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US-12624012-B2 - 14-chloro-β-elemene nitric oxide donor derivative and preparation method and use thereof

US12624012B2US 12624012 B2US12624012 B2US 12624012B2US-12624012-B2

Abstract

Disclosed are a 14-chloro-β-elemene nitric oxide donor derivative and a preparation method and use thereof in the preparation of anti-tumor drugs. The 14-chloro-β-elemene nitric oxide donor derivative has a general formula shown in formula (I): in formula (I): R 1 represents a linear or cyclic alcohol amine structure containing nitrogen and oxygen atoms; and each of R 2 and R 3 is independently selected from the group consisting of C 1-10 alkyl, C 3-12 cycloalkyl, C 6-12 aryl, 5- to 10-membered cyclic heteroaryl, C 2-10 alkenyl, C 2-10 alkynyl, and C 2-10 alkoxy.

Inventors

  • Tian XIE
  • Renren Bai
  • Xiangyang Ye
  • Junlong Zhu
  • Ziqiang BAI

Assignees

  • HANGZHOU NORMAL UNIVERSITY

Dates

Publication Date
20260512
Application Date
20220902
Priority Date
20211011

Claims (10)

  1. 1 . A 14-chloro-β-elemene nitric oxide donor derivative, or a pharmaceutically acceptable salt, a solvate, an enantiomer, or a diastereoisomer thereof, the 14-chloro-β-elemene nitric oxide donor derivative having a structural general formula as shown in formula (I): wherein in formula (I), R 1 is any one selected from the group consisting of and each of R 2 and R 3 is independently selected from the group consisting of C 1-10 alkyl, C 3-12 cycloalkyl, C 6-12 aryl, 5- to 10-membered cyclic heteroaryl, C 2-10 alkenyl, C 2-10 alkynyl, and C 2-10 alkoxy.
  2. 2 . The 14-chloro-β-elemene nitric oxide donor derivative, or a pharmaceutically acceptable salt, a solvate, an enantiomer, or a diastereoisomer thereof of claim 1 , wherein in formula (I): each of R 2 and R 3 is independently selected from the group consisting of C 2-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl.
  3. 3 . The 14-chloro-β-elemene nitric oxide donor derivative, or a pharmaceutically acceptable salt, a solvate, an enantiomer, or a diastereoisomer thereof of claim 1 , wherein in formula (I): each of R 2 and R 3 is independently any one selected from the group consisting of —CH 2 CH 2 —, —CH 2 CH 2 CH 2 —, —CH 2 CH 2 CH 2 CH 2 —, —CH 2 CH 2 CH 2 CH 2 CH 2 —, —CH═CH—, —CH 2 CH═CH—, —CH ═CHCH 2 —, —CH 2 CH═CHCH 2 —, —CH 2 CH 2 CH═CH—, —CH═CHCH 2 CH 2 —, —CH 2 C≡C—, —C≡CCH 2 —, —CH 2 C≡CCH 2 —, —CH 2 CH 2 C≡CCH 2 —, —CH 2 CH 2 C≡CCH 2 CH 2 —, and —CH 2 C≡CCH 2 CH 2 —.
  4. 4 . The 14-chloro-β-elemene nitric oxide donor derivative, or a pharmaceutically acceptable salt, a solvate, an enantiomer, or a diastereoisomer thereof of claim 1 , wherein the 14-chloro-β-elemene nitric oxide donor derivative is any one selected from the group consisting of compounds having a structure shown in formulas I-1 to I-6: and in the formulas I-1 to I-6, each of R 2 and R 3 is independently any one selected from the group consisting of C 2-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl.
  5. 5 . The 14-chloro-β-elemene nitric oxide donor derivative, or a pharmaceutically acceptable salt, a solvate, an enantiomer, or a diastereoisomer thereof of claim 1 , wherein the 14-chloro-β-elemene nitric oxide donor derivative is any one selected from the group consisting of compounds having a structure shown in formulas 1 to 24:
  6. 6 . A method for treating a tumor, wherein the tumor is lung cancer, colon cancer or malignant brain glioma; comprising administering the 14-chloro-β-elemene nitric oxide donor derivative, or a pharmaceutically acceptable salt, a solvate, an enantiomer, or a diastereoisomer thereof of claim 1 to a subject in need thereof.
  7. 7 . The method of claim 6 , wherein in formula (I): R 1 represents a linear C 2-5 alcohol amine structure containing nitrogen and oxygen atoms or a cyclic C 5-6 alcohol amine structure containing nitrogen and oxygen atoms; and each of R 2 and R 3 is independently selected from the group consisting of C 2-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl.
  8. 8 . The method of claim 6 , wherein in formula (I): each of R 2 and R 3 is independently and one selected from the group consisting of —CH 2 CH 2 —, —CH 2 CH 2 CH 2 —, —CH 2 CH 2 CH 2 CH 2 —, —CH 2 CH 2 CH 2 CH 2 CH 2 —, —CH═CH—, —CH 2 CH═CH—, —CH ═CHCH 2 —, —CH 2 CH═CHCH 2 —, —CH 2 CH 2 CH═CH—, —CH═CHCH 2 CH 2 —, —CH 2 C≡C—, —C≡CCH 2 —, —CH 2 C≡CCH 2 —, —CH 2 CH 2 C≡CCH 2 —, —CH 2 CH 2 C≡CCH 2 CH 2 —, and —CH 2 C≡CCH 2 CH 2 —.
  9. 9 . The method of claim 6 , wherein the 14-chloro-β-elemene nitric oxide donor derivative is any one selected from the group consisting of compounds having a structure shown in formulas I-1 to I-6: and in the formulas I-1 to I-6, each of R 2 and R 3 is independently any one selected from the group consisting of C 2-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl.
  10. 10 . The method of claim 6 , wherein the 14-chloro-β-elemene nitric oxide donor derivative is any one selected from the group consisting of compounds having a structure shown in formulas 1 to 24:

Description

CROSS REFERENCE TO RELATED APPLICATION This patent application is a national stage application of International Patent Application No. PCT/CN2022/116672, filed on Sep. 2, 2022, which claims the priority of Chinese Patent Application No. 2021111804247, entitled “14-chloro-beta- elemene nitric oxide donor derivative and preparation method and use thereof” filed with the China National Intellectual Property Administration on Oct. 11, 2021, the disclosure of which is incorporated herein by reference in its entirety. TECHNICAL FIELD The present disclosure relates to the field of medicinal chemistry, and specifically relates to a 14-chloro-β-elemene NO donor derivative and a preparation method and use thereof. BACKGROUND Elemene is a sesquiterpene natural product exacted and isolated from Curcuma zedoaria and has broad anti-tumor activity. In 1994, elemene oral emulsion and injection were approved by the China Food and Drug Administration (CFDA) as broad-spectrum anti-tumor drugs for the treatment of lung, liver, esophageal, nasopharyngeal, and brain cancers. In the elemene extract mixture, β-elemene has the highest content and is also the most important anti-tumor active ingredient. However, the structure of β-elemene only contains two elements of carbon and hydrogen, leading to β-elemene having great-fat solubility, poor water solubility, and low bioavailability. β-elemene is not easily absorbed by the human body, thus limiting its clinical application. Taking β-elemene injection as an example, patients often need to be administered high-dose injections during treatment. The medical solution highly irritate to the patient's blood vessels, which may easily cause phlebitis. Therefore, it is necessary to carry out structural transformation and modification of β-elemene to improve its physicochemical properties on the one hand and enhance its anti-tumor activity on the other hand. Nitric oxide (NO) is involved in various physiological and pathological processes. High levels of nitric oxide can inhibit the growth of tumor cells through various signaling pathways, such as ERKs and Akt. However, as a small gas molecule, NO is difficult to quantify and transport, so the preparation of a portable and stable nitric oxide donor has become a research hotspot. Studies have found that phenylsulfonylfurazan, a classic nitric oxide donor, can produce high levels of nitric oxide in vitro and in vivo. Therefore, the introduction of nitric oxide donors into the structure of β-elemene will significantly enhance the anti-tumor activity of β-elemene, improve the drug-likeness of β-elemene, and hopefully obtain anti-tumor drugs with better efficacy. Chinese Patent Application No. 201710066664.1 discloses a synthesis of a nitric oxide donator β-elemene derivative. The specific synthetic route and general structure are shown in FIG. 1. The compound reported in this patent is prepared by using 13-alcohol of β-elemene as an intermediate and connecting it with a furoxan-type nitric oxide donor through an esterification reaction to prepare an ester-type nitric oxide β-elemene derivative. Although this series of compounds exhibited good in vitro anti-tumor activity and in vivo tumor suppressive activity, such as shown in FIG. 1, the ester bond at the 13-position of β-elemene in this series of compounds is easy to be hydrolyzed by esterases in vivo to metabolize to 13-β-elemenol. Subsequently, 13-β-elemenol would be rapidly metabolized through oxidation to 13-β-elemenal. However, 13-β-elemenal has strong cytotoxicity. The administration of medium and high doses for a long time can directly cause the death of administered animals. Therefore, long-term administration has a greater risk to safety and is not suitable for the human body. In addition, because the compounds disclosed in this patent are easy to metabolize and decompose, the stability of the compound is poor, and it is difficult to penetrate the blood-brain barrier, so it cannot effectively treat intracerebral tumors, such as malignant brain glioma. SUMMARY In the present disclosure, an alcohol amine structure in the 14-chloro-β-elemene nitric oxide donor derivative functions as a linker. A 13-β-elemene amine intermediate is firstly prepared and then connected with a furazan nitric oxide donor to finally prepare a β-elemene nitric oxide donor derivative with a novel linker, which has excellent activities, and is absent of the toxicity problem that may occur in CN201710066664.1. In the present disclosure, the synthetic route of 13,14-dichloro-β-elemene is shown in FIG. 2. The reaction conditions and reagents used are as follows: N-chlorosuccinimide (NCS), ytterbium trifluoromethanesulfonate (Yb(OTf)3), and trimethylchlorosilane (TMSCl), dichloromethane (CH2Cl2):tetrahydrofuran (THF) (4:1, v/v), at 0° C. In the present disclosure, 13,14-dichloro-β-elemene is chosen as a skeleton to provide anti-tumour activity, which has the following important advantages: 1) In the chlorination reacti