WO2018214463A1 - 新型抗生素及其制备方法、用途、应用 - Google Patents

新型抗生素及其制备方法、用途、应用 Download PDF

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WO2018214463A1
WO2018214463A1 PCT/CN2017/114644 CN2017114644W WO2018214463A1 WO 2018214463 A1 WO2018214463 A1 WO 2018214463A1 CN 2017114644 W CN2017114644 W CN 2017114644W WO 2018214463 A1 WO2018214463 A1 WO 2018214463A1
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compound
formula
group
condensation reaction
optionally substituted
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French (fr)
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饶燏
宗昱
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清华大学
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • 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
    • 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
    • A61P31/10—Antimycotics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/06—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K11/00—Depsipeptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K11/02—Depsipeptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof cyclic, e.g. valinomycins ; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the invention relates to the field of medicinal chemistry, in particular to a novel antibiotic and a preparation method, use and application thereof.
  • Gram-positive bacterial infections are common and frequently-occurring, endangering human health.
  • Gram-positive cocci infections have increased, the detection rate of methicillin-resistant Staphylococcus aureus (MRSA) has increased, and penicillin-resistant Streptococcus pneumoniae (PRSP) has spread in many countries and regions, resistant to glycopeptides and many others.
  • MRSA methicillin-resistant Staphylococcus aureus
  • PRSP penicillin-resistant Streptococcus pneumoniae
  • VRE vancomycin-resistant enterococci
  • multidrug-resistant tubercle bacilli increased.
  • bacterial exposure to antibacterial drugs can be mutated to obtain drug resistance.
  • the surviving bacteria have accumulated rich “combat experience” and become resistant varieties, and then evolved cross-resistance, multi-drug resistance, pan-drug resistance, and total resistance.
  • Super bacteria such as medicine. Not long ago, a joint study by Chinese and foreign researchers published results in the new issue of the "Lancet Infectious Diseases" magazine. The study showed that there is a special gene, MCR-1, and the bacteria carrying the gene show strong resistance to polymyxin, and this resistance can be quickly transferred to other strains, which means a new The "super bacteria” were discovered.
  • carbapenem antibiotics are recognized as the "ultimate line of defense" of bacteria, and are often used to treat severely resistant bacteria. Heavy infection.
  • carbapenem-resistant bacteria have caused serious bacterial resistance problems through inter-plasmid propagation, including the recently discovered colistin resistance.
  • These life-saving drugs are often limited in clinical use because of their high toxicity. Therefore, there is a need to provide a novel antibacterial compound.
  • the invention proposes a compound.
  • the compound is a stereoisomer, a tautomer, an oxynitride, a hydrate, a solvate, a metabolite, or a metabolite of a compound of formula I or a compound of formula I,
  • a pharmaceutically acceptable salt or prodrug :
  • R 1 is hydrogen, optionally substituted C 1 ⁇ 15 alkyl, optionally substituted C 2 ⁇ 15 alkylene group, optionally substituted C 2 ⁇ 15 alkynyl group, optionally substituted aryl or optionally substituted acyl group
  • R 2 is hydrogen, halogen, optionally substituted C 1 ⁇ 15 alkyl, optionally substituted C 2 ⁇ 15 alkylene group, optionally substituted C 2 ⁇ 15 alkynyl, optionally substituted acyl, or any An aryl group substituted by a halogen, an alkyl group or a trifluoromethyl group
  • R 3 is an amino group, a fluorenyl group, a ureido group or a carboxamide group
  • R 4 is an optionally substituted C 1-5 alkyl group, optionally substituted C 2 ⁇ 15 alkenyl, optionally substituted C 2-15 alkynyl group, an optionally substituted aryl group
  • R 5 is amino, guanidin
  • the above compound further comprises at least one of the following additional technical features:
  • the compound comprises: R 1 is hydrogen; R 2 is benzoyl or an optionally substituted aryl-substituted aryl; R 3 is R 4 is an optionally substituted C 1-5 alkyl group; R 5 is Amino group; m is an integer between 1 and 4, inclusive; X is O, S or NH.
  • the compound is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the invention provides a process for the preparation of the above compounds.
  • the method comprises the steps of: (1) contacting a compound of Formula 3 with Fmoc-L-isoleucine to obtain a compound of Formula 4; (2) bringing the compound of Formula 4 Deprotection reaction occurs to obtain a compound of formula 5; (3) contacting a compound of formula 6 with benzyloxycarbonyl-L-alanine to obtain a compound of formula 7; (4) making said formula 7
  • the compound shown is subjected to a reduction reaction to obtain a compound of the formula 8; (5) a condensation reaction of the compound of the formula 5 with the compound of the formula 8 is carried out to obtain a compound of the formula 9; (6)
  • the compound of Formula 9 undergoes an intramolecular condensation reaction to obtain a compound of Formula 10; (7) a compound obtained by the formula 10 is deprotected to give a compound of Formula 11; (8)
  • the Formula 11 is made The compound shown is contacted with a compound of the
  • Bn is benzyl, t-Bu is tert-butyl, Boc is tert-butoxycarbonyl, Y is -N 3 , -OH or -SH, Fmoc is 9-fluorenylmethoxycarbonyl, and X is O, S or NH.
  • m is an integer between 1 and 4, inclusive;
  • Cbz is benzyloxycarbonyl .
  • the above method further comprises at least one of the following additional technical features:
  • the method comprises: (1) subjecting the compound of the formula 3 to a condensation reaction with the Fmoc-L-isoleucine after azide reduction, or making the formula 3
  • the compound is directly subjected to a condensation reaction with the Fmoc-L-isoleucine to obtain the compound of the formula 4, wherein when Y represents -N 3 , the compound of the formula 3 is subjected to azide reduction.
  • the compound of the formula 3 is directly condensed with the Fmoc-L-isoleucine; (2) subjecting the compound of the formula 4 to a deprotection reaction under basic conditions to obtain the compound of the formula 5; (3) bringing the compound of the formula 6 to the benzyloxycarbonyl group- a condensation reaction of L-alanine to obtain the compound of the formula 7; (4) a reduction reaction of the compound of the formula 7 to obtain a compound of the formula 8; (5) the formula 5 The compound shown is subjected to a condensation reaction with the compound of the formula 8 to obtain the compound of the formula 9; (6) the compound of the formula 9 is reduced.
  • the method comprises: in the step (1), the compound of the formula 3 is obtained by the step of: N-Boc-O-tert-butyl-L-serine and Formula 1 a condensation reaction of the compound shown to obtain the compound of formula 3;
  • condensation reaction is carried out in the presence of 6-chlorobenzotriazole-1,1,3,3-tetramethyluronium hexafluorophosphate and N,N-diisopropylethylamine;
  • the molar ratio of the compound of the formula 1 to the N-Boc-O-tert-butyl-L-serine is 1: (1.0 to 1.5); the N-Boc-O-tert-butyl-L-serine
  • the molar ratio of the 6-chlorobenzotriazole-1,1,3,3-tetramethyluronium hexafluorophosphate to the N,N-diisopropylethylamine is 1: (1.0 ⁇ 1.5): (1.0 to 1.5);
  • the condensation reaction is carried out at a temperature of 20 to 25 ° C for 2 to 3 hours.
  • the azide reduction reaction is carried out in the presence of triphenylphosphine; in the step (1) and the step (3), the condensation reaction is Separately in the presence of carbodiimide and 4-dimethylaminopyridine; the molar ratio of the Fmoc-L-isoleucine to the compound of the formula 3 is 1: (0.5-1.0)
  • the molar ratio of the Fmoc-L-isoleucine, the carbodiimide and the 4-dimethylaminopyridine is 1: (1.0-1.5): (0.1-0.5);
  • the benzyloxy a molar ratio of carbonyl-L-alanine to the compound of the formula 6 is 1: (0.5 to 1.0); the benzyloxycarbonyl-L-alanine, the carbodiimide and the 4-
  • the molar ratio of dimethylaminopyridine is 1: (1.0 to 1.5): (0.1 to 0.5); in the step (1) and the step (3), the
  • the basic condition is formed by using a 33% by weight solution of diethylamine in acetonitrile; in the step (4), the reduction reaction is in the presence of hydrogen.
  • the molar ratio of the compound of the formula 7 to the lithium hydroxide is 1: (1 to 5); in the step (5), the condensation reaction is in the presence of 2- ( 7-oxidized benzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate and N,N-diisopropylethylamine;
  • the molar ratio of the compound to the compound of the formula 5 is 1: (1.0 to 1.5); the compound of the formula 8, the 2-(7-oxobenzotriazole)-N, N, N
  • the molar ratio of 'N'-tetramethylurea hexafluorophosphate to the N,N-diisopropylethylamine is 1: (1.0 to 1.5): (
  • the reduction reaction is carried out in the presence of palladium hydroxide/carbon; the intramolecular condensation reaction is in the presence of 2-(7-oxidized benzotriene) Azole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, 1-hydroxy-7-azobenzotriazole and N,N-diisopropylethylamine
  • the deprotection reaction is carried out in the presence of hydrochloric acid; in the step (8), the condensation reaction is in the presence of 3-diethoxyphosphoryl group.
  • the reaction is carried out under the conditions of keto-1,2,3-oxazolyl 4(3H)-one and N,N-diisopropylethylamine; the compound of the formula 11 and the 3-diethoxyphosphoryl group
  • the molar ratio of -1,2,3-oxazol 4(3H)-one to the N,N-diisopropylethylamine is 1: (1 to 2): (1 to 2), step (9)
  • the alkaline condition is formed by using a 33% by weight solution of diethylamine in acetonitrile; the acidic condition is formed using a mixed aqueous solution of trifluoroacetic acid and triisopropylsilane.
  • the invention provides an inhibitor of Gram positive bacteria.
  • the inhibitor comprises a compound as described above.
  • the invention proposes a pharmaceutical composition.
  • the pharmaceutical composition comprises a compound as described above.
  • the above pharmaceutical composition may further comprise at least one of the following additional technical features:
  • the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle, or a combination thereof.
  • the invention provides the use of a compound as described above for the preparation of a medicament.
  • the medicament is for inhibiting the growth and/or reproduction of Gram positive bacteria.
  • the invention provides a method of inhibiting the growth and/or reproduction of Gram-positive bacteria.
  • the method comprises contacting the Gram positive bacteria with a compound as described above.
  • the invention provides the use of a compound as described above for inhibiting the growth and/or reproduction of Gram positive bacteria. According to an embodiment of the invention, the use of a compound as described above for inhibiting the growth and/or reproduction of Gram-positive bacteria.
  • the invention provides the use of a compound as described above for the manufacture of a product which inhibits the growth and/or reproduction of Gram positive bacteria. According to an embodiment of the invention, the use of a compound as described above for the preparation of a product which inhibits the growth and/or reproduction of Gram positive bacteria.
  • the invention provides the aforementioned inhibitors, the aforementioned uses, the methods previously described, and the applications described above.
  • the Gram-positive bacteria comprise a bacterium selected from the group consisting of Streptococcus, Staphylococcus, Enterococcus, Corynebacterium, Listeria, Bacillus, Streptomyces, Actinomycetes, Helicobacter pylori, and hobby Legionella, Mycobacterium tuberculosis, Mycobacterium tuberculosis, Mycobacterium avium, Staphylococcus aureus, Staphylococcus epidermidis, Neisseria gonorrhoeae, Neisseria meningitidis, Streptococcus pyogenes, At least one of Streptococcus faecalis, Streptococcus bovis, Streptococcus pneumoniae, Haemophilus, P
  • the group R 1 is hydrogen, an alkyl group having 1 to 15 carbon atoms, an alkenyl group having 2 to 15 carbon atoms, an alkynyl group having 2 to 15 carbon atoms, an aryl group or an acyl group;
  • the group R 2 is hydrogen, halogen, an alkyl group having 1 to 15 carbon atoms, an alkenyl group having 2 to 15 carbon atoms, an alkynyl group having 2 to 15 carbon atoms, an aryl group, a substituted aryl group or an acyl group.
  • the substituted aryl group is a halogen-substituted aryl group, an alkyl-substituted aryl group or a trifluoromethyl-substituted aryl group;
  • the group R 3 is an amino group, a mercapto group, a urea group or a formamide group
  • the group R 4 is an alkyl group having 1 to 15 carbon atoms, an alkenyl group having 2 to 15 carbon atoms, or an alkynyl group or an aryl group having 2 to 15 carbon atoms;
  • the group R 5 is an amino group, a mercapto group or a urea group
  • n is a natural number between 1 and 4;
  • X is O, S or NH.
  • a method of preparing a compound of formula I comprising the steps of:
  • Bn represents a benzyl group
  • t-Bu represents a tert-butyl group
  • Boc represents a tert-butoxycarbonyl group
  • Y represents -N 3 , -OH or -SH, that is, when Y represents -N 3 , azide reduction is first performed.
  • the condensation reaction is carried out later, and when Y represents -OH or -SH, the condensation reaction is directly carried out;
  • Fmoc represents 9-fluorenylmethoxycarbonyl
  • Bn, t-Bu and Boc are as defined in Formula 3
  • X is O, S or NH
  • Equation 4 Fmoc is defined as in Equation 4, and m is a natural number between 1 and 4;
  • Cbz represents a benzyloxycarbonyl group
  • the group R 1 is hydrogen, an alkyl group having 1 to 15 carbon atoms, an alkenyl group having 2 to 15 carbon atoms, an alkynyl group having 2 to 15 carbon atoms, an aryl group or Acyl group
  • the group R 2 is hydrogen, halogen, an alkyl group having 1 to 15 carbon atoms, an alkenyl group having 2 to 15 carbon atoms, an alkynyl group having 2 to 15 carbon atoms, an aryl group, a substituted aryl group or an acyl group.
  • the substituted aryl group is a halogen-substituted aryl group or a trifluoromethyl-substituted aryl group;
  • the group R 4 is an alkyl group having 1 to 15 carbon atoms, an alkenyl group having 2 to 15 carbon atoms, or an alkynyl group or an aryl group having 2 to 15 carbon atoms;
  • the compound of the formula 13 is obtained by subjecting the compound of the formula 13 to deprotection under basic conditions and acidic conditions in order to obtain the compound of the formula (I).
  • N-Boc-O-tert-butyl-L-serine is condensed with a compound of formula 1 to give a compound of formula 3;
  • Bn represents a benzyl group
  • t-Bu represents a tert-butyl group
  • Boc represents a tert-butoxycarbonyl group
  • Y is as defined in the formula 3;
  • the condensation reaction is carried out under the catalysis of 6-chlorobenzotriazole-1,1,3,3-tetramethyluronium hexafluorophosphate and N,N-diisopropylethylamine;
  • the molar ratio of the compound of the formula 1 to the N-Boc-O-tert-butyl-L-serine is 1:1.0 to 1.5;
  • N-Boc-O-tert-butyl-L-serine, the 6-chlorobenzotriazole-1,1,3,3-tetramethyluronium hexafluorophosphate and the N,N- The molar ratio of diisopropylethylamine is 1:1.0 to 1.5:1.0 to 1.5;
  • the condensation reaction has a temperature of 20 to 25 ° C and a time of 2 to 3 hours.
  • the condensation reaction is carried out under the catalysis of carbodiimide and 4-dimethylaminopyridine;
  • the molar ratio of the Fmoc-L-isoleucine to the compound of Formula 3 is 1:0.5 to 1.0;
  • the molar ratio of the Fmoc-L-isoleucine, the carbodiimide and the 4-dimethylaminopyridine is 1:1.0 to 1.5:0.1-0.5;
  • the molar ratio of the benzyloxycarbonyl-L-alanine to the compound of Formula 6 is 1:0.5 to 1.0;
  • the molar ratio of the benzyloxycarbonyl-L-alanine, the carbodiimide and the 4-dimethylaminopyridine is 1:1.0 to 1.5:0.1 to 0.5;
  • the condensation reaction has a temperature of 20 to 25 ° C and a time of 2 to 3 hours.
  • the alkaline condition is prepared by a solution of diethylamine in an amount of 33% by mass of acetonitrile.
  • step (4) the reduction reaction is carried out under the catalysis of lithium hydroxide
  • the molar ratio of the compound of formula 7 to the lithium hydroxide is 1:1 to 5;
  • the condensation reaction is carried out in 2-(7-oxobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate and N,N-diisopropyl Catalyzed by ethylamine;
  • the molar ratio of the compound of the formula 8 to the compound of the formula 5 is 1:1.0 to 1.5;
  • the condensation reaction has a temperature of 20 to 25 ° C and a time of 2 to 3 hours.
  • the intramolecular condensation reaction is carried out in 2-(7-oxobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, 1-hydroxy-7-azobenzotriene Catalyzed by azole and N,N-diisopropylethylamine;
  • step (7) the deprotection reaction is carried out in the presence of hydrochloric acid
  • step (8) the condensation reaction is carried out under the catalysis of 3-diethoxyphosphoryl-1,2,3-oxazol 4(3H)-one and N,N-diisopropylethylamine;
  • the compound of the formula 11, the molar ratio of the 3-diethoxyphosphoryl-1,2,3-oxazol 4(3H)-one to the N,N-diisopropylethylamine is 1: 1 to 2: 1 to 2.
  • the basic condition is prepared by a solution of diethylamine in acetonitrile having a mass percentage of 33%;
  • the acidic conditions are prepared by mixing a mixed aqueous solution of trifluoroacetic acid and triisopropylsilane.
  • the Gram-positive bacteria are Streptococcus, Staphylococcus, Enterococcus, Corynebacterium, Listeria, Bacillus, and erysipelas Helicobacter, Helicobacter pylori, Legionella pneumophila, Mycobacterium tuberculosis, Mycobacterium tuberculosis, Mycobacterium avium, Staphylococcus aureus, Staphylococcus epidermidis, Neisseria gonorrhoeae, Neisseria meningitidis At least one of bacteria, Streptococcus pyogenes, Streptococcus faecalis, Streptococcus bovis, Streptococcus pneumoniae, Haemophilus, Pseudomonas aeruginosa, Bacillus anthracis, and Bacillus subtilis.
  • the group R 1 is hydrogen, an alkyl group having 1 to 15 carbon atoms, an alkenyl group having 2 to 15 carbon atoms, an alkynyl group having 2 to 15 carbon atoms, an aryl group or an acyl group;
  • the group R 2 is hydrogen, halogen, an alkyl group having 1 to 15 carbon atoms, an alkenyl group having 2 to 15 carbon atoms, an alkynyl group having 2 to 15 carbon atoms, an aryl group, a substituted aryl group or an acyl group.
  • the substituted aryl group is a halogen-substituted aryl group, an alkyl-substituted aryl group or a trifluoromethyl-substituted aryl group;
  • the group R 3 is an amino group, a mercapto group, a urea group or a formamide group
  • the group R 4 is an alkyl group having 1 to 15 carbon atoms, an alkenyl group having 2 to 15 carbon atoms, or an alkynyl group or an aryl group having 2 to 15 carbon atoms;
  • the group R 5 is an amino group, a mercapto group or a urea group
  • n is a natural number between 1 and 4;
  • X is O, S or NH.
  • R 2 may specifically be a phenyl group, a halogen-substituted phenyl group or an alkyl group substituted with an alkyl group having 1 to 15 carbon atoms, and the alkyl group having 1 to 15 carbon atoms.
  • the phenyl group may be specifically an alkyl substituted phenyl group having 1 to 6 carbon atoms, preferably a methyl substituted phenyl group, an ethyl substituted phenyl group, a propyl substituted phenyl group, an isopropyl substituted phenyl group, or a n-butyl group.
  • a substituted phenyl group an isobutyl substituted phenyl group, a tert-butyl substituted phenyl group, a pentyl substituted phenyl group or a hexyl substituted phenyl group.
  • the alkyl group having 1 to 15 carbon atoms in R 1 , R 2 and R 4 is preferably an alkyl group having 1 to 6 carbon atoms, such as methyl group, ethyl group or ethyl group.
  • Base isopropyl, n-butyl, isobutyl, tert-butyl, pentyl or hexyl;
  • the alkenyl group having 2 to 15 carbon atoms in R 1 , R 2 and R 4 is preferably an alkenyl group having 2 to 6 carbon atoms, such as a vinyl group, a propenyl group, a butenyl group, an isobutenyl group, a pentenyl group or a hexyl group.
  • the alkynyl group having 2 to 15 carbon atoms in R 1 , R 2 and R 4 is preferably an alkynyl group having 2 to 6 carbon atoms, such as an ethynyl group, a propynyl group, a butynyl group, an isobutynyl group or a pentyne group. Or hexynyl group and the like.
  • R 3 may specifically be a formyl group or a fluorenyl group
  • R 5 may specifically be an amino group
  • n may specifically be 1, 2, 3 or 4;
  • X may specifically be O or NH.
  • the compound of formula I provided by the present invention is specifically as shown in formula I-1, formula I-2 or formula I-3.
  • the invention still further provides a process for the preparation of the compound of formula I, comprising the steps of:
  • Bn represents a benzyl group
  • t-Bu represents a tert-butyl group
  • Boc represents a tert-butoxycarbonyl group
  • Y represents -N 3 , -OH or -SH, that is, when Y represents -N 3 , azide reduction is first performed.
  • the condensation reaction is carried out later, and when Y represents -OH or -SH, the condensation reaction is directly carried out;
  • Fmoc represents 9-fluorenylmethoxycarbonyl
  • Bn, t-Bu and Boc are as defined in Formula 3
  • X is O, S or NH
  • Equation 4 Fmoc is defined as in Equation 4, and m is a natural number between 1 and 4;
  • Cbz represents a benzyloxycarbonyl group
  • Equation 8 the definition of Fmoc is the same as in Equation 4, the definition of Cbz is the same as in Equation 7, and the definition of m is the same as Equation 6;
  • the group R 1 is hydrogen, an alkyl group having 1 to 15 carbon atoms, an alkenyl group having 2 to 15 carbon atoms, an alkynyl group having 2 to 15 carbon atoms, or an aryl group or Acyl group
  • the group R 2 is hydrogen, halogen, an alkyl group having 1 to 15 carbon atoms, an alkenyl group having 2 to 15 carbon atoms, an alkynyl group having 2 to 15 carbon atoms, an aryl group, a substituted aryl group or an acyl group.
  • the substituted aryl group is a halogen-substituted aryl group or a trifluoromethyl-substituted aryl group;
  • the group R 4 is an alkyl group having 1 to 15 carbon atoms, an alkenyl group having 2 to 15 carbon atoms, or an alkynyl group or an aryl group having 2 to 15 carbon atoms;
  • the compound of the formula 13 is obtained by subjecting the compound of the formula 13 to deprotection under basic conditions and acidic conditions in order to obtain the compound of the formula (I).
  • the compound represented by the formula 3 can be produced by the following method:
  • N-Boc-O-tert-butyl-L-serine is condensed with a compound of formula 1 to give a compound of formula 3;
  • Bn represents a benzyl group
  • t-Bu represents a tert-butyl group
  • Boc represents a tert-butoxycarbonyl group
  • Y is as defined in the formula 3;
  • the condensation reaction is carried out under the catalysis of 6-chlorobenzotriazole-1,1,3,3-tetramethyluronium hexafluorophosphate and N,N-diisopropylethylamine;
  • the molar ratio of the compound of the formula 1 to the N-Boc-O-tert-butyl-L-serine is 1:1.0 to 1.5;
  • N-Boc-O-tert-butyl-L-serine, the 6-chlorobenzotriazole-1,1,3,3-tetramethyluronium hexafluorophosphate and the N,N- The molar ratio of diisopropylethylamine is 1:1.0 to 1.5:1.0 to 1.5;
  • the condensation reaction has a temperature of 20 to 25 ° C and a time of 2 to 3 hours.
  • step (1) azide reduction is carried out under the catalysis of triphenylphosphine
  • the condensation reaction is carried out under the catalysis of carbodiimide and 4-dimethylaminopyridine;
  • the molar ratio of the Fmoc-L-isoleucine to the compound of Formula 3 is 1:0.5 to 1.0;
  • the molar ratio of the Fmoc-L-isoleucine, the carbodiimide and the 4-dimethylaminopyridine is 1:1.0 to 1.5:0.1-0.5;
  • the molar ratio of the benzyloxycarbonyl-L-alanine to the compound of Formula 6 is 1:0.5 to 1.0;
  • the molar ratio of the benzyloxycarbonyl-L-alanine, the carbodiimide and the 4-dimethylaminopyridine is 1:1.0 to 1.5:0.1 to 0.5;
  • the condensation reaction has a temperature of 20 to 25 ° C and a time of 2 to 3 hours.
  • the basic condition is prepared by preparing a 33% by mass solution of diethylamine in acetonitrile
  • step (4) the reduction reaction is carried out under the catalysis of lithium hydroxide
  • the molar ratio of the compound of formula 7 to the lithium hydroxide is 1:1 to 5;
  • the condensation reaction is carried out in 2-(7-oxobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate and N,N-diisopropyl Catalyzed by ethylamine;
  • the molar ratio of the compound of the formula 8 to the compound of the formula 5 is 1:1.0 to 1.5;
  • the condensation reaction has a temperature of 20 to 25 ° C and a time of 2 to 3 hours.
  • the reduction reaction is carried out under the catalysis of palladium hydroxide/carbon;
  • the intramolecular condensation reaction is carried out in 2-(7-oxobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, 1-hydroxy-7-azobenzotriene Catalyzed by azole and N,N-diisopropylethylamine;
  • step (7) the deprotection reaction is carried out in the presence of hydrochloric acid
  • step (8) the condensation reaction is carried out under the catalysis of 3-diethoxyphosphoryl-1,2,3-oxazol 4(3H)-one and N,N-diisopropylethylamine;
  • the compound of the formula 11, the molar ratio of the 3-diethoxyphosphoryl-1,2,3-oxazol 4(3H)-one to the N,N-diisopropylethylamine is 1: 1 to 2: 1 to 2.
  • the basic condition is prepared by a solution of diethylamine in acetonitrile having a mass percentage of 33%;
  • the acidic conditions are prepared by mixing a mixed aqueous solution of trifluoroacetic acid and triisopropylsilane.
  • the compounds of formula I provided herein can be used to inhibit the growth and/or reproduction of Gram positive bacteria.
  • the Gram-positive bacteria may be Streptococcus, Staphylococcus, Enterococcus, Corynebacterium, Listeria, Bacillus, erysipelas, actinomycetes, Helicobacter pylori, Legionella pneumophila, Mycobacterium tuberculosis, birds Mycobacterium tuberculosis, Mycobacterium tuberculosis, Staphylococcus aureus, Staphylococcus epidermidis, Neisseria gonorrhoeae, Neisseria meningitidis, Streptococcus pyogenes, Streptococcus faecalis, Streptococcus bovis, At least one of Streptococcus pneumoniae, Haemophilus, Pseudomonas aeruginosa, Bacillus anthracis, and Bacillus subtilis.
  • Inhibitors of Gram-positive bacteria whose active ingredient is a compound of formula I are also within the scope of the invention.
  • the present invention Based on the current severe resistance of Gram-positive bacteria, the present invention provides a novel antibacterial compound. For the first time, the present invention synthesizes a series of teixobactin analogs by solid phase and liquid phase combination, and a convergent synthesis strategy is helpful for synthesizing a wide variety of compounds. The present invention produces a compound equivalent to the activity of teixobactin.
  • the articles used herein are used to refer to the articles of one or more than one (ie, at least one).
  • a component refers to one or more components, that is, there may be more than one component contemplated for use or use in embodiments of the embodiments.
  • Stereoisomer refers to a compound that has the same chemical structure but differs in the way the atoms or groups are spatially aligned. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotomers), geometric isomers (cis/trans) isomers, atropisomers, etc. .
  • “Chirality” is a molecule that has properties that cannot overlap with its mirror image; “non-chiral” refers to a molecule that can overlap with its mirror image.
  • Enantiomer refers to two isomers of a compound that are not superimposable but are mirror images of each other.
  • Diastereomer refers to a stereoisomer that has two or more centers of chirality and whose molecules are not mirror images of each other. Diastereomers have different physical properties such as melting point, boiling point, spectral properties and reactivity. The mixture of diastereomers can be separated by high resolution analytical procedures such as electrophoresis and chromatography, such as HPLC.
  • optically active compounds Many organic compounds exist in optically active forms, i.e., they have the ability to rotate a plane of plane polarized light.
  • the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule with respect to one or more of its chiral centers.
  • the prefixes d and l or (+) and (-) are symbols for specifying the rotation of plane polarized light caused by the compound, wherein (-) or l indicates that the compound is left-handed.
  • Compounds prefixed with (+) or d are dextrorotatory.
  • a particular stereoisomer is an enantiomer and a mixture of such isomers is referred to as a mixture of enantiomers.
  • a 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process.
  • any asymmetric atom (e.g., carbon, etc.) of the compounds disclosed herein may exist in racemic or enantiomerically enriched form, such as the (R)-, (S)- or (R, S)-configuration presence.
  • each asymmetric atom has at least 50% enantiomeric excess in the (R)- or (S)-configuration, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess.
  • the compounds of the invention may be one of the possible isomers or mixtures thereof, such as racemates and mixtures of diastereomers (depending on the number of asymmetric carbon atoms) The form exists.
  • Optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the substituent of the cycloalkyl group may have a cis or trans configuration.
  • the resulting mixture of any stereoisomers can be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, for example, by chromatography, depending on the difference in physicochemical properties of the components. Method and / or step crystallization.
  • racemate of any of the resulting end products or intermediates can be resolved into the optical antipodes by methods known to those skilled in the art by known methods, for example, by obtaining the diastereomeric salts thereof. Separation. Racemic products can also be separated by chiral chromatography, such as high performance liquid chromatography (HPLC) using a chiral adsorbent.
  • HPLC high performance liquid chromatography
  • enantiomers can be prepared by asymmetric synthesis, for example, see Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis (2 nd Ed. Robert) E.
  • tautomer or "tautomeric form” means a low energy barrier with different energies (low energy) Barrier) A structural isomer that is converted to each other. If tautomerism is possible (as in solution), the chemical equilibrium of the tautomers can be achieved.
  • proton tautomers also known as prototropic tautomers
  • Valence tautomers include interconversions by recombination of some bonding electrons.
  • keto-enol tautomerization is the interconversion of a pentane-2,4-dione and a 4-hydroxypent-3-en-2-one tautomer.
  • Another example of tautomerization is phenol-keto tautomerization.
  • a specific example of phenol-keto tautomerization is the interconversion of pyridin-4-ol and pyridine-4(1H)-one tautomers. All tautomeric forms of the compounds of the invention are within the scope of the invention unless otherwise indicated.
  • the compounds of the present invention may be optionally substituted with one or more substituents, such as the compounds of the above formula, or specific examples, subclasses, and inclusions of the present invention.
  • substituents such as the compounds of the above formula, or specific examples, subclasses, and inclusions of the present invention.
  • a class of compounds A class of compounds.
  • substituents such as the compounds of the above formula, or specific examples, subclasses, and inclusions of the present invention.
  • a class of compounds A class of compounds.
  • substituents such as the compounds of the above formula, or specific examples, subclasses, and inclusions of the present invention.
  • a class of compounds A class of compounds.
  • C 1 - 6-alkyl refers particularly disclosed independently methyl, ethyl, C 3 alkyl, C 4 alkyl, C 5 and C 6 alkyl group.
  • linking substituents are described.
  • the Markush variable recited for that group is understood to be a linking group.
  • the definition of the Markush group for the variable is "alkyl” or "aryl”
  • the “alkyl” or “aryl” respectively represent the attached An alkylene group or an arylene group.
  • alkyl or "alkyl group” as used herein, denotes a saturated straight or branched monovalent hydrocarbon group containing from 1 to 20 carbon atoms, wherein the alkyl group may be optionally selected The ground is replaced by one or more substituents described herein. Unless otherwise specified, an alkyl group contains from 1 to 20 carbon atoms. In one embodiment, the alkyl group contains from 1 to 12 carbon atoms; in another embodiment, the alkyl group contains from 1 to 6 carbon atoms; in yet another embodiment, the alkyl group contains 1 - 4 carbon atoms; also in one embodiment, the alkyl group contains 1-3 carbon atoms.
  • alkyl groups include, but are not limited to, methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), n-propyl (n-Pr, -CH 2 CH 2 CH 3 ), isopropyl (i-Pr, -CH(CH 3 ) 2 ), n-butyl (n-Bu, -CH 2 CH 2 CH 2 CH 3 ), isobutyl (i-Bu, -CH 2 CH) (CH 3 ) 2 ), sec-butyl (s-Bu, -CH(CH 3 )CH 2 CH 3 ), tert-butyl (t-Bu, -C(CH 3 ) 3 ), n-pentyl (-CH) 2 CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (-CH(CH 3 )CH 2 CH 2 CH 3 ), 3-pentyl (-CH(CH 2 CH 3 ) 2 ), 2-methyl -2-butyl (-C(CHCH
  • alkenyl denotes a straight or branched chain monovalent hydrocarbon radical containing from 2 to 15 carbon atoms, wherein there is at least one site of unsaturation, i.e., having a carbon-carbon sp 2 double bond, wherein the alkenyl group
  • the group may be optionally substituted with one or more substituents described herein, including the positioning of "cis” and “tans", or the positioning of "E” and "Z”.
  • the alkenyl group contains 2-8 carbon atoms; in another embodiment, the alkenyl group contains 2-6 carbon atoms; in yet another embodiment, the alkenyl group comprises 2 - 4 carbon atoms.
  • alkynyl denotes a straight or branched chain monovalent hydrocarbon radical containing from 2 to 15 carbon atoms, wherein at least one site of unsaturation, i.e., has a carbon-carbon sp triple bond, wherein the alkynyl group It may be optionally substituted with one or more of the substituents described herein.
  • the alkynyl group contains 2-8 carbon atoms; in another embodiment, the alkynyl group contains 2-6 carbon atoms; in yet another embodiment, the alkynyl group comprises 2 - 4 carbon atoms.
  • alkynyl groups include, but are not limited to, ethynyl (-C ⁇ CH), propargyl (-CH 2 C ⁇ CH), 1-propynyl (-C ⁇ C-CH 3 ), and the like. .
  • prodrug denotes a compound which is converted in vivo to a compound of formula (I). Such transformation is affected by the hydrolysis of the prodrug in the blood or by enzymatic conversion to the parent structure in the blood or tissue.
  • the prodrug-like compound of the present invention may be an ester.
  • the ester may be used as a prodrug such as a phenyl ester, an aliphatic (C 1-24 ) ester, an acyloxymethyl ester, or a carbonate. , carbamates and amino acid esters.
  • a compound of the invention comprises a hydroxyl group, i.e., it can be acylated to give a compound in the form of a prodrug.
  • Other prodrug forms include phosphates, such as those obtained by phosphorylation of a hydroxy group on the parent.
  • Metal product refers to a product obtained by metabolism of a specific compound or a salt thereof in vivo. Metabolites of a compound can be identified by techniques well known in the art, and the activity can be characterized by experimental methods as described herein. Such a product may be obtained by administering a compound by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage and the like. Accordingly, the invention includes metabolites of a compound, including metabolites produced by intimate contact of a compound of the invention with a mammal for a period of time.
  • the "pharmaceutically acceptable salt” as used in the present invention means an organic salt and an inorganic salt of the compound of the present invention.
  • Pharmaceutically acceptable salts are well known in the art, as described in the literature: SMBerge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19.
  • Salts formed by pharmaceutically acceptable non-toxic acids include, but are not limited to, mineral acid salts formed by reaction with amino groups, hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, And organic acid salts such as acetates, oxalates, maleates, tartrates, citrates, succinates, malonates, or by other methods described in the literature, such as ion exchange These salts.
  • salts include adipate, alginate, ascorbate, aspartate, besylate, benzoate, disulfate, borate, butyrate, camphoric acid Salt, camphor sulfonate, cyclopentylpropionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate Salt, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, Malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulphate, 3 -Phenylpropionate
  • Salts obtained by appropriate bases include the alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4 salts.
  • the present invention also contemplates quaternary ammonium salts formed from any of the compounds comprising a group of N. Water soluble or oil soluble or dispersed products can be obtained by quaternization.
  • Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Pharmaceutically acceptable salts further comprise suitable amine cation nontoxic ammonium, quaternary ammonium, and the counterion, such as halide, hydroxide, carboxylate, sulfated, phosphorylated compounds, nitrate compounds, C 1 -8 sulfonate and aromatic sulfonate.
  • suitable amine cation nontoxic ammonium, quaternary ammonium, and the counterion such as halide, hydroxide, carboxylate, sulfated, phosphorylated compounds, nitrate compounds, C 1 -8 sulfonate and aromatic sulfonate.
  • Solvent-forming solvents include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol.
  • hydrate means that the solvent molecule is an association formed by water.
  • any disease or condition as used in the present invention refers to ameliorating a disease or condition (ie, slowing or preventing or alleviating the progression of a disease or at least one of its clinical symptoms).
  • “treating” refers to alleviating or ameliorating at least one physical parameter, including physical parameters that may not be perceived by the patient.
  • “treating” refers to modulating a disease or condition from the body (eg, stabilizing a detectable symptom) or physiologically (eg, stabilizing the body's parameters) or both.
  • “treating” refers to preventing or delaying the onset, onset, or exacerbation of a disease or condition.
  • Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids, such as acetate, aspartate, benzoate, besylate, bromide/hydrobromide, bicarbonate/ Carbonate, hydrogen sulfate/sulfate, camphorsulfonate, chloride/hydrochloride, chlorophylline, citrate, ethanedisulfonate, fumarate, glucoheptonate, Portuguese Saccharate, glucuronate, hippurate, hydroiodide/iodide, isethionate, lactate, lactobionate, lauryl sulfate, malate, Malay Acid salt, malonate, mandelic acid salt, methanesulfonate, methyl sulfate, naphthoate, naphthalene sulfonate, nicotinate, nitrate, octadecanoate, oleate, oxalic acid Salt, palmitate
  • Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid. , ethanesulfonic acid, p-toluenesulfonic acid, sulfosalicylic acid, and the like.
  • Pharmaceutically acceptable base addition salts can be formed with inorganic bases and organic bases.
  • Inorganic bases from which salts can be derived include, for example, ammonium salts and metals of Groups I to XII of the Periodic Table.
  • the salt is derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include the ammonium, potassium, sodium, calcium, and magnesium salts.
  • Organic bases from which salts can be derived include primary, secondary and tertiary amines, and substituted amines include naturally occurring substituted amines, cyclic amines, basic ion exchange resins and the like.
  • Certain organic amines include, for example, isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine. .
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, basic or acidic moiety by conventional chemical methods.
  • such salts can be obtained by reacting the free acid form of these compounds with a stoichiometric amount of a suitable base such as a hydroxide, carbonate, bicarbonate, or the like of Na, Ca, Mg or K.
  • a suitable base such as a hydroxide, carbonate, bicarbonate, or the like of Na, Ca, Mg or K.
  • the free base form of these compounds is prepared by reaction with a stoichiometric amount of a suitable acid. This type of reaction is usually carried out in water or an organic solvent or a mixture of the two.
  • a non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile.
  • a non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile.
  • the compounds disclosed in the present invention may also be obtained in the form of their hydrates or in the form of their solvents (e.g., ethanol, DMSO, etc.) for their crystallization.
  • the compounds disclosed herein may form solvates either intrinsically or by design with a pharmaceutically acceptable solvent, including water; therefore, the invention is intended to include dissolution Both encapsulated and unsolvated forms.
  • any structural formula given by the present invention is also intended to indicate that these compounds are not isotopically enriched and isotopically enriched.
  • Isotopically enriched compounds have the structure depicted by the general formula given herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number.
  • Exemplary isotopes that may be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 17 O , 18 O, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I.
  • the compounds of the invention include isotopically enriched compounds of the invention, for example, those in which a radioisotope such as 3 H, 14 C and 18 F is present, or in which a non-radioactive isotope is present, such as 2 H and 13 C.
  • a radioisotope such as 3 H, 14 C and 18 F
  • a non-radioactive isotope such as 2 H and 13 C.
  • isotopically enriched compounds can be used for metabolic studies (using 14 C), reaction kinetic studies (using, for example, 2 H or 3 H), detection or imaging techniques such as positron emission tomography (PET) or including drugs or Single photon emission computed tomography (SPECT) of substrate tissue distribution assays, or may be used in patient radiation therapy.
  • 18 F enriched compounds are particularly desirable for PET or SPECT studies.
  • the isotopically enriched compound of formula (I) can be prepared by conventional techniques familiar to those skilled in the art or by the use of suitable isotopically labeled reagents in place of the previously used unlabeled reagents as described in the Examples and Preparations of the present invention.
  • substitution of heavier isotopes may provide certain therapeutic advantages resulting from higher metabolic stability. For example, increased in vivo half-life or reduced dose requirements or improved therapeutic index.
  • the hydrazine in the present invention is regarded as a substituent of the compound of the formula (I).
  • Isotopic enrichment factors can be used to define the concentration of such heavier isotopes, particularly ruthenium.
  • isotopic enrichment factor refers to the ratio between the isotope abundance and the natural abundance of a given isotope.
  • a substituent of a compound of the invention is designated as hydrazine
  • the compound has at least 3500 for each of the specified hydrazine atoms (52.5% of ruthenium incorporation at each of the specified ruthenium atoms), at least 4,000 (60% of ruthenium incorporation), At least 4,500 (67.5% of cerium incorporation), at least 5,000 (75% of cerium incorporation), at least 5,500 (82.5% of cerium incorporation), at least 6,000 (90% of cerium incorporation), at least 6333.3 (95%) Iridium enrichment factor with at least 6466.7 (97% cerium incorporation), at least 6600 (99% cerium incorporation) or at least 6633.3 (99.5% cerium incorporation).
  • the present invention can include pharmaceutically acceptable solvates wherein the solvent of crystallization may be isotopically substituted, for example D 2 O, acetone -d 6, DMSO-d 6 solvate of those.
  • the invention relates to an intermediate for the preparation of a compound encompassed by formula (I).
  • the invention relates to a process for the preparation, isolation and purification of a compound encompassed by formula (I).
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention, a pharmaceutically acceptable carrier, an excipient, a diluent, an adjuvant, a vehicle, or a combination thereof.
  • the pharmaceutical composition can be in the form of a liquid, solid, semi-solid, gel or spray.
  • “Combination” means a fixed combination in a single dosage unit form or a kit for a portion to be administered in combination, wherein the disclosed compounds and combination partners can be administered independently at the same time or can be administered separately at certain intervals In particular, the joint partner is shown to cooperate, such as synergy.
  • the terms "co-administered” or “co-administered” and the like as used herein are intended to encompass the administration of a selected combination partner to a single individual (eg, a patient) in need thereof, and is intended to include wherein the substance does not have to be administered by the same route of administration or simultaneously. Treatment plan.
  • pharmaceutical combination product denotes a product obtained by mixing or combining more than one active ingredient, and includes both a fixed combination of active ingredients and a non-fixed combination.
  • fixed combination means that the active ingredient, such as a compound of the present invention and a combination partner, is administered to a patient simultaneously in the form of a single entity or dosage.
  • non-fixed combination means that the active ingredient, such as a compound of the present invention and a combination partner, are administered to a patient as a separate entity simultaneously, together or without specific time constraints, wherein the administration provides therapeutic efficacy of the two compounds in the patient. Level. The latter also applies to cocktail therapy, for example the administration of three or more active ingredients.
  • N-Boc-O-tert-butyl-L-serine (11 mmol) was placed in a round bottom flask, and dichloromethane and N,N-dimethylformamide were added as a mixed solvent 50 ml, HCTU (6-chlorobenzophenone).
  • Triazole-1,1,3,3-tetramethyluronium hexafluorophosphate) (11 mmol) and DIEA (N,N-diisopropylethylamine) (11 mmol) were added to the reaction solution, followed by addition The compound (10 mmol) shown in 1-1 was stirred at room temperature for 3 hr.
  • the reaction mixture was diluted with 100 ml of dichloromethane, washed with aq. sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride, and dichloromethane was evaporated under reduced pressure.
  • the obtained product was separated by silica gel column ( petroleum ether: ethyl acetate 2:1). Compound of 3, isolated yield 92%.
  • the compound of the formula 4 (10 mmol) was placed in a round bottom flask, and a 33 wt% diethylamine acetonitrile solution was added thereto, and the mixture was stirred at room temperature for 15 min, and the solvent was evaporated under reduced pressure. 1) The compound of the formula 5 was obtained in an isolated yield of 86%.
  • the compound of the formula 7 (8 mmol) was placed in a round bottom flask, 20 ml of tetrahydrofuran was added, and lithium hydroxide (16 mmol) was dissolved in water (7 ml), and then added to the reaction mixture, stirred at room temperature for 5 min, then quenched with dilute hydrochloric acid. reaction.
  • the reaction mixture was diluted with 100 ml of ethyl acetate, washed with a saturated aqueous solution of sodium chloride, and the ethyl acetate was evaporated under reduced pressure.
  • the obtained product was separated on silica gel column (dichloromethane:methanol 10:1) to give the compound of formula 8. The rate is 86%.
  • the compound of the formula 8 (7 mmol) was placed in a round bottom flask, and dichloromethane and N,N-dimethylformamide were added as 50 ml of a mixed solvent, and HATU (7 mmol) and DIEA (8 mmol) were added to the reaction mixture. Further, compound 5 (7 mmol) was added, and the mixture was stirred at room temperature for three hours, then quenched with dilute hydrochloric acid. The reaction mixture was diluted with 100 ml of dichloromethane, washed with aq.
  • the compound (6 mmol) of the formula 9 and palladium hydroxide/carbon (1 mmol) were placed in a round bottom flask, 50 ml of methanol was added thereto, and the mixture was stirred under a hydrogen atmosphere of 1 atm. at room temperature for 15 min, and palladium hydroxide/carbon was removed by filtration. Spin the remaining methanol solution dry. The crude compound obtained.
  • the compound of formula 10 (0.5 mmol) was placed in a round bottom flask, 5 ml of 2M hydrochloric acid ethyl acetate solution was added, and the mixture was stirred at room temperature for 20 min, diluted with ethyl acetate 10 ml, washed with saturated aqueous sodium hydrogen carbonate The organic product was dried over sodium sulfate, and the ethyl acetate solvent was evaporated under reduced pressure to give crude compound.
  • the compound of the formula 11 (0.5 mmol) and the compound of the formula 12 (0.5 mmol) were placed in a round bottom flask, and tetrahydrofuran and N,N-dimethylformamide were added as a mixed solvent 10 ml, and placed in an ice water bath.
  • DIEA (1 mmol) was added, and after reacting for 1 hour, it was stirred at room temperature overnight.
  • the reaction was quenched by the addition of diluted hydrochloric acid.
  • the reaction mixture was diluted with ethyl acetate (100 ml), washed with saturated aqueous sodium chloride, and ethyl acetate was evaporated under reduced pressure.
  • the obtained product was purified by silica gel column (dichloromethane:methanol 10:1) to give compound of formula 13.
  • the compound of formula 13 (0.2 mmol) was placed in a round bottom flask, 33 wt% of diethylamine acetonitrile solvent was added to the round bottom flask, and stirred at room temperature for 15 minutes. After the Fmoc was completely removed, the solvent was spun dry, crude No need to cross the column. 5 ml of trifluoroacetic acid: triisopropylsilane:water (95:2.5:2.5, by volume) was added to the flask containing the crude product, and the mixture was stirred at room temperature for 1 hour, then the solvent was blown dry with nitrogen, precipitated by ice diethyl ether, and centrifuged.
  • the compound of the formula I-2 is obtained according to the above method, wherein the compound represented by the formula 1-2 is used in the step (1) instead of the compound of the formula 1-1;
  • group R 1 is hydrogen, R 2 is phenyl, R 3 is fluorenyl, R 4 is ethyl, and R 5 is n-butylamino.
  • the compound of the formula I-3 is obtained according to the above method, wherein the compound represented by the formula 1-2 is used in the step (1) instead of the formula a compound of 1-1;
  • R 1 is hydrogen, R 2 is p-methylphenyl, R 3 is formyl, R 4 is ethyl, and R 5 is n-butylamino;
  • R 1 is hydrogen
  • R 2 is p-phenyl
  • R 3 is carboxamide
  • R 4 is ethyl
  • R 5 is imidazolidinyl
  • R 1 is hydrogen
  • R 2 is a p-benzophenone group
  • R 3 is a carboxamide group
  • R 4 is an ethyl group
  • R 5 is an imidazolidinyl group
  • the MIC of the compound was tested according to the CLSI guidelines.
  • the culture medium was selected for THY medium, and the MHB medium was selected for testing.
  • the medium used was added with 0.002% Tween 80 to inhibit drug adherence.
  • the cell concentration was adjusted to 5 x 10 5 per ml.
  • the concentration of the compound was 8 ⁇ g/ml, 4 ⁇ g/ml, 2 ⁇ g/ml, 1 ⁇ g/ml, 0.5 ⁇ g/ml, and 0.25 ⁇ g/ml from high to low, and the medium was clarified after incubation at 37 ° C for 20 hours.
  • the drug concentration is the minimum inhibitory concentration.
  • the antibacterial activity of the compound prepared by the present invention is comparable to that of teixobactin, and the molecular structural formula and the synthesis cost are low.

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Abstract

一种化合物，其为式I所示的化合物或式I所示化合物的立体异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或前药：

Description

新型抗生素及其制备方法、用途、应用
优先权信息
本申请请求2017年05月22日向中国国家知识产权局提交的、专利申请号为201710363824.9的专利申请的优先权和权益，并且通过参照将其全文并入此处。
技术领域
本发明涉及药物化学领域，具体地，本发明涉及一种新型抗生素及其制备方法、用途、应用。
背景技术
革兰氏阳性细菌感染为常见病与多发病，危害人类健康。近年来，革兰氏阳性球菌感染日见增多，耐甲氧西林金黄色葡萄球菌(MRSA)检出率上升，耐青霉素肺炎链球菌(PRSP)在许多国家与地区传播，耐糖肽和其他多种抗生素的耐万古霉素肠球菌(VRE)出现，耐多药性结核杆菌有增无减。为了有效地控制此等现有抗生素与抗菌药的耐药菌感染，研究开发治疗革兰氏阳性耐药菌感染的药物已成为举世关注的点。
目前细菌接触抗菌药物可发生变异而获得耐药性，其机制主要有4种：①产生抗生素酶,灭活抗生素；②作用靶位变异，不应答药物；③外膜通透性改变，阻断药物进入；④增强外排，加速泵出进入菌体内的药物。在与抗菌药物一次次的“遭遇战”中，存活下来的细菌都积累了丰富的“战斗经验”，成为耐药品种，尔后又演进出交叉耐药、多重耐药、泛耐药、全耐药等“超级细菌”。不久前，一项由中外研究者联合进行的、成果发表在新一期《柳叶刀·传染病》杂志上的研究引发关注。该研究显示：存在一种特殊基因MCR-1，携带该基因的细菌对多粘菌素表现出强耐药性，且这种耐药性还能快速转移至其他菌株，这意味着一种新的“超级细菌”被发现。
2015年，我国大肠埃希菌对第三代头孢菌素的耐药菌检出率为59％，对喹诺酮类的耐药菌检出率为53.5％。肺炎克雷伯菌对第三代头孢菌素的耐药菌检出率是36.5％，甲氧西林耐药金黄色葡萄球菌检出率为35.8％，这些具有代表性的耐药菌检出率都处于较高水平。需要指出的是，万古霉素耐药屎肠球菌已成为发达国家的一大挑战，美国ICU患者的血流感染屎肠球菌万古霉素耐药率高达80.7％。全球来看，北美洲屎肠球菌万古霉素耐药平均检出率高达66.8％，拉丁美洲为39.4％。一些多重耐药、泛耐药的细菌已将临床逼到了绝境，加速研发新型抗菌药物迫在眉睫。
目前，碳青霉烯类抗生素是公认的细菌“终极防线”，常用于治疗由多重耐药菌引起严 重感染。近几年，碳青霉烯类耐药菌通过质粒间传播造成了严重的细菌耐药问题，包括近期发现的粘菌素耐药。这些救命药因其毒性较大，往往临床使用受限。因此，需要提供一种结构新颖的抗菌化合物。
发明内容
本发明的目的是提供一种用于耐药革兰氏阳性菌及结核治疗的新型抗生素，即提供了一类新型的化合物。
在本发明的第一方面，本发明提出了一种化合物。根据本发明的实施例，所述化合物，其为式I所示的化合物或式I所示化合物的立体异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或前药：
Figure PCTCN2017114644-appb-000001
其中，R1为氢、任选取代的C1～15烷基、任选取代的C2～15烯基、任选取代的C2～15炔基、任选取代的芳基或任选取代的酰基；R2为氢、卤素、任选取代的C1～15烷基、任选取代的C2～15烯基、任选取代的C2～15炔基、任选取代的酰基或者任选被卤素、烷基、三氟甲基取代的芳基；R3为氨基、胍基、脲基或甲酰胺基；R4为任选取代的C1～15烷基、任选取代的C2～15烯基、任选取代的C2～15炔基、任选取代的芳基；R5为氨基、胍基或脲基；m为1～4之间的整数，包括端点；X为O、S或NH。
根据本发明的实施例，上述化合物进一步包括如下附加技术特征至少之一：
根据本发明的实施例，所述化合物，包括：R1为氢；R2为苯甲酰基或任选取代的芳基取代的芳基；R3为
Figure PCTCN2017114644-appb-000002
R4为任选取代的C1～15烷基；R5为
Figure PCTCN2017114644-appb-000003
氨基；m为1～4之间的整数，包括端点；X为O、S或NH。
根据本发明的实施例，所述化合物为
Figure PCTCN2017114644-appb-000004
Figure PCTCN2017114644-appb-000005
在本发明的第二方面，本发明提出了一种制备上述化合物的方法。根据本发明的实施例，包括如下步骤：(1)使式3所示化合物与Fmoc-L-异亮氨酸接触，以便获得式4所示化合物；(2)使所述式4所示化合物发生脱保护反应，以便获得式5所示化合物；(3)使式6所示化合物与苄氧羰基-L-丙氨酸接触，以便获得式7所示化合物；(4)使所述式7所示化合物发生还原反应，以便获得式8所示化合物；(5)使所述式5所示化合物与所述式8所示化合物发生缩合反应得到式9所示化合物；(6)使所述式9所示化合物发生分子内缩合反应，以便获得式10所示化合物；(7)使所述式10所示化合物发生脱保护反应，以便式11所示化合物；(8)使所述式11所示化合物与式12所示化合物接触，以便获得式13所示化合物；(9)式13所示化合物依次在碱性条件和酸性条件下经脱保护反应即得前面所述的化合物，
Figure PCTCN2017114644-appb-000006
Figure PCTCN2017114644-appb-000007
其中，Bn为苄基，t-Bu为叔丁基，Boc为叔丁氧羰基，Y为-N3、-OH或-SH，Fmoc为9-芴甲氧羰基，X为O、S或NH；m为1～4之间的整数，包括端点；R6为-NH-、-NH-C(＝O)-NH-或-NH-C(＝NH)-NH-；Cbz为苄氧羰基。
根据本发明的实施例，上述方法进一步包括如下附加技术特征至少之一：
根据本发明的实施例，所述方法包括：(1)使所述式3所示化合物经叠氮还原后与所述Fmoc-L-异亮氨酸发生缩合反应，或者使所述式3所示化合物直接与所述Fmoc-L-异亮氨酸发生缩合反应，以便获得所述式4所示化合物，其中，当Y表示-N3时，使所述式3所示化合物经叠氮还原后与所述Fmoc-L-异亮氨酸发生缩合反应，当Y表示-OH或-SH时，使所述式3所示化合物直接与所述Fmoc-L-异亮氨酸发生缩合反应；(2)在碱性条件下，使所述式4所示化合物发生脱保护反应，以便获得所述式5所示化合物；(3)使所述式6所示化合物与所述苄氧羰基-L-丙氨酸发生缩合反应，以便获得所述式7所示化合物；(4)使所述式7所示化合物发生还原反应，以便获得式8所示化合物；(5)使所述式5所示化合物与所述式8所示化合物发生缩合反应，以便得到所述式9所示化合物；(6)使所述式9所示化合物发生还原反应和分子内缩合反应，以便获得所述式10所示化合物；(7)在酸性条件下，使所述式10所示化合物发生脱保护反应，以便获得所述式11所示化合物；(8)使所述式11所示化合物与所述式12所示化合物经缩合反应，以便获得所述式13所示化合物；(9)使所述式13所示化合物依次在碱性条件和酸性条件下发生脱保护反应，以便获得前面所述的化合物。
根据本发明的实施例，所述方法包括：在步骤(1)中，所述式3所示化合物是通过以下步骤获得的：使N-Boc-O-叔丁基-L-丝氨酸与式1所示化合物发生缩合反应，以便获得所述式3所示化合物；
Figure PCTCN2017114644-appb-000008
其中，所述缩合反应是在存在6-氯苯并三氮唑-1,1,3,3-四甲基脲六氟磷酸酯和N,N-二异丙基乙胺的条件下进行；所述式1所示化合物与所述N-Boc-O-叔丁基-L-丝氨酸的摩尔比为1：(1.0～1.5)；所述N-Boc-O-叔丁基-L-丝氨酸、所述6-氯苯并三氮唑-1,1,3,3-四甲基脲六氟磷酸酯与所述N,N-二异丙基乙胺的摩尔比为1：(1.0～1.5)：(1.0～1.5)；所述缩合反应是在20～25摄氏度的温度下进行2～3小时。
根据本发明的实施例，在步骤(2)中，所述叠氮还原反应是在存在三苯基膦的条件下进行的；在步骤(1)和步骤(3)中，所述缩合反应是分别独立地在存在碳化二亚胺和4-二甲氨基吡啶的条件下进行的；所述Fmoc-L-异亮氨酸与所述式3所示化合物的摩尔比为1：(0.5～1.0)；所述Fmoc-L-异亮氨酸、所述碳化二亚胺与所述4-二甲氨基吡啶的摩尔比为1：(1.0～1.5)：(0.1～0.5)；所述苄氧羰基-L-丙氨酸与所述式6所示化合物的摩尔比为1：(0.5～1.0)；所述苄氧羰基-L-丙氨酸、所述碳化二亚胺与所述4-二甲氨基吡啶的摩尔比为1：(1.0～1.5)：(0.1～0.5)；在步骤(1)和步骤(3)中，所述缩合反应是分别独立地在20～25的温度下进行2～3小时。
根据本发明的实施例，在步骤(2)中，所述碱性条件是通过采用33重量％的二乙胺的乙腈溶液形成的；在步骤(4)中，所述还原反应是在存在氢氧化锂的条件下进行的；所述式7所述化合物与所述氢氧化锂的摩尔比为1：(1～5)；在步骤(5)中，所述缩合反应是在存在2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯和N,N-二异丙基乙胺的条件下进行的；所述式8所述化合物与所述式5所示化合物的摩尔比为1：(1.0～1.5)；所述式8所述化合物、所述2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯与所述N,N-二异丙基乙胺的摩尔比为1：(1.0～1.5)：(0.1～0.5)；在步骤(5)中，所述缩合反应是在20～25的温度下进行2～3小时。
根据本发明的实施例，在步骤(6)中，所述还原反应是在存在氢氧化钯/碳的条件下进行的；所述分子内缩合反应是在存在2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯、1-羟基-7-偶氮苯并三氮唑和N,N-二异丙基乙胺的条件下进行的；步骤(7)中，所述脱保护反应是在存在盐酸的条件下进行的；步骤(8)中，所述缩合反应是在存在3-二乙氧基磷酰 基-1,2,3-苯唑4(3H)-酮和N,N-二异丙基乙胺的条件下进行；所述式11所示化合物、所述3-二乙氧基磷酰基-1,2,3-苯唑4(3H)-酮与所述N,N-二异丙基乙胺的摩尔比为1：(1～2)：(1～2)，步骤(9)中，所述碱性条件是采用33重量％的二乙胺的乙腈溶液形成的；所述酸性条件是采用三氟乙酸和三异丙基硅烷的混合水溶液形成的。
在本发明的第三方面，本发明提出了一种革兰氏阳性菌的抑制剂。根据本发明的实施例，所述抑制剂包括前面所述的化合物。
在本发明的第四方面，本发明提出了一种药物组合物。根据本发明的实施例，所述的药物组合物包含前面所述的化合物。
根据本发明的实施例，上述药物组合物还可以包括如下附加技术特征至少之一：
根据本发明的实施例，所述的药物组合物，进一步包含药学上可接受的载体、赋形剂、稀释剂、辅剂、媒介物或其组合。
在本发明的第五方面，本发明提出了前面所述化合物在制备药物中的用途。根据本发明的实施例，所述药物用于抑制革兰氏阳性菌生长和/或繁殖。
在本发明的第六方面，本发明提出了一种抑制革兰氏阳性菌生长和/或繁殖的方法。根据本发明的实施例，所述方法包括：使所述革兰氏阳性菌与前面所述的化合物接触。
在本发明的第七方面，本发明提出了一种前面所述的化合物在抑制革兰氏阳性菌生长和/或繁殖中的应用。根据本发明的实施例，前面所述的化合物在抑制革兰氏阳性菌生长和/或繁殖中的应用。
在本发明的第八方面，本发明提出了一种前面所述的化合物在制备抑制革兰氏阳性菌生长和/或繁殖的产品中的应用。根据本发明的实施例，前面所述的化合物在制备抑制革兰氏阳性菌生长和/或繁殖的产品中的应用。
在本发明的第九方面，本发明提出了前面所述的抑制剂、前面所述的用途、前面所述的方法、前面所述的应用。根据本发明的实施例，所述革兰氏阳性菌包括选自链球菌、葡萄球菌、肠球菌、棒状杆菌、李斯特氏菌、芽孢杆菌、丹毒丝菌、放线菌、幽门螺杆菌、嗜肺军团菌、结核杆菌、鸟型结核分枝杆菌、胞内鸟分枝杆菌、金黄色酿脓葡萄球菌、表皮葡萄球菌、淋病奈瑟氏菌、脑膜炎奈瑟氏菌、酿脓链球菌、粪链球菌、牛链球菌、肺炎链球菌、嗜血杆菌、绿脓杆菌、炭疽杆菌和枯草杆菌中至少一种。
在本发明的再一方面，根据本发明的实施例，本发明提出了
1、式I所示化合物，
Figure PCTCN2017114644-appb-000009
式Ⅰ中，基团R1为氢、碳原子数为1～15的烷基、碳原子数为2～15的烯基、碳原子数为2～15的炔基、芳基或酰基；
基团R2为氢、卤素、碳原子数为1～15的烷基、碳原子数为2～15的烯基、碳原子数为2～15的炔基、芳基、取代芳基或酰基，所述取代芳基为卤素取代芳基、烷基取代芳基或三氟甲基取代芳基；
基团R3为氨基、胍基、脲基或甲酰胺基；
基团R4为碳原子数为1～15的烷基、碳原子数为2～15的烯基、碳原子数为2～15的炔基或芳基；
基团R5为氨基、胍基或脲基；
m为1～4之间的自然数；
X为O、S或NH。
2、式Ⅰ所示化合物的制备方法，包括如下步骤：
(1)式3所示化合物经叠氮还原后或直接与Fmoc-L-异亮氨酸经缩合反应得到式4所示化合物；
Figure PCTCN2017114644-appb-000010
式3中，Bn表示苄基，t-Bu表示叔丁基，Boc表示叔丁氧羰基；Y表示-N3、-OH或-SH，即当Y表示-N3时，先进行叠氮还原后再进行所述缩合反应，当Y表示-OH或-SH时，直接进行所述缩合反应；
式4中，Fmoc表示9-芴甲氧羰基，Bn、t-Bu和Boc的定义同式3中；X为O、S或NH；
(2)在碱性条件下，式4所示化合物经脱保护反应得到式5所示化合物；
Figure PCTCN2017114644-appb-000011
式5中，Bn、t-Bu、Boc和X的定义同式3中；
(3)式6所示化合物与苄氧羰基-L-丙氨酸经缩合反应得到式7所示化合物；
Figure PCTCN2017114644-appb-000012
式6和式7中，Fmoc的定义同式4中，m为1～4之间的自然数；
式6中，R6表示-NH-、-NH-C(＝O)-NH-或-NH-C(＝NH)-NH-；
式7中，Cbz表示苄氧羰基；
(4)式7所示化合物经还原反应得到式8所示化合物；
Figure PCTCN2017114644-appb-000013
式8中，Fmoc的定义同式4中，Cbz的定义同式7中，m和R6的定义同式6；
(5)式5所示化合物与式8所示化合物经缩合反应得到式9所示化合物；
Figure PCTCN2017114644-appb-000014
式9中，Bn、t-Bu、Boc和X的定义同式3中，Fmoc的定义同式4中，Cbz的定义同式7中，m和R6的定义同式6；
(6)式9所示化合物经还原反应后再经分子内缩合反应得到式10所示化合物；
Figure PCTCN2017114644-appb-000015
式10中，t-Bu、Boc和X的定义同式3中，m和R6的定义同式6；
(7)在酸性条件下，式10所示化合物经脱保护反应得到式11所示化合物；
Figure PCTCN2017114644-appb-000016
式11中，t-Bu和X的定义同式3中，m和R6的定义同式6；
(8)式11所示化合物与式12所示化合物经缩合反应得到式13所示化合物；
Figure PCTCN2017114644-appb-000017
式12和式13中，基团R1为氢、碳原子数为1～15的烷基、碳原子数为2～15的烯基、碳原子数为2～15的炔基、芳基或酰基；
基团R2为氢、卤素、碳原子数为1～15的烷基、碳原子数为2～15的烯基、碳原子数为2～15的炔基、芳基、取代芳基或酰基，所述取代芳基为卤素取代芳基或三氟甲基取代芳基；
基团R4为碳原子数为1～15的烷基、碳原子数为2～15的烯基、碳原子数为2～15的炔基或芳基；
t-Bu和Boc的定义同式3中；
式13中，X的定义同式3中，m和R6的定义同式6；
(9)式13所示化合物依次在碱性条件和酸性条件下经脱保护反应即得权利要求1式Ⅰ所示化合物。
3、根据权利要求2所述的制备方法，其特征在于：步骤(1)中，式3所示化合物通过如下方法制备：
N-Boc-O-叔丁基-L-丝氨酸与式1所示化合物经缩合反应得到式3所示化合物；
Figure PCTCN2017114644-appb-000018
式1中，Bn表示苄基，t-Bu表示叔丁基，Boc表示叔丁氧羰基；Y的定义同式3；
所述缩合反应在6-氯苯并三氮唑-1,1,3,3-四甲基脲六氟磷酸酯和N,N-二异丙基乙胺的催化下进行；
式1所示化合物与所述N-Boc-O-叔丁基-L-丝氨酸的摩尔比为1：1.0～1.5；
所述N-Boc-O-叔丁基-L-丝氨酸、所述6-氯苯并三氮唑-1,1,3,3-四甲基脲六氟磷酸酯与所述N,N-二异丙基乙胺的摩尔比为1：1.0～1.5：1.0～1.5；
所述缩合反应的温度为20～25℃，时间为2～3小时。
4、根据权利要求2或3所述的制备方法，其特征在于：步骤(2)中，在三苯基膦的催化下进行叠氮还原；
步骤(1)和步骤(3)中，所述缩合反应均在碳化二亚胺和4-二甲氨基吡啶的催化下进行；
所述Fmoc-L-异亮氨酸与式3所示化合物的摩尔比为1：0.5～1.0；
所述Fmoc-L-异亮氨酸、所述碳化二亚胺与所述4-二甲氨基吡啶的摩尔比为1：1.0～1.5：0.1～0.5；
所述苄氧羰基-L-丙氨酸与式6所示化合物的摩尔比为1：0.5～1.0；
所述苄氧羰基-L-丙氨酸、所述碳化二亚胺与所述4-二甲氨基吡啶的摩尔比为1：1.0～1.5：0.1～0.5；
所述缩合反应的温度为20～25℃，时间为2～3小时。
5、根据权利要求2-4中任一项所述的制备方法，其特征在于：步骤(2)中，所述碱性条件由质量百分含量为33％的二乙胺的乙腈溶液调制得到；
步骤(4)中，所述还原反应在氢氧化锂的催化下进行；
式7所述化合物与所述氢氧化锂的摩尔比为1：1～5；
步骤(5)中，所述缩合反应在2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯和N,N-二异丙基乙胺的催化下进行；
式8所述化合物与式5所示化合物的摩尔比为1：1.0～1.5；
式8所述化合物、所述2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯与所述N,N-二异丙基乙胺的摩尔比为1：1.0～1.5：0.1～0.5；
所述缩合反应的温度为20～25℃，时间为2～3小时。
6、根据权利要求2-5中任一项所述的制备方法，其特征在于：步骤(6)中，所述还原反应在氢氧化钯/碳的催化下进行；
所述分子内缩合反应在2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯、1-羟基-7-偶氮苯并三氮唑和N,N-二异丙基乙胺的催化下进行；
步骤(7)中，所述脱保护反应盐酸存在的条件下进行；
步骤(8)中，所述缩合反应在3-二乙氧基磷酰基-1,2,3-苯唑4(3H)-酮和N,N-二异丙基乙胺的催化下进行；
式11所示化合物、所述3-二乙氧基磷酰基-1,2,3-苯唑4(3H)-酮与所述N,N-二异丙基乙胺的摩尔比为1：1～2：1～2。
步骤(9)中，所述碱性条件由质量百分含量为33％的二乙胺的乙腈溶液调制得到；
所述酸性条件由三氟乙酸和三异丙基硅烷的混合水溶液调制得到。
7、权利要求1所述化合物在抑制革兰氏阳性菌生长和/或繁殖中的应用。
8、权利要求1所述化合物在制备抑制革兰氏阳性菌生长和/或繁殖的产品中的应用。
9、根据权利要求7或8所述的应用，其特征在于：所述革兰氏阳性菌为链球菌、葡萄球菌、肠球菌、棒状杆菌、李斯特氏菌、芽孢杆菌、丹毒丝菌、放线菌、幽门螺杆菌、嗜肺军团菌、结核杆菌、鸟型结核分枝杆菌、胞内鸟分枝杆菌、金黄色酿脓葡萄球菌、表皮葡萄球菌、淋病奈瑟氏菌、脑膜炎奈瑟氏菌、酿脓链球菌、粪链球菌、牛链球菌、肺炎链球菌、嗜血杆菌、绿脓杆菌、炭疽杆菌和枯草杆菌中至少一种。
10、一种革兰氏阳性菌的抑制剂，其活性成分为权利要求1所述化合物。
根据本发明的实施例，本发明所提供的化合物的结构式如式I所示，
Figure PCTCN2017114644-appb-000019
式Ⅰ中，基团R1为氢、碳原子数为1～15的烷基、碳原子数为2～15的烯基、碳原子数为2～15的炔基、芳基或酰基；
基团R2为氢、卤素、碳原子数为1～15的烷基、碳原子数为2～15的烯基、碳原子数为2～15的炔基、芳基、取代芳基或酰基，所述取代芳基为卤素取代芳基、烷基取代芳基或三氟甲基取代芳基；
基团R3为氨基、胍基、脲基或甲酰胺基；
基团R4为碳原子数为1～15的烷基、碳原子数为2～15的烯基、碳原子数为2～15的炔基或芳基；
基团R5为氨基、胍基或脲基；
m为1～4之间的自然数；
X为O、S或NH。
本发明提供的式Ⅰ所示化合物中，R2具体可为苯基、卤素取代苯基或碳原子数为1～15的烷基取代的苯基，所述碳原子数为1～15的烷基取代苯基具体可为碳原子数为1～6的烷基取代苯基，优选为甲基取代苯基、乙基取代苯基、丙基取代苯基、异丙基取代苯基、正丁基取代苯基、异丁基取代苯基、叔丁基取代苯基、戊基取代苯基或己基取代苯基。
本发明提供的式Ⅰ所示化合物中，R1、R2和R4中碳原子数为1～15的烷基优选碳原子数为1～6的烷基，例如甲基、乙基、丙基、异丙基、正丁基、异丁基、叔丁基、戊基或己基等；
R1、R2和R4中碳原子数为2～15的烯基优选碳原子数为2～6的烯基，例如乙烯基、丙烯基、丁烯基、异丁烯基、戊烯基或己烯基等；
R1、R2和R4中碳原子数为2～15的炔基优选碳原子数为2～6的炔基，例如乙炔基、丙炔基、丁炔基、异丁炔基、戊炔基或己炔基等。
本发明提供的式I所示化合物中，R3具体可为甲酰基或胍基；
R5具体可为氨基；
m具体可为1、2、3或4；
X具体可为O或NH。
本发明提供的式I所示化合物具体如式I-1、式I-2或式I-3所示，
Figure PCTCN2017114644-appb-000020
Figure PCTCN2017114644-appb-000021
本发明还进一步提供了式Ⅰ所示化合物的制备方法，包括如下步骤：
(1)式3所示化合物经叠氮还原后或直接与Fmoc-L-异亮氨酸经缩合反应得到式4所示化合物；
Figure PCTCN2017114644-appb-000022
式3中，Bn表示苄基，t-Bu表示叔丁基，Boc表示叔丁氧羰基；Y表示-N3、-OH或-SH，即当Y表示-N3时，先进行叠氮还原后再进行所述缩合反应，当Y表示-OH或-SH时，直接进行所述缩合反应；
式4中，Fmoc表示9-芴甲氧羰基，Bn、t-Bu和Boc的定义同式3中；X为O、S或NH；
(2)在碱性条件下，式4所示化合物经脱保护反应得到式5所示化合物；
Figure PCTCN2017114644-appb-000023
式5中，Bn、t-Bu、Boc和X的定义同式3中；
(3)式6所示化合物与苄氧羰基-L-丙氨酸经缩合反应得到式7所示化合物；
Figure PCTCN2017114644-appb-000024
式6和式7中，Fmoc的定义同式4中，m为1～4之间的自然数；
式6中，R6表示-NH-、-NH-C(＝O)-NH-或-NH-C(＝NH)-NH-；
式7中，Cbz表示苄氧羰基；
(4)式7所示化合物经还原反应得到式8所示化合物；
Figure PCTCN2017114644-appb-000025
式8中，Fmoc的定义同式4中，Cbz的定义同式7中，m的定义同式6；
(5)式5所示化合物与式8所示化合物经缩合反应得到式9所示化合物；
Figure PCTCN2017114644-appb-000026
式9中，Bn、t-Bu、Boc和X的定义同式3中，Fmoc的定义同式4中，Cbz的定义同式7中，m和R6的定义同式6；
(6)式9所示化合物经还原反应后再经分子内缩合反应得到式10所示化合物；
Figure PCTCN2017114644-appb-000027
式10中，t-Bu、Boc和X的定义同式3中，m和R6的定义同式6；
(7)在酸性条件下，式10所示化合物经脱保护反应得到式11所示化合物；
Figure PCTCN2017114644-appb-000028
式11中，t-Bu和X的定义同式3中，m和R6的定义同式6；
(8)式11所示化合物与式12所示化合物经缩合反应得到式13所示化合物；
Figure PCTCN2017114644-appb-000029
式12和式13中，基团R1为氢、碳原子数为1～15的烷基、碳原子数为2～15的烯基、 碳原子数为2～15的炔基、芳基或酰基；
基团R2为氢、卤素、碳原子数为1～15的烷基、碳原子数为2～15的烯基、碳原子数为2～15的炔基、芳基、取代芳基或酰基，所述取代芳基为卤素取代芳基或三氟甲基取代芳基；
基团R4为碳原子数为1～15的烷基、碳原子数为2～15的烯基、碳原子数为2～15的炔基或芳基；
t-Bu和Boc的定义同式3中；
式13中，X的定义同式3中，m和R6的定义同式6；
(9)式13所示化合物依次在碱性条件和酸性条件下经脱保护反应即得权利要求1式Ⅰ所示化合物。
所述的制备方法中，步骤(1)中，式3所示化合物可通过如下方法制备：
N-Boc-O-叔丁基-L-丝氨酸与式1所示化合物经缩合反应得到式3所示化合物；
Figure PCTCN2017114644-appb-000030
式1中，Bn表示苄基，t-Bu表示叔丁基，Boc表示叔丁氧羰基；Y的定义同式3；
所述缩合反应在6-氯苯并三氮唑-1,1,3,3-四甲基脲六氟磷酸酯和N,N-二异丙基乙胺的催化下进行；
式1所示化合物与所述N-Boc-O-叔丁基-L-丝氨酸的摩尔比为1：1.0～1.5；
所述N-Boc-O-叔丁基-L-丝氨酸、所述6-氯苯并三氮唑-1,1,3,3-四甲基脲六氟磷酸酯与所述N,N-二异丙基乙胺的摩尔比为1：1.0～1.5：1.0～1.5；
所述缩合反应的温度为20～25℃，时间为2～3小时。
所述的制备方法中，步骤(1)中，在三苯基膦的催化下进行叠氮还原；
步骤(1)和步骤(3)中，所述缩合反应均在碳化二亚胺和4-二甲氨基吡啶的催化下进行；
所述Fmoc-L-异亮氨酸与式3所示化合物的摩尔比为1：0.5～1.0；
所述Fmoc-L-异亮氨酸、所述碳化二亚胺与所述4-二甲氨基吡啶的摩尔比为1：1.0～1.5：0.1～0.5；
所述苄氧羰基-L-丙氨酸与式6所示化合物的摩尔比为1：0.5～1.0；
所述苄氧羰基-L-丙氨酸、所述碳化二亚胺与所述4-二甲氨基吡啶的摩尔比为1：1.0～1.5：0.1～0.5；
所述缩合反应的温度为20～25℃，时间为2～3小时。
所述的制备方法中，步骤(2)中，所述碱性条件由质量百分含量为33％的二乙胺的乙腈溶液调制得到；
步骤(4)中，所述还原反应在氢氧化锂的催化下进行；
式7所述化合物与所述氢氧化锂的摩尔比为1：1～5；
步骤(5)中，所述缩合反应在2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯和N,N-二异丙基乙胺的催化下进行；
式8所述化合物与式5所示化合物的摩尔比为1：1.0～1.5；
式8所述化合物、所述2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯与所述N,N-二异丙基乙胺的摩尔比为1：1.0～1.5：0.1～0.5；
所述缩合反应的温度为20～25℃，时间为2～3小时。
所述的制备方法中，步骤(7)中，所述还原反应在氢氧化钯/碳的催化下进行；
所述分子内缩合反应在2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯、1-羟基-7-偶氮苯并三氮唑和N,N-二异丙基乙胺的催化下进行；
步骤(7)中，所述脱保护反应盐酸存在的条件下进行；
步骤(8)中，所述缩合反应在3-二乙氧基磷酰基-1,2,3-苯唑4(3H)-酮和N,N-二异丙基乙胺的催化下进行；
式11所示化合物、所述3-二乙氧基磷酰基-1,2,3-苯唑4(3H)-酮与所述N,N-二异丙基乙胺的摩尔比为1：1～2：1～2。
步骤(9)中，所述碱性条件由质量百分含量为33％的二乙胺的乙腈溶液调制得到；
所述酸性条件由三氟乙酸和三异丙基硅烷的混合水溶液调制得到。
本发明提供的式Ⅰ所示化合物可用于抑制革兰氏阳性菌的生长和/或繁殖。
所述革兰氏阳性菌可为链球菌、葡萄球菌、肠球菌、棒状杆菌、李斯特氏菌、芽孢杆菌、丹毒丝菌、放线菌、幽门螺杆菌、嗜肺军团菌、结核杆菌、鸟型结核分枝杆菌、胞内鸟分枝杆菌、金黄色酿脓葡萄球菌、表皮葡萄球菌、淋病奈瑟氏菌、脑膜炎奈瑟氏菌、酿脓链球菌、粪链球菌、牛链球菌、肺炎链球菌、嗜血杆菌、绿脓杆菌、炭疽杆菌和枯草杆菌中至少一种。
活性成分为式Ⅰ所示化合物的革兰氏阳性菌的抑制剂也属于本发明的保护范围。
本发明具有如下优点：
基于目前革兰氏阳性菌出现了严重的耐药性，本发明提供了一种新型的抗菌化合物。本发明首次通过固相与液相结合的方法合成了一系列teixobactin类似物，采用汇聚式的合成策略有助于合成种类繁多的化合物。本发明制备得到了与teixobactin活性相当的化合物。
本发明的详细说明书
定义和一般术语
现在详细描述本发明的某些实施方案，其实例由随附的结构式和化学式说明。本发明意图涵盖所有的替代、修改和等同技术方案，它们均包括在如权利要求定义的本发明范围内。本领域技术人员应认识到，许多与本文所述类似或等同的方法和材料能够用于实践本发明。本发明绝不限于本文所述的方法和材料。在所结合的文献、专利和类似材料的一篇或多篇与本申请不同或相矛盾的情况下(包括但不限于所定义的术语、术语应用、所描述的技术，等等)，以本申请为准。
应进一步认识到，本发明的某些特征，为清楚可见，在多个独立的实施方案中进行了描述，但也可以在单个实施例中以组合形式提供。反之，本发明的各种特征，为简洁起见，在单个实施方案中进行了描述，但也可以单独或以任意适合的子组合提供。
除非另外说明，本发明所使用的所有科技术语具有与本发明所属领域技术人员的通常理解相同的含义。本发明涉及的所有专利和公开出版物通过引用方式整体并入本发明。
除非另外说明，应当应用本文所使用得下列定义。出于本发明的目的，化学元素与元素周期表CAS版，和《化学和物理手册》，第75版，1994一致。此外，有机化学一般原理可参考"Organic Chemistry",Thomas Sorrell,University Science Books,Sausalito:1999,和"March's Advanced Organic Chemistry”by Michael B.Smith and Jerry March,John Wiley&Sons,New York:2007中的描述，其全部内容通过引用并入本文。
除非另有说明或者上下文中有明显的冲突，本文所使用的冠词“一”、“一个(种)”和“所述”旨在包括“至少一个”或“一个或多个”。因此，本文所使用的这些冠词是指一个或多于一个(即至少一个)宾语的冠词。例如，“一组分”指一个或多个组分，即可能有多于一个的组分被考虑在所述实施方案的实施方式中采用或使用。
术语“包含”为开放式表达，即包括本发明所指明的内容，但并不排除其他方面的内容。
“立体异构体”是指具有相同化学构造，但原子或基团在空间上排列方式不同的化合物。立体异构体包括对映异构体、非对映异构体、构象异构体(旋转异构体)、几何异构体(顺/反)异构体、阻转异构体，等等。
“手性”是具有与其镜像不能重叠性质的分子；而“非手性”是指与其镜像可以重叠的分子。
“对映异构体”是指一个化合物的两个不能重叠但互成镜像关系的异构体。
“非对映异构体”是指有两个或多个手性中心并且其分子不互为镜像的立体异构体。非对映异构体具有不同的物理性质，如熔点、沸点、光谱性质和反应性。非对映异构体混合物可通过高分辨分析操作如电泳和色谱，例如HPLC来分离。
本发明所使用的立体化学定义和规则一般遵循S.P.Parker，Ed.，McGraw-Hill Dictionary of Chemical Terms(1984)McGraw-Hill Book Company，New York；and Eliel，E.and Wilen，S.，“Stereochemistry of Organic Compounds”，John Wiley&Sons，Inc.，New York，1994。
许多有机化合物以光学活性形式存在，即它们具有使平面偏振光的平面发生旋转的能力。在描述光学活性化合物时，使用前缀D和L或R和S来表示分子关于其一个或多个手性中心的绝对构型。前缀d和l或(+)和(-)是用于指定化合物所致平面偏振光旋转的符号，其中(-)或l表示化合物是左旋的。前缀为(+)或d的化合物是右旋的。一种具体的立体异构体是对映异构体，这种异构体的混合物称作对映异构体混合物。对映异构体的50:50混合物称为外消旋混合物或外消旋体，当在化学反应或过程中没有立体选择性或立体特异性时，可出现这种情况。
本发明公开化合物的任何不对称原子(例如，碳等)都可以以外消旋或对映体富集的形式存在，例如(R)-、(S)-或(R,S)-构型形式存在。在某些实施方案中，各不对称原子在(R)-或(S)-构型方面具有至少50％对映体过量，至少60％对映体过量，至少70％对映体过量，至少80％对映体过量，至少90％对映体过量，至少95％对映体过量，或至少99％对映体过量。
依据起始物料和方法的选择，本发明化合物可以以可能的异构体中的一个或它们的混合物，例如外消旋体和非对映异构体混合物(这取决于不对称碳原子的数量)的形式存在。光学活性的(R)-或(S)-异构体可使用手性合成子或手性试剂制备，或使用常规技术拆分。如果化合物含有一个双键，取代基可能为E或Z构型；如果化合物中含有二取代的环烷基，环烷基的取代基可能有顺式或反式构型。
所得的任何立体异构体的混合物可以依据组分物理化学性质上的差异被分离成纯的或基本纯的几何异构体，对映异构体，非对映异构体，例如，通过色谱法和/或分步结晶法。
可以用已知的方法将任何所得终产物或中间体的外消旋体通过本领域技术人员熟悉的方法拆分成光学对映体，如，通过对获得的其非对映异构的盐进行分离。外消旋的产物也可以通过手性色谱来分离，如，使用手性吸附剂的高效液相色谱(HPLC)。特别地，对映异构体可以通过不对称合成制备，例如，可参考Jacques,et al.,Enantiomers,Racemates and Resolutions(Wiley Interscience,New York,1981)；Principles of Asymmetric Synthesis(2nd Ed.Robert E.Gawley,Jeffrey Aubé,Elsevier,Oxford,UK,2012)；Eliel,E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962)；Wilen,S.H.Tables of Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of Notre Dame Press,Notre Dame,IN 1972)；Chiral Separation Techniques:A Practical Approach(Subramanian,G.Ed.,Wiley-VCH Verlag GmbH&Co.KGaA,Weinheim,Germany,2007)。
术语“互变异构体”或“互变异构形式”是指具有不同能量的可通过低能垒(low energy  barrier)互相转化的结构异构体。若互变异构是可能的(如在溶液中)，则可以达到互变异构体的化学平衡。例如，质子互变异构体(protontautomer)(也称为质子转移互变异构体(prototropic tautomer))包括通过质子迁移来进行的互相转化，如酮-烯醇异构化和亚胺-烯胺异构化。价键互变异构体(valence tautomer)包括通过一些成键电子的重组来进行的互相转化。酮-烯醇互变异构的具体实例是戊烷-2,4-二酮和4-羟基戊-3-烯-2-酮互变异构体的互变。互变异构的另一个实例是酚-酮互变异构。酚-酮互变异构的一个具体实例是吡啶-4-醇和吡啶-4(1H)-酮互变异构体的互变。除非另外指出，本发明化合物的所有互变异构体形式都在本发明的范围之内。
像本发明所描述的，本发明的化合物可以任选地被一个或多个取代基所取代，如上面的通式化合物，或者像实施例里面特殊的例子，子类，和本发明所包含的一类化合物。应了解“任选取代的”这个术语与“取代或非取代的”这个术语可以交换使用。一般而言，术语“取代的”表示所给结构中的一个或多个氢原子被具体取代基所取代。除非其他方面表明，一个任选的取代基团可以在基团各个可取代的位置进行取代。当所给出的结构式中不只一个位置能被选自具体基团的一个或多个取代基所取代，那么取代基可以相同或不同地在各个位置取代。
另外，需要说明的是，除非以其他方式明确指出，在本发明中所采用的描述方式“各…独立地为”与“…各自独立地为”和“…独立地为”可以互换，均应做广义理解，其既可以是指在不同基团中，相同符号之间所表达的具体选项之间互相不影响，也可以表示在相同的基团中，相同符号之间所表达的具体选项之间互相不影响。
在本说明书的各部分，本发明公开化合物的取代基按照基团种类或范围公开。特别指出，本发明包括这些基团种类和范围的各个成员的每一个独立的次级组合。例如，术语“C1-6烷基”特别指独立公开的甲基、乙基、C3烷基、C4烷基、C5烷基和C6烷基。
在本发明的各部分，描述了连接取代基。当该结构清楚地需要连接基团时，针对该基团所列举的马库什变量应理解为连接基团。例如，如果该结构需要连接基团并且针对该变量的马库什基团定义列举了“烷基”或“芳基”，则应该理解，该“烷基”或“芳基”分别代表连接的亚烷基基团或亚芳基基团。
本发明使用的术语“烷基”或“烷基基团”，表示含有1至20个碳原子，饱和的直链或支链一价烃基基团，其中，所述烷基基团可以任选地被一个或多个本发明描述的取代基所取代。除非另外详细说明，烷基基团含有1-20个碳原子。在一实施方案中，烷基基团含有1-12个碳原子；在另一实施方案中，烷基基团含有1-6个碳原子；在又一实施方案中，烷基基团含有1-4个碳原子；还在一实施方案中，烷基基团含有1-3个碳原子。
烷基基团的实例包含，但并不限于，甲基(Me、-CH3)，乙基(Et、-CH2CH3)，正丙基(n-Pr、-CH2CH2CH3)，异丙基(i-Pr、-CH(CH3)2)，正丁基(n-Bu、-CH2CH2CH2CH3)，异丁基(i-Bu、 -CH2CH(CH3)2)，仲丁基(s-Bu、-CH(CH3)CH2CH3)，叔丁基(t-Bu、-C(CH3)3)，正戊基(-CH2CH2CH2CH2CH3)，2-戊基(-CH(CH3)CH2CH2CH3)，3-戊基(-CH(CH2CH3)2)，2-甲基-2-丁基(-C(CH3)2CH2CH3)，3-甲基-2-丁基(-CH(CH3)CH(CH3)2)，3-甲基-1-丁基(-CH2CH2CH(CH3)2)，2-甲基-1-丁基(-CH2CH(CH3)CH2CH3)，正己基(-CH2CH2CH2CH2CH2CH3)，2-己基(-CH(CH3)CH2CH2CH2CH3)，3-己基(-CH(CH2CH3)(CH2CH2CH3))，2-甲基-2-戊基(-C(CH3)2CH2CH2CH3)，3-甲基-2-戊基(-CH(CH3)CH(CH3)CH2CH3)，4-甲基-2-戊基(-CH(CH3)CH2CH(CH3)2)，3-甲基-3-戊基(-C(CH3)(CH2CH3)2)，2-甲基-3-戊基(-CH(CH2CH3)CH(CH3)2)，2,3-二甲基-2-丁基(-C(CH3)2CH(CH3)2)，3,3-二甲基-2-丁基(-CH(CH3)C(CH3)3)，正庚基，正辛基，等等。
术语“烯基”表示含有2-15个碳原子的直链或支链一价烃基，其中至少有一个不饱和位点，即有一个碳-碳sp2双键，其中，所述烯基基团可以任选地被一个或多个本发明所描述的取代基所取代，其包括“cis”和“tans”的定位，或者"E"和"Z"的定位。在一实施方案中，烯基基团包含2-8个碳原子；在另一实施方案中，烯基基团包含2-6个碳原子；在又一实施方案中，烯基基团包含2-4个碳原子。烯基基团的实例包括，但并不限于，乙烯基(-CH＝CH2)、烯丙基(-CH2CH＝CH2)等等。
术语“炔基”表示含有2-15个碳原子的直链或支链一价烃基，其中至少有一个不饱和位点，即有一个碳-碳sp三键，其中，所述炔基基团可以任选地被一个或多个本发明所描述的取代基所取代。在一实施方案中，炔基基团包含2-8个碳原子；在另一实施方案中，炔基基团包含2-6个碳原子；在又一实施方案中，炔基基团包含2-4个碳原子。炔基基团的实例包括，但并不限于，乙炔基(-C≡CH)、炔丙基(-CH2C≡CH)、1-丙炔基(-C≡C-CH3)等等。
本发明所使用的术语“前药”，代表一个化合物在体内转化为式(I)所示的化合物。这样的转化受前体药物在血液中水解或在血液或组织中经酶转化为母体结构的影响。本发明前体药物类化合物可以是酯，在现有的发明中酯可以作为前体药物的有苯酯类，脂肪族(C1-24)酯类，酰氧基甲基酯类，碳酸酯，氨基甲酸酯类和氨基酸酯类。例如本发明里的一个化合物包含羟基，即可以将其酰化得到前体药物形式的化合物。其他的前体药物形式包括磷酸酯，如这些磷酸酯类化合物是经母体上的羟基磷酸化得到的。关于前体药物完整的讨论可以参考以下文献：T.Higuchi and V.Stella,Pro-drugs as Novel Delivery Systems,Vol.14 of the A.C.S.Symposium Series,Edward B.Roche,ed.,Bioreversible Carriers in Drug Design,American Pharmaceutical Association and Pergamon Press,1987,J.Rautio et al.,Prodrugs:Design and Clinical Applications,Nature Review Drug Discovery,2008,7,255-270,and S.J.Hecker et al.,Prodrugs of Phosphates and Phosphonates,Journal of Medicinal Chemistry,2008,51,2328-2345。
“代谢产物”是指具体的化合物或其盐在体内通过代谢作用所得到的产物。一个化合物的代谢产物可以通过所属领域公知的技术来进行鉴定，其活性可以通过如本发明所描述的那样采用试验的方法进行表征。这样的产物可以是通过给药化合物经过氧化，还原，水解，酰氨化，脱酰氨作用，酯化，脱脂作用，酶裂解等等方法得到。相应地，本发明包括化合物的代谢产物，包括将本发明的化合物与哺乳动物充分接触一段时间所产生的代谢产物。
本发明所使用的“药学上可接受的盐”是指本发明的化合物的有机盐和无机盐。药学上可接受的盐在所属领域是为我们所熟知的，如文献：S.M.Berge et al.,describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences,1977,66:1-19.所记载的。药学上可接受的无毒的酸形成的盐包括，但并不限于，与氨基基团反应形成的无机酸盐有盐酸盐，氢溴酸盐，磷酸盐，硫酸盐，高氯酸盐，和有机酸盐如乙酸盐，草酸盐，马来酸盐，酒石酸盐，柠檬酸盐，琥珀酸盐，丙二酸盐，或通过书籍文献上所记载的其他方法如离子交换法来得到这些盐。其他药学上可接受的盐包括己二酸盐，藻酸盐，抗坏血酸盐，天冬氨酸盐，苯磺酸盐，苯甲酸盐，重硫酸盐，硼酸盐，丁酸盐，樟脑酸盐，樟脑磺酸盐，环戊基丙酸盐，二葡萄糖酸盐，十二烷基硫酸盐，乙磺酸盐，甲酸盐，反丁烯二酸盐，葡庚糖酸盐，甘油磷酸盐，葡萄糖酸盐，半硫酸盐，庚酸盐，己酸盐，氢碘酸盐，2-羟基-乙磺酸盐，乳糖醛酸盐，乳酸盐，月桂酸盐，月桂基硫酸盐，苹果酸盐，丙二酸盐，甲磺酸盐，2-萘磺酸盐，烟酸盐，硝酸盐，油酸盐，棕榈酸盐，扑酸盐，果胶酸盐，过硫酸盐，3-苯基丙酸盐，苦味酸盐，特戊酸盐，丙酸盐，硬脂酸盐，硫氰酸盐，对甲苯磺酸盐，十一酸盐，戊酸盐，等等。通过适当的碱得到的盐包括碱金属，碱土金属，铵和N+(C1-4烷基)4的盐。本发明也拟构思了任何所包含N的基团的化合物所形成的季铵盐。水溶性或油溶性或分散产物可以通过季铵化作用得到。碱金属或碱土金属盐包括钠，锂，钾，钙，镁，等等。药学上可接受的盐进一步包括适当的、无毒的铵，季铵盐和抗平衡离子形成的胺阳离子，如卤化物，氢氧化物，羧化物，硫酸化物，磷酸化物，硝酸化物，C1-8磺酸化物和芳香磺酸化物。
本发明的“溶剂化物”是指一个或多个溶剂分子与本发明的化合物所形成的缔合物。形成溶剂化物的溶剂包括，但并不限于，水，异丙醇，乙醇，甲醇，二甲亚砜，乙酸乙酯，乙酸和氨基乙醇。术语“水合物”是指溶剂分子是水所形成的缔合物。
如本发明所使用的术语“治疗”任何疾病或病症，在其中一些实施方案中指改善疾病或病症(即减缓或阻止或减轻疾病或其至少一种临床症状的发展)。在另一些实施方案中，“治疗”指缓和或改善至少一种身体参数，包括可能不为患者所察觉的身体参数。在另一些实施方案中，“治疗”指从身体上(例如稳定可察觉的症状)或生理学上(例如稳定身体的参数)或上述两方面调节疾病或病症。在另一些实施方案中，“治疗”指预防或延迟疾病或病症的发作、发生或恶化。
可药用的酸加成盐可与无机酸和有机酸形成，例如乙酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、溴化物/氢溴酸盐、碳酸氢盐/碳酸盐、硫酸氢盐/硫酸盐、樟脑磺酸盐、氯化物/盐酸盐、氯茶碱盐、柠檬酸盐、乙二磺酸盐、富马酸盐、葡庚糖酸盐、葡糖酸盐、葡糖醛酸盐、马尿酸盐、氢碘酸盐/碘化物、羟乙基磺酸盐、乳酸盐、乳糖醛酸盐、月桂基硫酸盐、苹果酸盐、马来酸盐、丙二酸盐、扁桃酸盐、甲磺酸盐、甲基硫酸盐、萘甲酸盐、萘磺酸盐、烟酸盐、硝酸盐、十八酸盐、油酸盐、草酸盐、棕榈酸盐、扑酸盐、磷酸盐/磷酸氢盐/磷酸二氢盐、聚半乳糖酸盐、丙酸盐、硬脂酸盐、琥珀酸盐、磺基水杨酸盐、酒石酸盐、甲苯磺酸盐和三氟乙酸盐。
可以由其衍生得到盐的无机酸包括例如盐酸、氢溴酸、硫酸、硝酸、磷酸等。
可以由其衍生得到盐的有机酸包括例如乙酸、丙酸、羟基乙酸、草酸、马来酸、丙二酸、琥珀酸、富马酸、酒石酸、柠檬酸、苯甲酸、扁桃酸、甲磺酸、乙磺酸、对甲苯磺酸、磺基水杨酸等。
可药用碱加成盐可与无机碱和有机碱形成。
可以由其衍生得到盐的无机碱包括，例如铵盐和周期表的I族至XII族的金属。在某些实施方案中，该盐衍生自钠、钾、铵、钙、镁、铁、银、锌和铜；特别适合的盐包括铵、钾、钠、钙和镁盐。
可以由其衍生得到盐的有机碱包括伯胺、仲胺和叔胺，取代的胺包括天然存在的取代的胺、环状胺、碱性离子交换树脂等。某些有机胺包括，例如，异丙胺、苄星青霉素(benzathine)、胆碱盐(cholinate)、二乙醇胺、二乙胺、赖氨酸、葡甲胺(meglumine)、哌嗪和氨丁三醇。
本发明的可药用盐可以用常规化学方法由母体化合物、碱性或酸性部分来合成。一般而言，该类盐可以通过使这些化合物的游离酸形式与化学计量量的适宜碱(如Na、Ca、Mg或K的氢氧化物、碳酸盐、碳酸氢盐等)反应，或者通过使这些化合物的游离碱形式与化学计量量的适宜酸反应来进行制备。该类反应通常在水或有机溶剂或二者的混合物中进行。一般地，在适当的情况中，需要使用非水性介质如乙醚、乙酸乙酯、乙醇、异丙醇或乙腈。在例如“Remington′s Pharmaceutical Sciences”，第20版，Mack Publishing Company，Easton，Pa.，(1985)；和“药用盐手册：性质、选择和应用(Handbook of Pharmaceutical Salts：Properties，Selection，and Use)”，Stahl and Wermuth(Wiley-VCH，Weinheim，Germany，2002)中可找到另外一些适宜盐的列表。
另外，本发明公开的化合物，包括它们的盐，也可以以它们的水合物形式或包含其溶剂(例如乙醇、DMSO，等等)的形式得到，用于它们的结晶。本发明公开化合物可以与药学上可接受的溶剂(包括水)固有地或通过设计形成溶剂化物；因此，本发明旨在包括溶 剂化的和未溶剂化的形式。
本发明给出的任何结构式也意欲表示这些化合物未被同位素富集的形式以及同位素富集的形式。同位素富集的化合物具有本发明给出的通式描绘的结构，除了一个或多个原子被具有所选择原子量或质量数的原子替换。可引入本发明化合物中的示例性同位素包括氢、碳、氮、氧、磷、硫、氟和氯的同位素，如2H，3H，11C，13C，14C，15N，17O，18O，18F，31P，32P，35S，36Cl和125I。
另一方面，本发明所述化合物包括同位素富集的本发明所定义的化合物，例如，其中存在放射性同位素，如3H，14C和18F的那些化合物，或者其中存在非放射性同位素，如2H和13C。该类同位素富集的化合物可用于代谢研究(使用14C)、反应动力学研究(使用例如2H或3H)、检测或成像技术，如正电子发射断层扫描术(PET)或包括药物或底物组织分布测定的单光子发射计算机断层成像术(SPECT)，或可用于患者的放疗中。18F富集的化合物对PET或SPECT研究而言是特别理想的。同位素富集的式(I)所示化合物可以通过本领域技术人员熟悉的常规技术或本发明中的实施例和制备过程所描述使用合适的同位素标记试剂替代原来使用过的未标记试剂来制备。
此外，较重同位素特别是氘(即，2H或D)的取代可提供某些治疗优点，这些优点是由代谢稳定性更高带来的。例如，体内半衰期增加或剂量需求降低或治疗指数得到改善带来的。应当理解，本发明中的氘被看做式(I)化合物的取代基。可以用同位素富集因子来定义该类较重同位素特别是氘的浓度。本发明所使用的术语“同位素富集因子”是指所指定同位素的同位素丰度和天然丰度之间的比例。如果本发明化合物的取代基被指定为氘，该化合物对各指定的氘原子而言具有至少3500(各指定氘原子处52.5％的氘掺入)、至少4000(60％的氘掺入)、至少4500(67.5％的氘掺入)，至少5000(75％的氘掺入)，至少5500(82.5％的氘掺入)、至少6000(90％的氘掺入)、至少6333.3(95％的氘掺入)、至少6466.7(97％的氘掺入)、至少6600(99％的氘掺入)或至少6633.3(99.5％的氘掺入)的同位素富集因子。本发明可药用的溶剂化物包括其中结晶溶剂可以是同位素取代的例如D2O、丙酮-d6、DMSO-d6的那些溶剂化物。
另一方面，本发明涉及制备式(I)所包含的化合物的中间体。
另一方面，本发明涉及式(I)所包含的化合物的制备、分离和纯化的方法。
另一方面，本发明提供一种药物组合物，所述药物组合物包含本发明化合物，药学上可接受的载体，赋形剂，稀释剂，辅剂，溶媒，或它们的组合。在一些实施方案，药物组合物可以是液体，固体，半固体，凝胶或喷雾剂型。
“联合”表示在单个剂量单位形式中的固定组合或用于组合施用的部分的药盒，其中本发明公开化合物和组合伴侣可以在同一时间独立施用或者可以在一定的时间间隔内分别施 用，特别是使联合合伴侣表现出合作、例如协同作用。如本文所用的术语“共同给药”或“联合给药”等意欲囊括将所选的组合伴侣施用于需要其的单个个体(例如患者)，并且意欲包括其中物质不必通过相同施用途径或同时施用的治疗方案。如本文所用的术语“药物组合产品”表示将一种以上活性成分混合或组合所得到的产品，并且既包括活性成分的固定组合也包括非固定组合。术语“固定联合”表示活性成分如本发明公开化合物和组合伴侣以单一实体或剂量的形式同时施用于患者。术语“非固定联合”表示活性成分如本发明公开化合物化合物和组合伙伴均作为单独实体同时、共同或无特定时间限制地先后施用于患者，其中该施用在患者体内提供了两种化合物的治疗有效水平。后者还适用于鸡尾酒疗法，例如施用3种或更多种活性成分。
具体实施方式
下面详细描述本发明的实施例，下面描述的实施例是示例性的，旨在用于解释本发明，而不能理解为对本发明的限制。
下述实施例中所使用的实验方法如无特殊说明，均为常规方法。
下述实施例中所用的材料、试剂等，如无特殊说明，均可从商业途径得到。
实施例1、式I-1、式I-2和式I-3式I-4、式I-5所示化合物制备
(1)式3所示化合物的制备
反应方程式如下所示：
Figure PCTCN2017114644-appb-000031
将N-Boc-O-叔丁基-L-丝氨酸(11mmol)置于圆底烧瓶中，加入二氯甲烷和N,N-二甲基甲酰胺当混合溶剂50ml，HCTU(6-氯苯并三氮唑-1,1,3,3-四甲基脲六氟磷酸酯)(11mmol)和DIEA(N,N-二异丙基乙胺)(11mmol)加入到反应液中，再加入式1-1所示化合物(10mmol)，室温搅拌3小时后，加入稀盐酸淬灭反应。加入100ml二氯甲烷稀释反应液，分别用碳酸氢钠，氯化钠饱和水溶液洗涤，减压蒸去二氯甲烷，所得产品采用硅胶柱分离(石油醚：乙酸乙酯2：1)，得式3所示化合物，分离产率92％。
(2)式4所示化合物的制备
反应方程式如下所示：
Figure PCTCN2017114644-appb-000032
将式3所示化合物(9mmol)溶解在30ml无水四氢呋喃中，加入三甲基磷(20mmol)，室温搅拌24小时后，悬掉过量的溶剂和试剂，再用10ml二氯甲烷溶解中解体。将Fmoc-L-异亮氨酸(10mmol)置于圆底烧瓶中，EDCI(碳化二亚胺)(10mmol)、DMAP(4-二甲氨基吡啶)(1mmol)加入到反应液中搅拌20min，再加入用二氯甲烷溶解的中间体，室温搅拌过夜后，加入稀盐酸淬灭反应。加入100ml二氯甲烷稀释反应液，分别用碳酸氢钠，氯化钠饱和水溶液洗涤，减压蒸去二氯甲烷，所得产品采用硅胶柱分离(石油醚：乙酸乙酯2：1)，得式4所示化合物，分离产率52％。
(3)式5所示化合物的制备
反应方程式如下所示：
Figure PCTCN2017114644-appb-000033
将式4所示化合物(10mmol)置于圆底烧瓶中，加入33wt％二乙胺乙腈溶液，室温搅拌15min，减压蒸去溶剂，所得产品采用硅胶柱分离(石油醚：乙酸乙酯2：1)，得式5所示化合物，分离产率86％。
(4)式6所示化合物的制备
反应方程式如下所示：
Figure PCTCN2017114644-appb-000034
零度下将二氯亚砜(20mmol)滴加到甲醇溶液里面，加入N-Boc-N'-Fmoc-L-赖氨酸(10mmol)，室温搅拌过夜后，减压蒸去甲醇溶液。加入100ml二氯甲烷稀释反应液，分别用碳酸氢钠，氯化钠饱和水溶液洗涤，减压蒸去二氯甲烷，所得产品采用硅胶柱分离(二氯甲烷：甲醇20：1)，得式6所示化合物，分离产率94％。
(5)式7所示化合物的制备
反应方程式如下所示：
Figure PCTCN2017114644-appb-000035
将苄氧羰基-L-丙氨酸(11mmol)置于圆底烧瓶中，加入二氯甲烷和N,N-二甲基甲酰胺当混合溶剂50ml，HCTU(11mmol)、DIEA(11mmol)加入到反应液中，再加入化合物6(10 mmol)，室温搅拌三小时后，加入稀盐酸淬灭反应。加入100ml二氯甲烷稀释反应液，分别用碳酸氢钠、氯化钠饱和水溶液洗涤，减压蒸去二氯甲烷，所得产品采用硅胶柱分离(石油醚：乙酸乙酯2：1)，得式7所示化合物，分离产率92％。
(6)式8所示化合物的制备
反应方程式如下所示：
Figure PCTCN2017114644-appb-000036
将式7所示化合物(8mmol)置于圆底烧瓶中，加入四氢呋喃20ml，将氢氧化锂(16mmol)溶解在水(7ml)中后加入反应液中，室温搅拌5min后，加入稀盐酸淬灭反应。加入100ml乙酸乙酯稀释反应液，氯化钠饱和水溶液洗涤，减压蒸去乙酸乙酯，所得产品采用硅胶柱分离(二氯甲烷：甲醇10：1)，得式8所示化合物，分离产率86％。
(7)式9所示化合物的制备
反应方程式如下所示：
Figure PCTCN2017114644-appb-000037
将式8所示化合物(7mmol)置于圆底烧瓶中，加入二氯甲烷和N,N-二甲基甲酰胺当混合溶剂50ml，HATU(7mmol)、DIEA(8mmol)加入到反应液中，再加入化合物5(7mmol)，室温搅拌三小时后，加入稀盐酸淬灭反应。加入100ml二氯甲烷稀释反应液，分别用碳酸氢钠，氯化钠饱和水溶液洗涤，减压蒸去二氯甲烷，所得产品采用硅胶柱分离(石油醚：乙酸乙酯1：1)，得式9所示化合物，分离产率82％。
(8)式10所示化合物的制备
反应方程式如下所示：
Figure PCTCN2017114644-appb-000038
将式9所示化合物(6mmol)、氢氧化钯/碳(1mmol)置于圆底烧瓶中，加入甲醇50ml，在1个大气压氢气的条件下，室温搅拌15min,过滤除去氢氧化钯/碳，将剩余甲醇溶液旋 干。所得粗品化合物。将粗品(1mmol)置于500ml圆底烧瓶中，加入二氯甲烷和N,N-二甲基甲酰胺当混合溶剂300ml，HATU(2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯-缩合剂(4mmol)、HOAT(1-羟基-7-偶氮苯并三氮唑)(4mmol)、DIEA(8mmol)加入到反应液中，室温搅拌48小时后，加入稀盐酸淬灭反应。分别用稀盐酸水溶液，氯化钠饱和水溶液洗涤，减压蒸去二氯甲烷，所得产品采用硅胶柱分离(二氯甲烷：甲醇10：1)，得式10所示化合物，分离产率72％。
(9)式11所示化合物的制备
反应方程式如下所示：
Figure PCTCN2017114644-appb-000039
将式10所示化合物(0.5mmol)置于圆底烧瓶中，加入2M盐酸乙酸乙酯溶液5ml，室温搅拌20min，加入乙酸乙酯10ml稀释，加入饱和碳酸氢钠水溶液洗涤，有机相用无水硫酸钠干燥，减压蒸去乙酸乙酯溶剂，得到粗品式11所示化合物。
(10)式12所示化合物的制备
反应方程式如下所示：
Figure PCTCN2017114644-appb-000040
按照多肽固相合成的方法，将2-Cl树脂(0.5mmol)置于固相合成管中，加入二氯甲烷和N,N-二甲基甲酰胺，活化20min，抽取溶剂，将Fmoc-L-异亮氨酸(5mmol)，DIEA(5mmol)溶解在DMF中加入反映仪器中，搅拌2h，抽去溶剂，用20％哌啶溶液脱去Fmoc 15min，将Fmoc-D-异亮氨酸(1.5mmol)，HATU(1.5mmol)，DIEA(3mmol)加入反应容器中，室温搅拌50min。接下来按照同样的方式条件，将N-Fmoc-N'-三苯甲基-D-谷氨酰胺、Fmoc-L-丝氨酸、Fmoc-L-异亮氨酸以及Boc-D-4,4'-二苯基苯胺或N-叔丁氧羰基-N-甲基-D-苯丙氨酸最末端的氨基酸接上去。最后将25wt％三氟乙醇(用二氯甲烷稀释)加入反应管中，室温搅拌4h，将溶剂旋干，得到式12所示化合物。
(11)式13所示化合物的制备
反应方程式如下所示：
Figure PCTCN2017114644-appb-000041
将式11所示化合物(0.5mmol)、式12所示化合物(0.5mmol)置于圆底烧瓶中，加四氢呋喃和N,N-二甲基甲酰胺当混合溶剂10ml，置于冰水浴下，加入DEPBT(1mmol)，DIEA(1mmol)，待反应1小时后，置于室温下搅拌过夜。加入稀盐酸淬灭反应。加入100ml乙酸乙酯稀释反应液，氯化钠饱和水溶液洗涤，减压蒸去乙酸乙酯，所得产品采用硅胶柱分离(二氯甲烷：甲醇10：1)，得式13所示化合物。
(12)目标化合物的制备
反应方程式如下所示：
Figure PCTCN2017114644-appb-000042
将式13所示化合物(0.2mmol)置于圆底烧瓶中，将33wt％的二乙胺乙腈溶剂加入圆底烧瓶中，室温搅拌15分钟，待Fmoc完全脱除之后，将溶剂旋干，粗品不需要过柱子。将三氟乙酸：三异丙基硅烷：水(95：2.5：2.5，体积比)5ml加入盛放粗品的烧瓶中，室温搅拌1小时后，用氮气将溶剂吹干，加入冰乙醚沉淀，离心得到粗品，用反相HPLC分离后冷冻干燥，得到最终纯品化合物式Ⅰ-1，其中，基团R1为氢，R2为苯基，R3为甲酰基，R4为乙基，R5为正丁氨基。
式I-1所示化合物的表征数据如下：
1H-NMR(400MHz,CD3OD)δ(ppm)7.70-7.55(m,4H),7.46-7.30(m,5H),5.60-5.50(m,1H),4.55-4.45(m,1H),4.45-4,28(m,4H),4.28-4.02(m,5H),3.98-3.70(m,4H),3.20-3.10(m,2H),2.95-2.85(m,2H),2.38-2.28(m,2H),2.20-1.90(m,3H),1.90-1.60(m,8H),1.60-1.40(m,7H),1.40-1.10(m,8H),1.10-0.85(m,18H),0.85-0.70(m,6H)HRMS(ESI)[M+H]+:1277.58,found 1277.74.
由上述数据可知，所制备的化合物结构正确。
按照上述方法得到式I-2所示化合物，其中步骤(1)中采用式1-2所示化合物代替式1-1所示化合物；
式I-2，基团R1为氢，R2为苯基，R3为胍基，R4为乙基，R5为正丁氨基。
Figure PCTCN2017114644-appb-000043
式I-2所示化合物的表征数据如下：
1H-NMR(400MHz,CD3OD)δ(ppm)7.40-7.20(m,5H),5.60-5.50(m,1H),4.55-4.45(m,1H),4.45-4,28(m,4H),4.28-4.02(m,5H),3.98-3.70(m,4H),3.20-3.10(m,2H),2.95-2.85(m,2H),2.69(s,1H)2.38-2.28(m,2H),2.20-1.90(m,3H),1.90-1.60(m,8H),1.60-1.40(m,7H),1.40-1.10(m,8H),1.10-0.85(m,18H),0.85-0.70(m,6H)HRMS(ESI)[M+H]+:1305.73,found1305.72.
由上述数据可知，所制备的化合物结构正确。
按照上述方法得到式I-3所示化合物，其中步骤(1)中采用式1-2所示化合物代替式 1-1所示化合物；
式I-3，基团R1为氢，R2为对甲基苯基，R3为甲酰基，R4为乙基，R5为正丁氨基；
式I-3所示化合物的表征数据如下：
1H-NMR(400MHz,CD3OD)δ(ppm)7.70-7.55(m,4H),7.46-7.30(m,5H),5.60-5.50(m,1H),4.55-4.45(m,1H),4.45-4,28(m,4H),4.28-4.02(m,5H),3.98-3.70(m,4H),3.20-3.10(m,2H),2.95-2.85(m,2H),2.47(s,3H),2.38-2.28(m,2H),2.20-1.90(m,3H),1.90-1.60(m,8H),1.60-1.40(m,5H),1.40-1.10(m,8H),1.10-0.85(m,18H),0.85-0.70(m,6H)HRMS(ESI)[M+H]+:1291.72,found 1291.74.
式I-4，基团R1为氢，R2为对苯基，R3为甲酰胺基，R4为乙基，R5为咪唑烷基；
式I-4所示化合物的表征数据如下：
1H-NMR(400MHz,CD3OD)δ(ppm)7.70-7.55(m,4H),7.46-7.30(m,5H),5.60-5.50(m,1H),4.55-4.45(m,1H),4.45-4,28(m,4H),4.28-4.02(m,5H),3.98-3.70(m,4H),3.52-3.42(m,1H),3.20-3.10(m,2H),2.95-2.85(m,2H),2.38-2.28(m,2H),2.20-1.90(m,3H),1.90-1.60(m,8H),1.60-1.40(m,7H),1.40-1.10(m,4H),1.10-0.85(m,18H),0.85-0.70(m,6H)HRMS(ESI)[M+H]+:1302.74,found 1302.58.
式I-5，基团R1为氢，R2为对苯酮基，R3为甲酰胺基，R4为乙基，R5为咪唑烷基；
式I-5所示化合物的表征数据如下：
1H-NMR(400MHz,CD3OD)δ(ppm)7.88-7.55(m,4H),7.67-7.51(m,5H),5.60-5.50(m,1H),4.55-4.45(m,1H),4.45-4,28(m,4H),4.28-4.02(m,5H),3.98-3.70(m,4H),3.52-3.42(m,1H),3.20-3.10(m,2H),2.95-2.85(m,2H),2.38-2.28(m,2H),2.20-1.90(m,3H),1.90-1.60(m,8H),1.60-1.40(m,7H),1.40-1.10(m,4H),1.10-0.85(m,18H),0.85-0.70(m,6H)HRMS(ESI)[M+H]+:1331.74,found 1331.68.
由上述数据可知，所制备的化合物结构正确。
实施例2、式I-1、式I-2、式I-3、式I-4和式I-5所示化合物的活性测试
根据CLSI指导原则，测试化合物的MIC。
培养细菌选择THY培养基，测试选择MHB培养基。所用的介质添加0.002％吐温80来抑制药物贴壁。细胞浓度调整到5×105个每毫升。化合物的浓度从高到低依次为8μg/ml、4μg/ml、2μg/ml、1μg/ml、0.5μg/ml和0.25μg/ml，于37℃下培养20小时后，培养基澄清的孔的药物浓度为最低抑菌浓度。
测试结果如表1中所示。
表1：各化合物的MIC(μg/ml)
Figure PCTCN2017114644-appb-000044
由表1中的数据可以看出，本发明制备的化合物的抗菌活性和teixobactin的抗菌活性对照相当，并且分子结构式和合成成本要低。
在本说明书的描述中，参考术语“一个实施例”、“一些实施例”、“示例”、“具体示例”、或“一些示例”等的描述意指结合该实施例或示例描述的具体特征、结构、材料或者特点包含于本发明的至少一个实施例或示例中。在本说明书中，对上述术语的示意性表述不必须针对的是相同的实施例或示例。而且，描述的具体特征、结构、材料或者特点可以在任一个或多个实施例或示例中以合适的方式结合。此外，在不相互矛盾的情况下，本领域的技术人员可以将本说明书中描述的不同实施例或示例以及不同实施例或示例的特征进行结合和组合。
尽管上面已经示出和描述了本发明的实施例，可以理解的是，上述实施例是示例性的，不能理解为对本发明的限制，本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。

Claims (17)

  1. 一种化合物，其为式I所示的化合物或式I所示化合物的立体异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或前药：
    Figure PCTCN2017114644-appb-100001
    其中，
    R1为氢、任选取代的C1～15烷基、任选取代的C2～15烯基、任选取代的C2～15炔基、任选取代的芳基或任选取代的酰基；
    R2为氢、卤素、任选取代的C1～15烷基、任选取代的C2～15烯基、任选取代的C2～15炔基、任选取代的酰基或者任选被卤素、烷基、三氟甲基取代的芳基；
    R3为氨基、胍基、脲基或甲酰胺基；
    R4为任选取代的C1～15烷基、任选取代的C2～15烯基、任选取代的C2～15炔基、任选取代的芳基；
    R5为氨基、胍基或脲基；
    m为1～4之间的整数，包括端点；
    X为O、S或NH。
  2. 根据权利要求1所述的化合物，其特征在于，
    R1为氢；
    R2为苯甲酰基或任选取代的芳基取代的芳基；
    R3为
    Figure PCTCN2017114644-appb-100002
    R4为任选取代的C1～15烷基；
    R5为
    Figure PCTCN2017114644-appb-100003
    氨基；
    m为1～4之间的整数，包括端点；
    X为O、S或NH。
  3. 根据权利要求1所述的化合物，其特征在于，所述化合物为
    Figure PCTCN2017114644-appb-100004
    Figure PCTCN2017114644-appb-100005
  4. 一种制备权利要求1～3任一项所述化合物的方法，包括如下步骤：
    (1)使式3所示化合物与Fmoc-L-异亮氨酸接触，以便获得式4所示化合物；
    (2)使所述式4所示化合物发生脱保护反应，以便获得式5所示化合物；
    (3)使式6所示化合物与苄氧羰基-L-丙氨酸接触，以便获得式7所示化合物；
    (4)使所述式7所示化合物发生还原反应，以便获得式8所示化合物；
    (5)使所述式5所示化合物与所述式8所示化合物发生缩合反应得到式9所示化合物；
    (6)使所述式9所示化合物发生分子内缩合反应，以便获得式10所示化合物；
    (7)使所述式10所示化合物发生脱保护反应，以便式11所示化合物；
    (8)使所述式11所示化合物与式12所示化合物接触，以便获得式13所示化合物；
    (9)式13所示化合物依次在碱性条件和酸性条件下经脱保护反应即得权利要求1～3任一项所述的化合物，
    Figure PCTCN2017114644-appb-100006
    Figure PCTCN2017114644-appb-100007
    其中，Bn为苄基，t-Bu为叔丁基，Boc为叔丁氧羰基，
    Y为-N3、-OH或-SH，Fmoc为9-芴甲氧羰基，
    X为O、S或NH；
    m为1～4之间的整数，包括端点；
    R6为-NH-、-NH-C(＝O)-NH-或-NH-C(＝NH)-NH-；Cbz为苄氧羰基。
  5. 根据权利要求4所述的方法，其特征在于，包括：
    (1)使所述式3所示化合物经叠氮还原后与所述Fmoc-L-异亮氨酸发生缩合反应，或者使所述式3所示化合物直接与所述Fmoc-L-异亮氨酸发生缩合反应，以便获得所述式4所示化合物，其中，当Y表示-N3时，使所述式3所示化合物经叠氮还原后与所述Fmoc-L-异亮氨酸发生缩合反应，当Y表示-OH或-SH时，使所述式3所示化合物直接与所述Fmoc-L-异亮氨酸发生缩合反应；
    (2)在碱性条件下，使所述式4所示化合物发生脱保护反应，以便获得所述式 5所示化合物；
    (3)使所述式6所示化合物与所述苄氧羰基-L-丙氨酸发生缩合反应，以便获得所述式7所示化合物；
    (4)使所述式7所示化合物发生还原反应，以便获得式8所示化合物；
    (5)使所述式5所示化合物与所述式8所示化合物发生缩合反应，以便得到所述式9所示化合物；
    (6)使所述式9所示化合物发生还原反应和分子内缩合反应，以便获得所述式10所示化合物；
    (7)在酸性条件下，使所述式10所示化合物发生脱保护反应，以便获得所述式11所示化合物；
    (8)使所述式11所示化合物与所述式12所示化合物经缩合反应，以便获得所述式13所示化合物；
    (9)使所述式13所示化合物依次在碱性条件和酸性条件下发生脱保护反应，以便获得权利要求1～3任一项所述的化合物。
  6. 根据权利要求4或5所述的方法，其特征在于：
    在步骤(1)中，
    所述式3所示化合物是通过以下步骤获得的：
    使N-Boc-O-叔丁基-L-丝氨酸与式1所示化合物发生缩合反应，以便获得所述式3所示化合物；
    Figure PCTCN2017114644-appb-100008
    其中，
    所述缩合反应是在存在6-氯苯并三氮唑-1,1,3,3-四甲基脲六氟磷酸酯和N,N-二异丙基乙胺的条件下进行；
    所述式1所示化合物与所述N-Boc-O-叔丁基-L-丝氨酸的摩尔比为1：(1.0～1.5)；
    所述N-Boc-O-叔丁基-L-丝氨酸、所述6-氯苯并三氮唑-1,1,3,3-四甲基脲六氟磷酸酯与所述N,N-二异丙基乙胺的摩尔比为1：(1.0～1.5)：(1.0～1.5)；
    所述缩合反应是在20～25摄氏度的温度下进行2～3小时。
  7. 根据权利要求5所述的方法，其特征在于：
    在步骤(2)中，所述叠氮还原反应是在存在三苯基膦的条件下进行的；
    在步骤(1)和步骤(3)中，所述缩合反应是分别独立地在存在碳化二亚胺和4-二甲氨基吡啶的条件下进行的；所述Fmoc-L-异亮氨酸与所述式3所示化合物的摩尔比为1：(0.5～1.0)；所述Fmoc-L-异亮氨酸、所述碳化二亚胺与所述4-二甲氨基吡啶的摩尔比为1：(1.0～1.5)：(0.1～0.5)；所述苄氧羰基-L-丙氨酸与所述式6所示化合物的摩尔比为1：(0.5～1.0)；所述苄氧羰基-L-丙氨酸、所述碳化二亚胺与所述4-二甲氨基吡啶的摩尔比为1：(1.0～1.5)：(0.1～0.5)；
    在步骤(1)和步骤(3)中，所述缩合反应是分别独立地在20～25的温度下进行2～3小时。
  8. 根据权利要求5所述的方法，其特征在于：在步骤(2)中，所述碱性条件是通过采用33重量％的二乙胺的乙腈溶液形成的；
    在步骤(4)中，所述还原反应是在存在氢氧化锂的条件下进行的；
    所述式7所述化合物与所述氢氧化锂的摩尔比为1：(1～5)；
    在步骤(5)中，所述缩合反应是在存在2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯和N,N-二异丙基乙胺的条件下进行的；
    所述式8所述化合物与所述式5所示化合物的摩尔比为1：(1.0～1.5)；
    所述式8所述化合物、所述2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯与所述N,N-二异丙基乙胺的摩尔比为1：(1.0～1.5)：(0.1～0.5)；
    在步骤(5)中，所述缩合反应是在20～25的温度下进行2～3小时。
  9. 根据权利要求5所述的方法，其特征在于：
    在步骤(6)中，所述还原反应是在存在氢氧化钯/碳的条件下进行的；
    所述分子内缩合反应是在存在2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯、1-羟基-7-偶氮苯并三氮唑和N,N-二异丙基乙胺的条件下进行的；
    步骤(7)中，所述脱保护反应是在存在盐酸的条件下进行的；
    步骤(8)中，所述缩合反应是在存在3-二乙氧基磷酰基-1,2,3-苯唑4(3H)-酮和N,N-二异丙基乙胺的条件下进行；
    所述式11所示化合物、所述3-二乙氧基磷酰基-1,2,3-苯唑4(3H)-酮与所述N,N-二异丙基乙胺的摩尔比为1：(1～2)：(1～2)；
    步骤(9)中，所述碱性条件是采用33重量％的二乙胺的乙腈溶液形成的；
    所述酸性条件是采用三氟乙酸和三异丙基硅烷的混合水溶液形成的。
  10. 一种革兰氏阳性菌的抑制剂，其特征在于，包括：权利要求1～3任一项所述的化合物。
  11. 一种药物组合物，其中所述的药物组合物包含权利要求1-3中任一项所述的 化合物。
  12. 根据权利要求11所述的药物组合物，进一步包含药学上可接受的载体、赋形剂、稀释剂、辅剂、媒介物或其组合。
  13. 权利要求1～3任一项所述的化合物在制备药物中的用途，所述药物用于抑制革兰氏阳性菌生长和/或繁殖。
  14. 一种抑制革兰氏阳性菌生长和/或繁殖的方法，其特征在于，包括：
    使所述革兰氏阳性菌与权利要求1～3任一项所述的化合物接触。
  15. 权利要求1～3任一项所述的化合物在抑制革兰氏阳性菌生长和/或繁殖中的应用。
  16. 权利要求1～3任一项所述的化合物在制备抑制革兰氏阳性菌生长和/或繁殖的产品中的应用。
  17. 根据权利要求10所述的抑制剂、权利要求13所述的用途、权利要求14所述的方法、权利要求15或16所述的应用，其特征在于，所述革兰氏阳性菌包括选自链球菌、葡萄球菌、肠球菌、棒状杆菌、李斯特氏菌、芽孢杆菌、丹毒丝菌、放线菌、幽门螺杆菌、嗜肺军团菌、结核杆菌、鸟型结核分枝杆菌、胞内鸟分枝杆菌、金黄色酿脓葡萄球菌、表皮葡萄球菌、淋病奈瑟氏菌、脑膜炎奈瑟氏菌、酿脓链球菌、粪链球菌、牛链球菌、肺炎链球菌、嗜血杆菌、绿脓杆菌、炭疽杆菌和枯草杆菌中至少一种。
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021013217A1 (en) * 2019-07-24 2021-01-28 Sunshine Lake Pharma Co., Ltd. A teixobactin analogue and use thereof

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014089053A1 (en) * 2012-12-03 2014-06-12 Novobiotic Pharmaceuticals, Llc Novel depsipeptide and uses thereof
CN106632604A (zh) * 2016-12-22 2017-05-10 深圳先进技术研究院 一种Teixobactin类似物及其制备方法和应用

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1814614A (zh) * 2005-02-06 2006-08-09 中国人民解放军军事医学科学院毒物药物研究所 核酸、肽核酸衍生物及它们的用途
WO2017181179A1 (en) * 2016-04-15 2017-10-19 The Regents Of The University Of California Antimicrobial compositions

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014089053A1 (en) * 2012-12-03 2014-06-12 Novobiotic Pharmaceuticals, Llc Novel depsipeptide and uses thereof
CN106632604A (zh) * 2016-12-22 2017-05-10 深圳先进技术研究院 一种Teixobactin类似物及其制备方法和应用

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
A. H. ABDEL MONAIM SHIMAA ET AL.: "Re-evaluation of the N-terminal substitu- tion and the D-residues of teixobactin", RSC ADVANCES, vol. 6, no. 77, 28 July 2016 (2016-07-28), pages 73827 - 73829, XP055467328 *
E. SCHUMACHER CHRISTIAN ET AL.: "Synthesis and biological evaluation of novel teixobactin analogues", ORGANIC & BIOMOLECULAR CHEMISTRY, vol. 15, no. 41, 4 October 2017 (2017-10-04), pages 8755 - 8760, XP055459636 *
PARMAR ANISH ET AL.: "Efficient total syntheses and biological activities of two teixobactin analogues", CHEMICAL COMMUNICATIONS, vol. 52, no. 36, 9 March 2016 (2016-03-09), pages 6060 - 6063, XP055612267 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021013217A1 (en) * 2019-07-24 2021-01-28 Sunshine Lake Pharma Co., Ltd. A teixobactin analogue and use thereof

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