HCl solution was added thereto. The reaction mixture was refluxed in an oil bath for 1 day, concentrated to remove acetone, and then ethyl acetate was added to give the title compound. The yield was 54%.

[0136] TLC (n-hexane:ethyl acetate:methanol=4:5:1) product Rf=0.28.

[0137] M / z 360.1(M+H)

[0138] 1 H NMR (DMSO-d 6 )δ8.62, 8.67, 9.07, 9.31 (4H, br, -OH), 8.75 (1H, d, J = 8.0Hz, NH), 7.20 (1H, d, J = 15.7Hz, CH), 6.93 (1H , d, J = 1.8Hz, aromatic), 6.74 (1H, d, J = 8.1Hz, aromatic), 6.62 (1H, d, J = 1.8Hz, aromatic), 6.61 (1H, J = 7.8Hz, aromatic), 6.57 (1H, d, J = 7.9, 1.8Hz, aromatic), 6.41 (1H, d, J = 15.7Hz, CH), 4.48 (1H, m, CH), 2.90 (1H...

Embodiment 3

[0139] Preparation of 3-(3,4-dihydroxy-phenyl)-(R)-2-[3-trans-(3,4-dihydroxy-phenyl)-acrylamido]-propane ethyl acetate

[0140] Except that ethanol is used as the reaction solvent instead of methanol in Step 1 of Example 1 to obtain D-DOPA ethyl ester, and D-DOPA ethyl ester is used as the starting material, the reaction is carried out in the same manner as described in Example 1, The title compound was obtained.

[0141] M / z 388.8(M+H)

[0142] 1 H NMR (DMSO-d6) δ8.62, 8.67, 9.07, 9.31 (4H, br, -OH), 8.75 (1H, d, J = 8.0Hz, NH), 7.20 (1H, d, J = 15.7Hz, CH), 6.93 (1H, d, J = 1.8Hz, aromatic), 6.74 (1H, d, J = 8.1Hz, aromatic), 6.62 (1H, d, J = 1.8Hz, aromatic) , 6.61 (1H, J=7.8Hz, aromatic), 6.57 (1H, d, J=7.9, 1.8Hz, aromatic), 6.41 (1H, d, J=15.7Hz, CH), 4.48 (1H , m, CH), 2.90 (1H, dd, J=13.7, 4.9Hz, CH 2 ), 2.72 (1H, dd, J=13.7, 4.9Hz, CH 2 )4.12 (2H, q, J = 10.1, CH 2 ) 1.30 (3H, t, J=10.1, CH 3 )

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Abstract

The present invention relates to derivatives of hydroxyphenyl, a method for preparing thereof and their pharmaceutical composition, more particularly the compounds of the present invention specifically inhibit the activation of T lymphocyte by src homology region 2(SH2) domain of T lymphocyte (lck), so that they can be used for the treatment, prevention and / or diagnosis of graft rejection, autoimmune diseases, inflammatory diseases, etc.

Description

technical field [0001] The present invention relates to hydroxyphenyl derivatives represented by the following formula 1, methods for preparing them and their pharmaceutical compositions. [0002] Formula 1 [0003] [0004] Among them, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , X 1 , X 2 , X 3 , Y 1 , Y 2 , B and * are the same as defined in the specification. Background technique [0005] Immunosuppressants are widely used to treat transplant rejection and autoimmune diseases. During the course of an immune response, the number of leukocytes, including T-lymphocytes, B-lymphocytes, monocytes and segmental cells, increases rapidly. The most common immunosuppressants are usually developed for the purpose of suppressing the immune response by inhibiting cytokine expression and cell metabolism to activate lymphocytes and promote their proliferation. In general, typical immunosuppressants are classified into metabolic inhibitors that block...

Claims

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Application Information

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IPC IPC(8): A61K45/00A61K31/165A61K31/198A61K31/216A61K31/223A61P1/10A61P17/00A61P17/06A61P17/08A61P19/02A61P21/04A61P25/00A61P29/00A61P31/10A61P37/02A61P37/06A61P43/00C07C69/732C07C229/36C07C233/51C07C235/34C07C275/24C07C327/44
CPCC07C327/44C07C235/34C07C69/732C07C229/36C07C275/24A61P1/10A61P17/00A61P17/06A61P17/08A61P19/02A61P21/04A61P25/00A61P29/00A61P31/10A61P37/02A61P37/06A61P43/00C07C233/51
Inventor 元钟和李键炯朴是衡金成柱尹秀映姜美爱许允卿尹只熙尹荣大朴斗鸿吴载泽
Owner MOGAM BIOTECH RES INST
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