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Phosphoric acid or phosphate ester derivative as well as preparation method and medical application thereof

A technology for medicines and compounds, applied in the fields of phosphoric acid or phosphoric acid ester derivatives and their preparation and their use in medicine, can solve problems such as effectiveness, safety or selectivity

Pending Publication Date: 2022-07-19
SHANGHAI CAERULUM PHARM DISCOVERY +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Various compounds have been disclosed as possible agonists of THRβ, including WO0039077, WO2004067482, US6,344,481, US6787652, US20070173548, WO2006128058, WO2007009913, WO20080221210, WO2009089093, WO72009, etc. Drugs still have problems in terms of effectiveness, safety or selectivity, and it is still necessary to research and develop new small molecule selective THRβ agonists

Method used

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  • Phosphoric acid or phosphate ester derivative as well as preparation method and medical application thereof
  • Phosphoric acid or phosphate ester derivative as well as preparation method and medical application thereof
  • Phosphoric acid or phosphate ester derivative as well as preparation method and medical application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1 and Embodiment 2

[0063]

[0064] first step

[0065] (4-(4-(Benzyloxy)-3-isopropylbenzyl)-3,5-dimethylphenoxy)triisopropylsilane

[0066] At room temperature, (4-(benzyloxy)-3-isopropylphenyl)(2,6-dimethyl-4-((triisopropylsilyl)oxy)phenyl)methanol 1a ( Prepared by the well-known method "Journal of the American Chemical Society, 2006, vol.128, #27, p.8868-8874") 15.0 g (28.2 mmol) was dissolved in 100 mL of dichloromethane, and triethylsilane was added 8.9 mL (56.3 mmol), 320 mg (2.8 mmol) of trifluoroacetic acid, and reacted at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to obtain the title product 1b (13.8 g, yellow liquid), yield: 95.1%

[0067] 1 H NMR(400MHz, CHLOROFORM-d)δppm 1.09-1.15(m,18H)1.18(d,J=6.85Hz,6H)1.23-1.34(m,3H)2.19(s,6H)3.37(spt,J=6.89 Hz,1H)3.92(s,2H)5.03(s,2H)6.61(s,2H)6.65-6.72(m,1H)6.77(d,J=8.31Hz,1H)6.93(d,J=2.20Hz, 1...

Embodiment 3 and Embodiment 4

[0089]

[0090] first step

[0091] (4-(4-(Benzyloxy)-3-isopropylbenzyl)-3,5-dimethylphenoxy)triisopropylsilane

[0092] Using the synthetic route of the first step of Example 1 and Example 2, 3b was obtained.

[0093] second step

[0094] 4-(4-(Benzyloxy)-3-isopropylbenzyl)-3,5-dimethylphenol

[0095] Using the synthetic route of the second step of Example 1 and Example 2, 3c was obtained.

[0096] third step

[0097] Ethyl 2-(4-(4-(benzyloxy)-3-isopropylbenzyl)-3,5-dimethylphenoxy)-2-methylpropanoate

[0098] The synthetic route of Example 1 and Example 2 is adopted, except that the raw material ethyl bromoacetate in the third step of Example 1 and Example 2 is replaced with ethyl 2-bromoisobutyrate to obtain the title product 3d.

[0099] the fourth step

[0100] 2-(4-(4-(Benzyloxy)-3-isopropylbenzyl)-3,5-dimethylphenoxy)-2-methylpropionic acid

[0101] The synthetic route of Example 1 and Example 2 is adopted, except that the raw material 1d in the fourth step of...

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PUM

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Abstract

The invention relates to phosphoric acid or phosphate ester derivatives, a preparation method thereof and application of the phosphoric acid or phosphate ester derivatives in medicine. Specifically, the invention relates to phosphoric acid or phosphate ester derivatives as shown in a general formula (I), a preparation method and medicinal salts thereof, and application of the phosphoric acid or phosphate ester derivatives and the medicinal salts thereof as therapeutic agents. The compound is used for treating metabolic diseases such as obesity, NASH, hypercholesterolemia, hyperlipidemia, diabetes, cardiovascular diseases, hypothyroidism, thyroid cancer and related conditions and diseases. Wherein the definition of each substituent group in the general formula (I) is the same as that in the specification.

Description

technical field [0001] The present invention relates to a preparation method of phosphoric acid or phosphoric acid ester derivatives, a pharmaceutical composition containing the series of compounds and its use as a therapeutic agent, especially for the treatment of metabolic diseases such as obesity, NASH, hypercholesterolemia, hyperlipidemia , diabetes, cardiovascular disease, hypothyroidism, thyroid cancer and related conditions and diseases. Background technique [0002] Thyroid hormone (TH) is a thyroid stimulating hormone secreted in response to the pituitary gland and plays a key role in growth, development, metabolism and homeostasis. It plays an important role in normal development, differentiation, maintaining metabolic balance and controlling cholesterol levels by interacting with thyroid hormone receptor (THR). Triiodothyronine (T3, triiodothyronine) is an important component of thyroid hormone. 20% of triiodothyronine is produced by the thyroid itself, and 80% ...

Claims

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Application Information

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IPC IPC(8): C07F9/38A61K31/662A61P35/00A61P5/14A61P9/00A61P3/10A61P3/04A61P3/06A61P1/16
CPCC07F9/3891A61P35/00A61P5/14A61P9/00A61P3/10A61P3/04A61P3/06A61P1/16
Inventor 林其先吕文川李昀
Owner SHANGHAI CAERULUM PHARM DISCOVERY
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