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Aminoalcohol derivative, pharmaceutical composition and use thereof

A technology of derivatives and amino alcohols, applied in the field of medicine

Active Publication Date: 2019-01-15
FORELAND PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Sphingosine-1-phosphate receptor 1 agonist FTY720 has been successfully developed by Novartis. However, FTY720 not only acts on sphingosine-1-phosphate receptor 1 (S1P1), but also acts on sphingosine-1-phosphate Receptor 3 (S1P3), has side effects such as bradycardia. Therefore, the need to develop S1P1 agonists with better receptor selectivity has become an important research direction in this field

Method used

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  • Aminoalcohol derivative, pharmaceutical composition and use thereof
  • Aminoalcohol derivative, pharmaceutical composition and use thereof
  • Aminoalcohol derivative, pharmaceutical composition and use thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation example 1

[0148]

[0149] Synthesis of Intermediate 2:

[0150] Dissolve 100 g (465 mmol) of compound 1 in 500 mL of dichloromethane, cool in an ice-salt bath to 0°C, add 120 g (930 mmol) of oxalyl chloride dropwise, and heat to reflux for 2 hours. After the TLC detection reaction finishes, evaporate to dryness, add dichloromethane and evaporate to dryness again, obtain yellow liquid intermediate 112g, be directly used in next step reaction. 210g (1410 mmol) aluminum trichloride is suspended in 400mL dichloromethane, Cool to -10°C to -5°C, add dropwise a solution of 112g of the intermediate obtained above dissolved in 100mL of dichloromethane, and feed ethylene gas into the reaction system for about 2 hours after dropping, and keep at -10°C to -5°C. After the reaction was detected by TLC, the reaction solution was poured into a mixed solution of ice and water, extracted with dichloromethane, the organic phases were combined, washed twice with saturated sodium bicarbonate and once wit...

Embodiment 1

[0182] Example 1: (S)-(2-amino-7-(5-(3-fluoro4-isopropoxyphenyl)-1,3,4-oxadiazol-2-yl)-1,2 , 3,4-tetrahydronaphthalen-2-yl)methanol

[0183]

[0184] Dissolve 0.6g (1.24mmol) of intermediate 23 in 13mL of methanol, add 0.01mL of concentrated hydrochloric acid, add 0.122g (20%m / m) of 10% palladium carbon after nitrogen replacement, and react at 95°C for 240min . TLC (DCM: MeOH = 10: 1) detection, after the reaction was completed, filtered, the filter cake was washed with a large amount of methanol, the filtrate was concentrated by rotary evaporation, 30 mL of saturated sodium carbonate solution and 30 mL of dichloromethane were added, stirred and allowed to separate liquids, and the aqueous phase was Extract with dichloromethane, combine the organic phases and dry. Filtration, rotary evaporation, the crude product was purified by silica gel column (eluent: DCM:MeOH=10 / 1+1%Et 3 N V / V) The target compound of Example 1 was obtained as a white solid 0.3 g with a yield of ...

preparation example 2

[0186] Synthesis of Intermediate 27:

[0187]

[0188] 2.0g (12mmol) of intermediate 26 was dissolved in 20mL of methanol, cooled to 0°C, 2.6mL (36mmol) of thionyl chloride was added dropwise, raised to room temperature, and stirred overnight. TLC detection, after the reaction, add saturated sodium bicarbonate to the reaction system to adjust the pH = 8, spin dry methanol, extract the aqueous phase with dichloromethane, combine the organic phase, dry, spin dry to obtain the product 1.9g white solid, yield 81.67 %.

[0189] Synthesis of Intermediate 28:

[0190]

[0191] Under nitrogen protection, 1.911g (9.8mmol) of intermediate 27 was dissolved in 7g (118.7mmol) of 85% hydrazine hydrate, heated to 85°C, and reacted for 7 hours. TLC detection, after the reaction, cooled to room temperature, filtered, and drained The product 1.728 g white solid was obtained, and the yield was 81.67%.

[0192] Synthesis of Intermediate 29:

[0193]

[0194] Dissolve 1.0g (2.84mmol) ...

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PUM

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Abstract

Belonging to the field of medicine, the invention in particular relates to an amino alcohol derivative shown as formula I, a pharmaceutically acceptable salt, a solvate, a polymorph or a prodrug thereof. In addition, the invention also relates to a pharmaceutical composition containing the above substances and use of the substances in preparation of drugs for preventing and treating immune inflammation or immune activity related diseases or illnesses, like multiple sclerosis, amyotrophic lateral sclerosis, CIDP, systemic lupus erythematosus, rheumatoid arthritis, ulcerative colitis, psoriasis,polymyositis, etc.

Description

technical field [0001] The application belongs to the field of medicine, and specifically relates to aminoalcohol derivatives, pharmaceutical compositions and uses thereof. Background technique [0002] The immune system is a defensive structure for the body to protect itself. It is mainly composed of lymphoid organs (thymus, lymph nodes, spleen, tonsils), lymphoid tissues in other organs, lymphocytes and antigen-presenting cells throughout the body, as well as other organs in the blood. Plasma cells and mast cells in white blood cells and connective tissue. The core component of the immune system is lymphocytes, which enable the immune system to have the ability to recognize and remember. Lymphocytes travel around the body through blood and lymph. Tissues to another lymphoid organ or lymphoid tissue, so that the scattered lymphoid organs and lymphoid tissues can be integrated into a functional whole. T cells and B cells are the most important immune cells in the body. The...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D271/107C07D413/04A61K31/4245A61P37/02A61P29/00A61P17/00A61P17/06A61P19/02A61P1/04A61P21/00A61P3/10A61P21/04A61P5/16A61P25/00
CPCC07D271/107C07D413/04A61K31/4245A61P1/04A61P3/10A61P5/16A61P17/00A61P17/06A61P19/02A61P21/00A61P21/04A61P25/00A61P29/00A61P37/02A61P37/06A61K45/06C07D271/06
Inventor 季奇张兴民杜镇建巩龙龙王磊高聪敏杜美静
Owner FORELAND PHARM CO LTD
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