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Substituted pyrrole chromone compound

A pyrrole chromone and compound technology, applied in organic chemistry, drug combination, cardiovascular system diseases, etc., can solve problems such as adverse reactions, digestive disorders, and congestion in patients with liver and kidney insufficiency

Active Publication Date: 2013-05-01
SUN YAT SEN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Nevertheless, the existing PDE5A inhibitors have non-negligible side effects: such as headache, blurred vision, flushing, nasal congestion, digestive disorders, muscle pain, etc.
On the other hand, existing drugs may also cause serious adverse reactions to patients with severe hepatic and renal insufficiency

Method used

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  • Substituted pyrrole chromone compound
  • Substituted pyrrole chromone compound
  • Substituted pyrrole chromone compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050] 1mmol of 1-(thienyl-2-)-3-(2-hydroxy-5-methoxyphenyl)propane-1,3-dione (a1) was dissolved in 1.8mmol Fmoc-Tyr(tBu)-OH In 10ml of pyridine, add 2mmol N,N-dicyclohexyldiimine, add 0.6mmol N,N-lutidine, stir at room temperature for about 3h, until TLC detects that raw material a1 disappears, heat up to 50°C to react 4- 6h to produce a predominantly yellow dot. After the reaction was completely evaporated to dry pyridine, ethyl acetate was added, N,N-dicyclohexyl urea would precipitate out, suction filtered, and the filtrate was obtained by column chromatography P0-1 , yellow solid, yield is 77%, its structure and NMR data are as follows:

[0051]

[0052] 1 H NMR (400 MHz, DMSO) δ 12.35 (1H), 8.02 (d, J = 3.5 Hz, 1H), 7.57 (dd, J = 13.4, 3.9 Hz, 2H), 7.43 (d, J = 9.1 Hz, 1H), 7.31 (dd, J = 9.0, 3.0 Hz, 1H), 7.20 – 7.13 (m, 3H), 6.91 (d, J = 8.4 Hz, 2H), 4.11 (1H), 3.85 (3H), 1.25 (9H); 13 C NMR (101 MHz, CDCl 3 ) δ 175.34, 155.11, 154.23, 151.58, 142.37, 1...

Embodiment 2

[0057] 1 mmol 1-(4-fluorophenyl)-3-(2-hydroxy-5-methylphenyl)propane-1,3-dione (a2) with 1.8 mmol Fmoc-Tyr(tBu)-OH, 2 mmol N , N-dicyclohexyldiimine, 0.6mmol N, N-lutidine, according to the method of Example 1, to obtain P0-2 , a yellow solid, which was directly used in the next step of synthesis. The structure is as follows:

[0058]

[0059] compound P0-2 Process according to the method of embodiment 1, obtain P2 , yellow solid, yield 56%, its structure and NMR data are as follows:

[0060]

[0061] 1 H NMR (400 MHz, DMSO) δ 12.30 (1H), 9.20(1H), 8.13 (s, 2H), 7.94 (s, 1H), 7.51 (d, J = 8.2 Hz, 1H), 7.37 (d, J = 8.3 Hz, 1H), 7.30 (t, J = 8.3 Hz, 2H), 7.10 (d, J = 7.6 Hz, 2H), 6.70 (d, J = 7.7 Hz, 2H), 4.04(2H), 2.40(3H); 13 C NMR (101 MHz, DMSO) δ 174.17, 162.79, 160.34, 155.69, 154.21, 141.53, 134.87, 131.74, 129.86, 129.78, 129.58, 128.96×2, 127.56, 127.54, 126.09, 125.80, 121.54, 117.22, 115.18×2 , 115.07, 114.86, 113.50, 107.28, 28.43, 20.29.

Embodiment 3

[0063] 1 mmol of 1-(thienyl-2-)-3-(2-hydroxy-5-bromophenyl)propane-1,3-dione (a3) ​​with 1.8 mmol of Fmoc-Tyr(tBu)-OH, 2 mmol of N , N-dicyclohexyldiimine, 0.6mmol N, N-lutidine, according to the method of Example 1, obtained P0-3 , a yellow solid, which was directly used in the next step of synthesis. The structure is as follows:

[0064]

[0065] compound P0-3 Obtain according to the method of embodiment 1 P3 , yellow solid, yield 32%, its structure and NMR data are as follows:

[0066]

[0067] 1 H NMR (400 MHz, DMSO) δ 12.41 (1H), 9.21(1H), 8.20 (d, J = 2.4 Hz, 1H), 8.02 (d, J = 3.2 Hz, 1H), 7.84 (dd, J = 8.8, 2.4 Hz, 1H), 7.58 (d, J = 4.9 Hz, 1H), 7.45 (d, J = 8.9 Hz, 1H), 7.19 – 7.14 (m, 1H), 7.08 (d, J = 8.3 Hz, 2H), 6.70 (d, J = 8.3 Hz, 2H), 4.04 (2H); 13 C NMR (101 MHz, DMSO) δ 172.39, 155.73, 155.06, 140.87, 136.41, 132.88, 129.29, 128.94×2, 128.35, 127.37, 126.43, 123.59, 122.08, 120.11, 115.20×2, 114.71, 113.69, 106.51, 28.28 .

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Abstract

The invention relates to a substituted pyrrole chromone compound, which adopts the following structure: R1, R2, R3 and R4 are selected from hydrogen, halogen, C1-3 alkyl, C1-3 substituted alkyl, alkoxy, acyl, a carboxylic acid group, carboxylate radical, a nitrogen group, a phosphorous group or a sulfur group; R5 is selected from a substituted or non-substituted cyclic group; and R6 is selected from hydrogen or C1-3 alkyl, acyl, carboxylic acid group, carboxylate radical group, nitrogen group, phosphorous group or sulfur group. A type-5 phosphodiesterase inhibitor can be used for preparing medicine for curing diseases related to type-5 phosphodiesterase and is particularly suitable for preparing medicine for cuing male sexual dysfunction or pulmonary hypertension diseases.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a substituted pyrrole chromone compound. Background technique [0002] Cyclic nucleotide phosphodiesterases (PDEs) are an important family of super enzymes, which effectively control the concentration of cAMP and cGMP in cells by hydrolyzing cAMP and cGMP, thereby regulating the transmission of second messengers in vivo biochemical effect. PDEs are widely distributed in mammalian tissues, and their diversity leads to specific distribution of different PDE enzymes at the cellular and subcellular levels, which can selectively regulate a variety of cellular functions, and are good drug design and therapeutic targets. [0003] Phosphodiesterase type 5 (PDE5), as a cGMP-specific PDE family, was first isolated and confirmed in mouse platelets, and then also found and purified in mouse lungs. Human PDE5A is mainly distributed in aortic vascular smooth muscle cells, heart, placenta, ...

Claims

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Application Information

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IPC IPC(8): C07D491/052A61P15/10A61P25/28A61P35/00A61P9/00A61P9/12
Inventor 罗海彬卜宪章商娜娜蔡颖红邵咏贤何琳于艳君杜军李哲
Owner SUN YAT SEN UNIV
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