CN102690331B - Monosaccharide glycopeptide derivative, pharmaceutical composition, preparation method and purpose thereof and preparation method of intermediate - Google Patents
Monosaccharide glycopeptide derivative, pharmaceutical composition, preparation method and purpose thereof and preparation method of intermediate Download PDFInfo
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Abstract
The invention discloses a monosaccharide glycopeptide derivative shown as a general formula (I), pharmaceutically acceptable salts thereof and a preparation method thereof. R1 and R2 respectively represent H, CH2-R3 or CH2-R4, and can be the same or not; R3 represents an aromatic group, which is an unsubstituted or substituted benzene ring or biphenyl ring, and a substituent of the benzene ring has one or more halogens, and one or more methoxy groups; and R4 represents C3-C9 saturated aliphatic alkyl. The invention also relates to a synthetic method of the compound shown as a general formula (II). In addition, the invention also provides a pharmaceutical composition containing the monosaccharide glycopeptide derivative and pharmaceutically acceptable salts as active components, and application thereof. The compound and pharmaceutical composition provided by the invention have good antibacterial activity and great significance for development of novel antibacterial medicament.
Description
Technical field
The invention belongs to pharmaceutical chemistry synthesis technical field, relate to the glycopeptide antibiotic derivative of a class novelty and the preparation method of pharmacologically acceptable salts, preparation method and application and intermediate thereof.
Background technology
Glycopeptide antibiotics is the choice drug that clinical treatment methicillin-resistant staphylococcus aureus (methicillin-resistant Staphylococcus aureus, MRSA) infects.But, result in the development of bacterial drug resistance as the experiential therapy of MRSA using glycopeptide antibiotics, the susceptibility of such as MRSA to vancomycin declines to some extent, this will produce serious threat to clinical anti-infective therapy, therefore, searching can be extremely urgent to the effective antimicrobial-oritavancin of Resistant strain.
Chinese patent 200910053905.4 and 200910053906.9 reports two novel glycopeptide compounds, the compound of structure as shown in general formula of the present invention (II) and the compound shown in general formula (III), there is anti-microbial activity, its novelty is that four hydroxyls of its peptide backbone six amino acids glycosyl are axial bond, has no bibliographical information to the research that these two compounds carry out structural modification.
Summary of the invention
An object of the present invention is glycopeptide derivant and the pharmacologically acceptable salts thereof of the various series in order to provide general formula (I):
Wherein: R
1and R
2h, CH respectively
2-R
3or CH
2-R
4, R
1and R
2for identical or different; Wherein R
3be aromatic group, this aromatic group is the phenyl ring or cyclohexyl biphenyl that do not replace or replace, and the substituting group of phenyl ring or cyclohexyl biphenyl is with one or more halogens, one or more methoxyl group; R
4for C
3-C
9saturated fatty alkyl.
Wherein, four hydroxyls of its peptide backbone six amino acids glycosyl are axial bond.
In the present invention, described derivative preferably: R
1, R
2hydrogen, benzyl, 4-chlorobenzyl, 4-bromobenzyl, 4-methoxy-benzyl, 4-phenylbenzyl, 4-(the chloro-phenyl of 4-)-benzyl, 3-chlorobenzyl, 2-bromobenzyl, 3-bromobenzyl, 2,4-dichloro benzyl, 3,4-dichloro benzyl, 3,4-dimethoxy-benzyl, 2,4,5-trifluoro-benzyl, positive decyl, n-nonyl, n-octyl, n-heptyl, n-hexyl, n-pentyl, normal-butyl.
In the present invention, described pharmaceutically acceptable salt is preferably alkali-metal salt, the salt of alkaline-earth metal or the salt that formed with acid.Wherein, described basic metal is preferably sodium or potassium; Described alkaline-earth metal is preferably calcium or magnesium; Described acid is preferably the mineral acids such as hydrochloric acid, Hydrogen bromide, sulfuric acid, nitric acid or phosphoric acid, the organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, propanedioic acid, succsinic acid, fumaric acid, toxilic acid, lactic acid, oxysuccinic acid, tartrate, citric acid, picric acid or methylsulfonic acid, the acidic amino acid such as aspartic acid or L-glutamic acid.
The invention still further relates to a class pharmaceutical composition, this pharmaceutical composition comprises the treatment above-mentioned glycopeptide derivant of significant quantity or its pharmaceutically acceptable salt and pharmaceutically acceptable carrier.In the present invention, described pharmaceutically acceptable carrier refers to the pharmaceutical carrier of pharmaceutical field routine, as thinner, vehicle (as water etc.), tackiness agent (as derivatived cellulose, gelatin, polyvinylpyrrolidone etc.), weighting agent (as starch etc.), agent of bursting apart (as calcium carbonate, sodium bicarbonate).In addition, other auxiliarys can also be added in the composition, as flavouring agent and sweeting agent etc.
Pharmaceutical composition of the present invention, can put on by intravenous injection, subcutaneous injection or oral form the patient needing treatment.For time oral, conventional solid preparation can be prepared into as tablet, pulvis or capsule etc.; During for injecting, injection liquid can be prepared into.The various formulations of pharmaceutical composition of the present invention can adopt the method for medical field routine to be prepared, wherein said glycopeptide derivant or its pharmaceutically acceptable salt is as activeconstituents, the content of activeconstituents is 0.1% ~ 99.5% (weight ratio).Preferably, the weight content of compound of the present invention is 0.1% ~ 99.5%, and most preferred content is 0.5 ~ 90%.
The application of aforementioned pharmaceutical compositions in preparation treatment bacterial infection disease medicine.Described pharmaceutical composition puts on the general dosage of the patient needing treatment can with reference to the existing dosage of vancomycin and Norvancomycin, and such as adult can be 0.1 ~ 2.0g/d, specifically can according to changes such as the age of patient and the state of an illness.Compound of the present invention can salify according to a conventional method, such as, make hydrochloride.
The invention provides synthesis and the separation method of the compound shown in general formula (II), obtained by following synthetic route:
Concrete grammar comprises as follows:
Compound shown in general formula (III) is dissolved in trifluoracetic acid (TFA), at 20 ~ 30 DEG C, reacts to obtain the compound shown in general formula (II).
A further object of the present invention is to provide the preparation method of the compound shown in above-mentioned general formula (I).
The compound shown in general formula (I) described in the present invention can be obtained by following synthetic route:
Wherein, R
1and R
2definition the same.
Concrete grammar comprises as follows:
Method A: work as R
1=R
2, R
3and R
4time described above:
1, condensation: the compound shown in general formula (II) and aromatic aldehyde R
3-CHO or alkanoic R
4-CHO reacts in suitable solvent and suitable temperature, generates intermediate Schiff 's base.Aromatic aldehyde R
3-CHO or alkanoic R
4the mol ratio of the compound shown in-CHO Yu general formula (II) is 5: 1 ~ 7: 1, preferably 6: 1.The solvent of condensation reaction is dimethyl sulfoxide (DMSO) (DMSO), DMF (DMF), C
1-C
4alcohol, acetonitrile, one or more in water, preferred solvent is DMF, C
1-C
4alcohol in one or more, preferred solvent is DMF/ methyl alcohol (1: 1); Described suitable temperature can be 0 DEG C ~ 100 DEG C, and preferably, temperature is 60 DEG C ~ 70 DEG C.
2, reduce: the product of condensation reaction is without separation and purification, and direct and reductive agent is obtained by reacting the compound shown in general formula (I).Wherein reductive agent can be sodium cyanoborohydride, sodium borohydride, sodium triacetoxy borohydride, pyridine/borine etc., and preferred reductive agent is sodium cyanoborohydride.
Method B: work as R
1=H, R
2=CH
2r
4, R
4time described above:
1, condensation: the compound shown in general formula (II) and alkanoic R
4-CHO reacts in suitable solvent and suitable temperature, generates intermediate Schiff 's base.Wherein alkanoic R
4the mol ratio of the compound shown in-CHO Yu general formula (II) is 1.8: 1 to 2.2: 1, preferably 2: 1.。Described suitable solvent can be selected from dimethyl sulfoxide (DMSO) (DMSO), DMF (DMF), C
1~ C
4alcohol, acetonitrile, one or more in water, preferred solvent is DMF, C
1~ C
4alcohol in one or more, preferred solvent is DMF/ methyl alcohol (1: 1); Described suitable temperature can be 0 DEG C ~ 100 DEG C, and preferably, temperature is 60 DEG C ~ 70 DEG C.
2, reduce: the product of condensation reaction is without separation and purification, and direct and reductive agent is obtained by reacting the compound shown in general formula (I).Wherein reductive agent can be sodium cyanoborohydride, sodium borohydride, sodium triacetoxy borohydride, pyridine/borine etc., and preferred reductive agent is sodium cyanoborohydride.
Method C: work as R
2=H, R
1=CH
2r
3, R
3time described above:
1, condensation: the compound shown in general formula (II) and aromatic aldehyde R
3-CHO reacts in suitable solvent and suitable temperature, generates intermediate Schiff 's base.Wherein the mol ratio of the compound shown in aldehyde and general formula (II) is 1.8: 1 ~ 2.2: 1, preferably 2: 1.Described suitable solvent can be selected from dimethyl sulfoxide (DMSO) (DMSO), DMF (DMF), C
1~ C
4alcohol, acetonitrile, one or more in water, preferred solvent is DMF, C
1~ C
4alcohol in one or more, preferred solvent is DMF: methyl alcohol=1: 1; Described suitable temperature can be 0 DEG C ~ 100 DEG C, and preferable temperature is 60 DEG C ~ 70 DEG C.
2, reduce: the product of condensation reaction is without separation and purification, and direct and reductive agent is obtained by reacting the compound shown in general formula (I).Wherein reductive agent can be sodium cyanoborohydride, sodium borohydride, sodium triacetoxy borohydride, pyridine/borine etc., and preferred reductive agent is sodium cyanoborohydride.
Another object of the present invention is to provide above-mentioned glycopeptide derivant or its pharmaceutically purposes of acceptable salt in the medicine preparing bacterial-infection resisting.Positive progressive effect of the present invention is that the derivative of the compound as shown in general formula (I) of the present invention and pharmacologically acceptable salts thereof have good anti-microbial effect.
Embodiment
In order to illustrate the present invention further, provide a series of embodiment below.It is pointed out that these embodiments are illustrative completely.The object providing these embodiments is to fully express meaning of the present invention and content, but does not therefore limit the present invention among described scope of embodiments.
In the examples below, following abbreviations has following implication.Undefined abbreviation has its generally accepted implication, and unless stated otherwise, all room temperatures all refer to temperature 20 DEG C-30 DEG C.
The related data of some Compound of Example of general formula (I) is in table 1.
In embodiment, preparation HPLC purification condition: with chromatographic column Sepax BR-C
1821.2 × 100mm (5 μm), gradient elution, moving phase forms:
| Time (min) | Methyl alcohol (%) | 0.1% formic acid |
| 0 | 20 | 80 |
| 20 | 60 | 40 |
Determined wavelength 240nm.By required flow point decompression removing organic solvent, adjust pH to 6 ~ 7 with saturated sodium bicarbonate, filter, washing; Or with n-butanol extraction, wash, pressure reducing and steaming propyl carbinol, obtain product after drying.Yield described in the present invention refers to molar yield.
Table 1
Embodiment 1: the synthesis of compound (II)
Compound shown in 10g general formula (III) is dissolved in 100mL TFA and stirs 22h in 20 DEG C, reclaim under reduced pressure TFA, by slow for residue impouring chloroform: ether=1: in the mixed solution of 1 (1 × 400mL), filter, gained solid is dissolved in 5% methanol solution, pH=8 is adjusted with aqueous sodium hydroxide solution, with Uni PS25-300 for filler fills post, with the methyl alcohol of 20% and the hydrochloric acid of 0.014% for moving phase, wash-out obtains the dihydrochloride 5.47g of the compound shown in general formula (II), and yield is 64.1%.
1H-NMR(400MHz，D
2O)δ(ppm)：7.58(2H)，7.33(2H)，6.86-7.10(4H)，6.51(1H)，6.43(1H)，6.30(1H)，5.18-5.46(6H)，4.97-4.67(4H)，4.30-3.96(2H)，3.49(1H)，2.77(3H)，2.54-2.06(4H)，1.78-1.23(9H)，0.84-0.82(6H)。
Embodiment 2: the synthesis of compound (II)
Compound shown in 5g general formula (III) is dissolved in 50mL TFA and stirs 8h in 30 DEG C, reclaim under reduced pressure TFA, by slow for residue impouring chloroform: ether=1: in the mixed solution of 1 (1 × 200mL), filter, gained solid is dissolved in 5% methanol solution, pH=8 is adjusted with aqueous sodium hydroxide solution, with Uni PS25-300 for filler fills post, with the methyl alcohol of 20% and the hydrochloric acid of 0.014% for moving phase, wash-out obtains the dihydrochloride 2.0g of the compound shown in general formula (II), and yield is 46.8%.
Embodiment 3: the synthesis of compound 1
By the dihydrochloride (400mg of the compound shown in general formula (II), 0.295mmol) be dissolved in the methyl alcohol of 4mL, add 4mL DMF, 0.01mL DIEA in stirring at room temperature 5min, then adds 4-bromobenzaldehyde (327mg, sodium cyanoborohydride (78mg is added after 1.768mmol) stirring 2 hours in 70 DEG C, 1.238mmol), continue stirring 20 hours, pressure reducing and steaming methyl alcohol after reaction solution cooling, add 40mL acetone in resistates and separate out precipitation, suction filtration.Obtain crude product with acetone, water washing successively, purify with preparation HPLC, obtain finished product (compound 1) 83mg, yield 17.2%.
1H-NMR(400MHz，DMSO-d
6+D
2O)δ(ppm)：7.71(1H)，7.47-7.00(14H)，6.79-6.28(4H)，5.51(1H)，5.23-5.05(4H)，4.85-4.15(7H)，3.60-2.52(4H)，2.30-2.10(5H)，1.62-1.20(9H)，0.86-0.84(6H)。
Embodiment 4: the synthesis of compound 1
By the dihydrochloride (300mg of the compound shown in general formula (II), 0.221mmol) be dissolved in the methyl alcohol of 4mL, add 4mL DMF, 0.01mL DIEA in stirring at room temperature 5min, then adds 4-bromobenzaldehyde (245mg, sodium cyanoborohydride (55mg is added after 1.324mmol) stirring 2 hours in 0 DEG C, 0.873mmol), stirring 25 hours is continued, pressure reducing and steaming methyl alcohol, add 40mL acetone in resistates and separate out precipitation, suction filtration.Obtain crude product with acetone, water washing successively, purify with preparation HPLC, obtain finished product (compound 1) 32mg, yield 8.9%.
Embodiment 5: the synthesis of compound 1
By the dihydrochloride (400mg of the compound shown in general formula (II), 0.295mmol) be dissolved in the methyl alcohol of 4mL, add 4mL DMF, 0.01mL DIEA is in stirring at room temperature 5min, add 4-bromobenzaldehyde (327mg again, sodium triacetoxy borohydride (250mg is added after 1.768mmol) stirring 2 hours in 60 DEG C, 1.179mmol), continue stirring 20 hours, pressure reducing and steaming methyl alcohol after reaction solution cooling, add 40mL acetone in resistates and separate out precipitation, suction filtration.Obtain crude product with acetone, water washing successively, purify with preparation HPLC, obtain finished product (compound 1) 70mg, yield 14.6%.
Embodiment 6: the synthesis of compound 1
By the dihydrochloride (200mg of the compound shown in general formula (II), 0.147mmol) be dissolved in 4mL dimethyl sulfoxide (DMSO) (DMSO), add 0.01mL DIEA in stirring at room temperature 5min, add 4-bromobenzaldehyde (163mg again, add sodium cyanoborohydride (39mg, 0.619mmol) after 0.881mmol) stirring 2 hours in 100 DEG C, continue stirring 10 hours, after reaction solution cooling, impouring 40mL acetone separates out precipitation, suction filtration.Obtain crude product with acetone, water washing successively, purify with preparation HPLC, obtain finished product (compound 1) 20.0mg, yield 8.4%.
Embodiment 7: the synthesis of compound 4
By the dihydrochloride (390mg of the compound shown in general formula (II), 0.287mmol) be dissolved in the ethanol of 4mL, add 4mL DMF, 0.01mL DIEA in stirring at room temperature 5min, then adds phenyl aldehyde (183mg, sodium cyanoborohydride (73mg is added after 1.726mmol) stirring 2 hours in 70 DEG C, 1.159mmol), continue stirring 20 hours, pressure reducing and steaming methyl alcohol after reaction solution cooling, add 40mL acetone in resistates and separate out precipitation, suction filtration.Obtain crude product with acetone, water washing successively, purify with preparation HPLC, obtain finished product (compound 4) 67mg, yield 15.9%.
1H-NMR(400MHz，DMSO-d
6+D
2O)δ(ppm)：7.72(1H)，7.54-7.03(13H)，6.80(2H)，6.70-6.30(3H)，5.44(1H)，5.24-5.00(4H)，4.80-3.90(7H)，3.42-2.52(5H)，2.34-1.95(6H)，1.77-1.15(9H)，0.88-0.86(6H)。
Embodiment 8: the synthesis of compound 17
By the dihydrochloride (350mg of the compound shown in general formula (II), 0.258mmol) be dissolved in the methyl alcohol of 4mL, add 4mL DMF, 0.01mL DIEA in stirring at room temperature 5min, then adds enanthaldehyde (176mg, 1.544mmol) stir 2h in 70 DEG C, add sodium cyanoborohydride (65mg, 1.032mmol) and continue stirring 6 hours in 70 DEG C, pressure reducing and steaming methyl alcohol after reaction solution cooling, add 40mL acetone in resistates and separate out precipitation, suction filtration.Obtain crude product with acetone, water washing successively, purify with preparation HPLC, obtain finished product (compound 17) 81mg, yield 21.2%.
1H-NMR(400MHz，DMSO-d
6+D
2O)δ(ppm)：7.73(1H)，7.60(1H)，7.45(1H)，7.30-7.18(3H)，7.00(1H)，6.79(2H)，6.32(1H)，6.30(1H)，5.48-5.15(4H)，4.94-3.90(7H)，3.40-2.52(4H)，2.40-2.00(6H)，1.80-1.17(29H)，0.85-0.80(12H)。
Embodiment 9: the synthesis of compound 17
By the dihydrochloride (400mg of the compound shown in general formula (II), 0.295mmol) be dissolved in the methyl alcohol of 4mL, add 4mL DMF, 0.01mL DIEA in stirring at room temperature 5min, then adds enanthaldehyde (168mg, 1.474mmol) stir 2h in 70 DEG C, add sodium cyanoborohydride (74mg, 1.175mmol) and continue stirring 6 hours in 70 DEG C, pressure reducing and steaming methyl alcohol after reaction solution cooling, add 40mL acetone in resistates and separate out precipitation, suction filtration.Obtain crude product with acetone, water washing successively, purify with preparation HPLC, obtain finished product (compound 17) 83mg, yield 19.0%.
Embodiment 10: the synthesis of compound 17
By the dihydrochloride (300mg of the compound shown in general formula (II), 0.221mmol) be dissolved in the methyl alcohol of 4mL, add 4mL DMF, 0.01mL DIEA in stirring at room temperature 5min, then adds enanthaldehyde (176mg, 1.544mmol) stir 2h in 70 DEG C, add sodium cyanoborohydride (56mg, 0.889mmol) and continue stirring 6 hours in 70 DEG C, pressure reducing and steaming methyl alcohol after reaction solution cooling, add 40mL acetone in resistates and separate out precipitation, suction filtration.Obtain crude product with acetone, water washing successively, purify with preparation HPLC, obtain finished product (compound 17) 59mg, yield 18.0%.
Embodiment 11: the synthesis of other compounds of compound 2 ~ 20
Identical with the preparation of compound 1, just use 4-chlorobenzaldehyde, 4-phenyl phenyl aldehyde, 2 respectively, 4-dichlorobenzaldehyde, 4-methoxybenzaldehyde, 3,4-dimethoxy benzaldehyde, 2-bromobenzaldehyde, 3-bromobenzaldehyde, 4-(the chloro-phenyl of 4-)-phenyl aldehyde, 2,4,5-trifluro benzaldehyde, 3-chlorobenzaldehyde, 3,4-dichlorobenzaldehydes, n-capric aldehyde, n-nonyl aldehyde, n-octaldehyde, n-hexyl aldehyde, valeraldehyde, butyraldehyde-n, replacement 4-bromobenzaldehyde.
Embodiment 12: the synthesis of compound 21
By the dihydrochloride (350mg of the compound shown in general formula (II), 0.258mmol) be dissolved in the methyl alcohol of 4mL, add 4mL DMF, 0.01mL DIEA in stirring at room temperature 5min, then adds 4-chlorobenzaldehyde (72mg, sodium cyanoborohydride (32mg is added after 0.514mmol) stirring 2 hours in 70 DEG C, 0.508mmol), continue stirring 20 hours, pressure reducing and steaming methyl alcohol after reaction solution cooling, add 40mL acetone in resistates and separate out precipitation, suction filtration.Obtain crude product with washing with acetone, purify with preparation HPLC, obtain finished product (compound 21) 70mg, yield 19.3%.
1H-NMR(400MHz，DMSO-d
6+D
2O)δ(ppm)：7.73(1H)，7.56-7.21(8H)，6.95(1H)，6.80(2H)，6.44-6.32(3H)，5.49-5.02(5H)，4.92-3.90(9H)，3.17-2.52(1H)，2.29-2.02(5H)，1.80-1.20(9H)，0.89-0.84(6H)。
Embodiment 13: the synthesis of compound 21
By the dihydrochloride (400mg of the compound shown in general formula (II), 0.295mmol) be dissolved in the methyl alcohol of 4mL, add 4mL DMF, 0.01mL DIEA in stirring at room temperature 5min, then adds 4-chlorobenzaldehyde (74mg, sodium cyanoborohydride (37mg is added after 0.529mmol) stirring 2 hours in 70 DEG C, 0.587mmol), continue stirring 20 hours, pressure reducing and steaming methyl alcohol after reaction solution cooling, add 40mL acetone in resistates and separate out precipitation, suction filtration.Obtain crude product with washing with acetone, purify with preparation HPLC, obtain finished product (compound 21) 62mg, yield 14.9%.
Embodiment 14: the synthesis of compound 21
By the dihydrochloride (330mg of the compound shown in general formula (II), 0.243mmol) be dissolved in the methyl alcohol of 4mL, add 4mL DMF, 0.01mL DIEA in stirring at room temperature 5min, then adds 4-chlorobenzaldehyde (75mg, sodium cyanoborohydride (30mg is added after 0.536mmol) stirring 2 hours in 70 DEG C, 0.476mmol), continue stirring 20 hours, pressure reducing and steaming methyl alcohol after reaction solution cooling, add 40mL acetone in resistates and separate out precipitation, suction filtration.Obtain crude product with washing with acetone, purify with preparation HPLC, obtain finished product (compound 21) 62mg, yield 18.1%.
Embodiment 15: the synthesis of compound 22 ~ 26
Identical with the preparation of compound 21, just use 3-chlorobenzaldehyde, 3,4-dichlorobenzaldehydes, 4-bromobenzaldehyde, 3-bromobenzaldehyde, 2-bromobenzaldehyde to replace 4-chlorobenzaldehyde respectively.
Embodiment 16: the synthesis of compound 27
By the dihydrochloride (300mg of the compound shown in general formula (II), 0.221mmol) be dissolved in the methyl alcohol of 4mL, add 4mL DMF, 0.02mL DIEA in stirring at room temperature 5min, then adds n-capric aldehyde (69mg, 0.442mmol), sodium cyanoborohydride (28mg, 0.444mmol) stir 1.5 hours in 70 DEG C, pressure reducing and steaming methyl alcohol after reaction solution cooling, adds 40mL acetone and separates out precipitation, suction filtration in resistates.Obtain crude product with washing with acetone, purify with preparation HPLC, obtain finished product 71mg, yield 22.4%.
1H-NMR(400MHz，DMSO-d
6+D
2O)δ(ppm)：7.72(1H)，7.58-7.18(4H)，6.94(1H)，6.78(2H)，6.52(1H)，6.32(2H)，5.48-5.16(5H)，4.89-4.22(6H)，3.30-2.52(3H)，2.33-2.00(6H)，1.96-1.20(25H)，0.89-0.80(9H)。
Embodiment 17: the synthesis of compound 27
By the dihydrochloride (350mg of the compound shown in general formula (II), 0.258mmol) be dissolved in the methyl alcohol of 4mL, add 4mL DMF, 0.02mL DIEA in stirring at room temperature 5min, then adds n-capric aldehyde (72mg, 0.462mmol), sodium cyanoborohydride (32mg, 0.508mmol) stir 1.5 hours in 70 DEG C, pressure reducing and steaming methyl alcohol after reaction solution cooling, adds 40mL acetone and separates out precipitation, suction filtration in resistates.Obtain crude product with washing with acetone, purify with preparation HPLC, obtain finished product 65mg, yield 17.7%.
Embodiment 18: the synthesis of compound 27
By the dihydrochloride (300mg of the compound shown in general formula (II), 0.221mmol) be dissolved in the methyl alcohol of 4mL, add 4mL DMF, 0.02mL DIEA in stirring at room temperature 5min, then adds n-capric aldehyde (76mg, 0.487mmol), sodium cyanoborohydride (28mg, 0.444mmol) stir 1.5 hours in 70 DEG C, pressure reducing and steaming methyl alcohol after reaction solution cooling, adds 40mL acetone and separates out precipitation, suction filtration in resistates.Obtain crude product with washing with acetone, purify with preparation HPLC, obtain finished product 67mg, yield 21.3%.
Embodiment 19: the synthesis of compound 28 ~ 33
Identical with the preparation of compound 27, just replace n-capric aldehyde with n-nonyl aldehyde, n-octaldehyde, enanthaldehyde, n-hexyl aldehyde, valeraldehyde, butyraldehyde-n.
Embodiment 20: the preparation of compound 34 (i.e. compound 16 dihydrochloride)
Weigh Compound 1640mg is dissolved in 5mL methyl alcohol, adds the saturated hydrogen chloride methanol solution of 0.3mL, stirring at room temperature, after desolventizing, adds acetone and stirs, filters, washs, dries.Cl ultimate analysis: theoretical value (C
76h
97cl
2n
9o
19.2HCl) 8.95%, measured value 8.46%.
Embodiment 21: effect example
The antibacterial activity in vitro test-results of target compound of the present invention is in table 2.Method is as follows:
1, test strain
Streptococcus aureus 26003 (Staphylococcus aureus)
2, test method
Sample: solid-stately treat that examination thing first dissolves with a small amount of DMSO, then is diluted to 0.5mg/ml with sterilized water.
Measuring method: agar plate paper disk method.It is 10 that agar plate carries bacterium amount
5cFU/ml.Scraps of paper diameter 6.0mm, each scraps of paper loading 20 μ l.Cultivate in 37 DEG C of incubators and observe for 18 hours, measure antibacterial circle diameter.
3, active description (see table 2)
+++ represent antibacterial circle diameter > 13mm
++ represent antibacterial circle diameter 9-13mm
+ represent antibacterial circle diameter 7-9mm (containing 9mm)
The anti-microbial activity result of table 2 compound 1-34
| Compound | Active | Compound | Active |
| 1 | +++ | 18 | +++ |
| 2 | +++ | 19 | +++ |
| 3 | + | 20 | ++ |
| 4 | + | 21 | +++ |
| 5 | ++ | 22 | ++ |
| 6 | + | 23 | ++ |
| 7 | + | 24 | ++ |
| 8 | ++ | 25 | ++ |
| 9 | ++ | 26 | ++ |
| 10 | + | 27 | + |
| 11 | ++ | 28 | + |
| 12 | +++ | 29 | + |
| 13 | ++ | 30 | + |
| 14 | + | 31 | + |
| 15 | + | 32 | + |
| 16 | +++ | 33 | + |
| 17 | +++ | 34 | + |
From table 2, compound of the present invention all shows anti-microbial activity.
Embodiment 22: effect example
The external MIC of partial target compound of the present invention the results are shown in Table 3.Method is as follows:
1, test strain
Totally 3 kinds: streptococcus aureus 26003 (Staphylococcus aureus), Staphylococcus albus 260101 (Staphylococcus albus), faecalis 32220 (Enterococcus faecium).
2, test method
Sample: first dissolve with DMSO, then be diluted to suitable concn with sterilized water, then two-fold dilution successively.
Measure: agar plate dilution method.Quantitative with multiple spot inoculation instrument, inoculate often 10
5cFU.Cultivate 18-24 hour observations in 37 DEG C of incubators, read minimum inhibitory concentration value (MIC).
3, positive control drug is vancomycin hydrochloride
The MIC value of part of compounds is in table 3.
The MIC (μ g/ml) of table 3 part of compounds
From table 3, part of compounds of the present invention, compared with vancomycin hydrochloride, has better anti-microbial activity.
It should be noted that, foregoing invention content and embodiment are intended to the practical application proving technical scheme provided by the present invention, should not be construed as limiting the scope of the present invention.Those skilled in the art in spirit of the present invention and principle, when doing various amendment, equivalent replace or improve.Protection scope of the present invention is as the criterion with appended claims.
Claims (22)
1. the monose glycopeptide derivant shown in general formula (I) and pharmacologically acceptable salts thereof,
Wherein: R
1and R
2h, CH respectively
2-R
3or CH
2-R
4, R
1and R
2difference or R
1and R
2be CH simultaneously
2-R
3or CH
2-R
4; Wherein R
3be aromatic group, this aromatic group is the phenyl ring or cyclohexyl biphenyl that do not replace or replace, and the substituting group of phenyl ring or cyclohexyl biphenyl is with one or more halogens, one or more methoxyl group; R
4for C
3-C
9saturated fatty alkyl.
2. monose glycopeptide derivant as claimed in claim 1 and pharmacologically acceptable salts thereof, wherein, four hydroxyls of its peptide backbone six amino acids glycosyl are axial bond.
3. monose glycopeptide derivant as claimed in claim 1 and pharmacologically acceptable salts thereof, wherein, R
1, R
2be respectively hydrogen, benzyl, 4-chlorobenzyl, 4-bromobenzyl, 4-methoxy-benzyl, 4-phenylbenzyl, 4-(the chloro-phenyl of 4-)-benzyl, 3-chlorobenzyl, 2-bromobenzyl, 3-bromobenzyl, 2,4-dichloro benzyl, 3,4-dichloro benzyl, 3,4-dimethoxy-benzyl, 2,4,5-trifluoro-benzyl, positive decyl, n-nonyl, n-octyl, n-heptyl, n-hexyl, n-pentyl or normal-butyl.
4. the monose glycopeptide derivant as described in as arbitrary in claims 1 to 3 and pharmacologically acceptable salts thereof, wherein, described pharmacy acceptable salt is alkali-metal salt, the salt of alkaline-earth metal or the salt that formed with acid.
5. monose glycopeptide derivant as claimed in claim 4 and pharmaceutically acceptable salt, wherein, described basic metal is sodium or potassium; Described alkaline-earth metal is calcium or magnesium; Described acid is hydrochloric acid, Hydrogen bromide, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, propanedioic acid, succsinic acid, fumaric acid, toxilic acid, lactic acid, oxysuccinic acid, tartrate, citric acid, picric acid, methylsulfonic acid, aspartic acid or L-glutamic acid.
6. a preparation method for the monose glycopeptide derivant as described in as arbitrary in Claims 1 to 5 and pharmaceutically acceptable salt, described preparation method comprises: by the compound shown in general formula (II) and aromatic aldehyde R
3-CHO or alkanoic R
4-CHO reacts in polar solvent and 0 DEG C ~ 100 DEG C temperature, generates intermediate Schiff 's base, then reacts with reductive agent, obtains the monose glycopeptide derivant shown in general formula (I).
7. preparation method as claimed in claim 6, wherein, works as R
2=R
1, R
3and R
4as claim 1 define time, aromatic aldehyde R
3-CHO or alkanoic R
4the mol ratio of the compound shown in-CHO Yu general formula (II) is 5:1 ~ 7:1.
8. preparation method as claimed in claim 7, wherein, aromatic aldehyde R
3-CHO or alkanoic R
4the mol ratio of the compound shown in-CHO Yu general formula (II) is 6:1.
9. preparation method as claimed in claim 6, wherein, works as R
1=H, R
2=CH
2r
4, R
4as claim 1 define time, aromatic aldehyde R
3-CHO or alkanoic R
4the mol ratio of the compound shown in-CHO Yu general formula (II) is 1.8:1 ~ 2.2:1.
10. preparation method as claimed in claim 9, wherein, aromatic aldehyde R
3-CHO or alkanoic R
4the mol ratio of the compound shown in-CHO Yu general formula (II) is 2:1.
11. preparation methods as claimed in claim 6, wherein, work as R
2=H, R
1=CH
2r
3, R
3as claim 1 define time, aromatic aldehyde R
3-CHO or alkanoic R
4the mol ratio of the compound shown in-CHO Yu general formula (II) is 1.8:1 ~ 2.2:1.
12. preparation methods as claimed in claim 11, wherein, aromatic aldehyde R
3-CHO or alkanoic R
4the mol ratio of the compound shown in-CHO Yu general formula (II) is 2:1.
13. preparation methods as claimed in claim 6, wherein, described polar solvent is selected from dimethyl sulfoxide (DMSO), DMF, C
1-C
4alcohol in one or more.
14. preparation methods as claimed in claim 13, wherein, described polar solvent is DMF: methyl alcohol=1:1.
15. preparation methods as claimed in claim 6, wherein, described temperature is 60 DEG C ~ 70 DEG C.
16. preparation methods as claimed in claim 6, wherein, described reductive agent is sodium cyanoborohydride, sodium triacetoxy borohydride.
The preparation method of the compound shown in 17. 1 kinds of general formulas (II), wherein, described preparation method comprises the compound shown in general formula (III) and trifluoracetic acid stirring reaction at 20 DEG C ~ 30 DEG C temperature obtains the compound shown in general formula (II).
18. 1 kinds as arbitrary in Claims 1 to 5 as described in glycopeptide derivant or its pharmaceutically application of acceptable salt in preparation treatment bacterial infection disease medicine.
19. 1 kinds of pharmaceutical compositions with good anti-microbial activity, wherein, described pharmaceutical composition comprise treatment significant quantity as arbitrary in Claims 1 to 5 as described in glycopeptide derivant or its pharmaceutically acceptable salt and pharmaceutically acceptable carrier.
20. pharmaceutical compositions as claimed in claim 19, wherein, described glycopeptide derivant or its pharmaceutically acceptable salt as activeconstituents, in this pharmaceutical composition containing 0.1wt.% ~ 99.5wt.% activeconstituents.
21. pharmaceutical compositions as claimed in claim 20, wherein, the activeconstituents containing 0.5wt.% ~ 90wt.% in this pharmaceutical composition.
22. 1 kinds as the application of the pharmaceutical composition as described in arbitrary in claim 19 ~ 21 in preparation treatment bacterial infection disease medicine.
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| CN101928331A (en) * | 2009-06-26 | 2010-12-29 | 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 |
| CN102050866A (en) * | 2009-11-04 | 2011-05-11 | 上海来益生物药物研究开发中心有限责任公司 | Method for purifying glycopeptide compound |
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| CN101928331A (en) * | 2009-06-26 | 2010-12-29 | 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 |
| CN102050866A (en) * | 2009-11-04 | 2011-05-11 | 上海来益生物药物研究开发中心有限责任公司 | Method for purifying glycopeptide compound |
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Effective date of registration: 20161008 Address after: 312500 No. 59 East Ring Road, Zhejiang, Xinchang Patentee after: Xinchang Pharmaceutical Factory, Zhejiang Medicine Co., Ltd. Patentee after: Shanghai Laiyi Biomedical Research and Development Center LLC Address before: 312500 No. 59 East Ring Road, Zhejiang, Xinchang Patentee before: Xinchang Pharmaceutical Factory, Zhejiang Medicine Co., Ltd. Patentee before: Shanghai Laiyi Biomedical Research and Development Center LLC Patentee before: Shanghai Institute of pharmaceutical industry |