Azaspirocycle, polycyclic andrographolide compound and preparation method thereof, pharmaceutical composition and application thereof
A technology of ester compounds and azaspiro rings, applied in the field of medicinal chemistry, can solve the problems of low water solubility, weak stability, and low bioavailability
Active Publication Date: 2022-05-31
SHENZHEN BAY LAB +1
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Problems solved by technology
Nevertheless, due to the low bioavailability, low water solubility (74μg / mL), and relatively weak stability of andrographolide, its anti-tumor application is limited, and the structural modification work has become a solution to its low bioavailability. , the main method to enhance the clinical efficacy
Method used
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preparation example Construction
[0085]
[0092] Preferably, the reaction is carried out at a temperature of 25°C to 100°C (preferably 50°C) for 2h to 5h.
[0097]
[0099]
[0100] In this reaction, the imide salt is subjected to a cyclic amination of the double bond at the 8 and 17 positions. Specifically, the imide salt can be methanesulfonyl
[0104]
[0106]
[0107] In this step, an intermolecular 3+2 cycloaddition reaction occurs, and a copper catalyst is utilized to carry out the cycloaddition reaction.
[0111]
[0113]
[0114] In this step, the 12-position is subjected to an amination substitution reaction with an amine.
[0115] Specifically, the amine can be various aliphatic or aromatic amines. ‑R
[0119]
[0121]
[0126]
[0128]
Embodiment 1
[0135]
[0136] In an 8 mL sample vial, add acetoxy-protected andrographolide A (46 mg, 0.1 mmol) sequentially, TsN=
[0137]
Embodiment 2
[0141] Compound A was prepared with reference to the preparation method in Example 1. In an 8mL sample vial, add acetoxy
[0142]
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The invention discloses an azaspirocyclic and polycyclic andrographolide compound with antitumor activity and a preparation method thereof, a pharmaceutical composition comprising the azaspirocyclic and polycyclic andrographolide compound and application thereof. This azaspirocyclic, polycyclic andrographolide compound breaks through the existing modification of the 3-, 19-, and 14-position hydroxyl groups in the structural modification attempt, and creatively double bonds at the 8 and 17 positions Carry out aziridine, and on this basis, through intermolecular 3+2 cycloaddition between aziridine and acetonitrile, C12 Michael‑amination, intramolecular nucleophilic attack on aziridine ring opening and nitrogen Heterocyclopropyl group and intramolecular double bond 3+2 cycloaddition form a series of novel amino-substituted polycyclic azaspirocyclic and polycyclic andrographolide compounds, which enhance the biological activity and bioavailability of the compounds and stability. Combined with the experimental data in the specific examples, the azaspirocyclic and polycyclic andrographolide compound has significantly improved tumor inhibitory effect compared with andrographolide.
Description
Azaspirocycle, polycyclic andrographolide compound, preparation method and pharmaceutical combination thereof objects and their applications technical field The present invention relates to the field of medicinal chemistry, particularly relate to a kind of azaspirocycle, polycyclic andrographolide compounds The preparation method thereof, the pharmaceutical composition and the application thereof. Background technique Natural products have important significance to the field of pharmaceutical research, the diversity structure of natural products and the ease with which biological The characteristics of macromolecular binding determine its incomparable advantages in participating in the physiological process of life. It gives natural products an irreplaceable important position in the research and development of new drugs, and is an important factor in the discovery of candidate drugs and drug lead structures. source. To date, more than one-third of drugs in clinic...
Claims
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IPC IPC(8): C07D405/06C07D409/14C07D405/04C07D405/14A61K31/396A61K31/4184A61K31/473A61K31/403A61P35/00A61P35/02
CPCC07D405/06C07D409/14C07D405/04C07D405/14A61P35/00A61P35/02Y02A50/30
Inventor 朱振东邢琦车超黎婷蒋顶张家银张传冰杨震
Owner SHENZHEN BAY LAB