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Substituted indolo azaketone compound and preparation method and application thereof

A technology for indoloazepinones and compounds, applied in the field of substituted indoloazepinones and their preparations, capable of solving problems such as adverse reactions, congestion, and digestive disorders in patients with liver and kidney insufficiency

Active Publication Date: 2020-09-15
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 side effects that cannot be ignored: 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 indolo azaketone compound and preparation method and application thereof
  • Substituted indolo azaketone compound and preparation method and application thereof
  • Substituted indolo azaketone compound and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0062] Example 1. Synthesis of Compound C1

[0063] (1) Synthesis of intermediate M1

[0064]

[0065] Under ice bath, sodium borohydride (57 mg, 1.5 mmol) was slowly added to 10 mL of 7-fluoro-3-(2-nitrovinyl)-1H-indole-4-carboxylic acid methyl ester (264 mg, 1.0 mmol) without Water tetrahydrofuran solution, then slowly drop into 3.0mL of methanol, and react for 1 hour under ice-bath conditions. After the reaction was completed, a saturated ammonium chloride solution was added to quench the reaction, the system was concentrated to remove most of the organic solvent, and then extracted with ethyl acetate, the organic phase was dried with anhydrous sodium sulfate, and separated by column chromatography to obtain intermediate M1 (165 mg). White solid, 62% yield. 1 H NMR (400MHz, CDCl 3 )δ8.56(s,1H),7.84(dd,J=8.4,5.2Hz,1H),7.25(d,J=2.5Hz,1H),6.95(dd,J=9.9,8.5Hz,1H), 4.73 (t, J = 6.5Hz, 2H), 3.96 (s, 3H), 3.71 (t, J = 6.5Hz, 2H).

[0066] (2) Synthesis of Intermediate M2 ...

Embodiment 2

[0075] Example 2. Synthesis of Compound C2

[0076] (1) Synthesis of Intermediate M4

[0077]

[0078] The raw material was replaced by M2 and reacted with 4-chlorobenzyl bromide, and the intermediate M4 was obtained as a white solid according to the method of Example 1, and the yield was 85%. 1 H NMR (400MHz, DMSO-d 6 )δ8.08(t, J=5.7Hz, 1H), 7.68(dd, J=8.4, 4.7Hz, 1H), 7.50(s, 1H), 7.38(d, J=8.4Hz, 2H), 7.15( d,J=8.4Hz,2H),7.01(dd,J=12.4,8.4Hz,1H),5.48(s,2H),3.40(dd,J=9.6,5.4Hz,2H),2.93(s,2H ).

[0079] (2) Synthesis of the final product C2

[0080]

[0081]The raw material was replaced by M4 and reacted in polyphosphoric acid, and the final product C2 was obtained as a white solid with a yield of 40% according to the method of Example 1. Purity: 97%. 1 H NMR (400MHz, DMSO-d 6 )δ11.69(s,1H),7.99(t,J=5.4Hz,1H),7.65(dd,J=8.3,4.8Hz,1H),7.34(d,J=8.3Hz,2H),7.26( d,J=8.3Hz,2H),6.96(dd,J=10.7,8.5Hz,1H),4.07(s,2H),3.39(s,2H),2.85(s,2H). 13 C NMR (126MHz, DMSO-d 6 )δ16...

Embodiment 3

[0082] Example 3. Synthesis of Compound C3

[0083] (1) Synthesis of intermediate M5

[0084]

[0085] The raw material was replaced by M2 to react with 3,4-difluorobenzyl bromide, and the intermediate M5 was obtained as a white solid according to the method of Example 1, and the yield was 85%. 1 H NMR (400MHz, CDCl 3 )δ7.97 (dd, J=8.4, 4.6Hz, 1H), 7.12 (dt, J=10.0, 8.3Hz, 1H), 7.03–6.91 (m, 3H), 6.88 (dd, J=5.2, 3.2Hz , 1H), 6.54 (s, 1H), 5.42 (s, 2H), 3.62 (dd, J=9.8, 5.7Hz, 2H), 3.13–2.97 (m, 2H).

[0086] (2) Synthesis of the final product C3

[0087]

[0088] The raw material was replaced by M5 and reacted in polyphosphoric acid, and the final product C3 was obtained as a white solid with a yield of 30% according to the method of Example 1. Purity: 99%. 1 H NMR (400MHz, CDCl 3 )δ8.49(s,1H),7.93(dd,J=8.0,4.8Hz,1H),7.09(dd,J=18.2,8.4Hz,1H),7.03–6.92(m,2H),6.90(dd , J=6.7, 3.1Hz, 1H), 6.60(s, 1H), 4.07(s, 2H), 3.62(s, 2H), 2.96(s, 2H).

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Abstract

The invention discloses a substituted indolo azaketone compound or pharmaceutically acceptable salt thereof and a preparation method and application of the substituted indolo azaketone compound. The structure of the compound is shown as (I). The substituted indolo azaketone compound disclosed by the invention is novel in structure; the excellent inhibition effect is shown on the phosphodiesterasetype 5; the compound disclosed by the invention can be used as a phosphodiesterase type 5 inhibitor to be made into a medicine for treating and / or preventing related diseases caused by phosphodiesterase type 5, such as male sexual dysfunction, pulmonary hypertension, pulmonary fibrosis, organ fibrosis, tumor drug resistance and the like. The invention also provides a synthesis method of the substituted indoloazaketone compound, which comprises the following steps of: by using nitroolefin and halogenated hydrocarbon as initial raw materials, carrying out reduction, cyclization, alkylation, rearrangement and other reactions to obtain the final product. The synthesis method has the advantages of cheap and easily available raw materials, low toxicity, mild reaction conditions, safe operation,simple synthesis steps and the like.

Description

technical field [0001] The present invention relates to the technical field of medicinal chemistry, more specifically, to a substituted indoloazepinone compound and its preparation method and application. Background technique [0002] Cyclic nucleotide phosphodiesterases (PDEs) are an important super-enzyme family, which can 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 (PDE1-PDE11) 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 point. [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 ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/06A61K31/55A61P11/00A61P9/12A61P15/10A61P15/08A61P35/00
CPCC07D487/06A61P11/00A61P9/12A61P15/10A61P15/08A61P35/00
Inventor 罗海彬吴德燕姜赞黄仪有周倩黄雅丹
Owner SUN YAT SEN UNIV