A kind of toddacoumalone compound or its pharmaceutically acceptable salt and its preparation method and application

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

Active Publication Date: 2020-10-23
SUN YAT SEN UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

At present, there is no literature report on the synthesis of such compounds

Method used

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  • A kind of toddacoumalone compound or its pharmaceutically acceptable salt and its preparation method and application
  • A kind of toddacoumalone compound or its pharmaceutically acceptable salt and its preparation method and application
  • A kind of toddacoumalone compound or its pharmaceutically acceptable salt and its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0065] Example 1 Preparation of Compound F1

[0066] 1. Preparation of intermediate product (B1): quinolinone A1 (5mmol, 1eq) and aldehyde G1 (6mmol, 1.2eq) as substrates (see Table 1 for the specific structure of the substrate), and pyridine as base and solvent ( 10mL), reflux at 100°C for 3 hours, cool and concentrate, then wash away residual pyridine with dilute hydrochloric acid, and then wash the organic phase twice with saturated brine. Combine the organic phases, dry over anhydrous sodium sulfate, and concentrate. The residue was separated by column chromatography to obtain the intermediate product (B1) with a yield of 79%. The characterization data of the above 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=162.80,157.23,138.02,130.77,126.15,122.51,122.07,117.21,116.06,115.27,105.70,79.05,28.34.

[...

Embodiment 2

[0075] Example 2 Preparation of Compound F2

[0076] 1. Preparation of intermediate product (B2)

[0077] It was prepared according to the method of 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%. The 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] The preparation was carried out according to the method for preparing intermediate product D1 in Example 1, and the yield was 65%. The 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] Example 3 Preparation of Compound F3

[0090] 1. Preparation of intermediate product (B3):

[0091] The intermediate product B1 was prepared according to the method of 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%. The 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] It was prepared according to the method for preparing intermediate product D1 in Example 1, and the yield was 62%. The 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(t,J= 6.4Hz, 2H), 3.74 (dd, J = ...

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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 particularly relates to a Toddacoumalone compound or a pharmaceutically acceptable salt thereof, and a preparation method and application thereof. Background technique [0002] Phosphodiesterase (PDEs) consists of 11 isoenzyme families (PDE1-PDE11) with various characteristics, which can regulate the cellular levels of secondary signal messengers cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) (Pharmacol. Rev. 2006, 58, 488-520). Phosphodiesterase-4 can specifically hydrolyze cyclic adenosine monophosphate, and is an important target for a variety of lung, dermatological and severe neurological diseases. Recently, the phosphodiesterase-4 inhibitors Roflumilast, Apremilast, and Crisaborole were approved by the FDA for the treatment of chronic obstructive pulmonary disease, psoriatic arthritis and allergic dermatitis. However, most PDE4 inhibitors in cli...

Claims

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Application Information

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Patent Type & Authority Patents(China)
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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