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Phosphoric acid or phosphate derivatives, preparation method and medical application thereof

A compound, selected technology, applied in the field of metabolic related disorders and diseases, which can solve problems such as unsatisfactory

Active Publication Date: 2021-03-30
SHANGHAI CAERULUM PHARM DISCOVERY +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although the research and application of ACC inhibitors have made staged progress, the existing technology is still unsatisfactory. The compound firsocostat (ND-630) mentioned above also needs to be combined with other target compounds such as cilofexor (GS- 9674) and so on

Method used

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  • Phosphoric acid or phosphate derivatives, preparation method and medical application thereof
  • Phosphoric acid or phosphate derivatives, preparation method and medical application thereof
  • Phosphoric acid or phosphate derivatives, preparation method and medical application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0083] (R)-[2-[1-[2-(2-methoxyphenyl)-2-[(tetrahydro-2H-pyran-4--yl)oxy]ethyl]-5-methyl Base-6-(oxazol-2-yl)-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl]-2-methyl Propionyl] diethyl phosphate (compound 1)

[0084] Diethyl

[0085] (R)-(2-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-5-methyl-6-(oxazol-2-yl )-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)-2-methylpropanoyl)phosphonate(1)

[0086]

[0087] first step:

[0088] (R)-2-[1-[2-(2-methoxyphenyl)-2-[(tetrahydro-2H-pyran-4-yl)oxy]ethyl]-5-methyl- 6-(oxazol-2-yl)-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl]-2-methylpropionyl chloride (Compound 1B)

[0089] (R)-2-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-5-methyl-6-(oxazol-2-yl) -2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)-2-methylpropanoyl chloride(1B)

[0090] Compound (R)-2-[1-[2-(2-methoxyphenyl)-2-[(tetrahydro-2H-pyran-4-yl)oxy]ethyl]-5-methyl Base-6-(oxazol-2-yl)-2,4-dioxo-1,4-dih...

Embodiment 2

[0100] (R)-[2-[1-[2-(2-methoxyphenyl)-2-[(tetrahydro-2H-pyran-4--yl)oxy]ethyl]-5-methyl Base-6-(oxazol-2-yl)-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl]-2-methyl propionyl]phosphate (compound 2)

[0101] (R)-(2-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-5-methyl-6-(oxazol-2-yl )-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)-2-methylpropanoyl)phosphonic acid(2)

[0102]

[0103] Compound 1 (70 mg, 0.1 mmol) was dissolved in 2 mL of acetonitrile, trimethylbromosilane (47 mg, 0.3 mmol) was added dropwise, and reacted at 65° C. for 2 hours. After the reaction was completed, it was concentrated under reduced pressure to obtain compound 2 as a light yellow solid (60 mg, 0.1 mmol, yield 99%).

[0104] 1 H NMR (400MHz, d6-DMSO): δ8.26(s, 1H), 7.50(dd, J=7.6, 1.6Hz, 1H), 7.41(s, 1H), 7.31(t, J=7.2Hz, 1H ),6.95–7.05(m,2H),5.26-5.30(m,1H),4.11–4.23(m,2H),3.86(s,3H),3.35-3.75(m,5H),3.20-3.30(m ,2H),2.85(s,3H),1.68-1.83(m,8H),1.31-1.52(m,2H)....

Embodiment 3

[0108] [2-[1-[(R)-2-(2-methoxyphenyl)-2-[(tetrahydro-2H-pyran-4-yl)oxy]ethyl]-5-methyl -6-(oxazol-2-yl)-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl]-2-methylpropane Acyl] ethyl methyl phosphate (compound 3)

[0109] Ethyl

[0110] (2-(1-((R)-2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-5-methyl-6-(oxazol-2-yl )-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)-2-methylpropanoyl)(methyl)phosphinate(3)

[0111]

[0112] Compound 1B (2.06g, 3.5mmol) was dissolved in 20ml of dichloromethane, diethyl methylphosphonite (0.96g, 7.0mmol) was slowly added dropwise at 10°C, reacted overnight at room temperature, concentrated under reduced pressure, and the residue The product was separated and purified by silica gel column chromatography (eluent: system B). Compound 3 was obtained as a white solid (1.3 g, 2.0 mmol, yield 56%).

[0113] 1 H NMR (400MHz, CDCl 3 ):δ7.71(s,1H),7.59(dd,J=7.6,1.2Hz,1H),7.26-7.30(m,1H),7.22(s,1H),7.03–7.04(m,1H), 6.85-6.9...

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Abstract

The invention relates to phosphoric acid or phosphate derivatives, and a preparation method and medical application thereof. Specifically, the present invention relates to phosphoric acid or phosphatederivatives represented by a general formula (I), a preparation method therefor, pharmaceutically acceptable salts thereof, and uses of the derivatives and salts as therapeutic agents, especially inthe treatment of metabolic-related disorders and diseases such as non-alcoholic fatty liver disease, wherein the definition of each substituent in the general formula (I) is the same as the definitionin the specification.

Description

technical field [0001] The 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-related disorders and diseases such as alcoholic fatty liver. Background technique [0002] Acetyl-CoA carboxylase (ACC) is a biotin carboxylase and the rate-limiting enzyme in fatty acid synthesis and metabolism. It catalyzes the ATP-dependent condensation of acetyl-CoA (acetyl-CoA) and carbonate to generate malonyl-CoA (malonyl-CoA), thereby providing substrates for subsequent fatty acid synthesis or regulating fatty acid oxidation signals. [0003] In humans and other mammals, this enzyme has tissue specificity, and there are two isoforms, ACC1 and ACC2, which are encoded and expressed by two genes, ACACA and ACACB, respectively. There are differences in tissue distribution and function: ACC1 is a cytoplasmi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/6561A61K31/675A61P35/00A61P31/10A61P31/04A61P33/00A61P3/00A61P3/04A61P3/06A61P1/16A61P3/10
CPCA61P1/16A61P3/00A61P3/04A61P3/06A61P3/10A61P31/04A61P31/10A61P33/00A61P35/00C07F9/6561
Inventor 林其先宫爱申盛首一宋俊梁旭锋
Owner SHANGHAI CAERULUM PHARM DISCOVERY
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