Nicotinic acid derivatives and preparation method and applications thereof

A compound and solvate technology, applied in the field of medicinal chemistry, can solve problems such as infertility, affecting physiological functions, and damaging normal cells

Inactive Publication Date: 2017-12-15
XIAMEN INST OF RARE EARTH MATERIALS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Surgical treatment sometimes fails to eradicate cancer cells, leading to the spread and recurrence of cancer cells; in addition, surgical treatment may lead to serious consequences, such as cervical cancer and bladder cancer surgery may lead to infertility and sexual dysfunction, etc.; radiation therapy for cancer can hurt and normal cells; therefore, drug therapy is a better option for cancer
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 killed together, seriously affecting normal physiological functions, and accompanied by has many side effects

Method used

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  • Nicotinic acid derivatives and preparation method and applications thereof
  • Nicotinic acid derivatives and preparation method and applications thereof
  • Nicotinic acid derivatives and preparation method and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation example 1

[0070] Synthesis of Preparation Example 1 intermediate (II-1) and intermediate (II-2):

[0071] 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. See the following process for details:

[0072]

[0073] For the specific synthesis process of intermediate (II-1) and intermediate (II-2), please refer to Chinese patent applications CN103360382A, CN103664991A and CN103601762A, and these three applications are fully incorporated into the present invention.

[0074] According to the present invention, for compounds where Z is other substituents, such as NR 3 Or S, can use the corresponding substituted aminopropyne compound or propyne thiol as raw material, according to the preparation process of intermediate (II-2) to prepare.

Embodiment 1

[0075] Synthesis of niacin derivatives shown in embodiment 1 formula (I)

[0076] Among them, the reaction of nicotinic acid and 3-phenyl-5-hydroxymethyl-isoxazole is exemplified:

[0077] Synthesis of [(3-phenyl-isoxazol-5-yl)-methyl]-pyridine-3-carboxylate (YP-1)

[0078]

[0079] 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 in an ice bath for 30min, and dissolve 0.175g (1mmol) of 3-phenyl-5-hydroxy A 10 mL THF solution of methyl-isoxazole and 0.122 g (1 mmol) DMAP was 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 completion of the TLC detection reaction, the reaction solution was concentrated in vacuo, and the residue was directly separated from the column. (石油醚) :V (乙酸乙酯) =5:1~2:1), the target compound [(3-phenyl-isoxazol-5-yl)-methyl]-pyridine-3-carboxylate (YP-1) was obtained. Other compo...

Embodiment 2

[0080] Synthesis of nicotinic acid amide derivatives shown in embodiment 2 formula (I)

[0081] Wherein the reaction of nicotinic acid and 3-phenyl-5-aminomethyl-isoxazole is exemplified:

[0082] Synthesis of N-[(3-phenyl-isoxazol-5-yl)-methyl]-pyridine-3-carboxamide (YP-115)

[0083]

[0084] Add 0.123g (1mmol) nicotinic acid, 0.206g (1mmol) DCC and 0.135g (1mmol) HOBT into a 50mL round bottom flask, add 10mL dry THF, stir in an ice bath for 30min, and dissolve 0.174g (1mmol) 3 -Phenyl-5-aminomethyl-isoxazole and 0.122 g (1 mmol) 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 completion of the TLC detection reaction, the reaction solution was concentrated in vacuo, and the residue was directly separated from the column. (石油醚) :V (乙酸乙酯) =5:1~2:1), the target compound N-[(3-phenyl-isoxazol-5-yl)-methyl]-pyridine-3-carboxamide (YP-115) was obtained....

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Abstract

The invention relates to a nicotinic acid derivative shown in the formula (I), and pharmaceutically acceptable salt or solvate thereof, wherein Z is selected from O, S and NR3, and R3 is hydrogen or C1-6 alkyl; R1 or R2 is independently selected from hydrogen, C1-6 alkyl, C1-6 alkoxy group, halogenated C1-6 alkyl, halogen, nitro, aryl, aryl oxygroup, heteroaryl, heteroaryl oxygroup, heterocyclic radical, and heterocyclic oxygroup; C1-6 alkoxy group, halogenated C1-6 alkyl, aryl, heteroaryl, and heterocyclic radical can be optionally substituted by substituent groups which can be C1-6 alkyl, C1-6 alkoxy group, halogenated C1-6 alkyl, halogen, cycano, nitro and aryl; m is an integer of 0 to 4; and n is an integer of 0 to 5. The compound or salts thereof have strong inhibition activity to colorectal cancer cell line HCT-116, human lung cancer cell line A549 and breast cancer cell line MCF-7. In addition, the compound is broad-spectrum in anti-cancer activity, and can be used as a candidate drug or a pilot compound for treating diseases of tumors, cancers and the like.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry and relates to a class of niacin derivatives, in particular to a niacin derivative containing an isoxazole heterocycle and a preparation method and use thereof. 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. The main types of cancers that lead to death are: lung cancer, stomach cancer, liver cancer, colon cancer and breast cancer. Especially in recent years, lung cancer has become the tumor with the highest incidence rate. According to the statistics of the World Health Organization, as of 2017, 1,688,780 new cancer patients have been diagnosed worldwide, and 600,920 cancer patients will die in the United States. Cancer facts and figures 2017: (h...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D413/12A61K31/455A61P35/00A61K45/06
CPCC07D413/12A61P35/00C07D261/08A61P35/04Y02P20/55
Inventor 雍建平卢灿忠
Owner XIAMEN INST OF RARE EARTH MATERIALS
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