CN1827638A - Vancomycin and nor-vancomycin derivatives and their preparation process and use - Google Patents

Vancomycin and nor-vancomycin derivatives and their preparation process and use Download PDF

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Publication number
CN1827638A
CN1827638A CNA2005100524703A CN200510052470A CN1827638A CN 1827638 A CN1827638 A CN 1827638A CN A2005100524703 A CNA2005100524703 A CN A2005100524703A CN 200510052470 A CN200510052470 A CN 200510052470A CN 1827638 A CN1827638 A CN 1827638A
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compound
vancomycin
norvancomycin
derivative
alkaryl
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CNA2005100524703A
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CN1827638B (en
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D·楚
Z·-J·倪
J·J·-X·王
Y·雷
Y·白
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Huabei Pharmaceutical Group Co., Ltd.
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CHRION Co Ltd
HUABEI PHARMACEUTICAL GROUP CO Ltd
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Abstract

The invention relates to the derivative of Vanoomycin or Norvancomycin having a general formula (I) or their medicinal salts, solvates, stereoisomers or prodrugs, wherein R1, R2, R3 and R4 are defined in the specification.

Description

The derivative of novel vancomycin of one class and Norvancomycin, preparation method and purposes
Invention field
The present invention relates to the derivative of novel vancomycin of a class and Norvancomycin, preparation method and anti-infective, the especially purposes in the medicine of severe infections in preparation.
Background technology
Glycopeptide antibiotic (dipropyl peptide in heptan) is to nearly all G +The property bacterium has activity, is used for serious G clinically +The property bacterium treatment infected, representing the last line of defense that tackles this class refractory disease, see Glycopeptide Antibiotics, edited by R.Nagarajan, MarcelDekker, Inc.New York (1994)).Along with 80 years resistance of vancomycin property of medicine faecalis (VRE) appearance, the glycopeptide resistance is on the increase by faecalis, in the recent period even the phenomenon that the glycopeptide drug resistant gene shifts to other bacterium from faecalis occurred, as the increase of streptococcus aureus to β-Nei Xiananleikangshengsu and drug resistance of vancomycin strain; Faecalis is to increase of β-Nei Xiananleikangshengsu, aminoglycosides antibiotics and drug resistance of vancomycin strain or the like, owing to still lack the medicine of controlling effective treatment glycopeptide drug-fast bacteria infection, the glycopeptide resistance has become a great problem that threatens human survival and health, see Hospital Infection Control Practices AdvisoryCommittee, Infection Control Hopital Epidemiology, 1995,17,364-369; A.P.Johnson et al., Clinical MicrobiologyRev., 1990,3,280-291; G.M.Eliopoulos, European J.ClinicalMicrobiol., Infection Disease, 1993,12,409-412; And P.Courvalin, Antimicrob.Agents Chemother, 1990,34,2291-2296).
Send from existing research, enterococcal glycopeptide resistance phenotype has 5 kinds, i.e. VanA, VanB, VanC, VanD and VanE type.For more effective control resistant organism, take much count of the exploitation of glycopeptide kind new medicine in recent years.Many glycopeptide antibiotic derivatives are studied, seen United States Patent (USP), the patent No. 4,639,433,4,643,987,4,497,802,4,698,327,5,591,714,5,840,684,5,843,889.Other derivative is at EP 0 802 199; EP 0 801 075; EP 0 667 353; WO 97/28812; WO 97/38702; WO 98/52589; WO 98/52592; J.Amer.Chem.Soc., 1996,118,13107-13108; J.Amer.Chem.Soc., 1997,119,12041-12047; J.Amer.Chem.Soc., 1994,116, open among the 4573-4590.Oritavancin by Eli Lilly company exploitation has entered III phase clinical stage.However, still need to develop has a broad antifungal spectrum, anti-microbial activity is higher, the glycopeptide derivatives lower to the human body toxic side effect.
Summary of the invention
General introduction of the present invention
The contriver has carried out structure of modification to vancomycin and Norvancomycin, has obtained a series of derivative, through preliminary MIC test, confirms to resistance staphylococcus and the enterococcal effect of resistance it is the several times of Norvancomycin (vancomycin).
Therefore, an object of the present invention is to provide a series of vancomycins of general formula (I) and derivative and pharmacologically acceptable salt, solvate, steric isomer or the prodrug of Norvancomycin:
Figure A20051005247000101
Wherein:
R 1Be H or-CH 2-R 5, R wherein 5Be C 1-C 20The aliphatic group of saturated or undersaturated hydrocarbon character, for example C 1-C 20Alkyl (alkyl), C 2-C 20Alkenyl (alkenyl), or C 3-C 20Saturated or unsaturated cycloaliphatic groups, for example C 3-C 20Cycloalkyl or C 3-C 20Cycloalkenyl group, or C 5-C 20Heterocyclic group (heterocycle contains the one or more heteroatomss that are selected among N, O or the S), or C 6-C 30Aryl, alkaryl or aralkyl (aryl, alkaryl, aralkyl group), this aryl, alkaryl or aralkyl can contain one or more aromatic rings or condensed ring,
Above-mentioned all groups are unsubstituted, or by for example halogen, aryl, OH, replacements such as amino, its carbochain is optional can insert the one or more heteroatomss (heteroatom) that are selected among O, N and the S;
R 2Be OH, or-NH-R 8, R wherein 8Be alkyl, alkenyl, cycloalkyl, cycloalkenyl group, aralkyl, alkaryl and heterocyclic radical, these groups can be to replace or unsubstituted, its carbochain is optional can insert one or more among N, O or the S;
R 3Be-H or-CH 2-NH-R 7, R wherein 7Be alkyl, alkenyl, cycloalkyl, cycloalkenyl group, aralkyl, alkaryl and heterocyclic radical, these groups can be to replace or unsubstituted, its carbochain is optional can insert one or more among N, O or the S;
R 4Be hydrogen or methyl.
Preferably, R 1Be-CH 2-4-(4-Cl-Ph)-Ph ,-CH 2-4-(Ph-O)-Ph ,-CH 2-4-Ph-Ph ,-CH 2CH 2CH 2-Ph ,-CH 2-4-(Butyl-O)-Ph ,-CH 2-(CH 2) 9-CH 3,-CH 2CH 2-NH-(CH 2) 9-CH 3,-CH 2CH 2-S-(CH 2) 9-CH 3,-CH 2CH 2-NH-CH 2-4-(4-Cl-Ph)-Ph ,-H ,-CH 2-(CH 2) 9-CH 3
R 2Be OH ,-NH (CH 2) 3N (CH 3) 2,-N-(D-glucosamine);
R 3Be-H-CH 2-NH-CH 2-4-Ph-Ph ,-CH 2-NH (CH 2) 3N (CH 3) 2-CH 2-N-(N-CH 2-D-glucosamine); With
R 4Be-H or-CH 3
Second purpose of the present invention provides the preparation method of above-mentioned general formula compound, may further comprise the steps:
A, with (for example 40-120 ℃) the down reaction that in the presence of trifluoroacetic acid, heats up of Norvancomycin or vancomycin, obtain compound N CPC4850 or NCPC4851 that glucosyl residue is removed:
R wherein 4Be H or CH 3
The preparation method of The compounds of this invention may further include:
B, NCPC4850 or NCPC4851 carry out the compound that amino protection obtains following formula:
Wherein Pro is a protecting group,
Following formula compound and aldehyde R 5The CHO reaction obtains following compound:
Figure A20051005247000122
Deprotection again obtains the compound of following formula:
Figure A20051005247000131
R wherein 5As defined above, Pro is a protecting group;
Or/and
The product of C, above steps A or B:
Figure A20051005247000132
R wherein 4As defined above, R 1For H or-CH 2-R 5, R 5As defined above, with formaldehyde and amine R 7NH 2Under alkaline condition, react, obtain the compound of following formula:
Figure A20051005247000141
R wherein 7As defined above;
Or
The product of D, above steps A or B:
Figure A20051005247000142
R wherein 1For H or-CH 2-R 5, R 5As defined above, with R 8NH 2Reaction, the compound of the following structural formula of formation:
R wherein 8As defined above.
Another purpose of the present invention provides above-claimed cpd at the anti-serious G of preparation +The medicine that bacterium infects, especially treatment is or/and the purposes in the medicine of assisting therapy endocarditis, meningitis, pneumonia, septicemia, acute and chronic osteomyelitis, burn infection, skin or soft tissue purulent infection.
A further object of the present invention provides the pharmaceutical composition of the invention described above compound that contains significant quantity, and pharmaceutical composition of the present invention can also contain carrier well known in the art, as excipient, and thinner, flavouring agent, sweeting agent etc.
Detailed description of the present invention
We with Norvancomycin (vancomycin) under the condition that trifluoroacetic acid exists, after the reacting by heating through a series of aftertreatments, obtained the single compound of structure, analysis technology such as process high resolution mass spectrum, NMR have been determined the chemical structure of this compound, NCPC4850 (NCPC4851).
Figure A20051005247000161
R＝H，Norvancomycin R＝H，NCPC4850
R＝CH 3，Vancomycin R＝CH 3，NCPC4851
Molecular Formula ＝C 65H 73Cl 2N 9O 24 Molecular Formula＝C 59H 63Cl 2N 9O 19
Formula Weight ＝1435.227 Formula Weight ＝1273.086
Exact Mass Calcd. ＝1433.414557 Da Exact Mass Calcd.＝1271.381732 Da
Exact Mass Obsd. ＝1433.4146 Da Exact Mass Obsd. ＝1271.3617 Da
Norvancomycin NCPC4850
The possible formation mechanism of this compound be glucosyl residue (glucose moiety) in the Norvancomycin molecule (structure such as a top left side) hydrolysis is sloughed, and another one sugar (saccharide residue vancosmine moiety through the ages) is directly linked on the Norvancomycin polypeptide backbone by intramolecular rearrangement (shown in top arrow).The chemical structure of compound has obtained confirmation by the further chemical reaction to NCPC4850.
Norvancomycin and NCPC4850's 13C NMR (500MHz, D 2O, ppm) data such as following table:
Table 1
Carbon atom position Norvancomycin NCPC4850 Carbon atom position Norvancomycin NCPC4850
A-CO 170.4 170.5 D-1’ 56.9 56.9
A-1 139.7 139.9 E-CO 169.4 169.2
A-2 127.3 127.2 E-1 127.3 127.3
A-3 124.0 124.4 E-2 135.7 135.7
A-4 149.9 149.8 E-3 121.7 121.7
A-5 126.1 126.1 E-4 155.0 156.5
A-6 128.7 128.7 E-5 116.2 116.2
A-1’ 71.5 71.6 E-6 125.4 125.5
A-2” 58.8 58.3 E-1’ 53.7 53.8
B-CO 169.1 169.2 Asn-CO 167.3 167.3
B-1 134.7 134.6 Asn-α 51.1 50.9
B-2 107.1 107.0 Asn-β 37.3 37.5
B-3 151.2 151.4 Asn-γ-CO 171.1 170.8
B-4 131.9 131.9 Leu-CO 173.9 174
B-5 152.1 155.1 Leu-α 30.6 61.8
B-6 104.6 104.6 Leu-β 42.6 42.6
B-1’ 54.7 54.9 Leu-γ 23.9 24.1
C-CO 167.5 167.8 Leu-δ 23.2 22.9
C-1 142.5 142.6 Leu-δ 21.6 22.3
C-2 127.3 127.2 Glu-1 101.2 -
C-3 126.1 126.2 Glu-2 78.0 -
C-4 148.3 148.3 Glu-3 76.7 -
C-5 123.3 123.5 Glu-4 70.2 -
C-6 126.1 126.2 Glu-5 77.0 -
C-1’ 71.1 71.1 Glu-6 61.2 -
C-2” 61.8 61.9 Van-1 96.7 100.6
D-CO 172.8 172.7 Van-2 33.3 34.2
D-1 136.5 136.3 Van-3 53.9 54.8
D-2 105.9 105.8 Van-3-CH 3 22.3 22.6
D-3 157.1 159.6 Van-4 70.7 70.8
D-4 102.3 102.3 Van-5 63.1 63.2
D-5 156.4 157.2 Van-5-CH 3 16.8 16.9
D-6 118.0 118.0
The high resolution mass spectrum data of Norvancomycin and compound N CPCC4850 are as follows:
Molecular Formula＝C 65H 73Cl 2N 9O 24 Molecular Formula＝C 59H 63Cl 2N 9O 19
Formula Weight ＝1435.227 Formula Weight ＝1273.086
Exact Mass Calcd.＝1433.414557 Da Exact Mass Calcd.＝1271.361732 Da
Exact Mass Obsd.＝1433.4146 Da Exact Mass Obsd. ＝1271.3617 Da
Norvancomycin NCPC4850
By being carried out following reaction (reducing aminated), compound N CPC4850 (NCPC4851 is also together) obtains derivative suc as formula (1):
Figure A20051005247000191
Synthetic (the amino protection) of Cbz-NCPC4850: (128mg 0.10mmol) is dissolved into 1 of 5ml 1: 1, in 4-dioxane/water, adds NaHCO with NCPC4850 3(17mg, 0.20mmol), under the situation of ice bath and vigorous stirring, dropwise add then Cbz-Cl (17mg, 0.11mmol).Reaction solution at room temperature stirs after 1 hour and pours the 75ml acetone precipitation into.Throw out washs at twice with 10ml acetone, and is dry under the vacuum.
Cbz-NCPC4850-CH 2Synthetic (aminated) of R: with the Cbz-NCPC4850 of 0.10mmol, the aldehyde of 0.15mmol is dissolved into the DMF/MeOH of 5ml (1: 1).Reaction solution adds the NaCNBH of 0.20mmol after stirring 48 hours under 65 ℃ 3, continue to stir 24 hours, pour the 75ml acetone precipitation into after the reaction solution cooling.Throw out washs at twice with 10ml acetone, and is dry under the vacuum.
NCPC4850-CH 2Synthetic (reduction) of R be the above resolution of precipitate of the 0.10mmol RMF to 7ml, the Pd/C (5%) of adding 50mg, and hydrogenation is 3 hours under～1atm, room temperature, pours reaction solution into 80ml acetone after catalyzer removes by filter, and precipitates and uses the reversed-phase HPLC purifying.Omnidistance yield 30-65%.
The common aldehyde of R-CHO wherein, formaldehyde for example, acetaldehyde, propenal, propionic aldehyde, valeral, hexanal, enanthaldehyde, phenyl aldehyde, phenylacetic aldehyde etc., promptly R is an alkyl, thiazolinyl, aryl, aralkyl, alkaryl etc.
The compound of formula (1) also can obtain by following reactions steps:
Figure A20051005247000201
Synthetic (the amino protection) of Boc-NCPC4850: with NCPC4850 (128mg, 0.10mmol), (Boc) 2O (21.8mg, 0.11mmol) and NaHCO 3(17mg 0.20mmol) is dissolved into 1 of 5ml, and in 4-dioxane/water (1: 1), reaction solution at room temperature stirs after 6 hours and pours the 75ml acetone precipitation into.Throw out washs at twice with 10ml acetone, and is dry under the vacuum.
Boc-NCPC4850-CH 2Synthetic (aminated) of R: with the Boc-NCPC4850 of 0.10mmol, the aldehyde of 0.15mmol is dissolved among the DMF/MeOH of 5ml (1: 1).Reaction solution adds the NaCNBH of 0.20mmol after stirring 48 hours under 65 ℃ 3, continue to stir 24 hours, pour the 75ml acetone precipitation into after the reaction solution cooling.Throw out washs at twice with 10ml acetone, and is dry under the vacuum.
NCPC4850-CH 2The above precipitation of synthetic (reduction): the 0.10mmol of R is suspended to the 10ml chloroform, slowly drips 2ml TFA.Solution is poured the 50ml ether sedimentation in stirring at room after 20 minutes, precipitation preparation HPLC purifying.Omnidistance yield 20-60%.
The common aldehyde of R-CHO wherein, formaldehyde for example, acetaldehyde, propenal, propionic aldehyde, valeral, hexanal, enanthaldehyde, phenyl aldehyde, phenylacetic aldehyde etc., promptly R is an alkyl, thiazolinyl, aryl, aralkyl, alkaryl etc.
Above-describedly be general aldehyde, also available amino end replaces aldehyde and carries out reductive alkylation, and the amino aldehyde that replaces can prepare with the following method;
Figure A20051005247000211
With 2-aminoacetaldehyde dimethyl acetal (1eq.), above-described common aldehyde RCHO (1.05eq), and NaCNBH 3(1eq) at CH 2Cl 2In solution at room temperature stirred 1-4 hour.This reaction detects with TLC.0 ℃ of downhill reaction mixture adds FmocCl (1eq) and DIPEA (2eq).Continue under the room temperature to stir 1-2 hour.Remove in the vacuum and desolvate, and obtain the amino acetal that replaces by reversed-phase HPLC purifying resistates.Add 6N HCl (1.5eq.) in the solution of acetal in acetone to above-mentioned amino the replacement.To react under the room temperature and stir 5-16 hour.Remove in the vacuum desolvate and under high vacuum dried residue, obtain the amino crude product that replaces aldehyde, do not need to be further purified and can use.
Also available sulphur replacement aldehyde carries out aminated, and sulphur replaces being prepared as follows of aldehyde:
With bromoacetal (1eq.) (as dimethyl 2-bromoacetal (dimethyl 2-bromoacetaldehyde)) and sodium iodide (1eq.), the solution in DMF at room temperature stirred 0.5 hour.In this solution, add and replace mercaptan RSH (R is an alkyl, thiazolinyl, aryl, alkaryl, aralkyl etc.) (1.eq), add salt of wormwood (1eq) then.Under 25-80 ℃, this mixture was stirred 4-16 hour.Be dissolved in the ethyl acetate with afterreaction, wash with water 2 times and wash 1 time with saturated sodium-chloride.Organic layer MgSO 4Remove in drying and the vacuum and desolvate.Use the reversed-phase HPLC purifying, obtain corresponding sulphur and replace acetal.
Replace adding 6N HCl (1.5eq.) in the solution of acetal in acetone at sulphur.To react under the room temperature and stir 5-16 hour.Go out to desolvate in the vacuum and under high vacuum dried residue, obtain the crude product that sulphur replaces aldehyde, it does not need to be further purified and can to use usually.
Carry out the amine-methylated compound that obtains suc as formula (2) by compound (NCPC481 is also together) to formula (1):
With the NCPC4850 of 0.10mmol, the amine R of 1.0mmol 7NH 2And the formalin of 0.12mmol is dissolved into the acetonitrile/water (1: 1) of 10ml, transfers pH to 9.5～10 with the NaOH of 1M, after reaction solution at room temperature stirs 6～10 hours, transfers pH to 4～5 with the HCl of 1M, pours the 200ml acetone precipitation into.Precipitation reversed-phase HPLC purifying, yield 30-85%.By obtaining compound suc as formula (3) to the condensation of the hydroxyl and the amine of formula (2) (NCPC4851 also with):
Figure A20051005247000222
Amine R with the NCPC4850 of 0.10mmol or its reduction alkanisation derivative, 1.0mmol 8NH 2The DMSO that (or amine salt) is dissolved into 5ml uses Et 3N transfers pH to 8.5～9, and reaction solution stirs the PyBOP that adds 0.12mmol after 1 hour.Reaction solution continues to stir 3 hours in room temperature.The 150ml ether joined obtain the oily dope in the reaction mixture, the oily dope just obtains white or faint yellow solid with the 15ml acetone treatment after shaking washing at twice with the 30ml ether again.Use the reversed-phase HPLC purifying, yield 60-90%.
With all cpds of the present invention various resistant organisms have been carried out antibacterial activity test, the result, compound of the present invention is better than vancomycin greatly and removes vancomycin the minimal inhibitory concentration of various resistant organisms, thereby confirms that compound of the present invention can be effective to anti-serious G +Bacterium infects, and is particularly useful for treatment or/and assisting therapy endocarditis, meningitis, pneumonia, septicemia, acute and chronic osteomyelitis, burn infection, skin or soft tissue purulent infection.
Compound of the present invention can be made the parenterai administration formulation or through the enterally administering formulation, as oral or intravenous form.The consumption of compound of the present invention can be with reference to the existing dosage of vancomycin and Norvancomycin, and for example the adult can be 0.8-2.0g/d, can divide 2-3 administration, and children's consumption cuts down according to the circumstance.Compound of the present invention is salify according to a conventional method, for example makes hydrochloride.
Embodiment
In order further to illustrate the present invention, provide a series of embodiment below.It is pointed out that these embodiment are illustrative fully.The purpose that provides these embodiment is in order fully to express meaning of the present invention and content, never the present invention to be caused any type of restriction.
In following examples, following abbreviation has following implication.Undefined abbreviation has its generally accepted implication, and unless stated otherwise, all temperature are degree centigrade.
BOC, Boc=tert-butoxycarbonyl
Cbz-Cl=benzyloxy acyl chloride
DIPEA=diisopropylethylamine
DMF=N, dinethylformamide
DMSO=dimethyl sulfoxide (DMSO)
Eq.=equivalent
Et=ethyl
EtOAc=ethyl acetate
Fmoc=9-fluorenyl methoxy carbonyl
HPLC=high performance liquid chromatography
Me=methyl
PyBOP=benzotriazole-1-base oxygen three (pyrrolidino) phosphine hexafluorophosphate
TFA=trifluoroacetic acid
THF=tetrahydrofuran (THF)
TLC, tlc=thin-layer chromatography
In following embodiment, the Norvancomycin hydrochloride is produced by North China pharmacy group, and other reagent and reactant are bought from Aldrich Chemical Co..
In an embodiment, the derivative (seeing Table 2 compound number 1～32) that has synthesized a series of NCPC4850 (NCPC4851) by some above-mentioned chemical processes.
It may be noted that in addition embodiment passes through the reversed-phase HPLC purification condition in responding: pass through preparation reversed phase high efficiency liquid phase (HPLC) purifying with DIKMA 10 * 50mm (5 μ m) C18 post and TFA buffer system.10ml/ minute the linear gradient wash-out of 80% acetonitrile/0.1%TFA when 10% acetonitrile/0.1%TFA is 15 minutes to the time when being zero with the time.Stream part of containing product is by detecting in 254nm place UV scanning.Part lyophilize of required stream is become white solid.The yield that is mentioned among the present invention is molar yield.
The derivative of NCPC4850 and NCPC4851
Figure A20051005247000241
Table 2
Compound number R 1 R 2 R 3 R 4
1 -CH 2-4-(4-Cl-Ph)-Ph -OH -H -H
2 -CH 2-4-(Ph-O)-Ph -OH -H -H
3 -CH 2-4-Ph-Ph -OH -H -H
4 -CH 2CH 2CH 2-Ph -OH -H -H
5 -CH 2-4-(Butyl-O)-Ph -OH -H -H
6 -CH 2-(CH 2) 9-CH 3 -OH -H -H
7 -CH 2CH 2-NH-(CH 2) 9-CH 3 -OH -H -H
8 -CH 2CH 2-S-(CH 2) 9-CH 3 -OH -H -H
9 -CH 2CH 2-NH-CH 2-4-(4-Cl-Ph)-Ph -OH -H -H
10 -CH 2CH 2-NH-(CH 2) 9-CH 3 -NH(CH 2) 3N(CH 3) 2 -H -H
11 -CH 2CH 2-NH-(CH 2) 9-CH 3 -N-(D-glucosamine) -H -H
12 -CH 2-4-(4-Cl-Ph)-Ph -NH(CH 2) 3N(CH 3) 2 -H -H
13 -CH 2-4-(4-Cl-Ph)-Ph -N-(D-glucosamine) -H -H
14 -H -OH -CH 2-NH-CH 2-4-Ph-Ph -H
15 -CH 2CH 2-NH-(CH 2) 9-CH 3 -OH -CH 2-NH(CH 2) 3N(CH 3) 2 -H
16 -CH 2CH 2-NH-(CH 2) 9-CH 3 -OH -CH 2-N-(N-CH 3-D-glucosamine) -H
17 -CH 2-4-(4-Cl-Ph)-Ph -OH -H -CH 3
18 -CH 2-4-(Ph-O)-Ph -OH -H -CH 3
19 -CH 2-4-Ph-Ph -OH -H -CH 3
20 -CH 2CH 2CH 2-Ph -OH -H -CH 3
21 -CH 2-4-(Butyl-O)-Ph -OH -H -CH 3
22 -CH 2-(CH 2) 9-CH 3 -OH -H -CH 3
23 -CH 2CH 2-NH-(CH 2) 9-CH 3 -OH -H -CH 3
24 -CH 2CH 2-S-(CH 2) 9-CH 3 -OH -H -CH 3
25 -CH 2CH 2-NH-CH 2-4-(4-Cl-Ph)-Ph -OH -H -CH 3
26 -CH 2CH 2-NH-(CH 2) 9-CH 3 -NH(CH 2) 3N(CH 3) 2 -H -CH 3
27 -CH 2CH 2-NH-(CH 2) 9-CH 3 N-(D-glucosamine) -H -CH 3
28 -CH 2-4-(4-Cl-Ph)-Ph -NH(CH 2) 3N(CH 3) 2 -H -CH 3
29 -CH 2-4-(4-Cl-Ph)-Ph -N-(D-glucosamine) -H -CH 3
30 -H -OH -CH 2-NH-CH 2-4-Ph-Ph -CH 3
31 -CH 2CH 2-NH-(CH 2) 9-CH 3 -OH -CH 2-NH(CH 2) 3N(CH 3) 2 -CH 3
32 -CH 2CH 2-NH-(CH 2) 9-CH 3 -OH -CH 2-N-(N-CH 3-D-glucosamine) -CH 3
The mass-spectrometric data of these compounds is as shown in the table:
Table 3
Compound number MW(free base) Observed MH + Oberved MH 2+
1 1473.8 1474.9 739.0
2 1455.3 1456.7 729.9
3 1439.3 1440.3 721.7
4 1391.3 1392.9 697.45
5 1435.3 1436.5 719.8
6 1427.4 1428.4 715.7
7 1456.4 1458.0 730.1
8 1473.5 1474.8 738.7
9 1516.8 1518.2 760.6
10 1540.6 1541.6 772.3
11 1617.6 1618.9 811.0
12 1601.0 1602.5 802.8
13 1678.0 1679.1 841.0
14 1502.8 1504.0 753.5
15 1541.6 1543.0 772.5
16 1618.6 1620.2 811.3
17 1487.8 1489.0 746.1
18 1469.3 1470.7 736.9
19 1453.3 1454.3 728.7
20 1405.3 1407.1 704.6
21 1449.3 1451.0 727.0
22 1441.4 1442.5 722.8
23 1470.4 1471.4 737.2
24 1487.5 1489.0 746.1
25 1530.8 1531.9 767.5
26 1554.6 1556.1 779.6
27 1631.6 1632.5 817.8
28 1615.0 1616.2 809.7
29 1692.0 1693.9 848.5
30 1516.8 1518.1 760.6
31 1555.6 1556.8 779.9
32 1632.6 1633.5 818.3
Embodiment:
Embodiment 1
The chemosynthesis of NCPC4850 and NCPC4851
Figure A20051005247000261
R＝H，Norvancomycin R＝H，NCPC4850
R＝CH 3，Vancomycin R＝CH 3，NCPC4851
5.0 gram Norvancomycin hydrochlorides are dissolved into 20ml trifluoroacetic acid (TFA), in 50 ℃ of following stirring reactions 2 hours.Be dissolved in 20ml acetone behind the reaction solution vacuum concentration, pour 200ml chloroform precipitation into.Throw out washs back drying under vacuum at twice with the 20ml chloroform.Crude product gets the pure product 500mg of compound N CPC4850 (productive rate 10%) with the reversed-phase HPLC purifying.If with vancomycin hydrochloride is raw material,, then can obtain compound N CPC4851 by identical experimentation.
Embodiment 2
Synthesizing of compound 1
Figure A20051005247000271
Cbz-NCPC4850's is synthetic: (128mg 0.10mmol) is dissolved into 1 of 5ml, in 4-dioxane/water (1: 1), adds NaHCO with NCPC4850 3(17mg, 0.20mmol), under the situation of ice bath and vigorous stirring, dropwise add then Cbz-Cl (17mg, 0.11mmol).Reaction solution at room temperature stirs after 1 hour and pours the 75ml acetone precipitation into.Precipitate useless 10ml acetone and wash at twice, dry under the vacuum.
Cbz-NCPC4850-4-Chlorophenylbenzyl's is synthetic: with the Cbz-NCPC4850 of 0.10mmol, the 4-chlordiphenyl formaldehyde of 0.15mmol is dissolved into the DMF/MeOH (1: 1) of 5ml.Reaction solution adds the NaCNBH of 0.20mmol after stirring 48 hours under 65 ℃ 3, continue to stir 24 hours, pour the 75ml acetone precipitation into after the reaction solution cooling.Precipitation is washed at twice with 10ml acetone, and is dry under the vacuum.
Synthesizing of compound 1: the DMF that the above throw out of 0.10mmol is dissolved into 7ml, the Pd/C (5%) that adds 50mg, hydrogenation is 3 hours under～1atm, room temperature, after catalyzer removes by filter reaction solution is poured into 80ml acetone precipitation, throw out reversed-phase HPLC purifying.Omnidistance yield 50%.
Embodiment 3
Synthesizing of compound 2
Figure A20051005247000281
Boc-NCPC4850's is synthetic: with NCPC4850 (128mg, 0.10mmol), (Boc) 2O (21.8mg, 0.11mmol), NaCO 3(17mg 0.20mmol) is dissolved into 1 of 5ml, and in 4-dioxane/water (1: 1), reaction solution at room temperature stirs after 6 hours and pours the 75ml acetone precipitation into.Precipitation is washed at twice with 10ml acetone, and is dry under the vacuum.
Boc-NCPC4850-4-phenyoxylbenzyl's is synthetic: with the Boc-NCPC4850 of 0.10mmol, the 4-phenoxy benzaldehyde of 0.15mmol is dissolved into the DMF/MeOH (1: 1) of 5ml.Reaction solution adds the NaCNBH of 0.20mmol after stirring 48 hours under 65 ℃ 3, continue to stir 24 hours, pour the 75ml acetone precipitation into after the reaction solution cooling.Precipitation is washed at twice with 10ml acetone, and is dry under the vacuum.
Synthesizing of compound 2: the above precipitation of 0.10mmol is suspended to the 10ml chloroform, slowly drips 2ml TFA.Solution is poured the 50ml ether sedimentation in stirring at room after 20 minutes, precipitation reversed-phase HPLC purifying.Omnidistance yield 42%.
Embodiment 4
Synthesizing of compound 3
Identical with the preparation of compound 1, just replace 4-chlordiphenyl formaldehyde with 4-Ph-Ph-CHO.
Embodiment 5
Synthesizing of compound 4
Identical with the preparation of compound 1, just use Ph-CH 2CH 2-CHO replaces 4-chlordiphenyl formaldehyde.
Embodiment 6
Synthesizing of compound 5
Identical with the preparation of compound 1, just replace 4-chlordiphenyl formaldehyde with 4-(Butyl-O)-Ph-CHO.
Embodiment 7
Synthesizing of compound 6
Identical with the preparation of compound 1, just use CH 3-(CH 2) 9-CHO replaces 4-chlordiphenyl formaldehyde.
Embodiment 8
Synthesizing of compound 7
Identical with the preparation of compound 1, just use CH 3-(CH 2) 9-NH-CH 2CHO replaces 4-chlordiphenyl formaldehyde.
Embodiment 9
Synthesizing of compound 8
Identical with the preparation of compound 1, just use CH 3-(CH 2) 9-S-CH 2CHO replaces 4-chlordiphenyl formaldehyde.
Embodiment 10
Synthesizing of compound 9
Identical with the preparation of compound 1, just with 4-(4-Cl-Ph)-Ph-CH 2-NH-CH 2CHO replaces 4-chlordiphenyl formaldehyde.
Embodiment 11
Synthesizing of compound 10
With the compound 7 of 0.1mmol, the H of 1.0mmol 2N-(CH 2) 3N (CH 3) 2Be dissolved into the DMSO of 5ml, transfer pH to 8.5～9 with DIPEA, reaction solution stirs the PyBOP that adds 0.12mmol after 1 hour.Reaction solution continues to stir 3 hours in room temperature.The 150ml ether joined obtain the oily dope in the reaction mixture, the oily dope just obtains white solid with the 15ml acetone treatment after shaking washing at twice with the 30ml ether again.Use the reversed-phase HPLC purifying.Yield 65%.
Embodiment 12
Synthesizing of compound 11
With embodiment 11, just use H 2N-(D-glucosamine) replaces H 2N-(CH 2) 3N (CH 3) 2
Embodiment 13
Synthesizing of compound 12
Figure A20051005247000301
With the compound 1 of 0.1mmol, the H of 1.0mmol 2N-(CH 2) 3N (CH 3) 2Be dissolved into the DMSO of 5ml, transfer pH to 8.5～9 with DIPEA, reaction solution stirs the PyBOP that adds 0.12mmol after 1 hour.Reaction solution continues to stir 3 hours in room temperature.The 150ml ether joined obtain the oily dope in the reaction mixture, the oily dope just obtains white solid with the 15ml acetone treatment after shaking washing at twice with the 30ml ether again.Use the reversed-phase HPLC purifying.Yield 70%.
Embodiment 14
Synthesizing of compound 13
With embodiment 13, just use H 2N-(D-glucosamine) replaces H 2N-(CH 2) 3N (CH 3) 2
Embodiment 15
Synthesizing of compound 14
NCPC4850 with 0.10mmol, 1.0mmol the 4-phenylbenzylamine and the formalin of 0.12mmol be dissolved into 1: 1 acetonitrile/water of 10ml, NaOH with 1M transfers pH to 9.5～10, and reaction solution at room temperature stirred 8 hours, pours the 120ml acetone precipitation into behind HCl accent pH to 4～5 with 1M.Throw out reversed-phase HPLC purifying.Yield 65%.
Embodiment 16
Synthesizing of compound 15
Figure A20051005247000312
With the compound 7 of 0.10mmol, the H of 1.0mmol 2N-(CH 2) 3N (CH 3) 2And the formalin of 0.12mmol is dissolved into 1: 1 acetonitrile/water of 10ml, transfers pH to 9.5～10 with the NaOH of 1M, and reaction solution at room temperature stirred 8 hours, poured the 120ml acetone precipitation into behind HCl accent pH to 4～5 with 1M.Throw out reversed-phase HPLC purifying.Yield 50%.
Embodiment 17
Synthesizing of compound 16
Similar to Example 16, just with (N-CH 3-D-glucosamine) NH 2Replace H 2N-(CH 2) 3N (CH 3) 2
Embodiment 18
Synthesizing of compound 17
Figure A20051005247000321
5.0 gram vancomycin hydrochlorides are dissolved into 20ml TFA, in 50 ℃ of following stirring reactions 2 hours.Be dissolved in 20ml acetone behind the reaction solution vacuum concentration, pour 200ml chloroform precipitation into.Precipitation is washed the final vacuum drying at twice with the 20ml chloroform.Crude product gets the pure product 350mg of compound N CPC4851 with the reversed-phase HPLC purifying.
Synthesizing of compound 17: with the NCPC4851 of 0.10mmol, the 4-chlordiphenyl formaldehyde of 0.15mmol is dissolved into the DMF/MeOH (1: 1) of 5ml.Reaction solution adds the NaCNBH of 0.20mmol after stirring 48 hours under 65 ℃ 3, restir 24 hours is poured the 75ml acetone precipitation into after the reaction solution cooling.Precipitation is washed at twice with 10ml acetone, and is dry under the vacuum.Crude product reversed-phase HPLC purifying.
Embodiment 19-33
Compound 18-31's is synthetic
Synthetic synthetic identical with compound 2-16 respectively of compound 18-31 just replaces NCPC4850 with NCPC4851.
Embodiment 34
The The compounds of this invention of 2ml water for injection and 0.6g is made injection according to a conventional method.
The research of anti-microbial activity
The mensuration of anti-microbial activity
The mensuration of minimal inhibitory concentration (MIC)
12,13,14,15 No.2 Hospital, Hebei Medical Univ. provide by microorganism, microorganism 1,2,3,4,7,8,9,10,11 is provided by the People's Hospital, Hebei province, microorganism 5,6,16,17 is provided by U.S. CHIRON company, and microorganism 18,19 is provided by the national biological product calibrating.Based on the susceptibility to teicoplanin, the enterococcal phenotype of drug resistance of vancomycin is Van A or Van B.
In Microdilution liquid culture method (microdilution brothprocedure), measuring minimal inhibitory concentration (MIC) under the NCCLS criterion.Usually, with in the Mueller-Hinton nutrient solution of compound serial dilution in 96 hole microtitration flat boards.Based on absorbancy at 600nm, the bacterial strain of dilution incubated overnight, the ultimate density in each hole is 5 * 10 5Cfu/mL.Flat board placed again 35 ℃ incubator.Next day (or after in the situation of faecalis bacterial strain, being 24 hours), measure MIC by the flat board of range estimation.The bacterial strain of routine test comprises the streptococcus aureus (MSSA) of methicillinum sensitivity in initial screening, the streptococcus aureus of methicillin-resistance (MRSA), the staphylococcus epidermidis of methicillinum sensitivity (MSSE), the staphylococcus epidermidis of methicillin-resistance (MRSE), the faecium of vancomycin sensitivity (VSE Fm), the enterococcus faecalis of vancomycin sensitivity (VSE Fs), vancomycin resistance is also anti-carries the peaceful faecium of koala (VRE Fm Van A), vancomycin resistance but to carrying the peaceful responsive faecium (VRE Fm Van B) of koala, the also anti-peaceful enterococcus faecalis of koala (VRE Fs Van A) of carrying of vancomycin resistance, vancomycin resistance but the peaceful responsive enterococcus faecalis (VREFs Van B) of right koala.
The external activity MIC of compound (μ g/ml)
The microorganism numbering Microorganism Vancomycin Norvancomycin NCPC 4850 NCPC48 51 1 2 3 4 5 6 7 8 9
1 Streptococcus aureus 134 2 2 ＜0.25 ＜0.25 ≤0.125 0.25 0.25 0.25 ≤0.125 ≤0.125 ≤0.125 0.125 0.125
2 Streptococcus aureus 143 1 2 ＜0.25 0.5 ≤0.125 0.125 0.125 0.25 ≤0.125 0.125 0.125 0.25 0.25
3 Streptococcus aureus 68 1 2 ＜0.25 ＜0.25 ≤0.125 0.125 0.25 0.125 0.25 ≤0.125 ≤0.125 0.125 0.125
4 Streptococcus aureus 83 2 2 0.5 0.5 ≤0.125 0.25 0.25 0.25 ≤0.125 ≤0.125 0.125 ≤ 0.125 ≤0.125
5 Streptococcus aureus Stau Mu50-HIP5406 2 2 0.78 0.78 0.25 0.5 0.5 0.5 0.25 0.5 0.25 0.5 0.5
6 Streptococcus aureus Stau HIP5827 8 8 3.13 3.13 0.5 0.5 0.5 1 0.5 0.5 0.5 1 1
7 Staphylococcus epidermidis 24 2 1 - - ≤0.125 0.125 0.125 0.125 0.125 ≤0.125 ≤0.125 0.125 ≤0.125
8 Staphylococcus epidermidis 25 2 2 0.5 0.5 ≤0.125 0.125 0.125 0.25 0.125 0.25 0.125 0.25 0.25
9 Epidermis grape grape coccus 26 4 2 - - ≤0.125 0.25 0.25 0.25 0.25 0.25 ≤0.125 0.25 0.25
10 Staphylococcus epidermidis 3 4 2 - - ≤0.125 0.25 0.25 0.25 ≤0.125 ≤0.125 0.125 0.125 ≤0.125
11 Staphylococcus epidermidis 10 1 1 0.5 0.5 ≤0.125 0.25 0.25 0.25 ≤0.125 ≤0.125 ≤0.125 ≤ 0.125 0.125
12 Faecalis 9 2 2 0.5 0.5 ≤0.125 0.25 0.25 0.25 0.25 0.25 0.125 0.25 0.25
13 Faecalis 16 4 4 1 1 ≤0.125 0.25 0.25 0.25 0.125 0.125 ≤0.125 0.125 0.125
14 Faecalis 22 2 2 0.5 0.5 ≤0.125 0.25 0.25 0.25 0.125 0.125 0.125 ≤ 0.125 0.125
15 Faecalis 24 2 2 0.5 0.5 ≤0.125 0.25 0.25 0.25 0.25 0.25 ≤0.125 0.25 0.25
16 Faecalis Enfa_29212 ＞64 - ＞50 ＞50 0.5 0.5 0.5 1 0.5 0.5 0.5 0.5 0.5
17 Faecalis Enfa_t29882 ＞64 - ＞50 ＞50 0.125 0.5 0.5 0.5 0.125 0.125 0.25 1 0.5
18 ATCC 29213 2 2 0.5 0.5 ≤0.125 0.25 0.25 0.25 0.125 0.125 ≤0.125 0.25 0.25
19 ATCC 29213 2 2 0.5 1 ≤0.125 0.25 0.25 0.25 0.125 0.125 0.125 0.25 0.125

Claims (7)

1. the derivative of the vancomycin of general formula (I) or Norvancomycin or its pharmacologically acceptable salt, solvate, steric isomer or prodrug:
Wherein:
R 1Be H or-CH 2-R 5, R wherein 5Be C 1-C 20The aliphatic group of saturated or undersaturated hydrocarbon character, for example C 1-C 20Alkyl (alkyl), C 2-C 20Alkenyl (alkenyl), or C 3-C 20Saturated or unsaturated cycloaliphatic groups (cycloaliphatic group), for example C 3-C 20Cycloalkyl (cycloalkyl) or C 3-C 20Cycloalkenyl group (cycloalkenyl), or C 5-C 20Heterocyclic group (heterocycle) (heterocycle contains the one or more heteroatomss that are selected among N, O or the S), or C 6-C 30Aryl, alkaryl or aralkyl (aralkylgroup), this aryl, alkaryl or aralkyl can contain one or more aromatic rings or condensed ring for aryl, alkaryl,
Above-mentioned all groups are unsubstituted, or by for example halogen, aryl, OH, replacements such as amino, its carbochain is optional can insert the one or more heteroatomss (thechains of all group described above may be interupted by oneor more hetero atom) that are selected among O, N and the S;
R 2Be OH, or-NH-R 8, R wherein 8Be alkyl, alkenyl, cycloalkyl, cycloalkenyl group, aralkyl, alkaryl and heterocyclic radical, these groups can be to replace or unsubstituted, its carbochain is optional can insert one or more among N, O or the S;
R 3Be-H or-CN 2-NH-R 7, R wherein 7Be alkyl, alkenyl, cycloalkyl, cycloalkenyl group, aralkyl, alkaryl and heterocyclic radical, these groups can be to replace or unsubstituted, its carbochain is optional can insert one or more among N, O or the S;
R 4Be hydrogen or methyl.
2. according to the vancomycin of claim 1 or derivative or its pharmacologically acceptable salt, solvate, steric isomer or prodrug, the wherein R of Norvancomycin 1Be-CH 2-4-(4-Cl-Ph)-Ph ,-CH 2-4-(Ph-O)-Ph ,-CH 2-4-Ph-Ph ,-CH 2CH 2CH 2-Ph ,-CH 2-4-(Butyl-O)-Ph ,-CH 2-(CH 2) 9-CH 3,-CH 2CH 2-NH-(CH 2) 9-CH 3,-CH 2CH 2-S-(CH 2) 9-CH 3,-CH 2CH 2-NH-CH 2-4-(4-Cl-Ph)-Ph ,-H ,-CH 2-(CH 2) 9-CH 3
R 2Be OH ,-NH (CH 2) 3N (CH 3) 2,-N-(D-glucosamine);
R 3Be-H-CH 2-NH-CH 2-4-Ph-Ph ,-CH 2-NH (CH 2) 3N (CH 3) 2-CH 2-N-(N-CH 2-D-glucosamine); With
R 4Be-H or-CH 3
3. the preparation method of the derivative of the vancomycin of claim 1 or Norvancomycin may further comprise the steps:
A, with Norvancomycin or vancomycin:
Figure A2005100524700003C1
In the presence of trifluoroacetic acid, react the compound N CPC4850 (R that the glucosyl residue of acquisition following formula is removed down at heat up (for example 40-120 ℃) 4Be H) or NCPC4851 (R 4Be CH 3):
Figure A2005100524700004C1
R wherein 4Be H or CH 3
4. according to the preparation method of claim 3, further comprise:
B, NCPC4850 or NCPC4851 carry out the compound that amino protection obtains following formula:
Figure A2005100524700004C2
Wherein Pro is a protecting group,
Following formula compound and aldehyde R 5The CHO reaction obtains following compound:
Figure A2005100524700005C1
Deprotection again obtains the compound of following formula:
Figure A2005100524700005C2
R wherein 5Such as claim 1 definition, Pro is a protecting group;
Or/and
The product of C, above steps A or B:
Figure A2005100524700006C1
R wherein 4As defined above, R 1For H or-CH 2-R 5, R 5Such as claim 1 definition,
With formaldehyde and amine R 7NH 2Under alkaline condition, react, obtain the compound of following formula:
Figure A2005100524700006C2
R wherein 7Such as claim 1 definition;
Or
The product of D, above steps A or B:
R wherein 1For H or-CH 2-R 5, R 5Such as claim 1 definition,
With R 8NH 2Reaction, the compound of the following structural formula of formation:
Figure A2005100524700007C2
R wherein 8As defined above.
5. the derivative of claim 1 or 2 vancomycin or Norvancomycin or its pharmacologically acceptable salt, solvate, steric isomer or prodrug are at the anti-serious G of preparation +Purposes in the medicine that bacterium infects.
The derivative of claim 1 or 2 vancomycin or Norvancomycin or its pharmacologically acceptable salt, solvate, steric isomer or prodrug in the preparation treatment or/and the purposes in the medicine of assisting therapy endocarditis, meningitis, pneumonia, septicemia, acute and chronic osteomyelitis, burn infection, skin or soft tissue purulent infection.
7. contain the claim 1 of pharmacy effective dose or 2 vancomycin or the derivative of Norvancomycin or the pharmaceutical composition of its pharmacologically acceptable salt, solvate, steric isomer or prodrug.
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CN105985412A (en) * 2015-02-28 2016-10-05 爱斯医药科技(南京)有限公司 Vancomycin derivatives and preparation and application thereof
CN106188243A (en) * 2015-05-05 2016-12-07 博瑞生物医药（苏州）股份有限公司 A kind of preparation method of oritavancin
CN107365359A (en) * 2017-07-17 2017-11-21 昆明理工大学 A kind of Vancomycin chiral function monomer synthetic method
CN107759671A (en) * 2017-09-11 2018-03-06 昆明理工大学 The method that Vancomycin chiral function monomer is synthesized in aqueous phase

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WO2000069893A1 (en) * 1999-05-19 2000-11-23 Merck & Co., Inc. Glycopeptide antibacterial compounds, compositions containing same and methods of using same
WO2002079150A2 (en) * 2001-03-30 2002-10-10 Sloan-Kettering Institute For Cancer Research Glycorandomization and the production of novel erythronolide and coumarin analogs
US7348309B2 (en) * 2001-03-30 2008-03-25 Wisconsin Alumni Research Foundation Glycorandomization and production of novel vancomycin analogs

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CN105985412A (en) * 2015-02-28 2016-10-05 爱斯医药科技(南京)有限公司 Vancomycin derivatives and preparation and application thereof
CN106188243A (en) * 2015-05-05 2016-12-07 博瑞生物医药（苏州）股份有限公司 A kind of preparation method of oritavancin
CN106188243B (en) * 2015-05-05 2020-06-26 博瑞生物医药（苏州）股份有限公司 Preparation method of oritavancin
CN107365359A (en) * 2017-07-17 2017-11-21 昆明理工大学 A kind of Vancomycin chiral function monomer synthetic method
CN107759671A (en) * 2017-09-11 2018-03-06 昆明理工大学 The method that Vancomycin chiral function monomer is synthesized in aqueous phase

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