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CN-122011088-A - Cyclic peptide compound and preparation method and application thereof

CN122011088ACN 122011088 ACN122011088 ACN 122011088ACN-122011088-A

Abstract

The invention discloses a cyclic peptide compound and a preparation method and application thereof. Specifically, the invention discloses a compound shown as a formula (I), a stereoisomer, a tautomer, a crystal form, a pharmaceutically acceptable salt, a hydrate, a solvate or a prodrug thereof. The compound of the invention is an antibiotic and can be used for preparing medicines for treating and/or preventing diseases related to gram-negative bacteria.

Inventors

  • HUANG JINWEN
  • LIU YUNLI
  • Jin Huize
  • LI ZHONGYUAN
  • SHEN XIAOKUN

Assignees

  • 甫康生物科技(上海)股份有限公司
  • 浙江甫康制药有限公司

Dates

Publication Date
20260512
Application Date
20250728
Priority Date
20241029

Claims (11)

  1. 1. A compound of formula (I), stereoisomers, tautomers, crystalline forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof, Wherein X is Se or S, L is And does not include the following structure:
  2. 2. the compound of claim 1, wherein the compound is selected from the group consisting of:
  3. 3. a process for the preparation of a compound as claimed in claims 1 and 2, comprising the steps of: S6, in the presence of a palladium catalyst, carrying out a Suzuki or Ulmann coupling reaction on the compound III and the compound A to obtain a compound II; Wherein X is S or Se; R 1 is B (OH) 2 R a -、B(OR b ) 2 R a -; Wherein each R b is independently C 1-4 alkyl, OR two OR b together with the boron atom to which they are attached form a 4-7 membered heterocyclyl; R a is selected from the group consisting of C 6-10 arylene, 5-7 membered heteroarylene, C 4-7 carbocyclylene, 4-7 membered heterocyclylene; The palladium catalyst is selected from the group consisting of bis (tri-tert-butylphosphine) palladium, tetra-triphenylphosphine palladium, chloro (2-dicyclohexylphosphine-2 ',6' -dimethoxy-1, 1 '-biphenyl) [2- (2' -amino-1, 1 '-biphenyl) ] palladium (II), [1, 3-bis (2, 6-diisopropylphenyl) imidazol-2-ylidene ] (3-chloropyridinyl) palladium (II) dichloride, [2- (di-tert-butylphosphine) -2',4',6' -triisopropyl-1, 1 '-biphenyl ] [2- (2-aminoethyl) phenyl) ] palladium (II) chloride, bis triphenylphosphine palladium dichloride, bis [ tris (2-tolyl) phosphine ] palladium, bis (tricyclohexylphosphine) palladium dichloride, bis (dibenzylideneacetone) palladium (0), [1, 2-bis (diphenylphosphine) ethane ] palladium dichloride, [1,1' -bis (diphenylphosphine) ferrocene ] palladium (II) dichloride, 1 '-bis (dicyclohexylphosphine) palladium (ferrocene) dichloride, and bis (1, 1' -diphenylphosphine) ferrocene, or a combination thereof; s7, carrying out deprotection reaction on the compound II in the presence of acid A to obtain a compound I; Wherein the acid A is selected from the group consisting of hydrochloric acid, an organic solution of hydrogen chloride, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, trifluoromethanesulfonic acid, and the like, or a combination thereof.
  4. 4. A process according to claim 3, wherein the compound III is prepared by: S5, carrying out intramolecular condensation dehydration reaction on the compound IV in the presence of a condensing agent A to obtain a compound III; The condensing agent A is selected from the following group ：EDCI/HOBt、HATU/DIEA、HBTU/DIEA、EEDQ、TCFH/NMI、BOPCl/DIEA、TSTU/TEA、PyBOP/DIEA、T 3 P/TEA、T 4 P/TEA、DPPA/TEA, or a combination thereof.
  5. 5. The preparation method according to claim 4, wherein the compound IV is prepared by: S4-1, carrying out reductive amination reaction on a compound VII and a compound VI in the presence of sodium borohydride acetate and/or sodium cyanoborohydride to obtain a compound V; s4-2, carrying out deprotection reaction on the compound V in the presence of tetrabutylammonium fluoride to obtain a compound IV.
  6. 6. The method of claim 5, wherein compound VIII is prepared by: s3-1, carrying out condensation reaction on the compound X and the compound IX in the presence of a condensing agent B to obtain a compound VIII; s3-2, carrying out deprotection reaction on the compound VIII in the presence of a base B to obtain the compound VII.
  7. 7. The preparation method according to claim 6, wherein the compound X is prepared by: S2-1, in the presence of an acylation reaction catalyst and a dehydrating agent, performing an acylation reaction on the compound X-2 and 2- (trimethylsilyl) ethanol to obtain a compound X-1; s2-2, carrying out debenzylation reaction on the compound X-1 in the presence of a debenzylation catalyst to obtain the compound X.
  8. 8. The process of claim 5, wherein compound VI is prepared by: Wherein X is S or Se; S1-1, in the presence of alkali C, carrying out substitution reaction on a compound VI-4 and 2-bromo-6-fluorobenzonitrile to obtain a compound VI-3; S1-2, carrying out a reduction reaction on the compound VI-3 in the presence of a reducing agent to obtain a compound IV-2; s1-3, in the presence of alkali D, carrying out substitution reaction on the compound VI-2 and the compound C to obtain a compound VI-1; S1-4, carrying out oxidation reaction on the compound VI-1 in the presence of an oxidant to obtain a compound VI.
  9. 9. A pharmaceutical composition, wherein the composition comprises: (i) A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, and (Ii) One or more pharmaceutically acceptable carriers, excipients and/or excipients.
  10. 10. Use of a compound according to claims 1 and 2, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 8, for the preparation of a medicament for the prevention and/or treatment of infectious diseases caused by gram-negative bacteria; Preferably, the gram-negative bacterium is acinetobacter baumannii.
  11. 11. An intermediate compound, wherein the compound is selected from the group consisting of:

Description

Cyclic peptide compound and preparation method and application thereof Technical Field The invention belongs to the field of pharmaceutical chemistry, and in particular relates to a cyclic peptide compound, a preparation method and application thereof. Background Acinetobacter baumannii (Acinetobacter baumannii) is a gram-negative, aerobic, nonfermentable bacterium, which has been considered a emerging pathogen in recent years with very limited therapeutic options. This bacterium belongs to one of the so-called "ESKAPE" pathogen populations in the serious threat list of the american centers for disease control and prevention (CDC), which are currently the major sources of most nosocomial infections, and which are effective in "evading" the activity of antimicrobial agents. Acinetobacter baumannii is commonly found in intensive care units and surgical units, and extensive antibiotic use has led to selection of resistance to all known antimicrobial agents, which can cause a variety of infections including bacteremia, pneumonia, meningitis, urinary tract infections, and wound infections. Acinetobacter baumannii has up-regulation and acquisition capacity of abnormal resistance determinants and shows environmental persistence, making the organism a frequent cause of infection outbreaks and a hospital acquired pathogen. Due to the resistance to most available therapeutic options of antibiotics, particularly carbapenems, the treatment of Multiple Drug Resistant (MDR) acinetobacter baumannii infections becomes very difficult, if not impossible, with high mortality and increased morbidity and residence time in intensive care units. The Antimicrobial Availability Task Force (AATF) of the American society of Infectious Diseases (IDSA) defines Acinetobacter baumannii as a major example of a mismatch between "unmet medical needs and current antimicrobial research and development lines. Thus, there is an urgent need to identify compounds suitable for the treatment of diseases and infections caused by acinetobacter baumannii. Recently Claudia et al (Nature 2024, 625, 566-571) reported cyclic peptide compounds for the treatment of gram-negative bacteria such as Acinetobacter baumannii, but there still remains a highly unmet need for improved compounds suitable for the treatment of diseases and infections caused by Acinetobacter baumannii, such as the proliferation of microorganisms which are extremely fast and prone to drug resistance (J. Med. Chem. 2024, 67, 10, 7759-7787). Therefore, there is a need in the art for a cyclic peptide compound that has good therapeutic effects, high safety, and less susceptibility to drug resistance, so as to meet the clinical demands for treatment of gram-negative bacteria (e.g., acinetobacter baumannii). Disclosure of Invention In order to solve the problems, the invention provides a novel cyclic peptide compound which has good curative effect and high safety and is not easy to generate drug resistance, a preparation method thereof, a pharmaceutical composition containing the novel cyclic peptide compound and application of the novel cyclic peptide compound in preparing medicines for treating infection and diseases caused by bacteria. In a first aspect of the present invention there is provided a compound of formula (I), a stereoisomer, tautomer, crystalline form, pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, (I) Wherein X is Se or S, L is、Or (b); And does not include the following structure: 。 in a preferred embodiment, the compound is selected from the group consisting of: 。 in a second aspect of the present invention there is provided a process for the preparation of a compound according to the first aspect of the present invention comprising the steps of: S6, in the presence of a palladium catalyst, carrying out a Suzuki or Ulmann coupling reaction on the compound III and the compound A to obtain a compound II; Wherein X is S or Se; R 1 is B (OH) 2Ra-、B(ORb)2Ra -; Wherein each R b is independently C 1-4 alkyl, OR two OR b together with the boron atom to which they are attached form a 4-7 membered heterocyclyl; R a is selected from the group consisting of C 6-10 arylene, 5-7 membered heteroarylene, C 4-7 carbocyclylene, 4-7 membered heterocyclylene; The palladium catalyst is selected from the group consisting of bis (tri-tert-butylphosphine) palladium, tetra-triphenylphosphine palladium, chloro (2-dicyclohexylphosphine-2 ',6' -dimethoxy-1, 1 '-biphenyl) [2- (2' -amino-1, 1 '-biphenyl) ] palladium (II), [1, 3-bis (2, 6-diisopropylphenyl) imidazol-2-ylidene ] (3-chloropyridinyl) palladium (II) dichloride, [2- (di-tert-butylphosphine) -2',4',6' -triisopropyl-1, 1 '-biphenyl ] [2- (2-aminoethyl) phenyl) ] palladium (II) chloride, bis triphenylphosphine palladium dichloride, bis [ tris (2-tolyl) phosphine ] palladium, bis (tricyclohexylphosphine) palladium dichloride, bis (dibenzylideneacetone) palladium (0), [1, 2-bis (diphenylphosphine) ethane ] palladium dichlori