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CN-122010771-A - 6-Diazonium-5-oxo-norleucine derivative, preparation method and application

CN122010771ACN 122010771 ACN122010771 ACN 122010771ACN-122010771-A

Abstract

The 6-diazonium-5-oxo-norleucine derivative, the preparation method and the application thereof release DON through a cleavable amide bond, can realize immunoregulation on sepsis-related macrophages, have high safety, can effectively inhibit immune response of sepsis mice through M2 type macrophage polarization, and finally realize inflammatory treatment of sepsis. The derivative is a metabolic drug connected by DON and leucine-PEG, can be self-assembled into nano particles, releases DON to play an anti-inflammatory role at the inflammation part of the homoesterase and the amidase, reduces the toxicity of the system, has good chemical stability and drug development potential, is suitable for further pharmacological research, and has good synthesizability and pharmaceutical properties.

Inventors

  • WEI GAOFEI
  • WANG WENHUI
  • Hai Yongrui
  • CHEN YE

Assignees

  • 西北工业大学深圳研究院

Dates

Publication Date
20260512
Application Date
20260105

Claims (8)

  1. The 6-diazonium-5-oxo-norleucine derivative is characterized by comprising a compound with a structure shown in the following general formula or optical isomer, diastereoisomer and pharmaceutically acceptable salt formed by the compound, and pharmaceutically acceptable carrier, auxiliary materials and excipient, wherein the general formula is as follows: Wherein R is selected from the group consisting of a hydrogen atom, a halogen, a cyano group, a nitro group, a C1-6 alkyl group, a C3-8 cycloalkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a C1-6 alkoxy group, a C2-6 alkenyloxy group, a C2-6 alkynyloxy group, which may be the same or different, an amino group which is unsubstituted or substituted with a group selected from the group consisting of a C1-6 alkyl group, a C1-6 aminoalkyl group, a C1-6 hydroxyalkyl group, a C1-6 alkoxyalkyl group, a C1-6 cyanoalkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a C1-6 alkylsulfonyl group, a C1-6 alkylcarbonyl group, a C2-6 alkenylcarbonyl group, and a C2-6 alkynylcarbonyl group, an ester group or an amide group which is unsubstituted or substituted with a group selected from the group consisting of a C1-6 alkyl group, a C1-6 aminoalkyl group, a C1-6 hydroxyalkyl group, a C1-6 alkoxyalkyl group, a C1-6 cyanoalkyl group, a C2-6 alkenylcarbonyl group, a C2-6 alkynylcarbonyl group, a C2-6 alkenylcarbonyl group, and an unsubstituted or a substituted ester group.
  2. 2. The 6-diazo-5-oxo-norleucine derivative according to claim 1, wherein R is ethyl.
  3. 3. Process for the preparation of 6-diazo-5-oxo-norleucine derivatives according to claim 1 or 2, characterized in that the derivatives are obtained by reacting 6-diazo-5-oxo-norleucine DON with CY122, in the following reaction scheme: 。
  4. 4. A process for the preparation of 6-diazo-5-oxo-norleucine derivatives according to claim 3, comprising the steps of: s1, dissolving m-PEG7-CH 2 COOH and N-hydroxy-7-azabenzotriazol in dry DCM, adding DMF to assist dissolution, and carrying out reaction; S2, after the reaction mixture is cooled, adding N, N' -dicyclohexylcarbodiimide, continuously stirring, sequentially adding L-leucine tert-butyl ester hydrochloride and DIPEA, and reacting at room temperature to obtain a colorless oily compound CY122; S3, dissolving CY122 in anhydrous DCM, cooling to 0 ℃, slowly dropwise adding trifluoroacetic acid, then heating to room temperature and continuing stirring for reaction to obtain a free acid intermediate; S4, dissolving the free acid and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride in anhydrous DCM, cooling to 0 ℃, and adding 6-diazonium-5-carbonyl-L-norleucine ethyl ester for reaction at room temperature to obtain the 6-diazonium-5-oxo-norleucine derivative.
  5. 5. The method for producing 6-diazo-5-oxo-norleucine according to claim 4, wherein the molar ratio of m-PEG7-CH 2 COOH, N-hydroxy-7-azabenzotriazol to N, N' -dicyclohexylcarbodiimide is 2:3:3.
  6. 6. The method for producing 6-diazonium-5-oxo-norleucine derivative according to claim 5, wherein the molar ratio of L-leucine tert-butyl ester hydrochloride to DIPEA is 1:2.
  7. 7. The 6-diazonium-5-oxo-norleucine derivative according to claim 1, wherein said excipient comprises oral tablet, capsule, injection, lyophilized powder for injection and sustained release preparation.
  8. Use of a 6-diazo-5-oxo-norleucine derivative, characterized in that the derivative according to claim 1 or 2 is used for the preparation of a medicament for the treatment of sepsis and colitis.

Description

6-Diazonium-5-oxo-norleucine derivative, preparation method and application Technical Field The invention relates to the technical field of chemical medicines, in particular to a 6-diazonium-5-oxo-norleucine derivative, a preparation method and application thereof. Background Sepsis is a life threatening syndrome caused by infection and is characterized by a deregulation of the host response, leading to multiple organ dysfunction and high mortality. Despite advances in supportive care, effective pharmaceutical interventions remain elusive, mainly due to the complexity of sepsis pathophysiology and lack of therapies for immune dysfunction. Recent studies underscore the importance of immune metabolism in modeling macrophage phenotype. Notably, pathways associated with glutamate production in the peripheral blood mononuclear cell transcriptome of sepsis mice were significantly enriched. Glutamic acid has been found experimentally to promote macrophage transformation to the pro-inflammatory M1 phenotype and to result in pro-inflammatory cytokine production, which is detrimental to sepsis treatment. The glutamate production inhibitor 6-diazo-5-oxo-norleucine (DON) exhibits powerful immunomodulatory activity by promoting macrophage transformation to M2 phenotype function. On the other hand, DON has poor stability and other problems, and the direct and independent use of DON has no obvious treatment effect. In sepsis-affected organs, the lungs are particularly fragile, often the first part of the injury, and play a vital role in patient survival. Thus, there is a need to design a compound that modifies DON to increase its stability and more target inflamed tissue. It is noted that this section is intended to provide a background or context for the technical solutions of the present disclosure as set forth in the claims. The description herein is not admitted to be prior art by inclusion in this section. Disclosure of Invention The present invention is directed to a 6-diazonium-5-oxo-norleucine derivative, a preparation method and application thereof, and thus, at least in part, overcome one or more of the problems due to the limitations and disadvantages of the related art. The invention firstly provides a 6-diazonium-5-oxo-norleucine derivative, which comprises a compound with a structure shown in the following general formula or an optical isomer, a diastereoisomer and a pharmaceutically acceptable salt formed by the compound, and a pharmaceutically acceptable carrier, an auxiliary material and an excipient, wherein the general formula is as follows: Wherein R is selected from the group consisting of a hydrogen atom, a halogen, a cyano group, a nitro group, a C1-6 alkyl group, a C3-8 cycloalkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a C1-6 alkoxy group, a C2-6 alkenyloxy group, a C2-6 alkynyloxy group, which may be the same or different, an amino group which is unsubstituted or substituted with a group selected from the group consisting of a C1-6 alkyl group, a C1-6 aminoalkyl group, a C1-6 hydroxyalkyl group, a C1-6 alkoxyalkyl group, a C1-6 cyanoalkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a C1-6 alkylsulfonyl group, a C1-6 alkylcarbonyl group, a C2-6 alkenylcarbonyl group, and a C2-6 alkynylcarbonyl group, an ester group or an amide group which is unsubstituted or substituted with a group selected from the group consisting of a C1-6 alkyl group, a C1-6 aminoalkyl group, a C1-6 hydroxyalkyl group, a C1-6 alkoxyalkyl group, a C1-6 cyanoalkyl group, a C2-6 alkenylcarbonyl group, a C2-6 alkynylcarbonyl group, a C2-6 alkenylcarbonyl group, and an unsubstituted or a substituted ester group. In the invention, R is ethyl. In the invention, the derivative is obtained by reacting 6-diazonium-5-oxo-norleucine DON with CY122, and the reaction process is as follows: 。 The invention further provides a preparation method of the 6-diazonium-5-oxo-norleucine derivative, which comprises the following steps: s1, dissolving m-PEG7-CH 2 COOH and N-hydroxy-7-azabenzotriazol in dry DCM, adding DMF to assist dissolution, and carrying out reaction; S2, after the reaction mixture is cooled, adding N, N' -dicyclohexylcarbodiimide, continuously stirring, sequentially adding L-leucine tert-butyl ester hydrochloride and DIPEA, and reacting at room temperature to obtain a colorless oily compound CY122; S3, dissolving CY122 in anhydrous DCM, cooling to 0 ℃, slowly dropwise adding trifluoroacetic acid, then heating to room temperature and continuing stirring for reaction to obtain a free acid intermediate; S4, dissolving the free acid and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride in anhydrous DCM, cooling to 0 ℃, and adding 6-diazonium-5-carbonyl-L-norleucine ethyl ester for reaction at room temperature to obtain the 6-diazonium-5-oxo-norleucine derivative. In the invention, the reaction molar ratio of m-PEG7-CH 2 COOH, N-hydroxy-7-azabenzotriazol and N, N' -dicyclohexylcarbodiimide is 2:3:3. In th