WO2019096234A1

WO2019096234A1 - Compound having anti-drug-resistant bacteria activity, preparation for same, and applications thereof

Info

Publication number: WO2019096234A1
Application number: PCT/CN2018/115811
Authority: WO
Inventors: 邵昌; 戈梅; 阮林高; 魏维; 夏兴; 饶敏; 孟庆前; 罗敏玉
Original assignee: 上海来益生物药物研究开发中心有限责任公司; 浙江医药股份有限公司
Priority date: 2017-11-16
Filing date: 2018-11-16
Publication date: 2019-05-23
Also published as: CN107987131B; CN107987131A

Abstract

As represented by formula I, a glycopeptide antibiotic compound having anti-drug-resistant bacteria activity or a pharmaceutically acceptable salt of same, a pharmaceutical preparation of same, a preparation method for same, and applications thereof. The compound of formula I has enhanced inhibitory activity against drug-resistant strains, particularly methicillin-resistant Staphylococcus aureus (MRSA) or vancomycin-resistant Enterococcus (VRE), and is applicable in preparing a medicament for treating or preventing various diseases induced by bacterial infection such as skin and soft tissue infections, meningitis, sepsis, pneumonia, arthritis, peritonitis, bronchitis, and empyema.

Description

Group of compounds with anti-resistant bacterial activity, preparation method and application thereof

Technical field

The invention belongs to the technical field of medicinal chemical synthesis, and in particular relates to a group of novel glycopeptide compounds which are useful as medicaments for treating infectious diseases. The invention also relates to methods and uses for the preparation of such compounds.

Background technique

Infectious diseases have always been one of the major diseases faced by human beings. In China, the treatment of infectious diseases has always been an important and difficult problem. The situation of bacterial resistance is especially in developed countries and drugs against various resistant drugs. Demand is also higher than in developed countries. In fact, even if the use of antibiotics is well controlled clinically, resistant bacteria will gradually emerge. Therefore, the struggle between humans and bacterial infections is long-lasting and long-lasting. In the context of the dramatic reduction in research and development expenditures against drug-resistant bacteria in developed countries at the end of the last century, the death caused by “super bacteria” has revived social concerns about bacterial infections. Glycopeptide compounds are a class of compounds which have a high inhibitory activity against bacteria including methicillin-resistant Staphylococcus aureus (MRSA), and the representative drug is vancomycin. However, with clinical application, Vancomycin-resistant Enterococcus (VRE) and MRSA bacteria with reduced activity of vancomycin have appeared. By modifying the structure of existing glycopeptide compounds, a series of new structural compounds can be obtained. These new compounds can resist resistant bacteria and have potential advantages in terms of safety and the like. A number of vancomycin-like compounds and other glycopeptide compounds are known in the art, and are disclosed in, for example, US Pat. No. 6,663,618 B2, US Pat. No. 6,639, 022, US Pat. No. 5, 840, 684, US Pat. No. 6, 425, 052, B, WO 00 390 156 A1, WO 018 352 A2, WO 018 019 839 A2, EP 0 435 503 A1, and references: Bioorg Med Chem Lett , 2003, 13 (23): 4165-4168, Curr Med Chem, 2001, 8 (14): 1759-1773 and Expert Opin Invest Drugs, 2007, 16 (3): 347-357 and the like reported glycopeptide compounds.

In the prior report, the Chinese invention patent CN101928331A discloses a novel glycopeptide compound having a structure as shown in the structure II compound of the present invention, which is characterized in that the peptide skeleton has a 4- and 6-position amino acid disability. Vancoside, Compound II has a completely new structure relative to conventional glycopeptides and has higher antibacterial activity than vancomycin. The research of the present invention is based on the existing research, and continues to optimize the modification of its structure to obtain new compounds with outstanding features.

Summary of the invention

The inventors of the present invention chemically engineered the compound described in Chinese Patent No. CN101928331A to obtain a modified glycopeptide antibiotic compound. It has been tested that the glycopeptide antibiotic compound of the present invention has higher inhibitory activity against drug-resistant strains, especially MRSA or VRE, compared to conventional glycopeptide drugs (such as vancomycin, etc.); further tests found that the present invention The vast majority of glycopeptide compounds have higher safety than the existing drug oritavancin, and can be used to treat or prevent various bacterial infections such as skin and soft tissue infections, meningitis, sepsis, Drugs for diseases such as pneumonia, arthritis, peritonitis, bronchitis, and empyema.

A first object of the present invention is to provide a group of compounds having antibiotic resistant bacterial activity characterized by conforming to the glycopeptide compound of the formula I:

Or a pharmaceutically acceptable salt thereof, wherein:

R _{1 is} represented by the following formula: -A-D-E-G;

A is -(CH ₂ ) _m -, where m is 1 or 2;

D is -NH- or -O- or a nitrogen-containing heterocycle;

E is —(CH ₂ ) _n — wherein n is 1 or 2;

G is a structural formula:

Wherein L is any one of halogen or trifluoromethyl or methoxy;

R ₂ is -OH or -NH-OH.

According to a preferred embodiment of the invention, the nitrogen-containing heterocycle represented by D is a five- to six-membered saturated or unsaturated heterocyclic group having at least one nitrogen atom in the ring.

Further preferably, the heterocyclic group is a substituted or unsubstituted aromatic or non-aromatic group, including pyrrole, pyrrolidine, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, piperidine , piperazine, pyridazine, pyrazine, morpholine, pyrimidine, pyridine, dihydropyridine, more preferably pyrrolidine, piperidine, pyrrole and dihydropyridine.

According to a preferred embodiment of the invention, R ₁ is N-(4'-chlorobiphenyl-4-methylene)-amine ethyl, N-(4'-fluorobiphenyl-4-methylene)-amine Ethyl, N-(4'-trifluoromethylbiphenyl-4-methylene)-amine ethyl, N-(4'-methoxybiphenyl-4-methylene)-amine ethyl, N-(4'-chlorobiphenyl-4-ethyl)-amine methyl, N-(4'-fluorobiphenyl-4-ethyl)-amine methyl, N-(4'-trifluoromethyl Biphenyl-4-ethyl)-amine methyl, N-(4'-methoxybiphenyl-4-ethyl)-amine methyl, O-(4'-chlorobiphenyl-4-methylene )-Oxoethyl, O-(4'-fluorobiphenyl-4-methylene)-oxyethyl, O-(4'-trifluoromethylbiphenyl-4-methylene)-oxyethyl , O-(4'-methoxybiphenyl-4-methylene)-oxyethyl, O-(4'-chlorobiphenyl-4-ethyl)-oxymethyl, O-(4'- Fluorobiphenyl-4-ethyl)-oxymethyl, O-(4'-trifluoromethylbiphenyl-4-ethyl)-oxymethyl, O-(4'-methoxybiphenyl-4 -ethyl)-oxymethyl, 4-(4'-chlorobiphenyl-4-methylene)-3-methylenepyrrolidine, 4-(4'-fluorobiphenyl-4-methylene) 3-methylenepyrrolidine, 4-(4'-trifluoromethylbiphenyl-4-methylene)-3-methylenepyrrolidine, 4-(4'-methoxybiphenyl-4 -methylene)-3-methylenepyrrolidine, 5-(4'-chlorobiphenyl-4-methylene)-3-methylenepipe Pyridine, 5-(4'-fluorobiphenyl-4-methylene)-3-methylenepiperidine, 5-(4'-trifluoromethylbiphenyl-4-methylene)-3-arylene Methylpiperidine, 5-(4'-methoxybiphenyl-4-methylene)-3-methylenepiperidine, 4-(4'-chlorobiphenyl-4-methylene)-3 -methylene-1H-pyrrole, 4-(4'-fluorobiphenyl-4-methylene)-3-methylene-1H-pyrrole, 4-(4'-trifluoromethylbiphenyl-4 -methylene)-3-methylene-1H-pyrrole, 4-(4'-methoxybiphenyl-4-methylene)-3-methylene-1H-pyrrole, 5-(4' -chlorobiphenyl-4-methylene)-3-methylene-1,4-dihydropyridine, 5-(4'-fluorobiphenyl-4-methylene)-3-methylene-1 , 4-dihydropyridine, 5-(4'-trifluoromethylbiphenyl-4-methylene)-3-methylene-1,4-dihydropyridine, 5-(4'-methoxy Biphenyl-4-methylene)-3-methylene-1,4-dihydropyridine.

A second object of the present invention is to provide a pharmaceutical preparation comprising as an active ingredient a group of compounds having antibiotic-resistant bacterial activity as described above, which is an injection, an oral preparation, an infusion or a topical application. preparation. It can be administered to a patient in need of treatment by intravenous injection, subcutaneous injection or oral administration. For oral administration, it can be prepared into a solid preparation such as a tablet, a powder or a capsule, etc.; when it is used for injection, it can be prepared as an injection. When used in a topical preparation, it can be made into an ointment, a powder or loaded on a carrier. The various dosage forms of the pharmaceutical preparation of the present invention can be prepared by a conventional method in the medical field, wherein the active ingredient glycopeptide compound has a weight content of 0.1% to 99.9%, preferably a content of 0.5% to 90%.

The general dosage of the above pharmaceutical preparation applied to a patient in need of treatment can be referred to the existing dosage of vancomycin and norvancomycin, for example, 0.1 to 2.0 g/d for an adult, depending on the age and condition of the patient. The glycopeptide compound of the present invention can be prepared into a salt by a conventional method, for example, as a hydrochloride.

A third object of the present invention is to provide a process for the preparation of the above-mentioned group of compounds having antibiotic resistance bacterial activity.

Representative methods for preparing the compounds of the invention are described below. The preparation of the compounds is not intended to be limited to such methods and, of course, may be carried out by other methods. It will be appreciated that while typical or preferred process conditions (e.g., reaction solvent, reaction temperature, molar ratio, etc.) are given, other process conditions may be employed, unless otherwise specified. The optimum process conditions may vary depending on the particular reactants or solvents employed, but such conditions can be readily determined by one skilled in the art with the aid of customary process conditions.

Additionally, it will be apparent to those skilled in the art that conventional protecting groups may be necessary or desirable to prevent certain functional groups from undergoing undesired reactions. The selection of suitable protecting groups for a particular functional group and suitable conditions for protection and deprotection of such functional groups are well known in the art. If desired, those protecting groups other than those exemplified herein can be used. For example, various protecting groups and their introduction or removal are described in T. W. Greene and G. M. Wuts, Protective Groups in Organic Synthesis, 3rd, Wiley, New York, 1999 and references cited therein.

In the present invention, the compound of the formula I can be prepared by the following synthetic route:

(1) When R ₂ is -OH, the compound of the formula II is reacted with an aldehyde, borane tert-butylamine and diethylamine to obtain a compound of the formula I:

Typically, the reaction is carried out using one or more organic solvents (e.g., DMF, DMSO, methanol, ethanol, etc.), preferably a mixed solvent of DMF and methanol, in an excess of amine (typically about 2 equivalents), such as DIEA. In the presence of the compound II, the compound II is mixed with about 0.5 to 2.5 equivalents, preferably 1.3 equivalents, of aldehyde at a temperature of from about 0 ° C to about 100 ° C, preferably 65 ° C, for about 0.5 to about 4 hours, and then the reactant is cooled. To about 0 ° C to about 40 ° C, preferably to room temperature, an excess of acid (usually about 3 equivalents), such as trifluoroacetic acid, is added to the reaction, followed by the addition of a reducing agent (eg, sodium borohydride, cyanide) Sodium borohydride, sodium triacetoxyborohydride, borane t-butylamine, borane pyridine, etc., preferably borane t-butylamine (usually about 2 equivalents). The reactants are then mixed at about 0 ° C to about 100 ° C, preferably at room temperature until the reaction is substantially complete.

After the above reaction is completed, any protecting group present in the product is removed by well-known methods and generally applicable reagents, for example, organic acid, inorganic acid, organic base, inorganic base, catalytic hydrogenation, alkali hydrolysis, etc., preferably organic The base, for example using diethylamine, removes the Fmoc protecting group from the product. Once the reaction is complete, a compound of formula I is obtained by conventional separation and purification processes, such as silica gel, ion exchange resins, polymer fillers, _C18 preparative liquid phase, solvent precipitation, crystallization, and the like, preferably using a polymeric filler for separation and purification.

(2) When R ₂ is -NH-OH,

Step A, reacting a compound of the formula II with an aldehyde, borane tert-butylamine and diethylamine to obtain a compound of the formula III:

Generally, this step and the reaction process are as described in point (1).

Step B, reacting a compound of the formula III with hydroxylamine hydrochloride and a condensing agent to obtain a compound of the formula I:

Typically, this step is carried out using one or more organic solvents (e.g., DMF, DMSO, N-methylpyrrolidone, etc.), preferably DMSO, in the presence of an excess of base (usually about 3 equivalents), such as DIEA. Lowering the compound of formula III with from about 0.5 to 3.0 equivalents, preferably 1.5 equivalents of hydroxylamine hydrochloride, at a temperature of from about 0 ° C to about 100 ° C, preferably room temperature, followed by the addition of a condensing agent (typically about 2 equivalents), Mix for about 0.5 to about 8 hours at room temperature or until the reaction is substantially complete. Once the reaction is complete, the compound of formula I is obtained by the separation and purification method of method one above.

The condensing agent used in this step includes various commonly defined coupling agents, dehydrating agents such as sulfuric acid, phosphoric acid, polyphosphoric acid, boric acid, 4-(4,6-dimethoxytriazine)-4-methyl. Benzomorpholine chloride (DMTMM), dicyclohexylcarbodiimide (DCC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), N, N '-Diisopropylcarbodiimide (DIC), N,N'-carbonyldiimidazole (CDI), 2-(7-azobenzotriazole)-N,N,N',N'- Tetramethylurea hexafluorophosphate (HATU), O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU) or 1H-benzotriazole-1 - yl-oxytripyrrolidinyl hexafluorophosphate (PyBOP) or the like, preferably 1H-benzotriazol-1-yl-oxytripyrrolidinyl hexafluorophosphate (PyBOP).

Aldehydes, reagents, and purification devices suitable for the above routes are commercially available.

According to a preferred embodiment of the invention, the aldehyde is selected from the group consisting of N-Fmoc-N-(4'-chlorobiphenyl-4-methylene)-aminoacetaldehyde, N-Fmoc-N-(4'- Fluorobiphenyl-4-methylene)-aminoacetaldehyde, N-Fmoc-N-(4'-trifluoromethylbiphenyl-4-methylene)-aminoacetaldehyde, N-Fmoc-N -(4'-methoxybiphenyl-4-methylene)-aminoacetaldehyde, N-Fmoc-N-(4'-chlorobiphenyl-4-ethyl)-aminocarbaldehyde, N-Fmoc -N-(4'-fluorobiphenyl-4-ethyl)-aminocarbaldehyde, N-Fmoc-N-(4'-trifluoromethylbiphenyl-4-ethyl)-aminocarbaldehyde, N- Fmoc-N-(4'-methoxybiphenyl-4-ethyl)-aminocarbaldehyde, O-(4'-chlorobiphenyl-4-methylene)-oxy-acetaldehyde, O-(4 '-Fluorobiphenyl-4-methylene)-oxy-acetaldehyde, O-(4'-trifluoromethylbiphenyl-4-methylene)-oxy-acetaldehyde, O-(4'-A Oxybiphenyl-4-methylene)-oxy-acetaldehyde, O-(4'-chlorobiphenyl-4-ethyl)-oxy-formaldehyde, O-(4'-fluorobiphenyl-4-ethyl -oxy-formaldehyde, O-(4'-trifluoromethylbiphenyl-4-ethyl)-oxo-formaldehyde, O-(4'-methoxybiphenyl-4-ethyl)-oxygen- Formaldehyde, N-Fmoc-4-(4'-chlorobiphenyl-4-methylene)-3-pyrrolidinecarbaldehyde, N-Fmoc-4-(4'-fluorobiphenyl-4-methylene)- 3-pyrrolidine formaldehyde, N-Fmoc-4-(4'-three Fluoromethylbiphenyl-4-methylene)-3-pyrrolidinecarboxaldehyde, N-Fmoc-4-(4'-methoxybiphenyl-4-methylene)-3-pyrrolidinecarbaldehyde, N- Fmoc-5-(4'-chlorobiphenyl-4-methylene)-3-piperidinecarboxaldehyde, N-Fmoc-5-(4'-fluorobiphenyl-4-methylene)-3-piperidine Formaldehyde, N-Fmoc-5-(4'-trifluoromethylbiphenyl-4-methylene)-3-piperidinecarboxaldehyde, N-Fmoc-5-(4'-methoxybiphenyl-4- Methylene)-3-piperidinecarboxaldehyde, N-Fmoc-4-(4'-chlorobiphenyl-4-methylene)-3-pyrrolidine, N-Fmoc-4-(4'-fluorobiphenyl -4-methylene)-3-pyrrolidine, N-Fmoc-4-(4'-trifluoromethylbiphenyl-4-methylene)-3-pyrrolidine, N-Fmoc-4-(4 '-Methoxybiphenyl-4-methylene)-3-pyrrolidine, N-Fmoc-5-(4'-chlorobiphenyl-4-methylene)-1,4-dihydropyridine-3 -Formaldehyde, N-Fmoc-5-(4'-fluorobiphenyl-4-methylene)-1,4-dihydropyridine-3-carbaldehyde, N-Fmoc-5-(4'-trifluoromethyl Biphenyl-4-methylene)-1,4-dihydropyridine-3-carbaldehyde, N-Fmoc-5-(4'-methoxybiphenyl-4-methylene)-1,4-di Any one of hydropyridine-3-carbaldehyde.

A fourth object of the present invention is to provide the use of the glycopeptide compound as described above for the preparation of a medicament for treating a drug-resistant bacterial infectious disease.

According to a preferred embodiment of the invention, the drug resistant bacterium is a Gram positive resistant bacteria.

According to a preferred embodiment of the invention, the drug resistant bacterium is Staphylococcus aureus or vancomycin-resistant Enterococcus.

It has been tested that the glycopeptide antibiotic compound of the present invention has higher inhibitory activity against drug-resistant strains, especially MRSA or VRE, compared to conventional glycopeptide drugs (such as vancomycin, etc.); further tests found that the present invention The vast majority of glycopeptide compounds have higher safety than the existing drug oritavancin, and can be used to treat or prevent various bacterial infections such as skin and soft tissue infections, meningitis, sepsis, Drugs for diseases such as pneumonia, arthritis, peritonitis, bronchitis, and empyema.

Detailed ways

The invention will be further described below in conjunction with specific embodiments. It is to be understood that the following examples are merely illustrative of the invention and are not intended to limit the scope of the invention.

In the present invention, the following abbreviations have the following meanings. Undefined abbreviations have their generally accepted meanings, and unless otherwise stated, all room temperatures refer to temperatures between 20 ° C and 30 ° C.

DIEA N,N-diisopropylethylamine

DMF N,N-dimethylformamide

DMSO dimethyl sulfoxide

ESI electrospray ionization mass spectrometry

Fmoc 9-fluorenylmethoxycarbonyl

h hours

LD ₅₀ half lethal dose

MRSA methicillin-resistant Staphylococcus aureus

MIC minimum inhibitory concentration

MS mass spectrometry

PyBOP 1H-benzotriazol-1-yl-oxytripyrrolidinyl hexafluorophosphate

Rt room temperature

TFA trifluoroacetic acid

VRE vancomycin-resistant enterococci

In the present invention, the method for obtaining the starting compound II is described in the patent application file of the Chinese Patent No. CN101928331A, and other materials, materials, devices and the like in the present invention are commercially available.

In the following examples, the crude product obtained by the synthesis was purified using a reverse phase polymer filler Uni PS25-300 and Uni PSA 30-300. After the crude product was dissolved in a methanol (or acetonitrile) aqueous solution, it was applied to a glass column packed with a packing at a flow rate of 1 column volume/h. After the completion of the sample, it was pre-washed with a methanol (or acetonitrile) aqueous solution for 1 hour, and then eluted with a TFA-containing methanol (or acetonitrile) aqueous solution at a flow rate of 1.5 column volumes/h. After eluting 1 column volume, the eluate was collected, and the eluate was concentrated and dried to obtain a pure product of each sample.

In the following examples, the ratio of the eluent refers to the volume percentage, and the yield refers to the molar yield, unless otherwise specified.

The structures of the respective compounds involved in the following examples are shown in Table 1.

Table 1. Structure of each compound

Example 1 Preparation of Compound 1

Compound II (0.5 g, 0.3 mmol) was stirred with 10 mL DMF-methanol (1:1, v/v) and DIEA (0.1 mL, 0.6 mmol) and N-Fmoc-N-(4'-chlorobiphenyl- 4-methylene)-aminoacetaldehyde (0.2 g, 0.4 mmol), stirred at 65 ° C for 2 h then cooled to rt then EtOAc (EtOAc <RTIgt; After stirring at rt for 2 h, then diethylamine (1 mL) was added and stirred for 3 h, then methyl t-butyl ether (50 mL) was added to the reaction mixture, and the precipitate was collected by suction filtration, The mixture was eluted with a 0.04% aqueous solution of TFA (1:4, v/v), and concentrated to give compound 1 (white solid, 0.33 g, yield: 60%).

For C ₈₈ H ₁₀₂ Cl ₃ N ₁₁ O ₂₆ calc. </RTI>^</RTI>^</RTI>^< RTI ID=0.0></RTI>^</RTI>^<RTIgt;

Example 2 Preparation of Compound 2

Compound II (1.0 g, 0.6 mmol) was stirred with 15 mL DMF-methanol (1:1, v/v) and DIEA (0.2 mL, 1.2 mmol) and N-Fmoc-N-(4'-chlorobiphenyl) -4-Methylene)-aminoacetaldehyde (0.4 g, 0.8 mmol), stirred at 65 ° C for 2 h then cooled to rt. EtOAc (EtOAc: EtOAc. Stirring was continued at rt for 2 h, then additional diethylamine (1 mL) was added and stirred for 3 h, then methyl tert-butyl ether (70 mL) was added, and the precipitate was collected by suction filtration. The precipitate was washed with dichloromethane, and the crude product was dissolved in 10 mL of DMSO. Add DIEA (0.3 mL, 1.8 mmol), hydroxylamine hydrochloride (0.07 g, 0.9 mmol) and PyBOP (0.6 g, 1.2 mmol), rt for 2 h, then add acetone (70 mL). The precipitate was purified by chromatography, eluting with EtOAc-EtOAc (EtOAc:EtOAc)

_{_{_{_{C 88 H 103 Cl 3 N 12}}}} O 26 molecular weight Calculated: 1848.62, Found: m / z = 1849.62 [M + H] +.

Example 3 Preparation of Compound 3

Compound II (0.5 g, 0.3 mmol) was stirred with 10 mL DMF-methanol (1:1, v/v), and DIEA (0.1 mL, 0.6 mmol) and N-Fmoc-N-(4'-fluorobiphenyl) -4-Methylene)-aminoacetaldehyde (0.2 g, 0.4 mmol), stirred at 65 ° C for 2 h then cooled to rt, then EtOAc (EtOAc <RTIgt; Stirring was continued for 2 h at rt, then diethylamine (1 mL) was added and stirred for 3 h. Methyl tert-butyl ether (50 mL) was added to the reaction mixture, and the precipitate was collected by suction filtration. The mixture was eluted with a -0.04% aqueous solution of TFA (1:4, v/v), and concentrated to give compound 1 (white solid 0.25 g, yield 46%).

For C ₈₈ H ₁₀₂ Cl ₂ FN ₁₁ O ₂₆ calc.: 181.64, found: m/z = 187.64 [M+H] ⁺ .

Example 4 Preparation of Compound 4

The preparation of the compound 4 was carried out in the same manner as in the preparation of the compound 2, and the aldehyde used was replaced with N-Fmoc-N-(4'-fluorobiphenyl-4-methylene)-aminoacetaldehyde. Compound 4 (white solid 0.5 g, yield 45%) was obtained.

_{_{_{_{C 88 H 103 Cl 2 FN 12}}}} O 26 Calcd molecular weight: 1832.65, Found: m / z = 1833.67 [M + H] +.

Example 5 Preparation of Compound 5

The preparation of the compound 5 was carried out in the same manner as in the preparation of the compound 1, and the aldehyde used was replaced with N-Fmoc-N-(4'-trifluoromethylbiphenyl-4-methylene)-aminoacetaldehyde. Compound 5 (white solid 0.38 g, yield 68%) was obtained.

_{_{_{C 89 H Cl 2 F 3 N}}} 11 O 26 molecular weight ₁₀₂ calc: 1867.63, Found: m / z = 1868.63 [M + H] +.

Example 6 Preparation of Compound 6

Compound 6 was prepared in the same manner as in the preparation of Compound 2, and the aldehyde used was replaced with N-Fmoc-N-(4'-trifluoromethylbiphenyl-4-methylene)-aminoacetaldehyde. Compound 6 (white solid 0.66 g, yield 58%) was obtained.

_{_{_{_{C 89 103 Cl 2 F 3 N}}}} 12 O 26 molecular weight Calcd H: 1882.64, Found: m / z = 1883.64 [M + H] +.

Example 7 Preparation of Compound 7

Compound II (0.5 g, 0.3 mmol) was stirred with 10 mL DMF-methanol (1:1, v/v), DIEA (0.1 mL, 0.6 mmol) and N-Fmoc-N-(4'-methoxy Biphenyl-4-methylene)-aminoacetaldehyde (0.2 g, 0.4 mmol), stirred at 65 ° C for 2 h, then cooled to rt, then added TFA (0.07 mL, 0.9 mmol) and borane tert-butylamine (0.05 g, 0.6 The mixture was stirred at rt for 2 h, then diethylamine (1 mL) was added and stirred for 3h, and then ethyl t-butyl ether (50 mL) was added to the mixture. It was eluted with a methanol-0.04% aqueous solution of TFA (1:4, v/v), and concentrated to give Compound 1 (white solid, 0.2 g, yield 36%).

_{_{_{_{C 89 H 105 Cl 2 N 11}}}} O 27 molecular weight Calculated: 1829.66, Found: m / z = 1830.67 [M + H] +.

Example 8 Preparation of Compound 8

Compound 8 was prepared in the same manner as in the preparation of Compound 2, and the aldehyde used was replaced with N-Fmoc-N-(4'-methoxybiphenyl-4-methylene)-aminoacetaldehyde. Compound 8 (0.41 g of a white solid, yield 37%) was obtained.

For C ₈₉ H ₁₀₆ Cl ₂ N ₁₂ O _{27 <} /RTI>^</RTI>^< RTI ID=0.0></RTI>

Example 9 Preparation of Compound 9

Compound II (0.5 g, 0.3 mmol) was stirred with 10 mL DMF-methanol (1:1, v/v) and DIEA (0.1 mL, 0.6 mmol) and N-Fmoc-N-(4'-chlorobiphenyl- 4-Ethyl)-aminocarbaldehyde (0.2 g, 0.4 mmol), was stirred at 650C for 2 h then cooled to rt. EtOAc EtOAc EtOAc. After stirring for 2 h, then diethylamine (1 mL) was added and stirred for 3 h. Methyl tert-butyl ether (50 mL) was added to the reaction mixture, and the precipitate was collected by suction filtration. The TFA aqueous solution (1:4, v/v) was eluted, and concentrated to dryness to give compound 9 (white solid, 0.3 g, yield 55%).

For C ₈₈ H ₁₀₂ Cl ₃ N ₁₁ O ₂₆ calc.: </RTI>^</RTI>^</RTI>^< RTI ID=0.0></RTI>^</RTI>^<RTIgt;

Example 10 Preparation of Compound 10

Compound II (1.0 g, 0.6 mmol) was stirred with 15 mL DMF-methanol (1:1, v/v), DIEA (0.2 mL, 1.2 mmol) and N-Fmoc-N-(4'-chlorobiphenyl) -4-Ethyl)-aminocarbaldehyde (0.4 g, 0.8 mmol), stirred at 65 ° C for 2 h then cooled to rt. EtOAc EtOAc EtOAc. After stirring at rt for 2 h, additional diethylamine (1 mL) was added and stirred for 3h, then methyl tert-butyl ether (70mL) was added, and the precipitate was collected by suction filtration, and the precipitate was washed with dichloromethane, and the crude product was dissolved in 10 mL of DMSO and added to DIEA. (0.3 mL, 1.8 mmol), hydroxylamine hydrochloride (0.07 g, 0.9 mmol) and PyBOP (0.6 g, 1.2 mmol). After stirring at rt for 2 h, acetone (70 mL) was added. The precipitate was eluted with a methanol-0.04% aqueous solution of TFA (1:4, v/v) and concentrated to afford compound 10 (white solid, 0.58 g, yield 52%).

_{_{_{_{C 88 H 103 Cl 3 N 12}}}} O 26 molecular weight Calculated: 1848.62, Found: m / z = 1849.61 [M + H] +.

Example 11 Preparation of Compound 15

Compound II (0.5 g, 0.3 mmol) was stirred with 10 mL DMF-methanol (1:1, v/v), DIEA (0.1 mL, 0.6 mmol) and N-Fmoc-N-(4'-methoxy Biphenyl-4-ethyl)-aminocarbaldehyde (0.2 g, 0.4 mmol), stirred at 65 ° C for 2 h then cooled to rt, then EtOAc (EtOAc (EtOAc) Stirring was continued for 2 h at rt, then diethylamine (1 mL) was added and stirred for 3 h. Methyl tert-butyl ether (50 mL) was added to the reaction mixture, and the precipitate was collected by suction filtration. The mixture was eluted with a -0.04% aqueous solution of TFA (1:4, v/v), and concentrated to afford compound 15 (white solid 0.25 g, yield 46%).

_{_{_{_{C 89 H 105 Cl 2 N 11}}}} O 27 molecular weight Calculated: 1829.66, Found: m / z = 1830.66 [M + H] +.

Example 12 Preparation of Compound 16

The preparation of the compound 16 was carried out in the same manner as in the preparation of the compound 2, and the aldehyde used was replaced with N-Fmoc-N-(4'-methoxybiphenyl-4-ethyl)-aminocarbaldehyde. Compound 16 (white solid 0.35 g, yield 32%) was obtained.

Example 13 Preparation of Compound 17

Compound II (0.5 g, 0.3 mmol) was stirred with 10 mL of DMF-methanol (1:1, v/v), DIEA (0.1 mL, 0.6 mmol) and O-(4'-chlorobiphenyl-4-methyl Base-oxy-acetaldehyde (0.1 g, 0.4 mmol), stirred at 650 ° C for 2 h then cooled to rt, then EtOAc (EtOAc (EtOAc, EtOAc) 2h, methyl tert-butyl ether (50mL) was added to the reaction mixture, and the precipitate was collected by suction filtration. The residue was purified by reverse phase polymer packing and eluted with methanol-0.04% aqueous TFA (1:4, v/v) After concentration and drying, Compound 17 (0.31 g of white solid, yield 56%) was obtained.

For C ₈₈ H ₁₀₁ Cl ₃ N ₁₀ O ₂₇ calc.: </RTI>^< / RTI>^< / RTI>^< / RTI>^< / RTI>^<RTIgt;

Example 14 Preparation of Compound 18

Compound II (1.0 g, 0.6 mmol) was stirred with 15 mL of DMF-methanol (1:1, v/v), and DIEA (0.2 mL, 1.2 mmol) and O-(4'-chlorobiphenyl-4- Methyl)-oxy-acetaldehyde (0.2 g, 0.8 mmol), stirred at 65 ° C for 2 h then cooled to rt, then EtOAc (EtOAc <RTI ID=0.0> After stirring for 2 h, methyl tert-butyl ether (70 mL) was added, and the precipitate was collected by suction. The precipitate was washed with dichloromethane. The obtained crude product was dissolved in 10 mL of DMSO, and DIEA (0.3 mL, 1.8 mmol) and hydroxylamine hydrochloride (0.07 g) , 0.9 mmol) and PyBOP (0.6 g, 1.2 mmol). After stirring for 2 h rt, acetone (70 mL) was added and the precipitate was collected by suction filtration, and the precipitate was purified by reverse-phase polymer packing using methanol-0.04% TFA aqueous solution (1: 4, v / v) eluted, concentrated and dried to give compound 18 (white solid, 0.3 g, yield 27%).

Calculated for C ₈₈ H ₁₀₂ Cl ₃ N ₁₁ O ₂₇ : 1849.60, found: m/z=1852.61 [M+3] ⁺ .

Example 15 Preparation of Compound 23

Compound II (0.5 g, 0.3 mmol) was stirred with 10 mL of DMF-methanol (1:1, v/v), DIEA (0.1 mL, 0.6 mmol) and O-(4'-methoxybiphenyl-4- Methylene)-oxy-acetaldehyde (0.1 g, 0.4 mmol), stirred at 65 ° C for 2 h then cooled to rt. EtOAc (EtOAc <RTIgt; After stirring for 2 h, methyl tert-butyl ether (50 mL) was added to the reaction mixture, and the precipitate was collected by suction filtration, and the residue was purified with a reversed polymer filler, using methanol-0.04% TFA aqueous solution (1:4, v/v) After elution and concentration and drying, Compound 23 (white solid, 0.26 g, yield 47%) was obtained.

_{_{_{_{C 89 H 104 Cl 2 N 10}}}} O 28 molecular weight Calculated: 1830.64, Found: m / z = 1832.64 [M + 2] +.

Example 16. Preparation of Compound 24

The compound 24 was produced in the same manner as in the preparation of the compound 18, and the aldehyde used was replaced with O-(4'-methoxybiphenyl-4-methylene)-oxy-acetaldehyde. Compound 24 (white solid 0.43 g, yield 39%) was obtained.

_{_{_{_{C 89 H 105 Cl 2 N 11}}}} O 28 molecular weight Calculated: 1845.65, Found: m / z = 1846.69 [M + H] +.

Example 17 Preparation of Compound 29

Compound II (0.5 g, 0.3 mmol) was stirred with 10 mL of DMF-methanol (1:1, v/v), DIEA (0.1 mL, 0.6 mmol) and O-(4'-trifluoromethylbiphenyl-4) -ethyl)-oxo-formaldehyde (0.12 g, 0.4 mmol), stirred at 650 ° C for 2 h then cooled to rt, then EtOAc (EtOAc, EtOAc, EtOAc After stirring for 2 h, methyl tert-butyl ether (50 mL) was added to the reaction mixture, and the precipitate was collected by suction filtration, and the residue was purified by reverse phase polymer packing and washed with methanol-0.04% aqueous TFA (1:4, v/v) The mixture was concentrated and dried to give Compound 29 (yield: white solid, 0.36 g, yield: 64%).

_{_{_{C 89 H Cl 2 F 3 N}}} 10 O 27 molecular weight ₁₀₁ calc: 1868.62, Found: m / z = 1871.60 [M + 3] +.

Example 18 Preparation of Compound 30

The compound 30 was produced in the same manner as in the preparation of the compound 18, and the aldehyde used was replaced with O-(4'-trifluoromethylbiphenyl-4-ethyl)-oxy-carbaldehyde. Compound 30 (white solid 0.52 g, yield 46%) was obtained.

_{_{_{C 89 H Cl 2 F 3 N}}} 11 O 27 molecular weight ₁₀₂ calc: 1883.63, Found: m / z = 1884.60 [M + H] +.

Example 19 Preparation of Compound 31

The compound 31 was produced in the same manner as in the preparation of the compound 17, and the aldehyde used was replaced with O-(4'-methoxybiphenyl-4-ethyl)-oxy-carbaldehyde. Compound 31 (white solid 0.29 g, yield 53%) was obtained.

For C ₈₉ H ₁₀₄ Cl ₂ N ₁₀ O ₂₈ calc.: </RTI>^< / RTI>^< / RTI>^< / RTI>^< / RTI>^<RTIgt;

Example 20 Preparation of Compound 32

The compound 32 was produced in the same manner as in the preparation of the compound 18, and the aldehyde used was replaced with O-(4'-methoxybiphenyl-4-ethyl)-oxy-carbaldehyde. Compound 32 (white solid 0.4 g, yield 36%) was obtained.

_{_{_{_{C 89 H 105 Cl 2 N 11}}}} O 28 molecular weight Calculated: 1845.65, Found: m / z = 1847.65 [M + 2] +.

Example 21, Preparation of Compound 39

Compound II (0.5 g, 0.3 mmol) was stirred with 10 mL DMF-methanol (1:1, v/v) and DIEA (0.1 mL, 0.6 mmol) and N-Fmoc-4-(4'-methoxy Benzene-4-methylene)-3-pyrrolidinecarboxaldehyde (0.21 g, 0.4 mmol) was stirred at 65 ° C for 2 h then cooled to rt. EtOAc (EtOAc <RTIgt; The mixture was stirred at rt for 2 h, then diethylamine (1 mL) was added and stirred for 3h, and then ethyl t-butyl ether (50 mL) was added to the mixture. It was eluted with a methanol-0.04% aqueous solution of TFA (1:4, v/v), and concentrated to afford compound 39 (yel.

_{_{_{_{C 92 H 109 Cl 2 N 11}}}} O 27 molecular weight Calculated: 1869.69, Found: m / z = 1870.69 [M + H] +.

Example 22 Preparation of Compound 41

Compound II (0.5 g, 0.3 mmol) was stirred with 10 mL DMF-methanol (1:1, v/v) and DIEA (0.1 mL, 0.6 mmol) and N-Fmoc-5-(4'-chlorobiphenyl- 4-Methylene)-3-piperidinecarboxaldehyde (0.22 g, 0.4 mmol), stirred at 650 °C for 2 h then cooled to rt, then EtOAc (EtOAc (EtOAc) Stirring was continued for 2 h at rt, then diethylamine (1 mL) was added and stirred for 3 h. Methyl tert-butyl ether (50 mL) was added to the reaction mixture, and the precipitate was collected by suction filtration. The mixture was eluted with a -0.04% aqueous solution of TFA (1:4, v/v), and concentrated to give compound 41 (yield: white solid, 0.26 g, yield 46%).

_{_{_{_{C 92 H 108 Cl 3 N 11}}}} O 26 molecular weight Calculated: 1887.65, Found: m / z = 1888.66 [M + H] +.

Example Twenty-three, Preparation of Compound 47

Compound II (0.5 g, 0.3 mmol) was stirred with 10 mL DMF-methanol (1:1, v/v) and DIEA (0.1 mL, 0.6 mmol) and N-Fmoc-5-(4'-methoxy Benzene-4-methylene)-3-piperidinecarboxaldehyde (0.21 g, 0.4 mmol), was stirred at 65 ° C for 2 h then cooled to rt. EtOAc (EtOAc, EtOAc, EtOAc The mixture was stirred at rt for 2 h, then diethylamine (1 mL) was added and stirred for 3h, and then ethyl t-butyl ether (50 mL) was added to the mixture. It was eluted with a methanol-0.04% aqueous solution of TFA (1:4, v/v), and concentrated to afford compound 47 (white solid, 0.2 g, yield: 35%).

Calculated for C ₉₃ H ₁₁₁ Cl ₂ N ₁₁ O _{27 <} /RTI></RTI></RTI><RTIID=0.0></RTI></RTI>^<RTIgt;

Example 24 Preparation of Compound 49

Compound II (0.5 g, 0.3 mmol) was stirred with 10 mL DMF-methanol (1:1, v/v) and DIEA (0.1 mL, 0.6 mmol) and N-Fmoc-4-(4'-chlorobiphenyl- 4-Methylene)-3-pyrrolecarboxaldehyde (0.2 g, 0.4 mmol) was stirred at 65 ° C for 2 h then cooled to rt then EtOAc (EtOAc <RTIgt; After stirring at rt for 2 h, then diethylamine (1 mL) was added and stirred for 3 h, then methyl t-butyl ether (50 mL) was added to the reaction mixture, and the precipitate was collected by suction filtration, The mixture was eluted with a 0.04% aqueous solution of TFA (1:4, v/v), and concentrated to afford compound 49 (white solid, 0.2 g, yield 36%).

_{_{_{_{C 91 H 102 Cl 3 N 11}}}} O 26 molecular weight Calculated: 1869.61, Found: m / z = 1870.61 [M + H] +.

Example 25. Preparation of Compound 57

Compound II (0.5 g, 0.3 mmol) was stirred with 10 mL DMF-methanol (1:1, v/v) and DIEA (0.1 mL, 0.6 mmol) and N-Fmoc-5-(4'-chlorobiphenyl- 4-Methylene)-1,4-dihydropyridine-3-carbaldehyde (0.2 g, 0.4 mmol), was stirred at 650C for 2 h then cooled to rt then EtOAc (t. The mixture was stirred at rt for 2 h, then diethylamine (1 mL) was added and stirred for 3 h, then methyl tert-butyl ether (50 mL) was added to the reaction mixture, and the precipitate was collected by suction filtration. The material was purified by chromatography eluting with EtOAc-EtOAc (EtOAc:EtOAc:

For C ₉₂ H ₁₀₄ Cl ₃ N ₁₁ O ₂₆ calcd.: </RTI>^</RTI>^< RTI ID=0.0></RTI>^</RTI>^<RTIgt;

Example twenty-six, salt formation example

50 mg of the compound 1 was added to 1 mL of a saturated hydrogen chloride methanol solution, stirred at room temperature, and lyophilized to give 50 mg of the hydrochloride salt of Compound 1 as a white solid.

In addition, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid The methanesulfonic acid, aspartic acid or glutamic acid is substituted for the hydrogen chloride in the above saturated hydrogen chloride methanol solution to obtain the corresponding salt.

Example 27: Formulation Example

It is to be understood that the present invention is not intended to limit the scope of the invention. The term "active ingredient" refers to a compound, solvate, tautomer, optical isomer, prodrug, pharmaceutically acceptable salt thereof and the like of the present invention.

An intravenous preparation can be prepared as follows:

Active ingredient 100mg

Isotonic saline 1000mL

The solution of the above ingredients is usually administered intravenously to the patient at a rate of 1 mL/min.

Example 28: Determination of antibacterial activity of a compound

The compounds in Table 1 were tested for in vitro antibacterial activity and the minimum inhibitory concentration (MIC) was read. The method of determination was based on the method provided in the Pharmacopoeia of the People's Republic of China (2015 edition). The MRSA detection strain was purchased from ATCC. The VRE detection strain was obtained from the clinical isolate of drug-resistant strain 07-W3-45 from Shanghai Huashan Hospital. The known antibiotic vancomycin hydrochloride was used as the control drug. The comparison test results are shown in Table 2.

The zebrafish toxicity test of the compounds in Table 1 was also tested. Wild AB lineage zebrafish were randomly selected from six-well plates, and 50, 100, 150, 200 and 250 ng/tail doses of each test sample were intravenously injected, and a normal control group and a solvent control group (aqueous hydrochloric acid solution) were set at the same time; During the course, the death of zebrafish was recorded daily and the dead fish were removed; after 72 hours of treatment, the death of zebrafish was counted. The LD _{50 of} each test article for zebrafish was calculated separately. The results are combined in Table 2.

MIC (μg/mL) zebrafish LD ₅₀ of each compound in Table 2 and Table 1 for MRSA, VRE

As can be seen from Table 2, the glycopeptide compound of the present invention has higher inhibitory activity against the drug-resistant strain MRSA or VRE than the conventional glycopeptide drug vancomycin; or the glycopeptide compound of the present invention has a higher ratio than the present The drug Olivier has less toxicity and higher safety.

The specific embodiments of the present invention have been described in detail above, but are merely exemplary, and the invention is not limited to the specific embodiments described above. Any equivalent modifications and substitutions to the invention are also within the scope of the invention. Accordingly, equivalents and modifications may be made without departing from the spirit and scope of the invention.

Claims

A group of compounds having anti-resistant bacterial activity, characterized by conforming to the glycopeptide compound of formula I:

Or a pharmaceutically acceptable salt thereof, wherein:

R 1 is represented by the following formula: -A-D-E-G;

A is -(CH 2 ) m -, where m is 1 or 2;

D is -NH- or -O- or a nitrogen-containing heterocycle;

E is —(CH 2 ) n — wherein n is 1 or 2;

G is a structural formula:
Wherein L is any one of halogen or trifluoromethyl or methoxy;

R 2 is -OH or -NH-OH.
A group of compounds having antibiotic-resistant bacterial activity according to claim 1, wherein the nitrogen-containing heterocycle represented by D is a five- to six-membered saturated or unsaturated heterocyclic ring having at least one nitrogen atom in the ring. Group.
A group of compounds having anti-drug resistant bacterial activity according to claim 2, wherein the heterocyclic group is a substituted or unsubstituted aromatic or non-aromatic group, including pyrrole, pyrrolidine, Imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, piperidine, piperazine, pyridazine, pyrazine, morpholine, pyrimidine, pyridine, dihydropyridine.
A group of compounds having antibiotic resistant bacterial activity according to claim 2, wherein the nitrogen-containing heterocycle is pyrrolidine, piperidine, pyrrole and dihydropyridine.
A group of compounds having antibiotic-resistant bacterial activity according to claim 1, wherein R 1 is N-(4'-chlorobiphenyl-4-methylene)-amine ethyl, N-( 4'-Fluorobiphenyl-4-methylene)-amine ethyl, N-(4'-trifluoromethylbiphenyl-4-methylene)-amine ethyl, N-(4'-methoxy Base phenyl-4-methylene)-amine ethyl, N-(4'-chlorobiphenyl-4-ethyl)-amine methyl, N-(4'-fluorobiphenyl-4-ethyl) -Aminomethyl, N-(4'-trifluoromethylbiphenyl-4-ethyl)-aminemethyl, N-(4'-methoxybiphenyl-4-ethyl)-aminemethyl, O-(4'-chlorobiphenyl-4-methylene)-oxyethyl, O-(4'-fluorobiphenyl-4-methylene)-oxyethyl, O-(4'-trifluoro Methylbiphenyl-4-methylene)-oxyethyl, O-(4'-methoxybiphenyl-4-methylene)-oxyethyl, O-(4'-chlorobiphenyl-4 -ethyl)-oxymethyl, O-(4'-fluorobiphenyl-4-ethyl)-oxymethyl, O-(4'-trifluoromethylbiphenyl-4-ethyl)-oxymethyl , O-(4'-methoxybiphenyl-4-ethyl)-oxymethyl, 4-(4'-chlorobiphenyl-4-methylene)-3-methylenepyrrolidine, 4 -(4'-fluorobiphenyl-4-methylene)-3-methylenepyrrolidine, 4-(4'-trifluoromethylbiphenyl-4-methylene)-3-methylenepyrrole Alkane, 4-(4'-methoxybiphenyl-4-methylene)-3- Methylpyrrolidine, 5-(4'-chlorobiphenyl-4-methylene)-3-methylene piperidine, 5-(4'-fluorobiphenyl-4-methylene)-3-arylene Methylpiperidine, 5-(4'-trifluoromethylbiphenyl-4-methylene)-3-methylenepiperidine, 5-(4'-methoxybiphenyl-4-methylene )-3-Methylene piperidine, 4-(4'-chlorobiphenyl-4-methylene)-3-methylene-1H-pyrrole, 4-(4'-fluorobiphenyl-4-arylene Methyl)-3-methylene-1H-pyrrole, 4-(4'-trifluoromethylbiphenyl-4-methylene)-3-methylene-1H-pyrrole, 4-(4'- Methoxybiphenyl-4-methylene)-3-methylene-1H-pyrrole, 5-(4'-chlorobiphenyl-4-methylene)-3-methylene-1,4- Dihydropyridine, 5-(4'-fluorobiphenyl-4-methylene)-3-methylene-1,4-dihydropyridine, 5-(4'-trifluoromethylbiphenyl-4- Methylene)-3-methylene-1,4-dihydropyridine, 5-(4'-methoxybiphenyl-4-methylene)-3-methylene-1,4-dihydrogen Pyridine.
A pharmaceutical preparation comprising, as an active ingredient, a group of compounds having antibiotic-resistant bacterial activity as claimed in claim 1, wherein the preparation is an injection, an oral preparation, an infusion or an external preparation; The weight content of the compound is from 0.1% to 99.9%.
A method for producing a group of compounds having antibiotic-resistant bacterial activity according to any one of claims 1 to 5, wherein

When R 2 is -OH, the compound of formula II is reacted with an aldehyde, borane tert-butylamine and diethylamine to obtain a compound of formula I:

When R 2 is -NH-OH,

Step A, reacting a compound of the formula II with an aldehyde, borane tert-butylamine and diethylamine to obtain a compound of the formula III:

Step B, reacting a compound of the formula III with hydroxylamine hydrochloride and a condensing agent to obtain a compound of the formula I:
Use of a group of compounds having anti-drug resistant bacterial activity according to any one of claims 1 to 5 for the preparation of a medicament for treating a drug-resistant bacterial infectious disease.
The use according to claim 8, wherein the drug-resistant bacteria are Gram-positive bacteria.
The use according to claim 9, wherein the drug-resistant bacterium is Staphylococcus aureus or vancomycin-resistant Enterococcus.