CN107619432A - Glycopeptide derivant and its pharmaceutically acceptable salt, preparation method and application - Google Patents
Glycopeptide derivant and its pharmaceutically acceptable salt, preparation method and application Download PDFInfo
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Abstract
The invention discloses the glycopeptide derivant shown in logical formula (I) and its pharmaceutically acceptable salt：Wherein, R1For H, 2 alkylamine ethyls, the benzyl of substitution, the hydrocinnamoyl of substitution or the straight chain acyl of carbon-carbon double bonds; phenyl ring on the benzyl or hydrocinnamoyl carries halogen, hydroxyl, amino, dimethylamino, trifluoromethyl, or with the halogen phenyl ring that either hydroxyl or trifluoromethyl substitute；The straight chain acyl contains 1~6 carbon-carbon double bond；R2For C1~C5 straight chain amidos, the end of C1~C5 straight chains amido can carry dimethylamino or substituted-phenyl, halogen either cyano group or nitro are carried on the phenyl ring of the substituted-phenyl.Compound provided by the invention has good antibacterial activity, the antibiotic property of glycopeptide antibiotics drug-fast bacteria is strengthened, the exploitation for new antibacterials has great importance.
Description
Technical field
The invention belongs to pharmaceutical chemistry synthesis technical field, and in particular to a kind of glycopeptide derivant and its pharmaceutically acceptable
Salt, preparation method and application.
Background technology
Glycopeptide antibiotics are because it can interfere with the crosslinking of bacteria cell wall peptide glycan, so that bacterial cell generation is molten
Solution, therefore be clinical treatment methicillin-resistant staphylococcus aureus (methicillin-resistant
Staphylococcus aureus, MRSA) infection choice drug.However, largely it is used as MRSA's using glycopeptide antibiotics
Experiential therapy result in the development of bacterial drug resistance, such as MRSA has declined to the sensitiveness of vancomycin, clinically also goes out
Substantial amounts of vancomycin-resistant enterococcus (VRE) is showed.Therefore, glycopeptide antibiotics are treatment vancomycin-resistant bacteria strain VRE's
Effect reduces, and clinical anti-infective therapy constantly faces new challenges, and is badly in need of researchers and deeply develops antibacterial activity height, to resistance to
The strong glycopeptide compound of medicine bacterium antibacterial activity.
In the prior art, Chinese invention patent CN200910053906.9 reports a novel glycopeptide class compound, knot
Structure has antibacterial activity, its novelty is its amino acids glycosyl of peptide backbone six as shown in the compound (II) of the present invention
Four hydroxyls are axial bond.However, with the enhancing of bacterial drug resistance, the therapeutic effect of compound (II) reduces, therefore researches and develops
A kind of have an excellent antibacterial curative effect, and to antimicrobial-oritavancin of the antibody-resistant bacterium with good inhibition just with
Highly important meaning.
The content of the invention
Present inventor is using the compound of the patent application document record of Chinese patent 200910053906.9 to go out
Compound is sent out, chemical improvement is carried out to it, a series of improved glycopeptide antibiotic derivatives is obtained and its can pharmaceutically connect
The salt received, after tested, the glycopeptide antibiotic derivative have good bacteriostatic activity, Neng Gouyong for endurance strain VRE
In the medicine for preparing treatment drug resistant bacterial infections.
Therefore, first purpose of the invention is to provide glycopeptide derivant shown in logical formula (I) and its pharmacy and can connect
The salt received：
Wherein, R1For H, 2- alkylamine-ethyl, the benzyl of substitution, the hydrocinnamoyl of substitution or the straight chain of carbon-carbon double key
Acyl group, the phenyl ring on the benzyl or hydrocinnamoyl is with halogen, hydroxyl, amino, dimethylamino, trifluoromethyl, or with halogen
The element phenyl ring that either hydroxyl or trifluoromethyl substitute；The straight chain acyl contains 1~6 carbon-to-carbon double bond；R2Can be OH, C1~
C5Straight chain amido, the C1~C5The end of straight chain amido can carry dimethylamino or substituted-phenyl, the phenyl ring of the substituted-phenyl
It is upper to carry halogen either cyano group or nitro.
Wherein, R is worked as1For H when, R2It is not OH.
In the present invention, the glycopeptide derivant shown in the logical formula (I) is preferably：R1For H, 2- (n-Decylamine base) second
Base, 3- bromobenzyls, 4- luorobenzyls, 4- hydroxybenzyls, 4- aminobenzyls, 4- dimethylamino benzyl, 4- trifluoromethyl benzyls, 3 '-
Bromo biphenyl methyl, 4 '-chlordiphenyl methyl, 4 '-hydroxybiphenylmethyl, 4 '-trifluoromethyl-biphenyl methyl or two dodecahexaene acyls
Base, 4- fluorobenzene propiono or 4- trifluoromethyl hydrocinnamoyls；R2For N ', N '-dimethylamine propylamine base, 4- fluorin benzyl amines base, 4- cyanogen
Base benzamido group or 4- nitrobenzene ethylamino-s.
In the present invention, described pharmaceutically acceptable salt be preferably alkali metal, alkaline-earth metal salt or with sour shape
Into salt.Wherein, described alkali metal is preferably sodium or potassium；Described alkaline-earth metal is preferably calcium or magnesium；Described acid
The preferably inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, amber
The organic acids such as acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid or methanesulfonic acid, aspartic acid or
The acidic amino acids such as glutamic acid.
The invention further relates to a kind of pharmaceutical composition, the above-mentioned glycopeptide class that the pharmaceutical composition includes therapeutically effective amount derives
Thing or its pharmaceutically acceptable salt and pharmaceutically acceptable carrier.In the present invention, described pharmaceutically acceptable load
Body refers to the conventional pharmaceutical carrier of pharmaceutical field, such as diluent, excipient (such as water), adhesive (such as cellulose derivative, bright
Glue, polyvinylpyrrolidone etc.), filler (such as starch), agent of bursting apart (such as calcium carbonate, sodium acid carbonate).Furthermore it is also possible to
Other adjuvants, such as flavouring agent and sweetener are added in composition.
The pharmaceutical composition of the present invention, can be by being injected intravenously, being subcutaneously injected or oral form puts on needs and controlled
The patient for the treatment of.For it is oral when, conventional solid pharmaceutical preparation such as tablet, pulvis or capsule etc. can be prepared into；During for injecting,
Parenteral solution can be prepared into.The various formulations of the pharmaceutical composition of the present invention can use the conventional method of medical domain to carry out
Prepare, wherein the content of active component is 0.1%~99.5% (weight ratio).In preparation, the weight of compound of the invention contains
Measure as 0.1~99.9%, preferable content is 0.5~90%.
The general dosage that aforementioned pharmaceutical compositions put on the patient for needing to treat is referred to vancomycin and goes first ten thousand
The existing dosage of ancient mycin, such as adult can be 0.1~2.0g/d, can specifically be changed according to the age of patient and state of an illness etc..
The compound of the present invention can be according to a conventional method into salt, such as hydrochloride is made.
Second object of the present invention is to provide above-mentioned general formula compound (I) preparation method.
In the present invention, described logical formula (I) compound can be made by following synthetic route：
Method one：Work as R12- alkylamines-ethyl or substituted benzyl, the phenyl ring on the benzyl with halogen, hydroxyl,
Amino, dimethylamino, trifluoromethyl, or with halogen either hydroxyl or trifluoromethyl substitution phenyl ring when,
Step A：By the compound shown in logical formula (II) and aldehyde and sodium cyanoborohydride (NaBH3CN) react, obtain formula
(III) compound shown in：
Step B：Compound shown in logical formula (III) is reacted in the presence of solvent and condensing agent with amine, obtains formula
(I) compound shown in；
Wherein, R2For C1~C5Straight chain amido, the C1~C5The end of straight chain amido can carry dimethylamino or substituted benzene
Base, with halogen either cyano group or nitro on the phenyl ring of the substituted-phenyl；
Wherein, R is worked as2For OH when, by the compound shown in logical formula (II) and aldehyde and sodium cyanoborohydride reaction, obtain formula
(I) compound shown in；
Or method two：Work as R1For H when, by the compound shown in logical formula (II) and amine in the presence of solvent and condensing agent it is anti-
Should, the compound shown in logical formula (I) is obtained,
Wherein, R2For C1~C5Straight chain amido, the C1~C5The end of straight chain amido can carry dimethylamino or substituted benzene
Base, with halogen either cyano group or nitro on the phenyl ring of the substituted-phenyl.
Or method three：Work as R1For substituted hydrocinnamoyl or the straight chain acyl of carbon-carbon double key, on the hydrocinnamoyl
Phenyl ring carries halogen or trifluoromethyl；When the straight chain acyl contains 1~6 carbon-to-carbon double bond,
Step A：Compound shown in logical formula (II) and O- acyl-hydroxysuccinimides active ester and triethylamine is anti-
Should, obtain the compound shown in logical formula (III)：
Step B：Compound shown in logical formula (III) is reacted in the presence of solvent and condensing agent with amine, obtains formula
(I) compound shown in；
Wherein, R2For C1~C5Straight chain amido, the C1~C5The end of straight chain amido can carry dimethylamino or substituted benzene
Base, with halogen either cyano group or nitro on the phenyl ring of the substituted-phenyl；
Wherein, R is worked as2For OH when, by the compound shown in logical formula (II) and active ester and triethylamine react, obtain formula
(I) compound shown in,
Further, described aldehyde is selected from 4 '-chlordiphenyl -4- formaldehyde, 4 '-xenol -4- formaldehyde, 4 '-trifluoromethyl
Biphenyl -4- formaldehyde, 3 '-bromo biphenyl -4- formaldehyde, N-Fmoc-2- (n-Decylamine base)-acetaldehyde, 3- bromobenzaldehydes, 4- trifluoromethylbenzenes
One kind in formaldehyde, 4- dimethylamino benzaldehyde, 4- fluorobenzaldehydes, 4- hydroxy benzaldehydes and 4- aminobenzaldehydes.
Further, described solvent is selected from dimethyl sulfoxide (DMSO) (DMSO), DMF (DMF), N- methyl
One or more in pyrrolidones (NMP), glycol dimethyl ether (DME), preferably one kind in DMSO, DMF and NMP or
A variety of, preferred solvent is DMSO；
Further, described condensing agent is selected from dicyclohexylcarbodiimide (DCC), 1- (3- dimethylamino-propyls) -3-
Ethyl-carbodiimide hydrochloride (EDCI), N, N '-DIC (DIC), N, N '-carbonyl dimidazoles (CDI), 2-
(7- azos BTA)-N, N, N ', N '-tetramethylurea hexafluorophosphoric acid ester (HATU), O- BTAs-N, N, N ', N '-four
TBTU (TBTU), 1H- BTAs -1- bases-oxygen tripyrrole alkyl hexafluorophosphate (PyBOP), preferably
Condensing agent is the one or more in HATU, TBTU and PyBOP, more preferably PyBOP.
Further, described amine is selected from N ', N '-dimethylamino propane diamine, 4- cyano group benzylamine, 4- fluorin benzyl amines and 4- nitros
One or more in phenyl ethylamine.
Further, described active ester is the dodecahexaene acyl-hydroxysuccinimides of O- bis- or O-4- fluorobenzene third
Acyl-hydroxysuccinimide or O-4- trifluoromethyls hydrocinnamoyl-HOSu NHS.
Third object of the present invention is to provide above-claimed cpd (I) answering in the medicine for preparing treatment bacterium infection
With.Preferably, the application the invention provides above-claimed cpd (I) in the medicine for preparing treatment drug resistant bacterial infections.
It is highly preferred that the invention provides above-claimed cpd (I) prepare treatment MRSA, MSSA, VSE, VRE, PSSP,
Application in PRSP infectious disease medicaments.
Most preferably, the invention provides above-claimed cpd (I) in treatment MRSA or VRE infectious disease medicaments are prepared
Application.
The beneficial effects of the present invention are the present invention as lead to formula (I) compound derivative and its pharmaceutically acceptable salt
Effect with good antibacterial action, especially antimicrobial agent, the exploitation for new antibacterials have great importance.
Brief description of the drawings
Fig. 1 is compound L YSC-10 Mass Spectrometric Identification collection of illustrative plates.
Fig. 2 is compound L YSC-10's1H-NMR identifies collection of illustrative plates.
Fig. 3 is compound L YSC-14 Mass Spectrometric Identification collection of illustrative plates.
Fig. 4 is compound L YSC-14's1H-NMR identifies collection of illustrative plates.
Fig. 5 is compound L YSC-38 Mass Spectrometric Identification collection of illustrative plates.
Fig. 6 is compound L YSC-38's1H-NMR identifies collection of illustrative plates.
Embodiment
Below in conjunction with specific embodiment, the present invention will be further described.It should be understood that following examples are merely to illustrate this
Invention is not for limitation the scope of the present invention.
In the present invention, following abbreviations have following meanings.Undefined abbreviation has its generally accepted implication, unless separately
Outer statement, all room temperatures refer both to 20 DEG C~30 DEG C of temperature.
The preparation method for the compound of setting out (II) being related in the present invention is special with reference to Chinese patent 200910053906.9
The record of sharp application documents, the present invention in other raw materials be commercially available.
In following examples, (Suzhou is purchased from using inverted polymer filler Uni PS25-300 and Uni PSA30-300
Na Wei Science and Technology Ltd.s) crude product obtained by synthesis is purified.Dissolving crude product is taken after methanol (or acetonitrile) aqueous solution, on
Sample to equipped with Uni PS25-300 or Uni PSA30-300 fillers glass chromatography column in, loading flow velocity be 1 times of column volume/
h.With methanol (or acetonitrile) aqueous solution prewashing 1h after end of the sample, then with methanol (or acetonitrile) aqueous solution elution containing TFA, wash
Separation of flow speed is 1.50 times of column volume/h.Start to collect eluent after 1 times of column volume of elution, obtained after eluent is concentrated and dried
The sterling of each sample.
In following examples, the elution solution and the percentage of pre- dilution that use are percent by volume, described
Yield refer to molar yield.The structure for each compound being related in following examples is as shown in table 1.
The structure of table 1, each compound
The synthesis of embodiment 1, compound L YSC-10
At room temperature, compound (II) (2.0g, 1.2mmol) is dissolved in 15mLDMSO, then add DIEA (0.4mL,
2.4mmol) and N ', N '-dimethylamino propane diamine (0.18mL, 1.4mmol), stir, then put into PyBOP (0.73g,
1.4mmol), finish, 1h is stirred to reaction solution at room temperature.
250mL acetone is added into above-mentioned reaction solution, stirring separates out insoluble matter, stands, and filters, filter cake successively with acetone and
Dichloromethane washs, and removes solvent.Purified using inverted polymer filler UniPS25-300, with the first containing 0.04%TFA
Alcohol-water (volume ratio 1: 4 of methanol and water) solution is eluted, and eluent is concentrated and dried, obtains white solid 0.66g.
After testing, the chromatographic purity of gained white solid is 97.1%, yield 31.8%.The mass spectrum of product and1H-NMR
Identify collection of illustrative plates referring to Fig. 1 and Fig. 2.
1H-NMR spectrum analysis：1H-NMR (600MHz, DMSO-d6)δ(ppm)：8.15 (7H), 7.78-6.69 (13H),
6.39 (1H), 5.64-5.36 (2H), 5.30-5.26 (3H), 5.26-5.15 (7H), 4.79-4.51 (4H), 4.48-4.24
(3H), 3.96-3.02 (13H), 2.80-2.64 (2H), 2.50-2.00 (17H), 1.79-0.91 (14H), 0.87-0.86
(6H)。
The synthesis of embodiment 2, compound L YSC-14
At room temperature, compound (II) (0.8g, 0.5mmol) is dissolved in 8mL DMF, then add DIEA (0.25mL,
1.5mmol) and 4- cyano group benzylamine (0.1g, 0.75mmol), stir, then put into TBTU (0.24g, 0.75mmol), add
Finish, 2h is stirred to reaction solution at room temperature.
100mL acetone is added into above-mentioned reaction solution, stirring separates out insoluble matter, stands, and filters, filter cake successively with acetone and
Dichloromethane washs, and removes solvent.Using inverted polymer filler Uni PS25-300 purify, with the methanol containing 0.03%TFA-
Water (volume ratio 2: 3 of methanol and water) solution is eluted, and eluent is concentrated and dried, obtains white solid 243mg.
After testing, the chromatographic purity of gained white solid is 96.3%, yield 28.3%.The mass spectrum of product and1H-NMR
Identify collection of illustrative plates referring to Fig. 3 and Fig. 4.
The synthesis of embodiment 3, compound L YSC-38
At room temperature, compound (II) (500mg, 0.3mmol) is dissolved in 10mlDMF- methanol (mixing of volume ratio 1: 1),
Then add 4 '-chlordiphenyl -4- formaldehyde (85mg, 0.4mmol), be stirred at reflux after 2h add sodium cyanoborohydride (40mg,
0.6mmol), continuing the 2h that flows back, depressurized after reaction solution cooling and boil off methanol, residue is poured into 50ml acetone and separates out insoluble matter,
Stand, filter, filter cake is washed with acetone and dichloromethane successively, is removed solvent, is obtained solid crude product.
Gained solid crude product is dissolved with 5mLDMSO, sequentially adds DIEA (0.1mL, 0.6mmol) and N ', N '-dimethylamine
Base propane diamine (0.046mL, 0.36mmol), stirs, then puts into PyBOP (0.2g, 0.36mmol), finishes, at room temperature
1h is stirred to reaction solution.50mL acetone is added into reaction solution, stirring separates out insoluble matter, stands, and filters, and filter cake uses acetone successively
Washed with dichloromethane, remove solvent.Purified using inverted polymer filler UniPSA25-300, with the second containing 0.04%TFA
Nitrile-water (volume ratio 1: 4 of acetonitrile and water) solution is eluted, and eluent is concentrated and dried, obtains white solid 82mg.
After testing, the chromatographic purity of gained white solid is 98.4%, yield 13.9%.The mass spectrum of product and1H-NMR
Identify collection of illustrative plates referring to Fig. 5 and Fig. 6.
The synthesis of embodiment 4, compound L YSC-35
4- cyano group benzylamines in embodiment 2 are replaced with into 4- fluorin benzyl amines, other operations obtain white solid with embodiment 2
200mg。
After testing, the chromatographic purity of gained white solid is 95.0%, yield 23.4%.
1H-NMR spectrum analysis：1H-NMR (600MHz, DMSO-d6)δ(ppm)：7.70-6.52 (19H), 6.29-5.40
(3H), 5.36-5.30 (3H), 5.24-5.02 (7H), 4.85-4.61 (3H), 4.60-4.50 (2H), 4.33-4.12 (5H),
4.00-3.55 (8H), 3.50-3.21 (6H), 3.00-2.00 (20H), 1.98-0.90 (12H), 0.90-0.82 (6H).
The synthesis of embodiment 5, compound L YSC-37
4 '-chlordiphenyl -4- formaldehyde in embodiment 3 is replaced with into N-Fmoc-2- (n-Decylamine base)-acetaldehyde, remaining synthesis
With embodiment 3, post-reaction treatment finishes, and obtains solid crude product for operation.Solid crude product is uniformly dispersed with 10ml DMF, is stirred at room temperature
Lower addition 1ml diethylamine, reaction solution are poured into 100ml acetone after being stirred at room temperature 1 hour and separate out insoluble matter, filter, acetone
Washing, subsequent purification are operated with embodiment 3, obtain white solid 160mg.
After testing, the chromatographic purity of gained white solid is 97.3%, yield 28.7%.
1H-NMR spectrum analysis：1H-NMR (600MHz, DMSO-d6)δ(ppm)：7.78-6.60 (11H), 6.51-5.32
(3H), 5.31-5.02 (10H), 5.00-4.69 (3H), 4.55-4.38 (5H), 4.26-4.10 (3H), 4.13-3.20 (16H),
3.15-2.04 (14H), 2.00-0.98 (25H), 0.96-0.86 (9H).
The synthesis of embodiment 6, compound L YSC-39
4 '-chlordiphenyl -4- formaldehyde in embodiment 3 is replaced with into 3- bromobenzaldehydes, other operations obtain white with embodiment 3
Color solid 120mg.
After testing, the chromatographic purity of gained white solid is 95.5%, yield 21.7%.
1H-NMR spectrum analysis：1H-NMR (600MHz, DMSO-d6)δ(ppm)：7.77-7.54 (6H), 7.42-7.21
(6H), 6.83-6.35 (5H), 5.54-5.51 (3H), 5.44-5.30 (4H), 5.28-5.00 (2H), 4.86-4.50 (6H),
4.49-3.20 (7H), 3.19-2.50 (8H), 2.30-2.21 (5H), 2.06-1.05 (21H), 0.87-0.85 (6H).
The synthesis of embodiment 7, compound L YSC-41
At room temperature, compound (II) (500mg, 0.3mmol) is dissolved in 10mlDMF- methanol (1: 1, v/v), adds 4-
Trifluoromethylated benzaldehyde (90mg, 0.5mmol), sodium cyanoborohydride (40mg, 0.6mmol) is added after being stirred at reflux 2h, is continued
Flow back 2h, is depressurized after reaction solution cooling and boils off methanol, and residue is poured into 50ml acetone and separates out insoluble matter, stands, and filters, filter cake
Washed successively with acetone and dichloromethane, remove solvent, obtain solid crude product.
Operation is isolated and purified with embodiment 3, obtains white solid 105mg.
After testing, the chromatographic purity of gained white solid is 96.0%, yield 20.0%.
1H-NMR spectrum analysis：1H-NMR (600MHz, DMSO-d6)δ(ppm)：7.88-7.20 (11H), 6.70-6.51
(4H), 6.48-6.33 (2H), 5.83-5.66 (1H), 5.60-5.23 (4H), 5.21-5.10 (2H), 5.00-4.80 (2H),
4.75-4.69 (3H), 4.65-4.33 (6H), 4.10-3.70 (5H), 3.54-3.00 (6H), 2.78-2.22 (4H), 2.00-
1.05 (10H), 0.87-0.80 (6H).
The synthesis of embodiment 8, compound L YSC-45
At room temperature, compound (II) (300mg, 0.2mmol) is dissolved in 3mL DMSO, adds the dodecahexaene acyls of O- bis-
Base HOSu NHS (0.15g, 0.3mmol) and triethylamine (0.07mL, 0.5mmol), are stirred overnight at room temperature, reaction solution
It is poured into 25ml acetone and separates out insoluble matter, stand, filter, filter cake is washed with acetone and dichloromethane successively, is removed solvent, is obtained
Solid crude product.
Operation is isolated and purified with embodiment 3, obtains white solid 110mg.
After testing, the chromatographic purity of gained white solid is 97.5%, yield 29.0%.
1H-NMR spectrum analysis：1H-NMR (600MHz, DMSO-d6)δ(ppm)：7.77-7.01 (10H), 7.00-6.66
(4H), 6.51-6.49 (3H), 6.38-6.15 (12H), 6.10-5.12 (10H), 5.00-4.63 (10H), 4.54-4.42
(2H), 4.40-4.16 (13H), 4.10-3.98 (6H), 3.74-2.78 (15H), 2.60-0.98 (4H), 0.90-0.78 (9H).
The synthesis of embodiment 9, compound L YSC-48
At room temperature, compound (II) (500mg, 0.3mmol) is dissolved in 5mL DMSO, adds the dodecahexaene acyls of O- bis-
Base HOSu NHS (0.2g, 0.45mmol) and triethylamine (0.1mL, 0.7mmol), are stirred overnight at room temperature, reaction solution
It is poured into 50ml acetone and separates out insoluble matter, stand, filter, filter cake is washed with acetone and dichloromethane successively, removes solvent.
Gained solid is dissolved with 5mLDMSO, sequentially add DIEA (0.15mL, 0.9mmol) and 4- fluorin benzyl amines (80mg,
0.6mmol), stir, then put into PyBOP (0.3g, 0.6mmol), finish and 1h is stirred at room temperature.
50mL acetone is added into reaction solution, stirring separates out insoluble matter, stands, and filters, and filter cake uses acetone and dichloro successively
Methane wash, remove solvent.Purified using inverted polymer filler Uni PSA25-300, with the aqueous acetonitrile containing 0.04%TFA
Liquid is eluted, and eluent is concentrated and dried, obtains white solid 82mg.
After testing, the chromatographic purity of gained white solid is 98.2%, yield 13.8%.
1H-NMR spectrum analysis：1H-NMR (600MHz, DMSO-d6)δ(ppm)：7.79-6.86 (8H), 6.60-6.55
(9H), 6.43-5.12 (15H), 5.10-5.02 (11H), 4.98-4.48 (14H), 4.45-4.20 (15H), 4.16-4.05
(6H), 3.66-2.21 (18H), 2.11-0.98 (6H), 0.86-0.75 (9H).
The synthesis of embodiment 10, compound L YSC-59
4 '-chlordiphenyl -4- formaldehyde in embodiment 3 is replaced with into 4- dimethylamino benzaldehydes, N ', N '-dimethylamino third
Diamines replaces with 4- cyano group benzylamines, and other operations obtain white solid 96mg with embodiment 3.
After testing, the chromatographic purity of gained white solid is 95.5%, yield 21.7%.
1H-NMR spectrum analysis：1H-NMR (600MHz, DMSO-d6)δ(ppm)：7.86-7.77 (3H), 7.60-7.50
(3H), 7.48-7.10 (9H), 7.03-6.33 (13H), 5.55-5.45 (2H), 5.40-5.34 (6H), 5.30-5.28 (1H),
5.28-5.00 (4H), 4.97-4.71 (4H), 4.69-4.57 (8H), 4.50-4.04 (6H), 4.00-3.55 (8H), 3.46-
2.43 (18H), 2.36-1.05 (6H), 0.87-0.85 (6H).
The synthesis of embodiment 11, compound L YSC-68
4 '-chlordiphenyl -4- formaldehyde is replaced with into 3 '-bromo biphenyl -4- formaldehyde, N ', N '-dimethylamino propane diamine replaces with 4-
Fluorin benzyl amine, other operations obtain white solid 100mg with embodiment 3.
After testing, the chromatographic purity of gained white solid is 96.8%, yield 17.2%.
1H-NMR spectrum analysis：1H-NMR (600MHz, DMSO-d6)δ(ppm)：7.80-7.26 (20H), 6.83-6.66
(4H), 6.54-6.11 (3H), 5.86-5.56 (3H), 5.50-5.35 (7H), 5.20-4.86 (5H), 4.80-4.51 (4H),
4.43-4.33 (1H), 4.30-4.14 (3H), 4.00-3.76 (4H), 3.63-3.43 (2H), 3.10-2.80 (6H), 2.31-
1.86 (4H), 1.78-1.18 (13H), 0.88-0.80 (6H).
The synthesis of embodiment 12, compound L YSC-73
At room temperature, compound (II) (1.6g, 1.0mmol) is dissolved in 16ml DMF- methanol (mixing of volume ratio 1: 1),
Then 3- bromobenzaldehydes (0.24g, 1.3mmol) are added, are stirred at reflux 2h, standing is cooled to room temperature, adds sodium cyanoborohydride
(0.17g, 2.0mmol), 2h is stirred at room temperature, decompression boils off methanol, and stirring is lower toward addition 100ml methyl tertbutyls in residue
Ether, insoluble matter is separated out, stand, filter, filter cake is washed with acetone and dichloromethane successively, is removed solvent, is obtained solid crude product.
Gained solid crude product 5mL DMSO are dissolved, sequentially add DIEA (0.5mL, 3.0mmol) and 4- cyano group benzylamines
Hydrochloride (0.34g, 2.0mmol), stirs, then puts into PyBOP (1.6g, 3.0mmol), finishes, stirs 2h at room temperature.It is past
100mL acetone is added in reaction solution, stirring separates out insoluble matter, stands, filters, and filter cake is washed with acetone and dichloromethane successively,
Remove solvent.Purified using inverted polymer filler Uni PSA25-300, with acetonitrile-water (acetonitrile and water containing 0.04%TFA
Volume ratio 1: 4) solution elute, eluent is concentrated and dried, obtains white solid 0.66g.
After testing, the chromatographic purity of gained white solid is 97.0%, yield 35.3%.
1H-NMR spectrum analysis：1H-NMR (600MHz, DMSO-d6+D2O)δ(ppm)：8.50-8.15 (8H), 7.83-
7.50 (11H), 7.21-6.77 (3H), 5.65-5.25 (5H), 5.20-4.86 (3H), 4.77-4.44 (5H), 4.30-4.19
(2H), 4.01-3.86 (6H), 3.70-3.23 (7H), 3.22-3.08 (5H), 2.90-2.40 (8H), 2.33-2.00 (6H),
2.00-1.68 (7H), 1.50-1.30 (2H), 1.30-1.02 (3H), 0.95-0.70 (6H).
The synthesis of embodiment 13, compound L YSC-44
At room temperature, compound (II) (1.6g, 1.0mmol) is dissolved in 20ml DMF- methanol (mixing of volume ratio 1: 1),
Then 4- trifluoromethylated benzaldehydes (0.23g, 1.3mmol) are added, are stirred at reflux 2h, standing is cooled to room temperature, adds cyano group boron
Sodium hydride (0.17g, 2.0mmol), 2h is stirred at room temperature, decompression boils off methanol, and stirring is lower toward addition 100ml methyl- terts in residue
Butyl ether, insoluble matter is separated out, stand, filter, filter cake is washed with acetone and dichloromethane successively, is removed solvent, is obtained solids crude
Product.
Gained solid crude product 5mL DMSO are dissolved, sequentially add DIEA (0.5mL, 3.0mmol) and 4- fluorin benzyl amines
(0.25g, 2.0mmol), stirs, then puts into PyBOP (1.6g, 3.0mmol), finishes, stirs 2h at room temperature.Toward reaction solution
Middle addition 100mL acetone, stirring separate out insoluble matter, stand, filter, and filter cake is washed with acetone and dichloromethane successively, is removed molten
Agent.Purified using inverted polymer filler Uni PSA25-300, with the acetonitrile-water (volume of acetonitrile and water containing 0.04%TFA
Than 1: 4) solution is eluted, and eluent is concentrated and dried, obtains white solid 0.58g.
After testing, the chromatographic purity of gained white solid is 96.7%, yield 31.3%.
1H-NMR spectrum analysis：1H-NMR (600MHz, DMSO-d6+D2O)δ(ppm)：8.23-7.84 (7H), 7.61-
7.21 (8H), 7.12-6.97 (5H), 5.78-5.37 (4H), 5.36-5.00 (5H), 4.89-4.64 (6H), 4.54-4.11
(3H), 4.10-3.82 (6H), 3.81-3.23 (5H), 3.22-3.00 (3H), 2.99-2.50 (6H), 2.43-2.04 (6H),
2.00-1.30 (4H), 1.28-1.00 (2H), 0.89-0.80 (6H).
The synthesis of embodiment 14, compound L YSC-69
At room temperature, compound (II) (2.0g, 1.1mmol) is dissolved in 10ml DMF- methanol (mixing of volume ratio 1: 1),
Then N-Fmoc-2- (n-Decylamine base)-acetaldehyde (0.46g, 1.1mmol) is added, 2h is stirred at room temperature, adds sodium cyanoborohydride
(0.19g, 2.2mmol), continue to stir 2h, decompression boils off methanol, and stirring is lower toward addition 150ml methyl tertbutyls in residue
Ether, insoluble matter is separated out, stand, filter, filter cake is washed with acetone and dichloromethane successively, is removed solvent, is obtained solid crude product.
Gained solid crude product 10mL NMP are dissolved, sequentially add DIEA (0.4mL, 2.2mmol) and 4- cyano group benzylamines
Hydrochloride (0.4g, 2.2mmol), stirs, then puts into PyBOP (0.6g, 1.1mmol), stirs 3h at room temperature, adds
3mL diethylamine, stir 2h.150mL acetone is added into reaction solution, stirring separates out insoluble matter, stands, filters, filter cake is used successively
Acetone and dichloromethane washing, remove solvent.Purified using inverted polymer filler Uni PSA25-300, with containing 0.04%TFA
Acetonitrile-water (volume ratio 1: 4 of acetonitrile and water) solution elution, eluent is concentrated and dried, obtains white solid 0.56g.
After testing, the chromatographic purity of gained white solid is 96.0%, yield 27.0%.
1H-NMR spectrum analysis：1H-NMR (600MHz, DMSO-d6+D2O)δ(ppm)：7.50-6.77 (16H), 5.65-
5.22 (5H), 5.31-5.02 (4H), 5.00-4.87 (3H), 4.75-4.31 (7H), 4.20-4.00 (8H), 3.91-3.12
(18H), 3.10-2.03 (15H), 2.02-1.00 (23H), 0.97-0.80 (9H).
The synthesis of embodiment 15, compound L YSC-52
At room temperature, compound (II) (1.6g, 1.0mmol) is dissolved in 16ml DMF- methanol (mixing of volume ratio 1: 1),
Then 4- hydroxy benzaldehydes (0.16g, 1.3mmol) are added, are stirred at reflux 2h, standing is cooled to room temperature, adds cyano group hydroboration
Sodium (0.26g, 3.0mmol), 2h is stirred at room temperature, decompression boils off methanol, and stirring is lower toward addition 100ml methyl tertbutyls in residue
Ether, insoluble matter is separated out, stand, filter, filter cake is washed with acetone and dichloromethane successively, is removed solvent, is obtained solid crude product.
Gained solid crude product 5mL DMSO are dissolved, sequentially add DIEA (0.5mL, 3.0mmol) and 4- fluorin benzyl amines
(0.25g, 2.0mmol), stirs, then puts into PyBOP (1.6g, 3.0mmol), finishes, stirs 2h at room temperature.Toward reaction solution
Middle addition 100mL acetone, stirring separate out insoluble matter, stand, filter, and filter cake is washed with acetone and dichloromethane successively, is removed molten
Agent.Purified using inverted polymer filler Uni PSA25-300, with the acetonitrile-water (volume of acetonitrile and water containing 0.04%TFA
Than 1: 4) solution is eluted, and eluent is concentrated and dried, obtains white solid 0.52g.
After testing, the chromatographic purity of gained white solid is 96.7%, yield 28.8%.
1H-NMR spectrum analysis：1H-NMR (600MHz, DMSO-d6+D2O)δ(ppm)：7.56-7.02 (20H), 5.49-
5.30 (6H), 5.26-5.03 (3H), 5.00-4.05 (9H), 3.89-3.61 (5H), 3.57-3.04 (4H), 3.00-2.69
(8H), 2.33-2.00 (4H), 1.98-1.30 (6H), 1.29-1.01 (6H), 1.00-0.90 (6H).
The synthesis of embodiment 16, compound L YSC-64
At room temperature, compound (II) (1.6g, 1.0mmol) is dissolved in 30ml DMF- methanol (mixing of volume ratio 1: 1),
Then 4 '-xenol -4- formaldehyde (0.4g, 2.0mmol) is added, is stirred at reflux 2h, standing is cooled to room temperature, adds cyano group boron
Sodium hydride (0.17g, 2.0mmol), 2h is stirred at room temperature, decompression boils off methanol, and stirring is lower toward addition 150ml methyl- terts in residue
Butyl ether, insoluble matter is separated out, stand, filter, filter cake is washed with acetone and dichloromethane successively, is removed solvent, is obtained solids crude
Product.
Gained solid crude product 5mL DMSO are dissolved, sequentially add DIEA (0.5mL, 3.0mmol) and 4- fluorin benzyl amines
(0.25g, 2.0mmol), stirs, then puts into PyBOP (1.6g, 3.0mmol), finishes, stirs 2h at room temperature.Toward reaction solution
Middle addition 150mL acetone, stirring separate out insoluble matter, stand, filter, and filter cake is washed with acetone and dichloromethane successively, is removed molten
Agent.Purified using inverted polymer filler Uni PSA25-300, with the acetonitrile-water (volume of acetonitrile and water containing 0.04%TFA
Than 1: 4) solution is eluted, and eluent is concentrated and dried, obtains white solid 0.6g.
After testing, the chromatographic purity of gained white solid is 97.3%, yield 31.9%.
1H-NMR spectrum analysis：1H-NMR (600MHz, DMSO-d6+D2O)δ(ppm)：8.10-7.37 (15H), 7.30-
7.00 (9H), 5.58-5.37 (3H), 5.36-5.00 (6H), 5.00-4.06 (9H), 3.89-3.82 (2H), 3.81-3.46
(6H), 3.33-3.05 (3H), 3.00-2.72 (5H), 2.63-2.02 (7H), 2.01-1.60 (7H), 1.58-1.00 (5H),
0.88-0.70(6H)。
The synthesis of embodiment 17, compound L YSC-67
At room temperature, compound (II) (500mg, 0.3mmol) is dissolved in 10ml DMF- methanol (mixing of volume ratio 1: 1),
Then 3 '-bromo biphenyl -4- formaldehyde (157mg, 0.6mmol) and sodium cyanoborohydride (12mg, 0.3mmol) are added, room temperature is stirred
Mix 2h, decompression boils off methanol, adds 50ml acetone inward, and stirring separates out insoluble matter, stands, filters, filter cake successively with acetone and
Dichloromethane washs, and removes solvent, obtains solid crude product.
Gained solid crude product is dissolved with 5mLDMF, sequentially adds DIEA (0.2mL, 1.2mmol) and 4- cyanobenzyamine of derivative
Hydrochlorate (0.1g, 0.6mmol), stirs, then puts into TBTU (193mg, 0.6mmol), stirs 1h at room temperature.Into reaction solution
50mL acetone is added, stirring separates out insoluble matter, stands, filters, and filter cake is washed with acetone and dichloromethane successively, removes solvent.
Using inverted polymer filler Uni PSA25-300 purify, with containing 0.04%TFA acetonitrile-water (volume ratio 1 of acetonitrile and water:
4) solution is eluted, and eluent is concentrated and dried, obtains white solid 100mg.
After testing, the chromatographic purity of gained white solid is 96.5%, yield 17.1%.
1H-NMR spectrum analysis：1H-NMR (600MHz, DMSO-d6+D2O)δ(ppm)：8.00-7.65 (12H), 7.60-
7.13 (12H), 5.55-5.34 (5H), 5.32-5.12 (2H), 5.11-5.03 (2H), 5.01-4.71 (4H), 4.70-4.00
(5H), 3.89-3.63 (3H), 3.60-3.33 (5H), 3.30-3.20 (1H), 3.14-2.88 (6H), 2.80-2.13 (5H),
2.10-1.78 (8H), 1.77-1.03 (4H), 0.80-0.70 (6H).
The synthesis of embodiment 18, compound L YSC-76
At room temperature, compound (II) (1.6g, 1.0mmol) is dissolved in 20ml DMF- methanol (mixing of volume ratio 1: 1),
Then 4- fluorobenzaldehydes (0.16g, 1.3mmol) are added, are stirred at reflux 2h, standing is cooled to room temperature, adds sodium cyanoborohydride
(0.17g, 2.0mmol), 2h is stirred at room temperature, decompression boils off methanol, and stirring is lower toward addition 100ml methyl tertbutyls in residue
Ether, insoluble matter is separated out, stand, filter, filter cake is washed with acetone and dichloromethane successively, is removed solvent, is obtained solid crude product.
Gained solid crude product 5mL DMSO are dissolved, sequentially add DIEA (0.5mL, 3.0mmol) and N ', N '-diformazan
Amido propane diamine (0.25mL, 2.0mmol), stirs, then puts into PyBOP (1.6g, 3.0mmol), stirs 2h at room temperature.It is past
100mL acetone is added in reaction solution, stirring separates out insoluble matter, stands, filters, and filter cake is washed with acetone and dichloromethane successively,
Remove solvent.Purified using inverted polymer filler Uni PSA25-300, with acetonitrile-water (acetonitrile and water containing 0.04%TFA
Volume ratio 1: 4) solution elute, eluent is concentrated and dried, obtains white solid 0.52g.
After testing, the chromatographic purity of gained white solid is 97.0%, yield 29.2%.
1H-NMR spectrum analysis：1H-NMR (600MHz, DMSO-d6+D2O)δ(ppm)：8.43-8.10 (5H), 7.75-
7.00 (8H), 6.89-6.43 (3H), 5.88-5.35 (6H), 5.30-5.00 (3H), 4.82-4.57 (3H), 4.50-4.19
(4H), 4.04-3.71 (5H), 3.61-3.44 (5H), 3.40-3.12 (8H), 3.11-3.02 (2H), 2.98-2.61 (6H),
2.50-2.14 (11H), 2.13-2.10 (3H), 2.08-1.88 (7H), 1.80-1.43 (5H), 1.30-1.03 (2H), 0.95-
0.70(6H)。
The synthesis of embodiment 19, compound L YSC-79
At room temperature, compound (II) (1.6g, 1.0mmol) is dissolved in 10mL DMSO, then add DIEA (0.8mL,
5mmol) and 4- nitros phenethylamine hydrochloride (0.4g, 2.0mmol), stir, then put into PyBOP (1.6g,
3.0mmol), 2h is stirred at room temperature, 100mL acetone is added into above-mentioned reaction solution, stirring separates out white insoluble matter, stands, filters,
Filter cake is washed with acetone and dichloromethane successively, removes solvent.Using inverted polymer filler UniPS25-300 purify, with containing
Methanol-water (volume ratio 1: 4 of the methanol and water) solution for having 0.04%TFA is eluted, and eluent is concentrated and dried, and it is solid to obtain white
Body 0.74g.
After testing, the chromatographic purity of gained white solid is 97.0%, yield 42.6%.
1H-NMR spectrum analysis：1H-NMR (600MHz, DMSO-d6+D2O)δ(ppm)：8.44-7.73 (4H), 7.70-
7.10 (12H), 5.84-5.55 (6H), 5.43-5.05 (3H), 4.99-4.74 (3H), 4.66-4.21 (4H), 4.10-3.42
(6H), 3.30-3.13 (3H), 3.00-2.08 (14H), 1.90-1.03 (12H), 1.00-0.90 (6H)
The synthesis of embodiment 20, compound L YSC-84
At room temperature, compound (II) (2.0g, 1.1mmol) is dissolved in 10mL DMSO, adds O- to trifluoromethyl phenylpropyl alcohol
Acyl group HOSu NHS (0.52g, 1.6mmol) and triethylamine (0.4mL, 2.7mmol), 70 DEG C of stirring 2h, toward reaction
The stirring of 150ml acetone is added in liquid and separates out white insoluble matter, stands, filter, filter cake is washed with acetone and dichloromethane, removed successively
Solvent is removed, obtains solid crude product, is dissolved with 10mL DMSO, sequentially adds DIEA (0.4mL, 2.2mmol) and N ', N '-dimethylamine
Base propane diamine (0.27mL, 2.2mmol), stirs, then puts into PyBOP (1.8g, 3.3mmol), stirs 3h at room temperature.Toward instead
Addition 150mL acetone in liquid is answered, stirring separates out insoluble matter, stands, filters, filter cake is washed with acetone and dichloromethane, removed successively
Remove solvent.Purified using inverted polymer filler Uni PSA25-300, with the acetonitrile-water containing 0.04%TFA (acetonitrile and water
Volume ratio 1: 4) solution is eluted, and eluent is concentrated and dried, obtains white solid 0.56g.
After testing, the chromatographic purity of gained white solid is 96.0%, yield 27.2%.
1H-NMR spectrum analysis：1H-NMR (600MHz, DMSO-d6+D2O)δ(ppm)：8.02-7.56 (6H), 7.40-
7.00 (10H), 5.71-5.45 (2H), 5.40-5.14 (6H), 5.10-4.84 (6H), 4.83-4.50 (4H), 4.44-4.32
(2H), 4.20-4.10 (1H), 4.07-3.35 (8H), 3.34-3.05 (9H), 3.02-2.62 (5H), 2.33-2.00 (6H),
1.99-1.58 (4H), 1.37-1.00 (6H), 0.95-0.78 (6H).
The synthesis of embodiment 21, compound L YSC-86
At room temperature, compound (II) (2.0g, 1.1mmol) is dissolved in 10mL DMSO, adds O- to trifluoromethyl phenylpropyl alcohol
Acyl group HOSu NHS (0.52g, 1.6mmol) and triethylamine (0.4mL, 2.7mmol), 70 DEG C of stirring 2h, toward reaction
The stirring of 150ml acetone is added in liquid and separates out white insoluble matter, stands, filter, filter cake is washed with acetone and dichloromethane, removed successively
Solvent is removed, obtains solid crude product, is dissolved with 10mL DMSO, sequentially adds DIEA (0.4mL, 2.2mmol) and 4- nitro phenyl ethylamines
Hydrochloride (0.44g, 2.2mmol), stirs, then puts into PyBOP (1.8g, 3.3mmol), stirs 3h at room temperature.Toward reaction
150mL acetone is added in liquid, stirring separates out insoluble matter, stands, filters, and filter cake is washed with acetone and dichloromethane successively, is removed
Solvent.Purified using inverted polymer filler Uni PSA25-300, with the acetonitrile-water (body of acetonitrile and water containing 0.04%TFA
Product ratio 1: 4) solution is eluted, and eluent is concentrated and dried, obtains white solid 0.48g.
After testing, the chromatographic purity of gained white solid is 96.0%, yield 22.5%.
1H-NMR spectrum analysis：1H-NMR (600MHz, DMSO-d6+D2O)δ(ppm)：8.54-7.40 (8H), 7.40-
7.12 (8H), 7.10-6.87 (4H), 5.50-5.45 (1H), 5.40-5.10 (6H), 5.06-4.77 (5H), 4.55-4.24
(4H), 4.24-4.13 (3H), 4.07-3.65 (8H), 3.50-3.00 (7H), 2.98-2.62 (7H), 2.33-2.07 (5H),
2.02-1.58 (5H), 1.37-1.00 (6H), 0.95-0.78 (6H).
The synthesis of embodiment 22, compound L YSC-88
At room temperature, compound (II) (2.0g, 1.1mmol) is dissolved in 10mL DMSO, adds O- to fluorobenzene propiono hydroxyl
Base succinimide (0.44g, 1.6mmol) and triethylamine (0.4mL, 2.7mmol), 70 DEG C of stirring 2h, add into reaction solution
Enter the stirring of 150ml acetone and separate out white insoluble matter, stand, filter, filter cake is washed with acetone and dichloromethane successively, is removed molten
Agent, solid crude product is obtained, dissolved with 10mLDMSO, sequentially add DIEA (0.4mL, 2.2mmol) and 4- nitrobenzene ethamine hydrochloric acid
Salt (0.44g, 2.2mmol), stirs, then puts into PyBOP (1.8g, 3.3mmol), stirs 3h at room temperature.Into reaction solution
150mL acetone is added, stirring separates out insoluble matter, stands, filters, and filter cake is washed with acetone and dichloromethane successively, removes solvent.
Using inverted polymer filler Uni PSA25-300 purify, with containing 0.04%TFA acetonitrile-water (volume ratio 1 of acetonitrile and water:
4) solution is eluted, and eluent is concentrated and dried, obtains white solid 0.4g.
After testing, the chromatographic purity of gained white solid is 96.7%, yield 19.3%.
1H-NMR spectrum analysis：1H-NMR (600MHz, DMSO-d6+D2O)δ(ppm)：8.00-7.00 (10H), 7.40-
7.33 (4H), 5.58-5.05 (9H), 4.88-4.51 (5H), 4.45-4.22 (4H), 4.20-4.10 (3H), 4.07-3.11
(8H), 3.10-2.85 (7H), 2.66-2.07 (11H), 2.06-1.74 (7H), 1.73-1.00 (5H), 0.80-0.78 (6H).
The synthesis of embodiment 23, compound L YSC-89
At room temperature, compound (II) (2.0g, 1.1mmol) is dissolved in 10mL DMSO, adds O- to fluorobenzene propiono hydroxyl
Base succinimide (0.44g, 1.6mmol) and triethylamine (0.4mL, 2.7mmol), 70 DEG C of stirring 2h, add into reaction solution
Enter the stirring of 150ml acetone and separate out white insoluble matter, stand, filter, filter cake is washed with acetone and dichloromethane successively, is removed molten
Agent, obtain solid crude product, dissolved with 10mL DMSO, sequentially add DIEA (0.4mL, 2.2mmol) and 4- fluorin benzyl amines (0.24g,
2.2mmol), stir, then put into PyBOP (1.8g, 3.3mmol), stir 3h at room temperature.150mL is added into reaction solution
Acetone, stirring separate out insoluble matter, stand, filter, and filter cake is washed with acetone and dichloromethane successively, removes solvent.Using anti-phase
Polymer filler Uni PSA25-300 are purified, and are washed with acetonitrile-water (volume ratio 1: 4 of acetonitrile and water) solution containing 0.04%TFA
It is de-, eluent is concentrated and dried, obtains white solid 0.56g.
After testing, the chromatographic purity of gained white solid is 97.8%, yield 27.5%.
1H-NMR spectrum analysis：1H-NMR (600MHz, DMSO-d6+D2O)δ(ppm)：8.40-8.10 (8H), 7.81-
7.65 (12H), 5.65-5.25 (5H), 5.20-4.86 (3H), 4.77-4.44 (5H), 4.30-4.19 (2H), 4.01-3.86
(6H), 3.70-3.23 (7H), 3.22-3.08 (5H), 2.90-2.40 (8H), 2.33-2.00 (6H), 2.00-1.68 (7H),
1.50-1.30 (2H), 1.30-1.02 (3H), 0.95-0.70 (6H).
The synthesis of embodiment 24, compound L YSC-92
At room temperature, compound (II) (2.0g, 1.1mmol) is dissolved in 20ml DMF- methanol (1: 1, v/v), and addition 4 '-
Trifluoromethyl-biphenyl -4- formaldehyde (0.4g, 1.4mmol), 2h is stirred at reflux, standing is cooled to room temperature, adds sodium cyanoborohydride
(0.2g, 2.2mmol), 2h being stirred at room temperature, decompression boils off methanol, and stirring adds 100ml methyl tertiary butyl ether(MTBE)s in descending toward residue,
White insoluble matter is separated out, stands, filter, filter cake is washed with acetone and dichloromethane successively, is removed solvent, is obtained solid crude product,
Dissolved with 10mL DMSO, sequentially add DIEA (0.4mL, 2.2mmol) and 4- nitros phenethylamine hydrochloride (0.44g,
2.2mmol), stir, then put into PyBOP (1.8g, 3.3mmol), stir 3h at room temperature.150mL is added into reaction solution
Acetone, stirring separate out insoluble matter, stand, filter, and filter cake is washed with acetone and dichloromethane successively, removes solvent.Using anti-phase
Polymer filler Uni PSA25-300 are purified, and are washed with acetonitrile-water (volume ratio 1: 4 of acetonitrile and water) solution containing 0.04%TFA
It is de-, eluent is concentrated and dried, obtains white solid 0.5g.
After testing, the chromatographic purity of gained white solid is 97.0%, yield 23.0%.
1H-NMR spectrum analysis：1H-NMR (600MHz, DMSO-d6+D2O)δ(ppm)：8.50-8.05 (7H), 8.00-
7.32 (10H), 7.20-7.05 (7H), 6.53-6.46 (3H), 6.03-5.68 (3H), 5.50-5.02 (3H), 4.90-4.87
(1H), 4.84-4.52 (6H), 3.97-3.74 (4H), 3.55-3.17 (5H), 3.10-2.76 (7H), 2.70-2.30 (4H),
2.25-2.03 (1H), 2.05-1.13 (12H), 0.84-0.75 (6H).
Embodiment 25, into salt test one
100mg compound Ls YSC-35 is put into 5.0mL saturation hydrogen chloride methanol solutions, is stirred at room temperature 10 minutes, is depressurized
It is evaporated, adds the stirring of 30mL acetone inward, filters, removes solvent, obtain compound L YSC-35 hydrochloride salt as white solid
100mg, Cl elementary analysis：Theoretical value 9.80%, measured value 9.82%.
In addition, respectively with hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, butanedioic acid, richness
Horse acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, aspartic acid or glutamic acid replace above-mentioned
Hydrogen chloride in saturation hydrogen chloride methanol solution, obtain corresponding salt.
Embodiment 26, into salt test two
50mg compound Ls YSC-68 is put into 1mL saturation hydrogen chloride methanol solutions, is stirred at room temperature, evaporated under reduced pressure, inward
The stirring of 10mL acetone is added, is filtered, removes solvent, obtains compound L YSC-68 hydrochloride salt as white solid 50mg, Cl element point
Analysis：Theoretical value 5.37%, measured value 5.40%.
In addition, respectively with hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, butanedioic acid, richness
Horse acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, aspartic acid or glutamic acid replace above-mentioned
Hydrogen chloride in saturation hydrogen chloride methanol solution, obtain corresponding salt.
Embodiment 27, into salt test three
2mL methanol is added into 100mg compound Ls YSC-37, pH value is adjusted to 8~9 with 1mol/LNaOH solution, decompression
Methanol is evaporated off, adds the stirring of 10mL acetone inward, filters, remove solvent, obtain compound L YSC-37 sodium salt white solid
100mg。
The pharmaceutically acceptable salt of the glycopeptide derivant of the present invention is alternatively potassium or other alkali metal salts and calcium, magnesium etc.
The salt of alkaline-earth metal.
The Antibacterial Activity of embodiment 28, compound
In Vitro Bacteriostatic measure is carried out to the compound in table 1 and its pharmaceutically acceptable salt, read minimum antibacterial dense
Angle value (MIC), assay method reference《Pharmacopoeia of People's Republic of China》The method provided in (version in 2015).MRSA detects fungus strain
Purchased from ATCC, VRE detection fungus strains are clinically separated antibody-resistant bacterium 07-W3-45 to be derived from Shanghai Huashan Hospital, with vancomycin hydrochloride
It is comparison medicine with initial compounds (II), comparative test result is as shown in table 2.
MIC (μ g/mL) of each compound to MRSA and VRE in table 2, table 1
From the testing result of table 2, compared with vancomycin hydrochloride, compound and its pharmacy prepared by the present invention can connect
The salt received has good bacteriostatic activity for MRSA and VRE endurance strains；Compared with compound of setting out (II), present invention system
Standby compound and its pharmaceutically acceptable salt significantly improve for VRE bacteriostatic activity, can be applied to prepare treatment bacterium
Infection and the medicine of drug resistant bacterial infections.
The specific embodiment of the present invention is described in detail above, but it is only used as example, and the present invention is not intended to limit
In particular embodiments described above.To those skilled in the art, it is any to the invention carry out equivalent modifications and replace
In generation, is also all among scope of the invention.Therefore, the impartial conversion made without departing from the spirit and scope of the invention and repair
Change, all should be contained within the scope of the invention.
Claims (15)
1. glycopeptide derivant and its pharmaceutically acceptable salt shown in logical formula (I)：
Wherein, R1For H, 2- alkylamine-ethyl, substitution benzyl, substitution hydrocinnamoyl or carbon-carbon double key straight chain acyl,
Phenyl ring on the benzyl or hydrocinnamoyl with halogen, hydroxyl, amino, dimethylamino, trifluoromethyl, or with halogen or
Hydroxyl or the phenyl ring of trifluoromethyl substitution；The straight chain acyl contains 1~6 carbon-to-carbon double bond；R2For C1~C5Straight chain amido,
The C1~C5The end of straight chain amido carries dimethylamino or substituted-phenyl, on the phenyl ring of the substituted-phenyl with halogen or
Person's cyano group or nitro.
2. glycopeptide derivant as claimed in claim 1 and its pharmaceutically acceptable salt, it is characterised in that R1For H, 2- (positive last of the ten Heavenly stems
Amido) ethyl, 3- bromobenzyls, 4- luorobenzyls, 4- hydroxybenzyls, 4- aminobenzyls, 4- dimethylamino benzyl, 4- trifluoromethyl benzyls
Base, 3 '-bromo biphenyl methyl, 4 '-chlordiphenyl methyl, 4 '-hydroxybiphenylmethyl, 4 '-trifluoromethyl-biphenyl methyl or 22 carbon
Six enoyl-s, 4- fluorobenzene propiono or 4- trifluoromethyl hydrocinnamoyls；R2For N ', N '-dimethylamine propylamine base, 4- fluorin benzyl amines
Base, 4- cyano group benzamido group or 4- nitrobenzene ethylamino-s.
3. glycopeptide derivant as claimed in claim 1 and its pharmaceutically acceptable salt, it is characterised in that it is described pharmaceutically
Acceptable salt is alkali metal, the salt of alkaline-earth metal or the salt with acid formation.
4. glycopeptide derivant as claimed in claim 3 and its pharmaceutically acceptable salt, it is characterised in that described alkali metal
For sodium or potassium；Described alkaline-earth metal is calcium or magnesium；Described acid is hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, second
Acid, propionic acid, oxalic acid, malonic acid, butanedioic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, first
Sulfonic acid, aspartic acid or glutamic acid.
5. such as preparation method of glycopeptide derivant according to any one of claims 1 to 4 and its pharmaceutically acceptable salt, its
It is characterised by, methods described includes：
Method one：Work as R12- alkylamines-ethyl or substituted benzyl, the phenyl ring on the benzyl with halogen, hydroxyl, amino,
Dimethylamino, trifluoromethyl, or with halogen either hydroxyl or trifluoromethyl substitution phenyl ring when,
Step A：By the compound shown in logical formula (II) and aldehyde and sodium cyanoborohydride reaction, the change shown in logical formula (III) is obtained
Compound：
Step B：Compound shown in logical formula (III) is reacted in the presence of solvent and condensing agent with amine, obtains logical formula (I) institute
The compound shown；
Wherein, R2For C1~C5 straight chain amidos, the end of C1~C5 straight chains amido carries dimethylamino or substituted-phenyl, institute
State and halogen either cyano group or nitro are carried on the phenyl ring of substituted-phenyl；
Or method two：Work as R1For H when, the compound shown in logical formula (II) is reacted in the presence of solvent and condensing agent with amine, obtained
Obtain the compound shown in logical formula (I)：
Wherein, R2For C1~C5 straight chain amidos, the end of C1~C5 straight chains amido carries dimethylamino or substituted-phenyl, institute
State and halogen either cyano group or nitro are carried on the phenyl ring of substituted-phenyl；
Or method three：Work as R1For substituted hydrocinnamoyl or the straight chain acyl of carbon-carbon double key, the phenyl ring on the hydrocinnamoyl
With halogen or trifluoromethyl；When the straight chain acyl contains 1~6 carbon-to-carbon double bond,
Step A：By the compound shown in logical formula (II) and O- acyl-hydroxysuccinimides active ester and triethylamine react, obtain
Obtain the compound shown in logical formula (III)：
Step B：Compound shown in logical formula (III) is reacted in the presence of solvent and condensing agent with amine, obtains logical formula (I) institute
The compound shown；
Wherein, R2For C1~C5Straight chain amido, the C1~C5The end of straight chain amido carries dimethylamino or substituted-phenyl, described
Halogen either cyano group or nitro are carried on the phenyl ring of substituted-phenyl；
6. the preparation method of glycopeptide derivant as claimed in claim 5 and its pharmaceutically acceptable salt, it is characterised in that institute
State aldehyde be selected from 4 '-chlordiphenyl -4- formaldehyde, 4 '-xenol -4- formaldehyde, 4 '-trifluoromethyl-biphenyl -4- formaldehyde, 3 '-bromo biphenyl -
4- formaldehyde, N-Fmoc-2- (n-Decylamine base)-acetaldehyde, 3- bromobenzaldehydes, 4- trifluoromethylated benzaldehydes, 4- dimethylamino benzaldehyde,
One kind in 4- fluorobenzaldehydes, 4- hydroxy benzaldehydes and 4- aminobenzaldehydes.
7. the preparation method of glycopeptide derivant as claimed in claim 5 and its pharmaceutically acceptable salt, it is characterised in that institute
State the one kind or more of solvent in dimethyl sulfoxide (DMSO), DMF, 1-METHYLPYRROLIDONE, glycol dimethyl ether
Kind.
8. the preparation method of glycopeptide derivant as claimed in claim 7 and its pharmaceutically acceptable salt, it is characterised in that institute
It is dimethyl sulfoxide (DMSO) to state solvent.
9. the preparation method of glycopeptide derivant as claimed in claim 5 and its pharmaceutically acceptable salt, it is characterised in that institute
State condensing agent and be selected from dicyclohexylcarbodiimide, 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides, N, N '-two
Diisopropylcarbodiimide, N, N '-carbonyl dimidazoles, 2- (7- azos BTA)-N, N, N ', N '-tetramethylurea hexafluoro phosphorus
Acid esters, O- BTAs-N, N, N ', N '-tetramethylurea tetrafluoro boric acid ester or 1H- BTAs -1- bases-oxygen tripyrrole alkyl six
Fluorophosphate.
10. the preparation method of glycopeptide derivant as claimed in claim 9 and its pharmaceutically acceptable salt, it is characterised in that
The condensing agent is 1H- BTAs -1- bases-oxygen tripyrrole alkyl hexafluorophosphate.
11. the preparation method of glycopeptide derivant as claimed in claim 5 and its pharmaceutically acceptable salt, it is characterised in that
The amine is selected from N ', one kind or several in N '-dimethylamino propane diamine, 4- cyano group benzylamine, 4- fluorin benzyl amines and 4- nitro phenyl ethylamines
Kind.
12. the preparation method of glycopeptide derivant as claimed in claim 5 and its pharmaceutically acceptable salt, it is characterised in that
The active ester is the dodecahexaene acyl-hydroxysuccinimides of O- bis- or O-4- fluorobenzene propiono-HOSu NHS
Or O-4- trifluoromethyls hydrocinnamoyl-HOSu NHS.
13. as glycopeptide derivant according to any one of claims 1 to 4 and its pharmaceutically acceptable salt are preparing treatment carefully
Application in bacterium infectious disease medicament.
14. glycopeptide derivant as claimed in claim 13 and its pharmaceutically acceptable salt are preparing treatment drug tolerant bacteria sense
Application in infectious diseases medicine.
15. glycopeptide derivant as claimed in claim 14 and its pharmaceutically acceptable salt are preparing treatment MRSA or VRE senses
Application in infectious diseases medicine.
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| WO1996030401A1 (en) * | 1995-03-24 | 1996-10-03 | Eli Lilly And Company | Glycopeptide antibiotic derivatives |
| CN101397333A (en) * | 2007-09-27 | 2009-04-01 | 浙江医药股份有限公司新昌制药厂 | De-hydroxyl vancomycin, preparation method thereof, medicament composition and use thereof |
| CN101959849A (en) * | 2007-12-26 | 2011-01-26 | 利德治疗公司 | Novel semi-synthetic glycopeptides as antibacterial agents |
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| CN102690330A (en) * | 2011-03-23 | 2012-09-26 | 浙江医药股份有限公司新昌制药厂 | Tri-substituted glycopeptide derivative and pharmaceutical composition, and preparation method and purpose thereof |
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| US4639433A (en) * | 1985-08-14 | 1987-01-27 | Eli Lilly And Company | Glycopeptide derivatives |
| US4643987A (en) * | 1985-08-14 | 1987-02-17 | Eli Lilly And Company | Modified glycopeptides |
| EG18377A (en) * | 1986-09-19 | 1993-04-30 | Lilly Co Eli | Process for preparing glycopeptide antibiotics |
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| CN101928331B (en) * | 2009-06-26 | 2014-05-28 | 上海来益生物药物研究开发中心有限责任公司 | New compound and application thereof |
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