Toddacoumalone compound or pharmaceutically acceptable salt and preparation method and application thereof

A compound and pharmaceutical technology, applied in the fields of organic chemistry, organic chemistry, pharmaceutical formulations, etc., can solve problems such as synthesis that have not been reported in the literature, and achieve the effects of high yield and short reaction steps.

Active Publication Date: 2019-11-05
SUN YAT SEN UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

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  • Toddacoumalone compound or pharmaceutically acceptable salt and preparation method and application thereof
  • Toddacoumalone compound or pharmaceutically acceptable salt and preparation method and application thereof
  • Toddacoumalone compound or pharmaceutically acceptable salt and preparation method and application thereof

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Embodiment 1

[0065] The preparation of embodiment 1 compound F1

[0066] 1, the preparation of intermediate product (B1): with quinolinone A1 (5mmol, 1eq) and aldehyde G1 (6mmol, 1.2eq) as substrate (the specific structure of substrate is shown in Table 1), with pyridine as base and solvent ( 10 mL), refluxed at 100°C for 3 hours, cooled, concentrated, then washed with dilute hydrochloric acid to remove residual pyridine, then washed the organic phase twice with saturated brine, combined the organic phases, dried over anhydrous sodium sulfate, concentrated, and The residue was separated by column chromatography to obtain the intermediate product (B1) with a yield of 79%. The characterization data of above-mentioned intermediate product (B1) is:

[0067] 1 H NMR (400MHz, CDCl 3 )δ=10.76(s,1H),7.89(dd,J=8.0,0.8Hz,1H),7.50-7.44(m,1H),7.28(s,1H),7.23–7.16(m,1H),6.75 (d,J=10.0Hz,1H),5.55(d,J=10.0Hz,1H),1.63(s,6H). 13 C NMR (100MHz, CDCl 3 ) δ = 162.80, 157.23, 138.02, 130.77, 126.15, 122....

Embodiment 2

[0075] The preparation of embodiment 2 compound F2

[0076] 1, the preparation of intermediate product (B2)

[0077] It was prepared according to the method for preparing intermediate product B1 in Example 1, except that the substrates were quinolinone A2 and aldehyde G1 (see Table 1 for the specific structure of the substrate), and the yield was 87%. Its characterization data are:

[0078] 1 H NMR (400MHz, CDCl 3)δ=7.97(d, J=8.0Hz, 1H), 7.59–7.51(m, 1H), 7.32(d, J=8.4Hz, 1H), 7.23(t, J=7.6Hz, 1H), 6.76( d,J=10.0Hz,1H),5.54(d,J=10.0Hz,1H),3.70(s,3H),1.52(s,6H). 13 C NMR (100MHz, CDCl 3 )δ=161.01, 155.18, 139.37, 130.84, 126.33, 123.13, 121.69, 117.99, 116.11, 114.00, 105.88, 78.74, 29.26, 28.23.

[0079] 2. Preparation of intermediate product (D2)

[0080] According to the method for preparing intermediate product D1 in Example 1, the yield was 65%. Its characterization data are:

[0081] 1 H NMR (400MHz, CDCl 3 )δ=7.91(dd,J=8.0,1.2Hz,1H),7.57-7.52(m,1H),7.33(d,J=8....

Embodiment 3

[0089] The preparation of embodiment 3 compound F3

[0090] 1, the preparation of intermediate product (B3):

[0091] It was prepared according to the method for preparing intermediate product B1 in Example 1, except that the substrates were quinolinone A3 and aldehyde G1 (see Table 1 for the specific structure of the substrate), and the yield was 75%. Its characterization data are:

[0092] 1 H NMR (400MHz, CDCl 3 )δ=7.97(d, J=8.0Hz, 1H), 7.59–7.51(m, 1H), 7.23(t, J=7.6Hz, 1H), 6.76(d, J=10.0Hz, 1H), 5.54( d,J=10.0Hz,1H),3.70(s,3H),1.52(s,6H). 13 CNMR (100MHz, CDCl 3 )δ=161.01, 155.18, 130.84, 126.33, 123.13, 121.69, 117.99, 116.11, 114.00, 105.88, 78.74, 29.26, 28.23.

[0093] 2. Preparation of intermediate product (D3):

[0094] According to the method for preparing intermediate product D1 in Example 1, the yield was 62%. Its characterization data are:

[0095] 1 H NMR (400MHz, CDCl 3 )δ=7.91(dd,J=8.0,1.2Hz,1H),7.57-7.52(m,1H),7.26–7.19(m,1H),5.09–5.01(m,1H),3.98...

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Abstract

The invention belongs to the technical field of pharmaceutical chemistry, and discloses a Toddacoumalone compound or a pharmaceutically acceptable salt and a preparation method and application thereof. The general formula of the molecular structure of the Toddacoumalone compound is shown in the formula I or the formula II or formula II. The provided Toddacoumalone compound has good anti-phosphodiesterase 4 activity. According to the preparation method of the Toddacoumalone compound, a simple and easy-to-obtain quinolinone substrate and an aldehyde compound are used as raw materials, the reaction step is short, and the yield is relatively high. The preparation method has the advantages that the reaction substrate is easy to obtain, a catalytic system is simple, operation is simple, the functional group tolerance is good, the compound is economical and effective and the product structure is diversified and has very important academic value and further application and popularization significance.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and in particular relates to a Toddacoumalone compound or a pharmaceutically acceptable salt thereof and a preparation method and application thereof. Background technique [0002] Phosphodiesterases (PDEs) are composed of 11 isozyme families (PDE1-PDE11) with different characteristics, which can regulate the cellular levels of the secondary signaling messengers cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) (Pharmacol. Rev. 2006, 58, 488-520). Phosphodiesterase-4 specifically hydrolyzes cyclic AMP and is an important target in a variety of pulmonary, dermatological, and severe neurological diseases. Recently, phosphodiesterase-4 inhibitors Roflumilast, Apremilast, and Crisaborole were approved by the FDA for the treatment of chronic obstructive pulmonary disease, psoriatic arthritis, and atopic dermatitis, respectively. However, most PDE4 inhibitors...

Claims

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Application Information

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IPC IPC(8): C07D491/052C07D491/147C07D491/16A61K31/4375A61K31/436A61P11/00A61P17/06A61P19/02A61P17/00A61P37/08
CPCA61P11/00A61P17/00A61P17/06A61P19/02A61P37/08C07B2200/07C07D491/052C07D491/147C07D491/16
Inventor 熊小峰侯克强陈雪萍黄俊翔
Owner SUN YAT SEN UNIV
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