Isonicotinic acid derivative as well as preparation method and use thereof

A derivative, the technology of isonicotinic acid, applied in the field of isonicotinic acid amide derivatives and its preparation, isonicotinate derivatives, isonicotinic acid derivatives, can solve the inability to eradicate cancer cells, sexual dysfunction, Problems such as the spread and recurrence of cancer cells

Active Publication Date: 2019-06-28
XIAMEN INST OF RARE EARTH MATERIALS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Treatment with surgery sometimes fails to eradicate cancer cells, allowing cancer cells to spread and recur
In addition, surgical treatment may lead to irreversible serious consequences, such as cervical cancer and bladder cancer surgery may lead to infertility and sexual dysfunction, etc.; radiation therapy for cancer will damage normal cells; therefore drug treatment is a better choice
However, due to the continuous emergence of multidrug resistance, the treatment of cancer is difficult
In addition: the current clinically used anticancer drugs still cannot achieve a satisfactory level of specificity. When a patient undergoes chemotherapy, normal cells in the body are often also poisoned, which seriously affects the normal physiological functions and is associated with has many side effects

Method used

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  • Isonicotinic acid derivative as well as preparation method and use thereof
  • Isonicotinic acid derivative as well as preparation method and use thereof
  • Isonicotinic acid derivative as well as preparation method and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0080] Synthesis of embodiment 1 intermediate 3-substituted phenyl-5-hydroxymethyl-isoxazole (II-1) or intermediate 3-substituted phenyl-5-aminomethyl-isoxazole (II-2) :

[0081] Using substituted benzaldehyde as raw material, it is prepared by synthesis of oxime, 1,3-dipolar cycloaddition reaction, methylsulfonyl esterification reaction, azidation and reduction reaction (R 2 and n as defined above), see the following process for details:

[0082]

[0083]The specific synthetic process of intermediate 3-substituted phenyl-5-hydroxymethyl-isoxazole (II-1) or intermediate 3-substituted phenyl-5-aminomethyl-isoxazole (II-2) is detailed See the three applications of the applicant with publication numbers CN103360382A, CN103664991A and CN103601762A, the full texts of which are incorporated herein by reference.

Embodiment 2

[0084] Synthesis of isonicotinic acid lipid derivatives shown in embodiment 2 formula (I)

[0085] Wherein the reaction of isonicotinic acid and 3-phenyl-5-hydroxymethyl-isoxazole is exemplified:

[0086] Synthesis of [(3-phenyl-isoxazol-5-yl)-methyl]-pyridine-3-carboxylate (YP-77)

[0087]

[0088] Add 0.123g (1mmol) of nicotinic acid and 0.206g (1mmol) of DCC into a 50mL round bottom flask, add 10mL of dry THF, stir and react in an ice bath for 30min, and dissolve 0.175g (1mmol) of 5-hydroxymethyl-3- Phenyl-isoxazole and 0.122 g (1 mmol) of DMAP in 10 mL THF were slowly added dropwise to the reaction system, stirred in an ice bath for 30 min, and then naturally rose to room temperature for reaction. After the TLC detection reaction was completed, the reaction solution was concentrated in vacuo, and the residue was directly separated by column (V (石油醚) :V (乙酸乙酯) =5:1~2:1) to obtain the target compound [(3-phenyl-isoxazol-5-yl)-methyl]-pyridine-3-carboxylate (YP-77).

...

Embodiment 3

[0104] Embodiment 3 biological activity test

[0105] MTT method was used to test the activity of the specific compound against colorectal cancer cell line HCT-116, human lung cancer cell line A549 and breast cancer cell line MCF-7. The specific test process is as follows:

[0106] (1) Spread the lung cancer cell line A549 in a 96-well plate, add 100 μL of culture medium, and wait for the cells to grow to 90%, add 1 μL of drugs into the wells, and detect 8 different concentrations of each drug (respectively, the initial concentration of the drug Concentration, 50μM, 5μM, 500nM, 50nM, 5nM, 500pM, 50pM), for each drug concentration, do 3 replicate wells in parallel, after culturing for 18h, add 20μL of the prepared 5mg / mL MTT solution to each well, and after 4 hours Aspirate the culture medium, add 150 μL DMSO to each well, and measure the optical density (OD) value of the test compound at a wavelength of 595 nm. The negative control is DMSO. The inhibition rate was calculate...

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Abstract

The invention belongs to the field of medicinal chemistry and relates to an isonicotinic acid derivative with a novel structure as well as a preparation method and use thereof. The invention mainly relates to the isonicotinic acid derivative, a stereisomer, a racemate, a tautomer or pharmaceutically acceptable salt which is represented by a formula (I) (shown the description), pharmaceutically acceptable salt thereof, a preparation method thereof and use thereof in the preparation of anti-cancer drugs. In the formula (I), Z is selected from O, S and NR3, R3 represents hydrogen or C1-C6 alkyl;R1 is selected from C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, aryl, aryloxy, heteroaryl, heteroaryloxy, a heterocyclic radical, a heteroepoxy group or halogen; R2 is selected from halogen, cyan, C1-C6 alkyl, C1-C6 alkoxy or halogenated C1-C6 alkyl; m represents an integer of 0-4; n represents an integer of 0-5; and the condition is that R2 is not halogen when Z is selected from NR3, m is0 and n is 1.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry and relates to a class of isonicotinic acid derivatives with novel structures, in particular to isonicotinic acid ester derivatives and isonicotinic acid amide derivatives containing isoxazole heterocycles and their preparation methods and applications. Background technique [0002] Cancer is a large class of diseases characterized by abnormal cell proliferation and metastasis, and is the second leading cause of death in humans, second only to cardiovascular and cerebrovascular diseases. Cancer can occur in various organs and tissues at any age. According to the statistics of the World Health Organization, in 2018, there were about 18.1 million new cancer cases and 9.6 million cancer deaths worldwide. New cancer cases in Asia (8,751,000 people), the cancer incidence rate was 48.4%, cancer deaths (5,477,000 people), the cancer death rate was 57.3%; new cancer cases in Europe (4,230,000 people), ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D413/12A61K31/4439A61P35/00
Inventor 雍建平卢灿忠
Owner XIAMEN INST OF RARE EARTH MATERIALS
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