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Xanthine compounds and their pharmaceutical compositions and applications

A compound, purine technology, applied in the field of medicine, can solve problems such as affecting drug efficacy and drug loss

Active Publication Date: 2020-01-17
GUIZHOU MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although its oral bioavailability in rats is 50.9%, the oral bioavailability of the human body is only 30%, which to some extent causes the loss of the drug and affects the full play of the drug effect

Method used

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  • Xanthine compounds and their pharmaceutical compositions and applications
  • Xanthine compounds and their pharmaceutical compositions and applications
  • Xanthine compounds and their pharmaceutical compositions and applications

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0142] Example 1: 8-[(3R)-3-amino-1-piperidinyl]-7-(2-butyn-1-yl)-3,7-dihydro-3-methyl-1-[ 1-(4-Methylquinazolin-2-yl)ethyl]-1H-purin-2,6-one

[0143] Step 1) Synthesis of Intermediate II

[0144] Add sodium (11.5g, 0.5mol) and absolute ethanol (250ml) to a 1L reaction flask, stir at room temperature for 1h, add methylurea (18.6g, 0.25mol) and ethyl cyanoacetate (26.5ml, 0.25mol) , heated to reflux for 6h. The reaction solution was cooled to room temperature, and ethanol was recovered under reduced pressure. Add distilled water (50ml) to dissolve, add dropwise 4mol / L hydrochloric acid to adjust to pH7, stir in an ice bath for 1h, filter to obtain a crude product, and recrystallize with water to obtain white crystals (31.7g, 90%), ESI-MS (m / z ):164.1[M+Na] + ,305.1[2M+Na] + ; 1 HNMR (400MHz, DMSO-d 6 ): δ (ppm) 10.31 (s, 1H), 6.76 (s, 2H), 4.55 (s, 1H), 3.17 (s, 3H).

[0145] Step 2) Synthesis of Intermediate III

[0146] Intermediate II (5g, 35.45mmol), distilled wate...

Embodiment 2

[0160] Example 2: 8-[(3R)-3-amino-1-piperidinyl]-7-(2-butyn-1-yl)-3,7-dihydro-3-methyl-1-[ 1-(4-Nitrophenyl)ethyl]-1H-purin-2,6-one

[0161] ESI-MS(m / z):466.1[M+H] + ,488.3[M+Na] + ,953.3[2M+Na] + ; 1 H-NMR (400MHz, CDCl 3 ): δ (ppm) 8.15 (d, J = 8.8Hz, 2H), 7.55 (d, J = 8.4Hz, 2H), 6.42 (q, J = 6.8Hz, 1H), 4.84 (s, 2H), 3.71 –3.63(m,1H),3.60–3.53(m,1H),3.43(s,3H),3.12–3.02(m,2H),2.93–2.83(m,1H),2.04–1.95(m,1H) ,1.90(d,J=6.8Hz,3H),1.82(s,3H),1.42(m,1H),1.40–1.22(m,1H),0.92–0.80(m,1H); 13 C-NMR (100MHz, CDCl 3 ): δ (ppm) 156.5, 154.1, 150.9, 149.0, 148.2, 146.6, 127.7, 123.3, 104.2, 81.5, 73.0, 58.1, 50.3, 47.3, 35.8, 33.4, 29.5, 26.9, 23.3, 22.6, 15.8, 14.1, 3.7.

Embodiment 3

[0162] Example 3: 8-[(3R)-3-amino-1-piperidinyl]-7-(2-butyn-1-yl)-3,7-dihydro-3-methyl-1-[ 1-(Phenylethyl)]-1H-purin-2,6-one ESI-MS(m / z):421.2[M+H] + ; 1 H-NMR (400MHz, CDCl 3 ):δ(ppm)7.51–7.10(m,5H),5.26(q,J=5.8Hz,1H),4.79(s,2H),4.34–4.25(m,1H),4.22–4.16(m,1H ),4.09(s,3H),3.95–3.83(m,2H),3.78–3.70(m,1H),3.09–3.00(m,1H),2.94(d,J=5.6Hz,3H),2.90( s,3H),2.86–2.79(m,1H),2.57–2.49(m,1H),2.18–2.09(m,1H); 13 CNMR (100MHz, CDCl 3 ): δ (ppm) 156.1, 154.3, 151.5, 147.6, 144.2, 128.4, 127.3, 126.1, 104.5, 81.3, 73.2, 68.4, 58.2, 50.5, 47.3, 41.1, 33.4, 29.6, 27.4, 24.9, 24.3, 23.3, 3.8.

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Abstract

The invention discloses a xanthine derivative as shown in the formula (I) and a pharmaceutical composition and application thereof. The xanthine derivative is prepared from a compound as shown in theformula (I) or a stereoisomer, a geometrical isomer, a hydrate or a solvate thereof, or a pharmaceutically acceptable salt or prodrug as shown in the description. The invention also relates to application of the compound as shown in the formula (I) and the pharmaceutical composition thereof as a DPP-4 inhibitor, and especially application in preparation of medicines for treating and / or preventingmetabolic disorder diseases such as diabetes.

Description

[0001] field of invention [0002] The present invention relates to the field of medical technology, in particular to xanthine derivatives and their stereoisomers, geometric isomers, hydrates, solvates, or pharmaceutically acceptable salts or prodrugs, and pharmaceutical combinations containing the compounds things. The present invention also relates to the use of the xanthine compounds described in the present invention as DPP-IV inhibitors, and also relates to the use of such compounds in the preparation of medicines for preventing and / or treating metabolic disorders such as diabetes. [0003] Background of the invention [0004] Diabetes mellitus (DM) is a metabolic disorder characterized by chronic hyperglycemia caused by multiple etiologies (genetic factors, mental factors, autoimmune dysfunction, microbial infection, free radical toxins, eating habits, age, etc.), It is a syndrome caused by the relative or absolute deficiency of insulin in the blood or the insensitivity ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D473/06C07D473/04C07D519/00A61K31/522A61P3/00A61P3/10
CPCC07D473/04C07D473/06C07D519/00
Inventor 廖伟科汤磊郑萍张毅王建塔
Owner GUIZHOU MEDICAL UNIV
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