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Immunomodulator and preparation method thereof as well as application thereof

A technology of immunomodulator and general formula, applied in the field of preparation of compounds, immunomodulators, new generation of immunomodulators or their pharmaceutically acceptable salts, can solve problems such as short-term bradycardia response

Inactive Publication Date: 2012-05-23
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] However, FTY720 will cause short-term bradycardia after administration, and other side effects are mainly common in symptoms such as anemia, edema, hyperkalemia, hirsutism, gastrointestinal discomfort and bradycardia
Moreover, the occurrence of macular degeneration is the most serious side effect caused by FTY720, which eventually made FTY720 withdraw from the clinical trial of organ transplantation

Method used

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  • Immunomodulator and preparation method thereof as well as application thereof
  • Immunomodulator and preparation method thereof as well as application thereof
  • Immunomodulator and preparation method thereof as well as application thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation Embodiment 1

[0059] 1) Methyl (E)-4-(4-n-butylcyclohexyl)benzoate (Ⅲ-4)

[0060] Dissolve (E)-4-(4-n-butylcyclohexyl)benzoic acid (II-4) (purchased from Shandong Yantai Fangchen Chemical Material Technology Co., Ltd.) (26.0g, 0.1mol) in 200mL methanol, dropwise 98% sulfuric acid (0.9 mL, 0.014 mol). After the dropwise addition, the mixture was heated under reflux for 8 hours, and the reaction was complete. After cooling, a white solid precipitated out, filtered with suction, washed with water, washed with a small amount of methanol, and dried at low temperature to obtain 24.2 g of a white solid, with a yield of 88%.

[0061] mp 39-40℃. 1 H NMR (500MHz, CDCl 3 ): δ0.90(t, 3H), 1.04-1.08(m, 2H), 1.23-1.25(m, 2H), 1.30-1.31(m, 5H), 1.44-1.47(m, 2H), 1.87-1.90 (m, 4H), 2.50-2.53(m, 1H), 3.90(s, 3H), 7.27(d, J=8Hz, 2H), 7.95(d, J=8Hz, 2H).

[0062] 2) Methyl 4-cyclohexylbenzoate (Ⅲ-1)

[0063] The method was the same as above, and 20.0 g of compound II-1 (purchased from Shandong Yantai Fan...

preparation Embodiment 2

[0075] 1) (E)-4-(4-n-butylcyclohexyl)benzyl alcohol (IV-4)

[0076] (E)-4-(4-n-butylcyclohexyl) methyl benzoate (Ⅲ-4) (27.4g, 0.1mol), potassium borohydride (6.5g, 0.12mol) and lithium chloride (5g, 0.12mol ) was suspended and dissolved in 100mL of anhydrous tetrahydrofuran, refluxed for 8 hours, cooled to room temperature, slowly added dropwise with 200mL of saturated ammonium chloride solution, continued to stir for 2 hours, concentrated under reduced pressure to remove tetrahydrofuran, extracted with ethyl acetate, and the organic phase was washed with water respectively, Wash with saturated sodium chloride solution, dry over anhydrous magnesium sulfate, and concentrate to obtain 22.2 g of white solid, yield: 90%.

[0077] mp 47-48°C. 1 H NMR (500MHz, CDCl 3 ): δ0.92(t, 3H), 1.07-1.08(m, 2H), 1.24-1.32(m, 7H), 1.46-1.48(m, 2H), 1.86-1.90(m, 4H), 2.48-2.50 (m, 1H), 4.66(s, 2H), 7.21(d, J=9Hz, 2H), 7.29(d, J=9Hz, 2H). 13 C NMR (CDCl 3 , 100MHz): δ23.0, 29.2, 33.6, 34.4, ...

preparation Embodiment 3

[0091] 1) (E)-4-(4-n-butylcyclohexyl)benzyl bromide (Ⅴ-4)

[0092] Dissolve (E)-4-(4-n-butylcyclohexyl)benzyl alcohol (IV-4) (34.5g, 0.14mol) in 200mL of dichloromethane, cool to -10°C in an ice bath, and drop 5.3 mL of phosphorus tribromide, reacted at room temperature for 6 hours, after the reaction was completed, crushed ice was added to destroy excess phosphorus tribromide, the organic phase was washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and rotary evaporated to obtain a light yellow solid Product 41.5g, yield: 96%.

[0093] mp 33-35°C. 1 H NMR (500MHz, CDCl 3 ): δ0.92(t, 3H), 1.05-1.08(m, 2H), 1.25-1.34(m, 7H), 1.44-1.46(m, 2H), 1.88-1.90(m, 4H), 2.48-2.49 (m, 1H), 4.51(s, 2H), 7.20(d, J=9Hz, 2H), 7.33(d, J=9Hz, 2H). 13 C NMR (CDCl 3 , 100MHz): δ23.0, 29.2, 33.6, 33.7, 34.2, 37.1, 37.3, 44.4, 127.3, 129.0, 135.1, 148.3. MS (EI): m / z 308 (M + ,2).

[0094] 2) 4-cyclohexylbenzyl bromide (Ⅴ-1)

[0095] The method wa...

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Abstract

The invention discloses an immunomodulator and a preparation method thereof as well as an application thereof; and the specific structure of the immunomodulator is as shown in the general formula (I). The pharmacological screening shows that the immunomodulator has immune adjustment activity, thereby being capable of being applied to organ transplantation medicines.

Description

technical field [0001] The present invention relates to a class of immunomodulators with immunomodulatory activity, and the preparation methods of these compounds. More specifically, the present invention relates to a new generation of branched-chain engineered immunomodulators or pharmaceutically acceptable salts thereof, their preparation methods and the application of these new compounds in the field of immune regulation. Background technique [0002] Immunomodulators are a class of drugs with immunoregulatory effects, which can regulate the body's immune function by affecting the body's immune response and immunopathological reactions. Currently, they are widely used in the treatment of organ transplantation anti-rejection and autoimmune diseases. The rapid development of immunomodulators has laid the foundation for the great success of clinical organ transplantation. The continuous exploration and research of immunomodulatory drugs by medical researchers and the contin...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C215/38C07C213/00A61K31/137A61P37/02A61P37/06
CPCY02P20/55
Inventor 左建平吕伟丰祥军杨筱莹
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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