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Xanthine derivatives, their preparation methods and uses

A technology of xanthine and derivatives, applied in the field of medicine, can solve the problems of weakening the activity of T cells and affecting the immune function of the body

Active Publication Date: 2016-12-21
QILU PHARMA HAINAN
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Inhibition of human DPP-8 and DPP-9 may weaken the activity of T cells and affect the immune function of the body

Method used

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  • Xanthine derivatives, their preparation methods and uses
  • Xanthine derivatives, their preparation methods and uses
  • Xanthine derivatives, their preparation methods and uses

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0145] Example 1: 1-[(4,5-dihydrocyclopenta[de]quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)- Preparation of 8-(3-(R)-aminopiperidin-1-yl)xanthine (compound 1)

[0146] (1) Preparation of 3-methyl-7-(2-butyn-1-yl)-8-bromoxanthine

[0147]

[0148] At room temperature, 8-bromo-3-methyl-3,7-dihydro-purine-2,6-dione (24.5g, 100mmol) was suspended in 150mL N,N-dimethylformamide (abbreviated For: DMF), diisopropylethylamine (27mL, 150mmol) was added, mechanically stirred for 10 minutes, and then N,N-dimethyl Formamide solution (50 mL), after the dropwise addition, was stirred at room temperature for 10-12 hours. After the reaction was completed, the reaction solution was poured into ice water, stirred to precipitate a solid, filtered with suction, and dried in vacuo to obtain 25 g of a light yellow solid with a yield of 84.1%. ES-API(m / z):[M+H] + 297.0, 299.0.

[0149] (2) Preparation of 3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert-butoxycarbonylamino)piperidin-1-yl]xanthin...

Embodiment 2

[0174] Example 2: 1-[(4,5-dihydrocyclopenta[de]quinazolin-2-yl)methyl]-3-methyl-7-(3-methyl-2-butane Preparation of en-1-yl)-8-(3-(R)-aminopiperidin-1-yl)xanthine (compound 2)

[0175] (1) Preparation of 3-methyl-7-(3-methyl-2-buten-1-yl)-8-bromoxanthine

[0176]

[0177] At room temperature, 8-bromo-3-methyl-3,7-dihydro-purine-2,6-dione (24.5g, 100mmol) was suspended in 150mL N,N-dimethylformamide (abbreviated as: DMF), then added diisopropylethylamine (27mL, 150mmol), mechanically stirred for 10 minutes, then added dropwise 1-bromo-3-methyl-2-butene (16.5g, 110mmol) in N, 50 mL of N-dimethylformamide solution, after the dropwise addition, stirred at room temperature for 10-12 hours. After the reaction was completed, the reaction solution was poured into 300 ml of ice water to precipitate a solid, filtered by suction, and dried in vacuo to obtain 28.5 g of a light yellow solid, with a yield of 91.1%. ES-API(m / z):[M+H] + 313.0, 315.0.

[0178] (2) 3-methyl-7-(3-meth...

Embodiment 3

[0190] Example 3: 1-[(5,6,7,8-tetrahydro-4-methylquinazolin-2-yl)methyl]-3-methyl-7-(2-butyne-1- Base)-8-(3-(R)-aminopiperidin-1-yl)xanthine (compound 3)

[0191] (1) Preparation of 2-chloromethyl-5,6,7,8-tetrahydro-4-methylquinazoline (intermediate II(A)-1)

[0192]

[0193] Intermediate II(A)-1

[0194] 2-Acetylcyclohexanone (2.8g, 20mmol), potassium carbonate (4.1g, 30mmol) and chloroacetamidine hydrochloride (2.8g, 22mmol) were added to 30mL of n-butanol, and stirred under reflux for 5 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and the residue was poured into 50 mL of water, extracted with ethyl acetate (30 mL, extracted 3 times), the organic phases were combined, washed once with 30 mL of saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure A yellow solid was obtained, which was purified by column chromatography (eluent: petroleum ether / ethyl acetate=9:1) to obt...

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Abstract

The present invention relates to a class of xanthine derivatives, pharmaceutically acceptable salts thereof, solvates of said derivatives, solvates of pharmaceutically acceptable salts, chemically protected forms or prodrugs thereof, and preparation methods thereof and Use; also relates to the intermediate compound used to prepare the xanthine derivative and the preparation method of the intermediate compound. The xanthine derivatives and pharmaceutical compositions thereof can effectively inhibit the activity of DPP-IV, and can be used to prepare medicines for diseases related to dipeptidyl peptidase (DPP-IV).

Description

technical field [0001] The invention belongs to the technical field of medicine, and specifically relates to a new class of xanthine derivatives, a preparation method and application thereof, and also relates to an intermediate compound used to prepare the xanthine derivative and a preparation method of the intermediate compound. The xanthine derivative and the pharmaceutical composition thereof can effectively inhibit the activity of dipeptidyl peptidase (DPP-IV), and can be used to prepare medicines for preventing or treating diseases related to DPP-IV. Background technique [0002] Dipeptidyl peptidase (Dipeptidyl peptidase) can be divided into I, III, IV, 6, 7, 8, 9, 10 and other types. [0003] Dipeptidyl peptidase-8 (DPP-8) belongs to a member of peptidase SB9 and is a small family of dipeptidyl peptidases. The protein gene encoded by it is similar to the highly expressed dipeptidyl peptidase-IV (Dipeptidylpeptidase-IV, DPP-IV), and the hydrolysis substrate is also th...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D473/04C07D519/00A61K31/522A61P3/10A61P3/04A61P5/50A61P9/10A61P9/00
CPCC07D239/70C07D239/74C07D473/04C07D491/048C07D495/04C07D519/00A61K31/522A61P3/04A61P3/10A61P5/50A61P9/00A61P9/10
Inventor 陈栋范传文何绪军程哲李成龙
Owner QILU PHARMA HAINAN
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