WO2023274003A1 - Antibacterial use of heptamethine indocyanine or derivatives thereof - Google Patents

Antibacterial use of heptamethine indocyanine or derivatives thereof Download PDF

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WO2023274003A1
WO2023274003A1 PCT/CN2022/100605 CN2022100605W WO2023274003A1 WO 2023274003 A1 WO2023274003 A1 WO 2023274003A1 CN 2022100605 W CN2022100605 W CN 2022100605W WO 2023274003 A1 WO2023274003 A1 WO 2023274003A1
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heptamethine
compound
indole cyanine
indole
compounds
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PCT/CN2022/100605
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French (fr)
Chinese (zh)
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罗圣霖
覃容欣
杜在芝
黄燮
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中国人民解放军陆军军医大学
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • the invention belongs to the technical field of medicine, and specifically relates to the use of heptamethine indole cyanine or its derivatives in the preparation of antibacterial drugs, including the use of antibacterial drugs in combination with ⁇ -lactam antibiotics.
  • MRSA Metal-resistant Staphylococcus aureus
  • MRSA has become an important pathogen of hospital infection in the world.
  • MRSA has varying degrees of resistance to ⁇ -lactams, aminoglycosides, and quinolones, including penicillins, cephalosporins, and cephamycins.
  • Vancomycin is the last line of defense in the treatment of MRSA infection, but since 2002, vancomycin-resistant Staphylococcus aureus has been detected in succession around the world. Therefore, it is imminent to find and develop new antibacterial drugs for the treatment of MRSA infection.
  • Indocyanine Green is the only heptamethine indolecyanine molecule approved by the US FDA, including the Chinese SFDA for clinical use. Due to its highly sensitive near-infrared fluorescence characteristics and excellent biocompatibility, ICG has been clinically used in angiography and liver function testing for nearly half a century. In the past ten years, the applicant of this patent and researchers in the same field have been focusing on the structure derivation and synthesis of ICG, and have prepared and reported a new class of heptamethine indole cyanine small molecules with simultaneous tumor targeting, imaging and chemotherapy effects. Early tumor diagnosis and targeted therapy offer possibilities.
  • ICG and some of its heptamethine indole cyanine analogs have excellent photosensitivity properties, that is, they induce a large number of lethal reactive oxygen species (ROS) or local high temperature and hyperthermia under laser irradiation, thereby exerting photosensitive properties respectively.
  • ROS reactive oxygen species
  • PTT photothermal therapy
  • tumors, antibacterial, and promotion of infected wound healing such as:
  • the invention relates to a class of heptamethine indole cyanine dyes containing N-fatty ester or N-fatty amide side chains, their synthesis method and their application in tumor targeting imaging and treatment.
  • the invention relates to a class of mitochondria-targeted heptamethine indole cyanine dyes and a preparation method and application thereof.
  • the heptamethine indole cyanine dyes are composed of mitochondria-targeted indole heptamethine chains and N-alkyl groups of different lengths side chain composition.
  • the heptamethine indole cyanine dye is a multifunctional organic small molecule that targets tumor mitochondria and simultaneously realizes precise and efficient photothermal and photodynamic anti-tumor effects under the guidance of near-infrared fluorescence imaging.
  • CN106511337A A class of heptamethine indole cyanine dyes described in the present invention, by modifying the alkyl side chains of mitochondria-targeted near-infrared heptamethine indole cyanine dyes, synthesizing the above three kinds can promote cell resistance to oxidative stress damage, A small molecule fluorescent compound that reduces inflammatory damage and promotes tissue regeneration and repair.
  • ICG heptamethine indole cyanines
  • the object of the present invention is to provide a kind of heptamethine indole cyanine and derivatives thereof or pharmaceutically acceptable salt thereof in the manufacture of anti-gram-positive bacteria such as Methicillin resistant staphylococcus aureus (MRSA), gram-negative bacteria such as Escherichia coli
  • MRSA Methicillin resistant staphylococcus aureus
  • gram-negative bacteria such as Escherichia coli
  • E.coli Escherichia coli
  • P.A. Pseudomonas aeruginosa
  • a heptamethine indole cyanine and its derivatives or a pharmaceutically acceptable salt thereof of the present invention in the manufacture of antibacterial drugs (i.e. anti-bacterial infection drugs), the heptamethine indole cyanine or its derivatives
  • antibacterial drugs i.e. anti-bacterial infection drugs
  • the heptamethine indole cyanine or its derivatives for the compound shown in formula I,
  • R 1 and R 2 are the same or different, each independently selected from C 2 -C 11 aliphatic chain, C 2 -C 11 fatty carboxylic acid, C 2 -C 11 fatty ether hydrocarbon, C 2 -C 11 fatty carboxyl Any one of esters, C 2 -C 11 fatty carboxylic acid amides, etc., X is bromine atom, iodine atom, chlorine atom or perchlorate ion.
  • the bacteria are anti-gram-positive bacteria such as Methicillin resistant staphylococcus aureus (MRSA), gram-negative bacteria such as Escherichia coli Escherichia coli (E.coli) and/or Pseudomonas aeruginosa P.Aeruginosa (PA ).
  • MRSA Methicillin resistant staphylococcus aureus
  • E.coli Escherichia coli Escherichia coli
  • PA Pseudomonas aeruginosa P.Aeruginosa
  • X is a bromine atom, iodine atom, chlorine atom or perchlorate ion, and the side chains of R 1 and R 2 can be the same, symmetrical structures, or different, That is an asymmetric structure.
  • R 1 and R 2 are symmetrical structures, R 1 and R 2 have the same structure and can be C 2 -C 11 aliphatic chain (such as compound 1-2), fatty carboxylic acid (such as compound 3-5), fatty ether Hydrocarbons (such as compounds 7-9), fatty carboxylic acid esters (such as compounds 10-14), fatty carboxylic acid amides (such as compounds 15-19), aliphatic terminal nitrogen-containing heterocycles (such as compounds 20-22); , carboxylic acid ester, carboxylic acid amide structure is any one of alkyl, phenyl, carboxyl-substituted phenyl, halogen-substituted phenyl, nitrogen-containing heterocycle, etc.
  • R 1 and R 2 are asymmetric structures, the structures of R 1 and R 2 are inconsistent, and R 1 and R 2 can be respectively C 2 -C 11 aliphatic chains (such as compound 23), aliphatic ether hydrocarbons (such as compound 24) , aliphatic carboxylate (such as compound 25) or aliphatic nitrogen-containing heterocycle (such as compound 26), wherein, ether hydrocarbon, carboxylate is C 1 -C 6 alkyl, phenyl, carboxyl substituted phenyl, halogen substituted benzene group or nitrogen-containing heterocycle.
  • the heptamethine indole cyanine or its derivatives are compounds represented by formula I or their pharmaceutically acceptable salts,
  • R 1 and R 2 may be the same or different, each independently represents an unsubstituted or substituted alkyl group, and the substituted substituent is COR 3 , COOR 3 , CONR 3 or
  • R 3 is H, unsubstituted or substituted C 1 -C 4 alkyl, unsubstituted or phenyl substituted by formic acid, formate or halogen, acetate,
  • X is bromine, chlorine, iodine or perchloric acid.
  • the formate is methyl formate, ethyl formate, propyl formate;
  • the acetate is methyl acetate, ethyl acetate, propyl acetate or acetic acid Butyl ester; the substituted C 1 -C 4 alkyl, the substituent of which is phenyl or/and carboxylic acid or its ester.
  • the R 1 and R 2 are each independently a C 1 -C 6 alkyl group.
  • a heptamethine indole cyanine of the present invention or a derivative thereof or a pharmaceutically acceptable salt thereof is used in the manufacture of an antibacterial drug, and the derivative or a pharmaceutically acceptable salt thereof is selected from the following compounds:
  • the use of the present invention further includes combining heptamethine indole cyanine or its derivatives or pharmaceutically acceptable salts with other antibiotics, or forming a composition or compound preparation.
  • the other antibiotics For ⁇ -lactam antibiotics.
  • the ⁇ -lactam antibiotics include, but are not limited to, procaine penicillin, benzathine penicillin, oxacillin sodium, cloxacillin sodium, dicloxacillin, flucloxacillin, ampicillin, amoxicillin, pampicillin , carbenicillin, furbenicillin, sulbenicillin, ticarcillin, mecillin, cefalotin sodium, cefotaxime, cefazolin, cefradine, cefadroxil, cefamandole, cefuroxime, cefaclor, Cefotaxime, ceftriaxone, ceftazidime, cefoperazone, cefoxitin, latamoxef, imipenem, aztreonam.
  • the heptamethine indole cyanine compound has good anti-gram-positive bacteria such as MRSA, the effect of gram-negative bacteria such as Escherichia coli E.coli, Pseudomonas aeruginosa P.A., It even represents that the anti-MRSA effect of compounds 13, 16, and 22 is better or equivalent to that of the "ace antibiotic" vancomycin for the treatment of MRSA infection; on the other hand, when it is used in combination with ⁇ -lactam antibiotics, it can increase the anti-MRSA effect Sensitivity to ⁇ -lactam antibiotics. Therefore, this provides new research ideas and drug selection for clinical medication.
  • Figure 1 shows the antibacterial effect of heptamethine indole cyanine molecules 5 and 13 combined with ⁇ -lactam antibiotics on MRSA 252;
  • Fig. 2 is the antibacterial effect of heptamethine indole cyanine molecules 15, 22 and ⁇ -lactam antibiotics on MRSA 252;
  • Fig. 3 is the antibacterial effect of heptamethine indole cyanine molecules 6, 24 and ⁇ -lactam antibiotics in combination on MRSA 252;
  • Figure 4 shows the antibacterial effect of heptamethine indole cyanine molecules on Escherichia coli and Pseudomonas aeruginosa.
  • HRMS High resolution mass spectrum
  • Heptamethine indole cyanine compounds 1-4, 6-19, and 22-25 were prepared according to the preparation methods disclosed in CN102268191A, CN105566938A and CN105566938.
  • the preparation methods of the new heptamethine indole cyanine compounds 5,20-21,26 are as follows:
  • the product (c) was directly subjected to the next reaction without purification. Take product c (about 2mM) and add it to a 100ml single-mouth round bottom bottle, add 1mM chlorinated bisaldehyde condensing agent (d), add 2mM anhydrous sodium acetate, add 30ml absolute ethanol, stir at 70°C, and react for 4h. The reaction solution was transferred to a separatory funnel, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated by filtration under reduced pressure, and column chromatographed to obtain compound 5 as a dark green solid.
  • Embodiment 2 antibacterial activity test
  • test methods and standards are as follows:
  • the final concentrations of drugs in wells 1 to 10 are 512, 256, 128, 64, 32, 16, 8, 4, 2, 1 , 0.5 ⁇ g/mL, after adding the drug, place it in a 37°C incubator and incubate for 18-24 hours, read the positive and negative control wells, the negative control wells are clear, and the positive control wells are turbid.
  • the MIC of a drug against bacteria is the lowest drug concentration that inhibits the growth of bacteria visible to the naked eye within 18 to 24 hours. The results are shown in Table 1.
  • heptamethine indole cyanine molecule 5 (compound 5) (2 ⁇ g/mL), heptamethine indole cyanine molecule 13 (compound 13) (0.25 ⁇ g/mL), heptamethine indole cyanine molecule 15 (compound 15) (4 ⁇ g/mL), heptamethine indole cyanine molecule 22 (compound 22) (2 ⁇ g/mL), heptamethine indole cyanine molecule 6 ( Compound 6) (8 ⁇ g/mL), heptamethine indole cyanine molecule 24 (compound 24) (2 ⁇ g/mL), CFT (64 ⁇ g/mL), VAN (0.5 ⁇ g/mL) were added to the bacterial suspension, and after adding OD values were measured at 12h, 16h, 18h, and 24
  • Fig. 1 The antibacterial effect of ⁇ -lactam antibiotics and heptamethine indole cyanine molecules 5 and 13 on MRSA252
  • Fig. 2 The combination of ⁇ -lactam antibiotics and heptamethine indole cyanine molecules 15 and 22 on MRSA The antibacterial effect of 252
  • Figure 3 The antibacterial effect of ⁇ -lactam antibiotics and heptamethine indole cyanine molecules 6 and 24 on MRSA 252 when used in combination.
  • the present invention finds that heptamethine indole cyanine compounds have good antibacterial effect on MRSA, especially when these compounds are used in combination with ⁇ -lactam compounds, they can increase the sensitivity of MRSA to oxacillin.
  • the broth microwell two-fold dilution method and the agarose dilution method were used.
  • Broth microwell two-fold dilution method adjust the bacterial concentration to 1 ⁇ 10 5 CFU/mL, inoculate in a 96-well sterile culture plate, and mix ampicillin and heptamethine indole cyanine molecules (compounds 1, 4, 8, 10, 14, 15, 17, 21, 25) into the bacterial culture wells, and then serially diluted, the final concentrations of the drugs in the 1st to 10th wells were 512, 256, 128, 64, 32, 16, 8, 4, 2, 1, 0.5 ⁇ g/mL, after adding the drug, incubate in a 37°C incubator for 18-24 hours, read the positive and negative control wells, the negative control wells are clear, and the positive control wells are turbid.
  • the MIC of a drug against bacteria is the lowest drug concentration that inhibits the growth of bacteria visible to the naked eye within 18 to 24 hours. The results are shown in Table 2.
  • Table 2 The MIC of heptamethine indole cyanine molecules on Escherichia coli E.Coli 35218 and Pseudomonas aeruginosa P.A
  • Table 2 shows that the antibacterial effect of heptamethine indole cyanine molecules (compounds 10, 15, 25) on Gram-negative bacteria Escherichia coli 35218 and Pseudomonas aeruginosa P.A is better than that of ampicillin.
  • Agarose dilution method Dilute heptamethine indole cyanine molecules (compounds 10, 15, 25) to the corresponding concentration and prepare them on the agarose plate, adjust the bacterial concentration to 11*10 6 cfu/ml and inoculate the plate in 10ul37 Incubate in an incubator at °C for 18-24 hours, read the positive and negative control wells, the negative control wells have no colony growth, and the positive control wells have colony growth, and observe the inhibition of the drug on bacterial growth. The results are shown in Figure 4.
  • the heptamethine indole cyanine compounds of the present invention have strong antibacterial activity, especially the inhibitory activity against drug-resistant bacteria MRSA, especially when the heptamethine indole cyanine compounds are used in combination with ⁇ -lactam antibiotics.
  • the powerful synergistic antibacterial effect produced by these drugs, its antibacterial activity is significantly better than clinical antibiotic drugs oxacillin (Oxacillin, OXA), cefoxitin (cefoxitin, CFT), some even better than or equivalent to vancomycin (Vancomycin, VAN) antibacterial activity.
  • OXA oxacillin
  • cefoxitin cefoxitin
  • VAN vancomycin antibacterial activity
  • the compounds belong to the derivatives of the clinically used drug indocyanine green (ICG), and have development and application prospects.

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Abstract

Disclosed is a use of heptamethine indocyanine compounds in the preparation of antibacterial drugs, wherein the heptamethine indocyanine compounds have a strong synergistic antibacterial effect with β-lactam antibiotics.

Description

[根据细则37.2由ISA制定的发明名称]　一种七甲川吲哚花菁或其衍生物的抗菌用途[Title of the invention established by ISA under Rule 37.2] Antibacterial use of a heptamethine indole cyanine or derivatives thereof 技术领域technical field
本发明属于医药技术领域，具体涉及一种七甲川吲哚花菁或其衍生物在制备抗菌药物中的用途，包括与β-内酰胺类抗生素联合使用抗细菌的用途。The invention belongs to the technical field of medicine, and specifically relates to the use of heptamethine indole cyanine or its derivatives in the preparation of antibacterial drugs, including the use of antibacterial drugs in combination with β-lactam antibiotics.
背景技术Background technique
自1961年发现了第一株耐甲氧西林金黄色葡萄球菌The first methicillin-resistant Staphylococcus aureus was discovered in 1961
(Methicillin-resistant Staphylococcus aureus,MRSA)后，20世纪80年代至今,MRSA已成为全球医院感染的重要病原菌。MRSA对包括青霉素、头孢菌素和头霉素类等β-内酰胺类、氨基糖苷类、喹诺酮类抗菌药物都存在不同程度的耐药。万古霉素是治疗MRSA感染的最后防线，但从2002开始，全球陆续检出耐万古霉素的金黄色葡萄球菌。因此，寻找开发治疗MRSA感染的新型抗菌药物迫在眉睫。(Methicillin-resistant Staphylococcus aureus, MRSA), from the 1980s to the present, MRSA has become an important pathogen of hospital infection in the world. MRSA has varying degrees of resistance to β-lactams, aminoglycosides, and quinolones, including penicillins, cephalosporins, and cephamycins. Vancomycin is the last line of defense in the treatment of MRSA infection, but since 2002, vancomycin-resistant Staphylococcus aureus has been detected in succession around the world. Therefore, it is imminent to find and develop new antibacterial drugs for the treatment of MRSA infection.
吲哚菁绿(Indocyanine Green，ICG)是美国FDA,包括中国SFDA唯一批准临床上使用的七甲川吲哚花菁分子。由于其高灵敏的近红外荧光特性和优异的生物相容性，ICG在血管造影、肝功能检测等方面已经临床应用了近半个世纪。近十年，本专利申请人及同行领域科研人员一直聚焦于ICG的结构衍生合成，制备并报道了一类同步具有肿瘤靶向、成像、化疗作用的新型七甲川吲哚花菁小分子，为肿瘤早期诊断与靶向治疗提供可能性。近期研究还发现，ICG及其某些七甲川吲哚花菁类似物具有优异光敏特性，即在激光照射下诱导产生大量杀伤性的反应活性氧(ROS)或局部高温高热作用，从而分别发挥光动力(PDT)或光热治疗(PTT)肿瘤、抗菌、促进感染创面愈合等研究，例如：Indocyanine Green (Indocyanine Green, ICG) is the only heptamethine indolecyanine molecule approved by the US FDA, including the Chinese SFDA for clinical use. Due to its highly sensitive near-infrared fluorescence characteristics and excellent biocompatibility, ICG has been clinically used in angiography and liver function testing for nearly half a century. In the past ten years, the applicant of this patent and researchers in the same field have been focusing on the structure derivation and synthesis of ICG, and have prepared and reported a new class of heptamethine indole cyanine small molecules with simultaneous tumor targeting, imaging and chemotherapy effects. Early tumor diagnosis and targeted therapy offer possibilities. Recent studies have also found that ICG and some of its heptamethine indole cyanine analogs have excellent photosensitivity properties, that is, they induce a large number of lethal reactive oxygen species (ROS) or local high temperature and hyperthermia under laser irradiation, thereby exerting photosensitive properties respectively. Power (PDT) or photothermal therapy (PTT) research on tumors, antibacterial, and promotion of infected wound healing, such as:
CN102268191A本发明涉及一类含N-脂肪酯或N-脂肪酰胺侧链的七甲川吲 哚花菁染料及其合成方法和其在肿瘤靶向成像和治疗中的用途。CN102268191A The invention relates to a class of heptamethine indole cyanine dyes containing N-fatty ester or N-fatty amide side chains, their synthesis method and their application in tumor targeting imaging and treatment.
CN105566938A本发明涉及一类线粒体靶向的七甲川吲哚花菁染料和制备方法及应用，所述七甲川吲哚花菁染料由线粒体靶向的吲哚七甲川链和不同长度的N-烷基侧链构成。所述七甲川吲哚花菁染料是以肿瘤线粒体为靶向，在近红外荧光成像引导下，同步实现精确高效的光热和光动力抗肿瘤作用的多功能有机小分子。CN105566938A The invention relates to a class of mitochondria-targeted heptamethine indole cyanine dyes and a preparation method and application thereof. The heptamethine indole cyanine dyes are composed of mitochondria-targeted indole heptamethine chains and N-alkyl groups of different lengths side chain composition. The heptamethine indole cyanine dye is a multifunctional organic small molecule that targets tumor mitochondria and simultaneously realizes precise and efficient photothermal and photodynamic anti-tumor effects under the guidance of near-infrared fluorescence imaging.
CN106511337A本发明所述一类七甲川吲哚花菁染料，通过对线粒体靶向的近红外七甲川吲哚花菁染料烷基侧链进行修饰，合成上述3种能够促进细胞抗氧化应激损伤，减轻炎症损伤，促进组织再生修复的小分子荧光化合物。CN106511337A A class of heptamethine indole cyanine dyes described in the present invention, by modifying the alkyl side chains of mitochondria-targeted near-infrared heptamethine indole cyanine dyes, synthesizing the above three kinds can promote cell resistance to oxidative stress damage, A small molecule fluorescent compound that reduces inflammatory damage and promotes tissue regeneration and repair.
尽管前期已报道大量ICG类(七甲川吲哚花菁类)小分子类似物的化学合成及其各种生物医学医用，与生俱有抗菌活性的七甲川吲哚花菁分子未见报道。据文献调研发现，目前仅有ICG作为光敏剂(非本身具有抗菌活性)进行光热或光动力杀伤细菌及抗感染的报道，而本身具有抗生素活性的七甲川吲哚花菁分子未见报道。由于光疗需要配备特定照射光源和场所，并且由于光穿透组织能力非常有限，仅局限治疗浅表组织的肿瘤或感染，使其应用受到严重限制。本专利旨在报道并保护某些ICG类七甲川吲哚花菁分子，无需借助光疗或者外部手段，本身作为潜在的抗生素候选分子，在抗菌以及联合其他抗生素的抗菌用途与作用特性。上述新型功能性七甲川吲哚花菁化合物具有分子量小、合成方法简单、制备成本低、抗菌性能优异和广泛等优点，具有良好的转化应用前景。Although the chemical synthesis of a large number of ICG (heptamethine indole cyanines) small molecule analogues and their various biomedical applications have been reported in the early stage, no heptamethine indole cyanine molecules with inherent antibacterial activity have been reported. According to literature research, only ICG has been reported as a photosensitizer (not having antibacterial activity itself) for photothermal or photodynamic killing of bacteria and anti-infection, while the heptamethine indole cyanine molecule itself has antibiotic activity has not been reported. Because phototherapy needs to be equipped with a specific light source and location, and because the ability of light to penetrate tissue is very limited, it is only limited to the treatment of tumors or infections in superficial tissues, so its application is severely limited. This patent aims to report and protect certain ICG-like heptamethine indole cyanine molecules, without the need for phototherapy or external means, as potential antibiotic candidate molecules, and their antibacterial and antibacterial properties in combination with other antibiotics. The above-mentioned novel functional heptamethine indole cyanine compound has the advantages of small molecular weight, simple synthesis method, low preparation cost, excellent and wide antibacterial performance, etc., and has good prospects for transformation and application.
发明内容Contents of the invention
本发明的目的在于提供一种七甲川吲哚花菁及其衍生物或其药学上可接受的盐在制造抗革兰阳性菌如Methicillin resistant staphylococcus aureus(MRSA)，革兰阴性菌如大肠埃希菌Escherichia coli(E.coli)、铜绿假单胞菌P.Aeruginosa(P.A.)的用途，特别是与β-内酰胺类抗生素联合抗菌的用途。联合用药时表现出的协同抗菌作用。The object of the present invention is to provide a kind of heptamethine indole cyanine and derivatives thereof or pharmaceutically acceptable salt thereof in the manufacture of anti-gram-positive bacteria such as Methicillin resistant staphylococcus aureus (MRSA), gram-negative bacteria such as Escherichia coli The use of bacteria Escherichia coli (E.coli), Pseudomonas aeruginosa P.Aeruginosa (P.A.), especially the combined antibacterial use with β-lactam antibiotics. Synergistic antibacterial effect when used in combination.
本发明的一种七甲川吲哚花菁及其衍生物或其药学上可接受的盐在制造抗菌药物(即抗细菌感染药物)中的用途，所述七甲川吲哚花菁或其衍生物为式I所示的化合物，The use of a heptamethine indole cyanine and its derivatives or a pharmaceutically acceptable salt thereof of the present invention in the manufacture of antibacterial drugs (i.e. anti-bacterial infection drugs), the heptamethine indole cyanine or its derivatives For the compound shown in formula I,
Figure PCTCN2022100605-appb-000001
Figure PCTCN2022100605-appb-000001
式中，R 1，R 2相同或不同，各自独立选自C 2-C 11的脂肪链、C 2-C 11脂肪羧酸、C 2-C 11脂肪醚烃、C 2-C 11脂肪羧酸酯、C 2-C 11脂肪羧酸酰胺等中的任意一种,X为溴原子、碘原子、氯原子或高氯酸离子。优选的，所述菌为抗革兰阳性菌如Methicillin resistant staphylococcus aureus(MRSA)，革兰阴性菌如大肠埃希菌Escherichia coli(E.coli)和/或铜绿假单胞菌P.Aeruginosa(P.A.)。 In the formula, R 1 and R 2 are the same or different, each independently selected from C 2 -C 11 aliphatic chain, C 2 -C 11 fatty carboxylic acid, C 2 -C 11 fatty ether hydrocarbon, C 2 -C 11 fatty carboxyl Any one of esters, C 2 -C 11 fatty carboxylic acid amides, etc., X is bromine atom, iodine atom, chlorine atom or perchlorate ion. Preferably, the bacteria are anti-gram-positive bacteria such as Methicillin resistant staphylococcus aureus (MRSA), gram-negative bacteria such as Escherichia coli Escherichia coli (E.coli) and/or Pseudomonas aeruginosa P.Aeruginosa (PA ).
在一些实施方案中，上述本发明的用途，式I中，X为溴原子、碘原子、氯原子或高氯酸离子，R 1、R 2侧链可相同，为对称结构，也可不相同，即为非对称结构。当R 1、R 2为对称结构时，R 1，R 2结构一致，可为C 2-C 11的脂肪链(如化合物1-2)、脂肪羧酸(如化合物3-5)、脂肪醚烃(如化合物7-9)、脂肪羧酸酯(如化合物10-14)、脂肪羧酸酰胺(如化合物15-19)、脂肪末端含氮杂环(如化合物20-22)；其中醚烃、羧酸酯、羧酸酰胺结构为1-6碳链长的烷基、苯基、羧基取代苯基、卤素取代苯基、含氮杂环等中的任意一种。当R 1、R 2为不对称结构时，R 1、R 2结构不一致，R 1，R 2可分别为C 2-C 11的脂肪链(如化合物23)、脂肪醚烃(如化合物24)、脂肪羧酸酯(如化合物25)或脂肪含氮杂环(如化合物26)，其中，醚烃、羧酸酯为C 1-C 6烷基、苯基、羧基取代苯基、卤素取代苯基或含氮杂环。 In some embodiments, the above-mentioned uses of the present invention, in formula I, X is a bromine atom, iodine atom, chlorine atom or perchlorate ion, and the side chains of R 1 and R 2 can be the same, symmetrical structures, or different, That is an asymmetric structure. When R 1 and R 2 are symmetrical structures, R 1 and R 2 have the same structure and can be C 2 -C 11 aliphatic chain (such as compound 1-2), fatty carboxylic acid (such as compound 3-5), fatty ether Hydrocarbons (such as compounds 7-9), fatty carboxylic acid esters (such as compounds 10-14), fatty carboxylic acid amides (such as compounds 15-19), aliphatic terminal nitrogen-containing heterocycles (such as compounds 20-22); , carboxylic acid ester, carboxylic acid amide structure is any one of alkyl, phenyl, carboxyl-substituted phenyl, halogen-substituted phenyl, nitrogen-containing heterocycle, etc. with a chain length of 1-6 carbons. When R 1 and R 2 are asymmetric structures, the structures of R 1 and R 2 are inconsistent, and R 1 and R 2 can be respectively C 2 -C 11 aliphatic chains (such as compound 23), aliphatic ether hydrocarbons (such as compound 24) , aliphatic carboxylate (such as compound 25) or aliphatic nitrogen-containing heterocycle (such as compound 26), wherein, ether hydrocarbon, carboxylate is C 1 -C 6 alkyl, phenyl, carboxyl substituted phenyl, halogen substituted benzene group or nitrogen-containing heterocycle.
在一些优选实施方案中，本发明的用途，所述七甲川吲哚花菁或其衍生物为式I所示的化合物或它们的药用盐，In some preferred embodiments, for the purposes of the present invention, the heptamethine indole cyanine or its derivatives are compounds represented by formula I or their pharmaceutically acceptable salts,
Figure PCTCN2022100605-appb-000002
Figure PCTCN2022100605-appb-000002
式中，R 1和R 2或以相同或不同，各自独立的代表未取代或取代的烷基，所述取代的取代基为COR 3、COOR 3、CONR 3或
Figure PCTCN2022100605-appb-000003
In the formula, R 1 and R 2 may be the same or different, each independently represents an unsubstituted or substituted alkyl group, and the substituted substituent is COR 3 , COOR 3 , CONR 3 or
Figure PCTCN2022100605-appb-000003
其中，所述R 3为H，未取代或取代的C 1-C 4烷基，未取代或由甲酸、甲酸酯或卤素取代的苯基，乙酸酯，
Figure PCTCN2022100605-appb-000004
Wherein, the R 3 is H, unsubstituted or substituted C 1 -C 4 alkyl, unsubstituted or phenyl substituted by formic acid, formate or halogen, acetate,
Figure PCTCN2022100605-appb-000004
X为溴、氯、碘或高氯酸。X is bromine, chlorine, iodine or perchloric acid.
在一些优选实施方案中，本发明的的用途，所述甲酸酯为甲酸甲酯、甲酸乙酯、甲酸丙酯；所述乙酸酯为乙酸甲酯、乙酸乙酯、乙酸丙酯或乙酸丁酯；所述取代的C 1-C 4烷基，其取代基为苯基或/和羧酸或其酯。 In some preferred embodiments, the purposes of the present invention, the formate is methyl formate, ethyl formate, propyl formate; The acetate is methyl acetate, ethyl acetate, propyl acetate or acetic acid Butyl ester; the substituted C 1 -C 4 alkyl, the substituent of which is phenyl or/and carboxylic acid or its ester.
在一些优选实施方案中，本发明的用途，所述R 1和R 2，各自独立为C 1-C 6烷基。 In some preferred embodiments, in the use of the present invention, the R 1 and R 2 are each independently a C 1 -C 6 alkyl group.
在一些具体实施方案中，本发明的一种七甲川吲哚花菁或其衍生物或其药用盐在制造抗菌药物中的用途，所述衍生物或其药用盐选自下列化合物：In some specific embodiments, a heptamethine indole cyanine of the present invention or a derivative thereof or a pharmaceutically acceptable salt thereof is used in the manufacture of an antibacterial drug, and the derivative or a pharmaceutically acceptable salt thereof is selected from the following compounds:
Figure PCTCN2022100605-appb-000005
Figure PCTCN2022100605-appb-000005
Figure PCTCN2022100605-appb-000006
Figure PCTCN2022100605-appb-000006
Figure PCTCN2022100605-appb-000007
Figure PCTCN2022100605-appb-000007
在一些实施方案中，本发明的用途，进一步包括将七甲川吲哚花菁或其衍生物或其药用盐与其它抗生素联合用药，或形成组合物或复方制剂，优选的，所述其它抗生素为β-内酰胺类抗生素。In some embodiments, the use of the present invention further includes combining heptamethine indole cyanine or its derivatives or pharmaceutically acceptable salts with other antibiotics, or forming a composition or compound preparation. Preferably, the other antibiotics For β-lactam antibiotics.
所述β-内酰胺类抗生素包括但不限于普鲁卡因青霉素、苄星青霉素、苯唑西林钠、氯唑西林钠、双氯西林、氟氯西林、氨苄西林、阿莫西林、匹氨西林、羧苄西林、呋苄西林、磺苄西林、替卡西林、美西林、头孢噻吩钠、头孢噻啶、头孢唑啉、头孢拉定、头孢羟氨苄、头孢孟多、头孢呋辛、头孢克洛、头孢噻肟、头孢曲松、头孢他定、头孢哌酮、头孢西丁、拉氧头孢、亚胺培南、氨曲南。The β-lactam antibiotics include, but are not limited to, procaine penicillin, benzathine penicillin, oxacillin sodium, cloxacillin sodium, dicloxacillin, flucloxacillin, ampicillin, amoxicillin, pampicillin , carbenicillin, furbenicillin, sulbenicillin, ticarcillin, mecillin, cefalotin sodium, cefotaxime, cefazolin, cefradine, cefadroxil, cefamandole, cefuroxime, cefaclor, Cefotaxime, ceftriaxone, ceftazidime, cefoperazone, cefoxitin, latamoxef, imipenem, aztreonam.
上世纪八十年代以后，抗生素的研发进入瓶颈，少有全新结构抗生素问世。并且在药物使用过程中，细菌对新抗生素又会产生不同程度耐药。本发明的用途，一方面发现七甲川吲哚花菁类化合物具有很好的抗革兰阳性菌如MRSA，革兰阴性菌如大肠埃希菌E.coli、铜绿假单胞菌P.A.的作用，甚至代表化合物13、16、22的抗MRSA效应与治疗MRSA感染的“王牌抗生素”万古霉素更优或相当；另一方面，当其与β-内酰胺类抗生素联合使用时，可以增加MRSA对β-内酰胺类抗生素的敏感性。因此，这为临床用药提供新的研究思路和药物选择。After the 1980s, the research and development of antibiotics entered a bottleneck, and few antibiotics with new structures came out. And in the process of drug use, bacteria will develop resistance to new antibiotics to varying degrees. The purposes of the present invention, on the one hand, find that the heptamethine indole cyanine compound has good anti-gram-positive bacteria such as MRSA, the effect of gram-negative bacteria such as Escherichia coli E.coli, Pseudomonas aeruginosa P.A., It even represents that the anti-MRSA effect of compounds 13, 16, and 22 is better or equivalent to that of the "ace antibiotic" vancomycin for the treatment of MRSA infection; on the other hand, when it is used in combination with β-lactam antibiotics, it can increase the anti-MRSA effect Sensitivity to β-lactam antibiotics. Therefore, this provides new research ideas and drug selection for clinical medication.
附图说明Description of drawings
图1为七甲川吲哚花菁分子5、13与β-内酰胺类抗生素联合使用对MRSA 252的抗菌作用；Figure 1 shows the antibacterial effect of heptamethine indole cyanine molecules 5 and 13 combined with β-lactam antibiotics on MRSA 252;
图2为七甲川吲哚花菁分子15、22与β-内酰胺类抗生素联合使用对MRSA 252的抗菌作用；Fig. 2 is the antibacterial effect of heptamethine indole cyanine molecules 15, 22 and β-lactam antibiotics on MRSA 252;
图3为七甲川吲哚花菁分子6、24与β-内酰胺类抗生素联合使用对MRSA 252的抗菌作用；Fig. 3 is the antibacterial effect of heptamethine indole cyanine molecules 6, 24 and β-lactam antibiotics in combination on MRSA 252;
图4为七甲川吲哚花菁分子对大肠埃希菌、铜绿假单胞菌的抗菌作用。Figure 4 shows the antibacterial effect of heptamethine indole cyanine molecules on Escherichia coli and Pseudomonas aeruginosa.
具体实施方式detailed description
以下实施例仅是代表性的，用于进一步说明和理解本发明的实质，但不以任何方式限制本发明的范围。The following examples are only representative, and are used to further illustrate and understand the essence of the present invention, but do not limit the scope of the present invention in any way.
实施例中所采用的试剂与仪器：Reagent and instrument adopted in the embodiment:
除了溶剂乙醇、甲苯、正丁醇、二氯甲烷、甲醇经过蒸馏纯化与干燥处理以 外，其他所涉及的化学试剂和溶剂购买于sigma-aldrich或阿拉丁等试剂公司并直接使用；Except for the solvent ethanol, toluene, n-butanol, dichloromethane, and methanol, which were purified by distillation and dried, other chemical reagents and solvents involved were purchased from reagent companies such as sigma-aldrich or Aladdin and used directly;
所有反应均处于氮气及避光保护条件下进行，且硅胶薄层层析监测至反应结束。All reactions were carried out under nitrogen and protected from light, and were monitored by silica gel thin-layer chromatography until the end of the reaction.
柱层析用于染料分子的最终纯化，采用烟台市芝罘黄务硅胶开发试验厂生产的层析硅胶(10－40μ)。层析用有机溶剂均为分析纯，且经过重蒸干燥处理。Column chromatography is used for the final purification of dye molecules, and chromatography silica gel (10-40 μ) produced by Yantai Zhifu Huangwu Silica Gel Development and Experimental Factory is used. The organic solvents used in chromatography were all analytically pure, and were dried by reevaporation.
所有化合物 1H NMR由美国Varian公司生产的Mercury Plus-400核磁共振谱仪测定，TMS作内标，未经特殊说明，均用CDCl 3作溶剂，δ值单位为ppm。 All compounds 1 H NMR were measured by Mercury Plus-400 nuclear magnetic resonance spectrometer produced by Varian Company of the United States, TMS was used as internal standard, and CDCl 3 was used as solvent unless otherwise specified, and the unit of δ value was ppm.
高分辨质谱(HRMS)由HP5989A型质谱仪测定，IR由Testscan Schimadzu FTIR8000series测定。High resolution mass spectrum (HRMS) was determined by HP5989A mass spectrometer, and IR was determined by Testscan Schimadzu FTIR8000series.
实施例1化合物的制备The preparation of embodiment 1 compound
根据CN102268191A、CN105566938A和CN105566938公开的制备方法制备七甲川吲哚花菁化合物1-4,6-19，22-25。新七甲川吲哚花菁化合物5,20-21,26的制备方法分别如下：Heptamethine indole cyanine compounds 1-4, 6-19, and 22-25 were prepared according to the preparation methods disclosed in CN102268191A, CN105566938A and CN105566938. The preparation methods of the new heptamethine indole cyanine compounds 5,20-21,26 are as follows:
化合物5的制备：Preparation of Compound 5:
Figure PCTCN2022100605-appb-000008
Figure PCTCN2022100605-appb-000008
取3.84g(2.41×10 -2mol)2,3,3-三甲基-3H-吲哚(a)于100ml单口圆底瓶中，加入2.89×10 -2mol溴代11碳烷酸(b),加入30ml甲苯，110℃下反应12h,取样薄层层析(TLC)监控反应(二氯甲烷：甲醇＝15:1)，显示原料反应完全，旋蒸蒸除甲苯，得红棕色粘稠液体，用二氯甲烷-乙醚粗略重结晶得红棕色粘稠液体。产品(c)不经纯化直接进行下一步反应。取产品c(约2mM)加入100ml 单口圆底瓶中，加入1mM氯代双醛缩合剂(d),加入2mM无水乙酸钠，加入30ml无水乙醇，70℃下搅拌，反应4h。将反应液转移至分液漏斗中，用饱和氯化钠溶液洗涤，无水硫酸钠干燥，减压过滤浓缩，柱层析得墨绿色固体化合物5。 Take 3.84g (2.41×10 -2 mol) 2,3,3-trimethyl-3H-indole (a) in a 100ml single-necked round bottom bottle, add 2.89×10 -2 mol bromo-11-carbonic acid ( b), adding 30ml of toluene, reacting at 110°C for 12h, sampling the thin layer chromatography (TLC) to monitor the reaction (dichloromethane:methanol=15:1), showing that the raw materials were completely reacted, and the toluene was removed by rotary steaming to obtain a reddish-brown viscous Viscous liquid, roughly recrystallized with dichloromethane-ether to give reddish-brown viscous liquid. The product (c) was directly subjected to the next reaction without purification. Take product c (about 2mM) and add it to a 100ml single-mouth round bottom bottle, add 1mM chlorinated bisaldehyde condensing agent (d), add 2mM anhydrous sodium acetate, add 30ml absolute ethanol, stir at 70°C, and react for 4h. The reaction solution was transferred to a separatory funnel, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated by filtration under reduced pressure, and column chromatographed to obtain compound 5 as a dark green solid.
5(收率13.8％)， 1H NMR(400Hz,DMSO-d6)δ：8.26(d,J＝14.4Hz,2H),7.64(d,J＝7.2Hz,2H),7.47-7.41(m,4H),7.29(t,J＝7.6Hz,2H),6.33(d,J＝14.4Hz,2H),4.22(s，4H),2.71(s,4H),2.16(t,J＝7.6Hz,4H),1.86(s,2H),1.73-1.71(m,4H),1.67(s,12H),1.46(s,4H),1.34(s,8H),1.23(s,16H)；HRMS[M-Br]+：calculated 823.5175,found 823.4864。 5 (yield 13.8%), 1 H NMR (400Hz, DMSO-d6) δ: 8.26(d, J=14.4Hz, 2H), 7.64(d, J=7.2Hz, 2H), 7.47-7.41(m, 4H), 7.29(t, J=7.6Hz, 2H), 6.33(d, J=14.4Hz, 2H), 4.22(s, 4H), 2.71(s, 4H), 2.16(t, J=7.6Hz, 4H), 1.86(s,2H), 1.73-1.71(m,4H), 1.67(s,12H), 1.46(s,4H), 1.34(s,8H), 1.23(s,16H); HRMS[M -Br]+: calculated 823.5175, found 823.4864.
化合物20-21的制备：Preparation of Compound 20-21:
Figure PCTCN2022100605-appb-000009
Figure PCTCN2022100605-appb-000009
向50mL的反应瓶中加入17.69mmol的2-硝基咪唑(a)及35.38mmol的碳酸钾固体，氮气保护下加入15mL的N,N-二甲基甲酰胺(DMF)并搅拌溶解，随后加入70.76mmol的二溴代物(b1-b2)，完毕后于60℃下加热反应。5-6h后TLC监测反应结束。减压抽滤，并用丙酮洗涤固体。残留物柱分离纯化(正己醇：乙 酸乙酯＝2：1)得化合物c1(38.3％)及c2(47.3％)。Add 17.69mmol of 2-nitroimidazole (a) and 35.38mmol of solid potassium carbonate to a 50mL reaction flask, add 15mL of N,N-dimethylformamide (DMF) under nitrogen protection and stir to dissolve, then add 70.76 mmol of the dibromo compound (b1-b2), after completion, the reaction was heated at 60°C. After 5-6h, TLC monitored the reaction to be complete. Suction filtration under reduced pressure, and wash the solid with acetone. The residue was separated and purified by column (n-hexanol:ethyl acetate=2:1) to obtain compounds c1 (38.3%) and c2 (47.3%).
取25ml的反应瓶(含回流冷凝装置)，加入化合物c1或c2(5.45mmol),吲哚(d,3.66mmol)。氮气保护下加入7ml邻二氯苯溶解，于110℃下加热搅拌反应。10h后停止反应，反应液冷却至室温，直接减压浓缩除去溶剂。残留物用异丙醚洗涤，干燥得目标化合物粗品(e1、e2)。不需要进一步纯化即可进行下一步反应。Take a 25ml reaction flask (with reflux condenser), add compound c1 or c2 (5.45mmol), indole (d, 3.66mmol). Under the protection of nitrogen, 7ml o-dichlorobenzene was added to dissolve, and the reaction was heated and stirred at 110°C. After 10 h, the reaction was stopped, and the reaction solution was cooled to room temperature, and concentrated under reduced pressure to remove the solvent. The residue was washed with isopropyl ether and dried to obtain the crude target compound (e1, e2). The next reaction was carried out without further purification.
250ml反应瓶中加入500mg的c1或者c2，0.5mol缩合剂(f)，以正丁醇/甲苯(7ml:3ml)作溶剂，于130℃下加热回流反应。6h后反应液冷却至室温，减压蒸馏除去溶剂，经柱层纯化得墨绿色固体(20、21)。Add 500mg of c1 or c2, 0.5mol condensing agent (f) to a 250ml reaction bottle, use n-butanol/toluene (7ml:3ml) as solvent, and heat to reflux at 130°C for reaction. After 6 hours, the reaction liquid was cooled to room temperature, the solvent was distilled off under reduced pressure, and the dark green solid (20, 21) was obtained by column purification.
20(yield 18％). 1HNMR(400Hz,CDCl 3):8.25(d,J＝8.0Hz,1H)；7.74(S,2H)；7.62(d,J＝8.0Hz,2H)；7.45-7.42(m,4H)；7.27(t,J＝4.0Hz,2H)；7.19(s,2H)；6.24(d,J＝12.0Hz,2H)；4.53(t,J＝4.0Hz,4H)；4.31(J＝4.0Hz,4H)；2.65(t,J＝4.0Hz,4H)；2.28-2.25(m,4H),1.84-1.83(m,2H)；1.66(s,12H).HRMS[M-Br] +：calculated 761.3325,found 761.3354. 20 (yield 18%). 1 HNMR (400Hz, CDCl 3 ): 8.25 (d, J=8.0Hz, 1H); 7.74 (S, 2H); 7.62 (d, J=8.0Hz, 2H); 7.45-7.42 (m,4H);7.27(t,J=4.0Hz,2H);7.19(s,2H);6.24(d,J=12.0Hz,2H);4.53(t,J=4.0Hz,4H);4.31 (J=4.0Hz, 4H); 2.65(t, J=4.0Hz, 4H); 2.28-2.25(m, 4H), 1.84-1.83(m, 2H); 1.66(s, 12H).HRMS[M- Br] + : calculated 761.3325, found 761.3354.
21(yield 26％). 1HNMR(400Hz,CDCl 3):8.22(d,J＝8.0Hz,2H)；7.67(s,2H)；7.61(d,J＝2Hz,2H)；7.43-7.40(m,4H)；7.27-7.25(m,2H)；7.15(s,2H)；7.29(d,J＝6.0Hz,2H)；4.34(t,J＝8.0Hz,4H)；4.18(t,J＝4.0Hz,4H)；2.66(t,J＝4.0Hz,4H)；1.83-1.82(m,2H)；1.76-1.69(m,8H)；1.64(s,12H)；1.42-1.39(m,4H)；1.33-1.30(m,4H).HRMS[M-Br] +： 21 (yield 26%). 1 HNMR (400Hz, CDCl 3 ): 8.22 (d, J=8.0Hz, 2H); 7.67 (s, 2H); 7.61 (d, J=2Hz, 2H); 7.43-7.40 ( m,4H); 7.27-7.25(m,2H); 7.15(s,2H); 7.29(d,J=6.0Hz,2H); 4.34(t,J=8.0Hz,4H); 4.18(t,J =4.0Hz,4H); 2.66(t,J=4.0Hz,4H);1.83-1.82(m,2H);1.76-1.69(m,8H);1.64(s,12H);1.42-1.39(m, 4H); 1.33-1.30(m,4H).HRMS[M-Br] + :
calculated 845.4264,found 845.4262.calculated 845.4264,found 845.4262.
化合物26的制备：Preparation of compound 26:
Figure PCTCN2022100605-appb-000010
Figure PCTCN2022100605-appb-000010
取24mM 2,3,3-三甲基-3H-吲哚(a)于100ml单口圆底瓶中，加入24mM 6-溴己酸,加入30ml甲苯，110℃下反应12h,取样TLC监控反应(二氯甲烷：甲醇＝15:1)，显示原料反应完全，旋蒸蒸除甲苯，得红棕色粘稠液体，用二氯甲烷-乙醚粗略重结晶得各吲哚季铵盐中间体(b)。不经纯化，取吲哚季铵盐中间物b(1mM)加入100ml单口圆底瓶中，加入1mM缩合剂(c),加入1mM无水乙酸钠，加入15ml无水乙醇，搅拌，75℃下反应6h，显示原料反应完全。将反应液转移至分液漏斗中，用饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，减压浓缩得红棕色液体，用二氯甲烷-乙醚粗略重结晶得红棕色固体，柱层析得红色固定化合物(e).取(1mM)化合物(e)、吲哚季铵盐中间物f(1mM)加入100ml单口圆底瓶中，加入1mM无水乙酸钠，加入15ml无水乙醇，搅拌，75℃下反应2h，显示原料反应完全。将反应液转移至分液漏斗中，用饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，减压浓缩得绿色固体，柱层析得绿色固定化合物(26).Take 24mM 2,3,3-trimethyl-3H-indole (a) in a 100ml single-necked round bottom bottle, add 24mM 6-bromohexanoic acid, add 30ml toluene, react at 110°C for 12h, take a sample TLC to monitor the reaction ( Dichloromethane:methanol=15:1), it shows that the raw materials have reacted completely, and the toluene is removed by rotary steaming to obtain a reddish-brown viscous liquid, which is roughly recrystallized with dichloromethane-ether to obtain each indole quaternary ammonium salt intermediate (b) . Without purification, take the indole quaternary ammonium salt intermediate b (1mM) and add it to a 100ml single-mouth round bottom bottle, add 1mM condensing agent (c), add 1mM anhydrous sodium acetate, add 15ml absolute ethanol, stir, at 75°C Reacted for 6h, showing that the reaction of raw materials was complete. The reaction solution was transferred to a separatory funnel, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a reddish-brown liquid, which was roughly recrystallized with dichloromethane-ether to obtain a reddish-brown solid. The red fixed compound (e) was separated. Get (1mM) compound (e), indole quaternary ammonium salt intermediate f (1mM) and add in 100ml single-mouth round bottom bottle, add 1mM anhydrous sodium acetate, add 15ml absolute ethanol, Stir and react at 75°C for 2h, which shows that the reaction of the raw materials is complete. The reaction solution was transferred to a separatory funnel, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give a green solid, and column chromatography gave a green fixed compound (26).
26(yield 18％). 1H NMR(400Hz,CDCl 3):8.45(s,2H)；8.22(d,J＝8.0Hz,2H)；7.62(s,1H)；7.61(s,1H)；7.47(d,J＝8.0Hz,2H)；7.42(t,J＝4.0Hz,2H)；7.28(t,J＝4.0Hz,2H)；6.14(d,J＝8.0Hz,2H)；4.24(d,J＝4Hz,4H)；4.17(d,J＝4Hz,4H)；2.59(d,J＝4.0Hz,4H)；2.37(s,12H)；2.22-2.20(m,4H)；1.79-1.77(m,2H)；1.67(s,12H).HRMS[M-Br]+：calculated 736.3624, found 736.3212. 26 (yield 18%). 1 H NMR (400Hz, CDCl 3 ): 8.45 (s, 2H); 8.22 (d, J=8.0Hz, 2H); 7.62 (s, 1H); 7.61 (s, 1H); 7.47(d, J=8.0Hz, 2H); 7.42(t, J=4.0Hz, 2H); 7.28(t, J=4.0Hz, 2H); 6.14(d, J=8.0Hz, 2H); 4.24( d,J=4Hz,4H); 4.17(d,J=4Hz,4H); 2.59(d,J=4.0Hz,4H); 2.37(s,12H);2.22-2.20(m,4H);1.79- 1.77(m,2H); 1.67(s,12H).HRMS[M-Br]+: calculated 736.3624, found 736.3212.
实施例2抗菌活性试验Embodiment 2 antibacterial activity test
测试化合物1-26的抗菌活性Testing the antibacterial activity of compounds 1-26
测试方法和标准如下：The test methods and standards are as follows:
(1)测定化合物1-26与抗生素单独使用时，对MRSA的最低抑菌浓度(minimal inhibitory concentration，MIC)(1) Determination of the minimum inhibitory concentration (minimal inhibitory concentration, MIC) to MRSA when compounds 1-26 and antibiotics are used alone
采用肉汤微孔二倍稀释法，调整细菌浓度为1×10 5CFU/mL，接种于96孔无菌培养板内，将七甲川吲哚花菁分子(化合物1-26号)和β-内酰胺类抗生素苯唑西林(Oxacillin，OXA)、头孢西丁(cefoxitin，CFT)、万古霉素(Vancomycin，VAN)用无菌水稀释。加入七甲川吲哚花菁分子至含细菌培养孔内，依次倍比稀释，第1～10孔药物的最终浓度依次为512、256、128、64、32、16、8、4、2、1、0.5μg/mL，加完药后置于37℃培养箱孵育18～24h，读取阳性和阴性对照孔，阴性对照孔清亮，阳性对照孔混浊。药物对细菌的MIC为18～24h抑制细菌肉眼可见生长的最低药物浓度。结果示于表1。 Using broth microwell double dilution method, adjust the bacterial concentration to 1×10 5 CFU/mL, inoculate in a 96-well sterile culture plate, heptamethine indole cyanine molecules (compound No. 1-26) and β- Lactam antibiotics oxacillin (Oxacillin, OXA), cefoxitin (cefoxitin, CFT), vancomycin (Vancomycin, VAN) were diluted with sterile water. Add heptamethine indole cyanine molecules to the culture wells containing bacteria, and then serially dilute, the final concentrations of drugs in wells 1 to 10 are 512, 256, 128, 64, 32, 16, 8, 4, 2, 1 , 0.5 μg/mL, after adding the drug, place it in a 37°C incubator and incubate for 18-24 hours, read the positive and negative control wells, the negative control wells are clear, and the positive control wells are turbid. The MIC of a drug against bacteria is the lowest drug concentration that inhibits the growth of bacteria visible to the naked eye within 18 to 24 hours. The results are shown in Table 1.
表1 β-内酰胺类抗生素和七甲川吲哚花菁分子对MRSA 252的MICTable 1 MIC of β-lactam antibiotics and heptamethine indole cyanine molecules on MRSA 252
Figure PCTCN2022100605-appb-000011
Figure PCTCN2022100605-appb-000011
Figure PCTCN2022100605-appb-000012
Figure PCTCN2022100605-appb-000012
表1的数据表明，七甲川吲哚花菁分子(化合物1-26)单独抑制细菌的活性明显优于β-内酰胺类抗生素。The data in Table 1 show that the heptamethine indole cyanine molecules (compounds 1-26) have significantly better antibacterial activity than β-lactam antibiotics alone.
(2)七甲川吲哚花菁化合物与β-内酰胺类抗生素联合使用时，观察其对β-内酰胺类抗生素对MRSA 252抑制作用的影响。(2) When the heptamethine indole cyanine compound is used in combination with β-lactam antibiotics, observe its effect on the inhibitory effect of β-lactam antibiotics on MRSA 252.
采用抑菌曲线法，调整细菌浓度为1×10 5CFU/mL,七甲川吲哚花菁分子5(化合物5)(2μg/mL)、七甲川吲哚花菁分子13(化合物13)(0.25μg/mL)、七甲川吲哚花菁分子15(化合物15)(4μg/mL)、七甲川吲哚花菁分子22(化合物22)(2μg/mL)、七甲川吲哚花菁分子6(化合物6)(8μg/mL)、七甲川吲哚花菁分子24(化合物24)(2μg/mL)、CFT(64μg/mL)、VAN(0.5μg/mL)加入到细菌悬浮液中,于加入药物后的12h、16h、18h、24h测量OD值。结果见图1、图2、图3。 Using the inhibition curve method, adjust the bacterial concentration to 1×10 5 CFU/mL, heptamethine indole cyanine molecule 5 (compound 5) (2 μg/mL), heptamethine indole cyanine molecule 13 (compound 13) (0.25 μg/mL), heptamethine indole cyanine molecule 15 (compound 15) (4 μg/mL), heptamethine indole cyanine molecule 22 (compound 22) (2 μg/mL), heptamethine indole cyanine molecule 6 ( Compound 6) (8 μg/mL), heptamethine indole cyanine molecule 24 (compound 24) (2 μg/mL), CFT (64 μg/mL), VAN (0.5 μg/mL) were added to the bacterial suspension, and after adding OD values were measured at 12h, 16h, 18h, and 24h after the drug. The results are shown in Figure 1, Figure 2, and Figure 3.
图1β-内酰胺类抗生素和七甲川吲哚花菁分子5、13联合使用时对MRSA252的抗菌作用,图2β-内酰胺类抗生素和七甲川吲哚花菁分子15、22联合使用时对MRSA 252的抗菌作用,图3β-内酰胺类抗生素和七甲川吲哚花菁分子6、24联合使用时对MRSA 252的抗菌作用。Fig. 1 The antibacterial effect of β-lactam antibiotics and heptamethine indole cyanine molecules 5 and 13 on MRSA252, Fig. 2 The combination of β-lactam antibiotics and heptamethine indole cyanine molecules 15 and 22 on MRSA The antibacterial effect of 252, Figure 3 The antibacterial effect of β-lactam antibiotics and heptamethine indole cyanine molecules 6 and 24 on MRSA 252 when used in combination.
图1、图2、图3的结果表明上七甲川吲哚花菁类化合物与β-内酰胺类抗生素联合可以增加MRSA对β-内酰胺类抗生素的敏感性，表明七甲川吲哚花菁类化合物与β-内酰胺类抗生素具有协同抗菌作用。The results of Figure 1, Figure 2, and Figure 3 show that the combination of heptamethine indole cyanine compounds and β-lactam antibiotics can increase the sensitivity of MRSA to β-lactam antibiotics, indicating that heptamethine indole cyanines The compound has synergistic antibacterial effect with β-lactam antibiotics.
本发明发现七甲川吲哚花菁类化合物对MRSA有较好的抗菌作用，特别是当这些化合物与β-内酰胺类化合物联合使用时，可以增加MRSA对苯唑西林的敏感性。The present invention finds that heptamethine indole cyanine compounds have good antibacterial effect on MRSA, especially when these compounds are used in combination with β-lactam compounds, they can increase the sensitivity of MRSA to oxacillin.
(3)七甲川吲哚花菁化合物对大肠埃希菌、铜绿假单胞菌的抗菌作用测定。(3) Determination of the antibacterial activity of heptamethine indole cyanine compounds against Escherichia coli and Pseudomonas aeruginosa.
采用肉汤微孔二倍稀释法和琼脂糖稀释法进行，The broth microwell two-fold dilution method and the agarose dilution method were used.
肉汤微孔二倍稀释法：调整细菌浓度为1×10 5CFU/mL，接种于96孔无菌培养板内，将氨苄西林和七甲川吲哚花菁分子(化合物1、4、8、10、14、15、17、21、25号)至含细菌培养孔内，依次倍比稀释，第1～10孔药物的最终浓度依次为512、256、128、64、32、16、8、4、2、1、0.5μg/mL，加完药后置于37℃培养箱孵育18～24h，读取阳性和阴性对照孔，阴性对照孔清亮，阳性对照孔混浊。药物对细菌的MIC为18～24h抑制细菌肉眼可见生长的最低药物浓度。结果示于表2。 Broth microwell two-fold dilution method: adjust the bacterial concentration to 1×10 5 CFU/mL, inoculate in a 96-well sterile culture plate, and mix ampicillin and heptamethine indole cyanine molecules ( compounds 1, 4, 8, 10, 14, 15, 17, 21, 25) into the bacterial culture wells, and then serially diluted, the final concentrations of the drugs in the 1st to 10th wells were 512, 256, 128, 64, 32, 16, 8, 4, 2, 1, 0.5 μg/mL, after adding the drug, incubate in a 37°C incubator for 18-24 hours, read the positive and negative control wells, the negative control wells are clear, and the positive control wells are turbid. The MIC of a drug against bacteria is the lowest drug concentration that inhibits the growth of bacteria visible to the naked eye within 18 to 24 hours. The results are shown in Table 2.
表2七甲川吲哚花菁分子对大肠埃希菌E.Coli 35218和铜绿假单胞菌P.A的MICTable 2 The MIC of heptamethine indole cyanine molecules on Escherichia coli E.Coli 35218 and Pseudomonas aeruginosa P.A
Figure PCTCN2022100605-appb-000013
Figure PCTCN2022100605-appb-000013
表2的数据表明，七甲川吲哚花菁分子(化合物10、15、25)对革兰阴性菌大肠埃希菌E.coli 35218和铜绿假单胞菌P.A的抗菌作用优于氨苄西林。The data in Table 2 shows that the antibacterial effect of heptamethine indole cyanine molecules (compounds 10, 15, 25) on Gram-negative bacteria Escherichia coli 35218 and Pseudomonas aeruginosa P.A is better than that of ampicillin.
琼脂糖稀释法：将七甲川吲哚花菁分子(化合物10、15、25)稀释成相应浓度配制于琼脂糖平板中，调整细菌浓度为11*10 6cfu/ml按10ul接种于平板中37℃培养箱孵育18～24h，读取阳性和阴性对照孔，阴性对照孔没有菌落生长，阳性有菌落生长，观察药物对细菌生长的抑制情况，结果见图4。 Agarose dilution method: Dilute heptamethine indole cyanine molecules (compounds 10, 15, 25) to the corresponding concentration and prepare them on the agarose plate, adjust the bacterial concentration to 11*10 6 cfu/ml and inoculate the plate in 10ul37 Incubate in an incubator at ℃ for 18-24 hours, read the positive and negative control wells, the negative control wells have no colony growth, and the positive control wells have colony growth, and observe the inhibition of the drug on bacterial growth. The results are shown in Figure 4.
总之，本发明的七甲川吲哚花菁类化合物具有强的抗菌活性，尤其针对耐药菌MRSA的抑制活性，特别是七甲川吲哚花菁类化合物与β-内酰胺类抗生素联合使用时表现出的强大的协同抗菌作用，其抗菌活性显著优于临床抗生素药物苯唑西林(Oxacillin，OXA)、头孢西丁(cefoxitin，CFT)，个别甚至优于或者相当于万古霉素(Vancomycin，VAN)的抗菌活性。该类化合物属于临床上使用药物吲哚菁绿(ICG)的衍生物，具有发展和应用前景。In conclusion, the heptamethine indole cyanine compounds of the present invention have strong antibacterial activity, especially the inhibitory activity against drug-resistant bacteria MRSA, especially when the heptamethine indole cyanine compounds are used in combination with β-lactam antibiotics. The powerful synergistic antibacterial effect produced by these drugs, its antibacterial activity is significantly better than clinical antibiotic drugs oxacillin (Oxacillin, OXA), cefoxitin (cefoxitin, CFT), some even better than or equivalent to vancomycin (Vancomycin, VAN) antibacterial activity. The compounds belong to the derivatives of the clinically used drug indocyanine green (ICG), and have development and application prospects.

Claims (4)

  1. 一种七甲川吲哚花菁类化合物或其药用盐在制造抗菌药物中的用途，A use of a heptamethine indole cyanine compound or a medicinal salt thereof in the manufacture of antibacterial drugs,
    所述七甲川吲哚花菁类化合物为式I所示的化合物，The heptamethine indole cyanine compound is a compound shown in formula I,
    Figure PCTCN2022100605-appb-100001
    Figure PCTCN2022100605-appb-100001
    式中，R 1和R 2或以相同或不同，各自独立的代表未取代或取代的烷基，所述烷基为C 1-C 6烷基，所述取代的取代基为OR 3、COOR 3、CONHR 3或 In the formula, R 1 and R 2 may be the same or different, each independently represents an unsubstituted or substituted alkyl group, the alkyl group is a C 1 -C 6 alkyl group, and the substituted substituents are OR 3 , COOR 3 , CONHR 3 or
    Figure PCTCN2022100605-appb-100002
    Figure PCTCN2022100605-appb-100002
    其中，所述R 3为H，未取代或取代的C 1-C 4烷基，未取代或由甲酸、甲酸酯或卤素取代的苯基，乙酸酯，其中，所述C 1-C 4烷基的取代基为苯基或羧基，所述甲酸酯为甲酸甲酯、甲酸乙酯，所述乙酸酯为乙酸甲酯，X为溴、氯、碘或高氯酸。 Wherein, said R 3 is H, unsubstituted or substituted C 1 -C 4 alkyl, unsubstituted or phenyl substituted by formic acid, formate or halogen, acetate, wherein said C 1 -C The substituent of 4 alkyl groups is phenyl or carboxyl, the formate is methyl formate, ethyl formate, the acetate is methyl acetate, and X is bromine, chlorine, iodine or perchloric acid.
  2. 一种七甲川吲哚花菁类化合物在制造抗菌药物中的用途，所述化合物选自下列化合物：A use of heptamethine indole cyanine compounds in the manufacture of antibacterial drugs, said compound being selected from the following compounds:
    Figure PCTCN2022100605-appb-100003
    Figure PCTCN2022100605-appb-100003
    Figure PCTCN2022100605-appb-100004
    Figure PCTCN2022100605-appb-100004
    Figure PCTCN2022100605-appb-100005
    Figure PCTCN2022100605-appb-100005
  3. 如权利要求1-2任一所述的用途，进一步包括将七甲川吲哚花菁类化合物与其它抗生素联合用药。The use according to any one of claims 1-2, further comprising combining the heptamethine indole cyanine compound with other antibiotics.
  4. 如权利要求3所述的用途，所述其它抗生素为β-内酰胺类抗生素。The use according to claim 3, said other antibiotics are β-lactam antibiotics.
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