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Pyrrolopyrimidine compounds as TLR7 agonists

A compound, selected technology, applied in the field of the compound represented by the formula or its pharmaceutically acceptable salt, can solve problems such as side effects

Inactive Publication Date: 2016-03-02
CHIA TAI TIANQING PHARMA GRP CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Interferon α is one of the main drugs for the treatment of chronic hepatitis B or C, while TNF-α is a pro-inflammatory cytokine, excessive secretion may lead to serious side effects

Method used

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  • Pyrrolopyrimidine compounds as TLR7 agonists
  • Pyrrolopyrimidine compounds as TLR7 agonists
  • Pyrrolopyrimidine compounds as TLR7 agonists

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0098] 2-Butoxy-7-(3-((4-methylpiperazin-1-yl)methyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine

[0099]

[0100] Reaction flow:

[0101]

[0102] Example 1 process

[0103]Step A: 2,4-dichloro-5H-pyrrolo[3,2-d]pyrimidine (4 g, 21.4 mmol) was dissolved in anhydrous THF (30 mL) and sodium hydride ( 1.03 g, 60% mineral oil mixture, 25.6 mmol). The reaction solution was stirred at room temperature for 30 minutes, and (2-(chloromethoxy)ethyl)trimethylsilane (3.9 g, 23.5 mmol) was added dropwise. Stir at room temperature for another 2 hours, then, dilute with water (120 mL) and extract with ethyl acetate (100 mL x 2). The combined organic layers were washed with saturated aqueous sodium carbonate and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column (eluent: ethyl acetate / petroleum ether 5% to 10%) to give 2,4-dichloro-5-((2-(trimethylsilyl)ethoxy) Methyl)-5hydro-pyrrolo[3,2-d]pyrimidine (5....

Embodiment 2

[0119] 2-Butoxy-7-(3-(morpholinomethyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine

[0120]

[0121] Step A: (4-Amino-2-butoxy-5-((2-(trimethylsilyl)ethoxy)methyl)-5hydro-pyrrolo[3,2-d]pyrimidine- 7-yl)(3-(morpholinomethyl)phenyl)methanol was prepared according to Example 1, step F in which morpholine was substituted for 1-methylpiperazine.

[0122] LCMS(ESI)m / z:542[M+H + ].

[0123] Step B: According to the method used in Example 1, step G, 2-butoxy-7-(3-(morpholinomethyl)benzyl)-5hydro-pyrrolo[3,2-d] was prepared Pyrimidin-4-amine formate.

[0124] 1 HNMR (Methanol–d4, 400MHz): δ8.41(s, 2H), 7.35-7.24(m, 5H), 4.49(t, J=6.8Hz, 2H), 4.03(s, 2H), 3.82(s, 2H),3.77-3.75(m,4H),2.77-2.73(m,4H),1.83-1.79(m,2H),1.55-1.49(m,2H),1.01(t,J=6.8Hz,3H) .

[0125] MS(ESI)m / z:396[M+H + ].

Embodiment 3

[0127] 7-(3-(Aminomethyl)benzyl)-2-butoxy-5H-pyrrolo[3,2-d]pyrimidin-4-amine

[0128]

[0129] Step A: (4-Amino-2-butoxy-5-((2-(trimethylsilyl)ethoxy)methyl)-5hydro-pyrrolo[3,2-d]pyrimidine- 7-yl)(3-(aminomethyl)phenyl)methanol was prepared according to Example 1, step F in which ammonium acetate was substituted for 1-methylpiperazine.

[0130] LCMS(ESI)m / z:472[M+H + ].

[0131] Step B: 7-(3-(aminomethyl)benzyl)-2-butoxy-5hydro-pyrrolo[3,2-d]pyrimidin-4-amine was used in step G according to Example 1 method of preparation.

[0132] 1 HNMR (Methanol–d4, 400MHz): δ7.31-7.15(m, 4H), 7.06(s, 1H), 4.32(t, J=6.6Hz, 2H), 4.00(s, 2H), 3.80(s, 2H), 1.79-1.73 (m, 2H), 1.56-1.50 (m, 2H), 1.01 (t, J=7.4Hz, 3H).

[0133] MS(ESI)m / z:326[M+H + ].

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Abstract

The invention relates to pyrrolopyrimidine compounds as TLR7 agonists, and particularly relates to compounds of the formula (I) or pharmaceutically acceptable salts thereof, a preparing method of the compounds, pharmaceutical compositions containing the compounds or the salts, and uses of the compounds or the salts for preparation of antivirus medicines. The formula (I) is shown in the specification.

Description

technical field [0001] The present invention relates to a novel pyrrolopyrimidine ring compound or a pharmaceutically acceptable salt thereof as a TLR7 agonist, in particular to a compound represented by formula (I) or a pharmaceutically acceptable salt thereof. Background technique [0002] Toll-like receptors are expressed on a variety of immune cells. Toll-like receptors recognize highly conserved structural motifs: pathogen-associated microbial patterns (PAMPs) expressed by microbial pathogens or damage-associated molecular patterns (DAMPs) released by necrotic cells. Stimulation of Toll-like receptors via the corresponding pathogen-associated microbial patterns (PAMPs) or damage-associated molecular patterns (DAMPs) initiates signaling cascades leading to activation of transcription factors such as AP-1, NF-κB and interferon regulators (impulse response functions) activation. This results in a variety of cellular responses, including the production of interferons, pro...

Claims

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Application Information

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IPC IPC(8): C07D487/04C07D519/00A61K31/519A61K31/5377A61K31/551A61P31/12A61P31/14A61P31/20
Inventor 丁照中吴颢孙飞吴立方杨玲
Owner CHIA TAI TIANQING PHARMA GRP CO LTD
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