Indoleamine-2,3-dioxygenase inhibitor as well as preparation method and application thereof

A C3-C8, solvate technology, applied in the field of medicinal chemistry, can solve the problems of drug metabolism stability and toxicity, and achieve the effect of metabolic stability

Pending Publication Date: 2019-07-09
HINOVA PHARM INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition, INCB-24360, a series of oral small molecule inhibitors of IDO being developed by Incyte, is also undergoing phase III clinical trials, m...

Method used

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  • Indoleamine-2,3-dioxygenase inhibitor as well as preparation method and application thereof
  • Indoleamine-2,3-dioxygenase inhibitor as well as preparation method and application thereof
  • Indoleamine-2,3-dioxygenase inhibitor as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] Example 1, cis-N-(3-bromo-4-fluorophenyl)-N'-hydroxy-4-(((-3-(sulfonamide)cyclobutyl)methyl)amino)-1,2 , Synthesis of 5-oxadiazole-3-amidine (compound 83)

[0047]

[0048] Compound 3-(dibenzylamino)cyclobutylcarboxylate methyl ester 83c was synthesized by literature method (WO 2015039348A1). 1. Synthesis of compound 3-oxocyclobutyl carboxylate methyl ester (83b)

[0049] Under the protection of nitrogen, the raw material compound 83a (4.0g, 35.1mmol) was dissolved in 40mL of dichloromethane and 5mL of methanol, and 2M TMSCHN was added dropwise under an ice-water bath. 2 (30 mL, 59.6 mmol). Stir in an ice-water bath for 2h. 1 mL of glacial acetic acid was added dropwise to quench the reaction, the solvent was spin-dried, and purified by silica gel column to obtain compound 3-oxocyclobutylcarboxylate methyl ester (83b) (4.4 g, 34.3 mmol), yield: 96.7%.

[0050] 2. Synthesis of compound 3-(dibenzylamino)cyclobutylcarboxylic acid methyl ester (83c)

[0051] The com...

Embodiment 2

[0071] Example 2, cis-4-(((-3-aminocyclobutyl)methyl)amino)-N-(3-bromo-4-fluorophenyl)-N'-hydroxyl-1,2,5- Synthesis of Oxadiazole-3-amidine (Compound 82)

[0072]

[0073] Compound cis-tert-butyl-3-(((4-(4-(3-bromo-4-fluorophenyl)-5-carbonyl-4,5-dihydro-1,2,4-oxadiazole -3-yl)-1,2,5-oxadiazol-3-yl)amino)methyl)cyclobutyl)formamide (83k) (40.0mg, 0.073mmol) was dissolved in 2.0mL methanol, added 2.5 N sodium hydroxide 1mL, stirred at room temperature for 1h. Ethyl acetate and water were added to extract. The organic layer was washed twice with brine, dried, and spin-dried to obtain 35 mg of a foamy solid. The foamy solid was added to 2.0 mL of TFA and 1.0 mL of dichloromethane, and stirred at room temperature for 1 h. The solvent was spin-dried, and extracted with water and dichloromethane. Take the water layer, adjust the pH to 8-9, add dichloromethane for extraction, dry the organic layer, and spin dry. The compound cis-4-(((-3-aminocyclobutyl)methyl)amino)-N-(3-brom...

Embodiment 3

[0076] Example 3, HC-2507-01: N-(3-bromo-4-fluorophenyl)-N'-hydroxyl-4-((((1s,3s)-3-hydroxycyclobutyl)methyl) Synthesis of Amino)-1,2,5-oxadiazole-3-amidine (Compound 90)

[0077]

[0078] 1. Synthesis of N-phenyl-3-oxocyclobutylformamide (90a)

[0079] Under nitrogen protection, 3-oxocyclobutylcarboxylic acid (83a) (5.0g, 43.8mmol), benzylamine (7.4g, 57.0mmol) and HATU (16.0g, 48.0mmol) were dissolved in 200mL DMF, added dropwise Diisopropylamine (11.7 g, 109.0 mmol). Stir at room temperature for 3h. Extracted with ethyl acetate and saturated water, the organic layer was washed twice with saturated brine, dried, spin-dried, and purified by silica gel column chromatography. N-phenyl-3-oxocyclobutylcarboxamide (90a) (4.5 g, 22.1 mmol) was obtained, yield: 50.5%. MS (ESI) m / e 204.3 (M+H)+.

[0080] 2, Synthesis of 3-((benzylamino)methyl)cyclobutanol (90b)

[0081] N-Phenyl-3-oxocyclobutylcarboxamide (90a) (4.5g, 22.1mmol) was dissolved in 150mL tetrahydrofuran, and lit...

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Abstract

The invention provides a compound as shown in a formula (I). The invention also relates to a pharmaceutical composition containing the compound of the formula (I) and application of the compound to preparation of an indoleamine-2,3-dioxygenase (IDO) inhibitor drug. The compound prepared by the method of the invention has an obvious inhibiting effect on IDO protease and is stable in metabolism in vivo. The compound or a pharmaceutical composition thereof provided by the invention can be used for preparing the IDO inhibitor drug, and can also be used for preparing medicines for preventing and/ortreating diseases with pathological characteristics of an IDO-mediated tryptophan metabolic pathway.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry and relates to an indoleamine-2,3-dioxygenase inhibitor and its preparation method and application. Background technique [0002] Malignant tumors are currently one of the major diseases that threaten human health and life. According to statistics from the National Health and Family Planning Commission, the incidence of tumors in mainland my country is about 235 / 100,000, and the mortality rate is about 144.3 / 100,000. [0003] Due to the unrestricted growth of malignant tumors in invasion and metastasis, the three conventional treatment methods (surgery, radiotherapy and chemotherapy) currently used in clinical practice cannot completely remove or completely kill tumor cells, so tumor metastasis or recurrence often occurs. Tumor biotherapy is a new treatment for tumor prevention and treatment using modern biotechnology and related products. Because of its safety, effectiveness, and low adverse re...

Claims

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Application Information

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IPC IPC(8): C07D271/08A61P35/00A61P25/28A61P37/06A61P25/22A61P25/24A61P27/12A61P25/00A61P31/18A61K31/4245
CPCA61P25/00A61P25/22A61P25/24A61P25/28A61P27/12A61P31/18A61P35/00A61P37/06C07B2200/07C07D271/08
Inventor 杜武温坤艾朝武何锦云李兴海陈元伟
Owner HINOVA PHARM INC
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