CN102766198A - Glycopeptide antifungal compound, and preparation method and application thereof - Google Patents
Glycopeptide antifungal compound, and preparation method and application thereof Download PDFInfo
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- CN102766198A CN102766198A CN201210135311XA CN201210135311A CN102766198A CN 102766198 A CN102766198 A CN 102766198A CN 201210135311X A CN201210135311X A CN 201210135311XA CN 201210135311 A CN201210135311 A CN 201210135311A CN 102766198 A CN102766198 A CN 102766198A
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Abstract
The invention provides a glycopeptide antifungal compound and a pharmaceutically acceptable salt thereof, a preparation method and application thereof, and a pharmaceutical composition containing the active component. The glycopeptide antifungal compound has a general structural formula shown as below; n equals to 1, 2 or 3; and R represents monosaccharide or disaccharide, wherein the monosaccharide is glucose, galactose, xylose, rhamnose, mannose, ribose, glucosamine or acetyl glucosamine, and the disaccharide is maltose or lactose. Compared with existing clinical antifungal drugs, the compound provided by the invention has advantages of high efficiency, low toxicity and broad antibacterial spectrum, etc.; therefore, the compound can be applied to preparation of antifungal drugs. The preparation method provided by the invention successfully introduce different glycosyls onto primary amino group of Caspofungin, and has advantages of simple process and high yield.
Description
Technical field
The present invention relates to the medical compounds technical field, specifically, relate to a kind of glycopeptide class antifungal compound and preparation method thereof and application.
Background technology
In recent years; Because the increase of cancer radiation, chemotherapy and organ transplantation and PCI patient number; Being widely used of Broad spectrum antibiotics, cortin and immunosuppressor clinically, and AIDS is popular, and clinical deep fungal infection case is sharply increased; Nearly 300,000 examples of systemic fungal infection patient that the whole world is diagnosed out every year; In the AIDS patient, it is systemic fungal infection (Markus, R. Mucosal and systemic fungal infections in patients with AIDS:Prophylaxis and treatment. that 60% the direct cause of death is arranged
Drugs, 2004,64,1163-1180.).The life and health that the mycosis serious threat is human.In the medicine of treatment deep fungal infection, the nitrogen azole compounds is used the most extensive, and modal clinically at present fluconazole and itraconazole are exactly azole antifungals.But the day by day serious resistance problem of fluconazole has seriously limited its application.Other antifungal drug; Like polyene antibiotics, propylamine, morpholine class and fluorine miazines etc.; There are toxicity, side effect big (like amphotericin B), narrow antimicrobial spectrum more, are prone to recurrence many deficiencies (Owens, J. Antifungal drugs:A helping hand. such as (like 5-flurocytosines)
Nat. Rev.Drug. Discov.2005,1,884-885.).Development is efficient, wide spectrum, the anti-deep fungal infection medicine of low toxicity have become a urgent world subject, causes attention both domestic and external day by day.
The seventies in last century, scientist extracts one type of cyclic peptide compound---echinocandin (Echinocandins) (Denning, W. D. Echinocandin antifungal drugs. that can suppress multiple fungal growth breeding from aspergillus fumigatus
Lancet, 2003,362,1142-1151.).Discover that further the mechanism of action of this compounds suppresses in the fungal cell membrane for passing through
β-1,3-D-glucan synthase (Wiederhold, N. P.; Lewis, R. E. The echinocandin antifungals:an overview of the pharmacology, spectrum and clinical efficacy.
Expert. Opin. Investig. Drugs. 2003,12,1313-1333.), make the staple of fungal cell wall
β-1; The biosynthesis block of 3-D-VISOSE, and finally cause the cytoskeleton of fungi to form and dead (see figure 1), such antifungal compound and amphotericin B and azole antifungal medicine medicine do not have cross resistance; Because the mammal cell does not contain cell walls, does not produce
β-1; The 3-D-glucan synthase is so this type of drug selectivity is high, effect is powerful, toxicity is lower, adds easy to use, better tolerance; Have broad application prospects, at present the research of this compounds has been become the focus and new direction of current searching novel anti fungi-medicine.
At present; Three echinocandin-class antifungal drug listings have been arranged; Be respectively Caspofungin (Caspofungin, trade(brand)name: MK 0991, Cancidas), Mi Kafen is clean and anidulafungin; Such medicine is mainly used in invasive aspergillosis and moniliosis (Yalaz, the M. of treatment refractory clinically; Akisu, M.; Hilmioglu, S.; Calkavur, S.; Cakmak, B.; Kultursay, N. Successful caspofungin treatment of multidrug resistant Candida parapsilosis septicaemia in an extremely low birth weight neonate.
Mycoses. 2006,49,242-245.).Wherein, Caspofungin is released in calendar year 2001 by Merck & Co., Inc., is the echinocandin class medicine of first listing, and its chemical structural formula is shown in the following figure:
Because Most amino-acids is alpha-non-natural amino acid in the structure of Caspofungin, so its complete synthesis difficulty is very big, does not see the complete synthesis report of this compound so far as yet.Merck & Co., Inc. reported by echinocandin B in 2007
0Be raw material, realized semi-synthetic (Leonard, the W. R. of Caspofungin through three-step reaction; Belyk, K. M.; Conlon, D. A.; Bender, D. R.; DiMichele, L. M.; Liu, J.; Hughes, D. L. Synthesis of the antifungal beta-1,3-glucan synthase inhibitor CANCIDAS (caspofungin acetate) from pneumocandin B
0.
J. Org. Chem.2007,72,2335-2343.).In addition, to the segmental synthetic part report that also has of the part in the Caspofungin, for example, Leonard took the lead in realizing the chirality of the longer chain fatty acid in the Caspofungin structure synthetic (Leonard, W. R. in 2002; Belyk, K. M.; Bender, D. R.; Conlon, D. A.; Hughes, D. L.; Reider P. J. Determination of the Relative and Absolute Configuration of the Dimethylmyristoyl Side Chain of Pneumocandin B0 by Asymmetric Synthesis.
Org. Lett.2002,4,4201-4204.).
Although the Caspofungin as the echinocandin class antifungal drug has good anti-mycotic activity and has been applied to clinical anti-infective therapy.But still there is following defective in it: at first, Caspofungin is to neural genotoxic potential, mainly is because it good fat-solublely causes it to see through due to the hemato encephalic barrier easily; Secondly, the Caspofungin poorly water-soluble, need process acetate usually can patent medicine; Once more, the acetate of this medicine is deliquescence very easily, and poor stability has limited the variation of its formulation, and the formulation of this medicine has only lyophilized powder a kind of at present.More than these issues limit its clinical application (Pacetti, S.A.; Gelone, S. P. Caspofungin acetate for treatment of invasive fungal infections.
Ann. Pharmacother.2003,37,90-98.).Therefore, the structure of Caspofungin being optimized, reducing that it is fat-soluble, it is water-soluble to improve, to improve its stability and to reduce spinoff, promote its applying clinically, is very necessary.But also do not meet similar report at present.
Summary of the invention
The objective of the invention is to deficiency of the prior art, the glycopeptide class antifungal compound and the pharmacy acceptable salt thereof of a kind of efficient, low toxicity, wide spectrum is provided.
One purpose more of the present invention is that a kind of pharmaceutical composition is provided.
Another purpose of the present invention is that the preparation method of a kind of glycopeptide class antifungal compound and pharmacy acceptable salt thereof is provided.
The 4th purpose of the present invention is that the purposes of a kind of glycopeptide class antifungal compound and pharmacy acceptable salt thereof is provided.
For realizing above-mentioned purpose, the technical scheme that the present invention takes is:
A kind of glycopeptide class antifungal compound and pharmacy acceptable salt thereof, described Caspofungin glycosyl derivatives general structure is following:
Wherein, n equals 1,2 or 3; R is monose or disaccharides; Described monose is glucose, semi-lactosi, wood sugar, rhamnosyl, seminose, ribose, GS or acetylglucosamine; Described disaccharides is SANMALT-S or lactose.
Described n equals 3.
Described R is glucose or SANMALT-S.
Described pharmacy acceptable salt class is hydrochloride, vitriol, hydrosulfate, hydrobromate, acetate, oxalate, Citrate trianion or mesylate.
For realizing above-mentioned second purpose, the technical scheme that the present invention takes is:
A kind of pharmaceutical composition, it contains as above arbitrary described glycopeptide class antifungal compound and pharmacy acceptable salt thereof, and contains conventional pharmaceutical carrier.
For realizing above-mentioned the 3rd purpose, the technical scheme that the present invention takes is:
The preparation method of a kind of as above arbitrary described glycopeptide class antifungal compound and pharmacy acceptable salt thereof, described method comprises the following steps:
A) preparation key intermediate glycosyl Acibenzolar: with glycosyls such as glucose, semi-lactosi, wood sugar, rhamnosyl, SANMALT-S and lactose is starting raw material, obtains the glycosyl of full acetyl protection with sodium-acetate back flow reaction in acetic anhydride; Under the condition that trimethyl azide silane and BFEE exist substitution reaction takes place, the acetoxyl group of 1-position is become azido-then; Azido-generates amino back through 10% Pd-C catalytic hydrogenation and under the condition that 4-(N, N-dimethylamino) pyridine exists, is condensed into acid amides with corresponding acid anhydrides (malonic anhydride, Succinic anhydried, Pyroglutaric acid); The carboxyl that exposes out with N, generate corresponding glycosyl Acibenzolar with N-maloyl imines generation ester condensation under the condition that the N-NSC 57182 exists;
B) preparation target compound Caspofungin glycosyl derivatives: the Caspofungin glycosyl compound that condensation generates full acetyl protection takes place in key intermediate glycosyl Acibenzolar and Caspofungin acetate under the triethylamine alkaline condition, and then is that deacetylate protection promptly gets target compound Caspofungin glycosyl derivatives in sodium methylate/methanol solution of 8 at pH.
For realizing above-mentioned the 4th purpose, the technical scheme that the present invention takes is:
The application in preparation treatment fungi infestation medicine of as above arbitrary described glycopeptide class antifungal compound and pharmacy acceptable salt thereof.
The invention has the advantages that:
1, compound glycopeptide class antifungal compound of the present invention and pharmacy acceptable salt thereof are to have introduced different glycosyls on the primary amino in the Caspofungin structure, have solved shortcomings such as Caspofungin poor stability and neurotoxicity are strong; Simultaneously, can strengthen the interaction between it and the target enzyme introducing glycosyl on this Caspofungin molecule, thereby improve anti-mycotic activity.Pharmacological evaluation proves, it is active that compound of the present invention shows stronger inhibition to the part fungi, compares with the antifungal drug of existing clinical application, has advantages such as efficient, low toxicity, has a broad antifungal spectrum, therefore can be used for preparing antifungal drug.
2, preparation method of the present invention has successfully introduced different glycosyls on the primary amino of Caspofungin, prepare the Caspofungin glycosyl derivatives of efficient, low toxicity, has a broad antifungal spectrum, and technology is simple, productive rate is high.
Description of drawings
Accompanying drawing 1 is the formation of fungal cell's skeleton.
Accompanying drawing 2 is compounds
1a,
1eWith contrast medicine Caspofungin
1The stability experiment result: (A) high wet test; (B) high temperature test.
Embodiment
Below in conjunction with accompanying drawing embodiment provided by the invention is elaborated.
The high resolution mass spectrum of embodiment 1 The compounds of this invention 1a-f and nucleus magnetic hydrogen spectrum data
The compounds of this invention
1a-fHigh resolution mass spectrum and nucleus magnetic hydrogen spectrum data see table 1 and table 2.
Table 1 The compounds of this invention
1a-fThe high resolution mass spectrum table
| The compound sequence number | n | R | HR-Q-TOF-MS + |
| 1a | 3 |
 |
1642.8437 |
| 1b | 3 |
 |
1642.8458 |
| 1c | 3 |
 |
1582.8227 |
| 1d | 3 |
 |
1610.8553 |
| 1e | 3 | 1966.9497 | |
| 1f | 3 |
 |
1966.9497 |
Table 2 The compounds of this invention
1a-fThe nucleus magnetic hydrogen spectrum data sheet
The preparation of embodiment 2 The compounds of this invention 1a-f
The compounds of this invention
1a-fPreparation can slightly be divided into for two steps:
A) preparation key intermediate glycosyl Acibenzolar
7a-f, reaction scheme is following:
B) preparation target compound
1a-f, reaction scheme is following:
The concrete preparation method of The compounds of this invention 1a-f is following:
One, preparation midbody acetyl glucosides (3a-f)
(1) preparation 1,2,3,4,6-five-
O-ethanoyl-
β-D-glucopyranoside (3a)
Will
β-D-Glucopyranose
2a(40 g, 222 mmol) and sodium-acetate (30g, 330 mmol) place 500 mL three-necked bottles, add diacetyl oxide (350 mL, 3.71 mol).The reaction mixture mechanical stirring, behind 170 ℃ of back flow reaction 6 h, the room temperature cooling is poured in the mixture of ice and water (1.5 L) mixture and stirred overnight.Next day, observation had brown solid to separate out, and filtered, and filter cake gets midbody with recrystallizing methanol and with decolorizing with activated carbon
3a,Be the white powder solid, weigh 63 g, yield 72%.
(2) preparation 1,2,3,4,6-five-
O-ethanoyl-
β-D-galactopyranoside (3b)
Will
β-D-galactopyranose
2b(40 g, 222 mmol) and sodium-acetate (30g, 330 mmol) place 500 mL three-necked bottles, add diacetyl oxide (350 mL, 3.71 mol).The reaction mixture mechanical stirring, behind 170 ℃ of back flow reaction 6 h, the room temperature cooling is poured in the mixture of ice and water (1.5 L) mixture and stirred overnight.Next day, observation had brown solid to separate out, and filtered, and filter cake gets midbody with recrystallizing methanol and with decolorizing with activated carbon
3b,Be the white powder solid, weigh 65 g, yield 75%.
(3) preparation 1,2,3,4 – four-
O-ethanoyl-
β-D-xylopyranoside (3c)
Will
β-D-xylopyranose
2c(34 g, 222 mmol) and sodium-acetate (30g, 330 mmol) place 500 mL three-necked bottles, add diacetyl oxide (350 mL, 3.71 mol).The reaction mixture mechanical stirring, behind 170 ℃ of back flow reaction 6 h, the room temperature cooling is poured in the mixture of ice and water (1.5 L) mixture and stirred overnight.Next day, observation had brown solid to separate out, and filtered, and filter cake gets midbody with recrystallizing methanol and with decolorizing with activated carbon
3c,Be the white powder solid, weigh 51 g, yield 72 %.
(4) preparation 1,2,3,4-four-
O-ethanoyl-
β-D-pyrans rhamnoside (3d)
Will
β-D-pyrans rhamnosyl
2d(36 g, 222 mmol) and sodium-acetate (30 g, 330 mmol) place 500 mL three-necked bottles, add diacetyl oxide (350 mL, 3.71 mol).The reaction mixture mechanical stirring, behind 170 ℃ of back flow reaction 6 h, the room temperature cooling is poured in the mixture of ice and water (1.5 L) mixture and stirred overnight.Next day, observation had brown solid to separate out, and filtered, and filter cake gets midbody with recrystallizing methanol and with decolorizing with activated carbon
3d,Be the white powder solid, weigh 55 g, yield 74 %.
(5) preparation 2,3,4,6-four-
O-ethanoyl-
β-D-glucopyranosyl-(1-4)-1,2,3,6-four-
O-ethanoyl-
β-D-glucopyranoside (3e)
Will
β-D-pyrans SANMALT-S
2e(76 g, 222 mmol) and sodium-acetate (30 g, 330 mmol) place 500 mL three-necked bottles, add diacetyl oxide (350 mL, 3.71 mol).The reaction mixture mechanical stirring, behind 170 ℃ of back flow reaction 6 h, the room temperature cooling is poured in the mixture of ice and water (1.5 L) mixture and stirred overnight.Next day, observation had brown solid to separate out, and filtered, and filter cake gets midbody with recrystallizing methanol and with decolorizing with activated carbon
3e,Be the white powder solid, weigh 107 g, yield 71 %.
(6) preparation 2,3,4,6-four-
O-ethanoyl-
β-D-galactopyranose base-(1-4)-1,2,3,6-four-
O-ethanoyl-
β-D-glucopyranoside (3f)
Will
β-D-pyrans lactose
2f(76 g, 222 mmol) and sodium-acetate (30g, 330 mmol) place 500 mL three-necked bottles, add (350 mL, 3.71 mol) diacetyl oxide.The reaction mixture mechanical stirring, behind 170 ℃ of back flow reaction 6 h, the room temperature cooling is poured in the mixture of ice and water (1.5 L) mixture and stirred overnight.Next day, observation had brown solid to separate out, and filtered, and filter cake gets midbody with recrystallizing methanol and with decolorizing with activated carbon
3f,Be the white powder solid, weigh 102 g, yield 68 %.
Two, preparation midbody 1-azido-acetyl glucosides (4a-f)
(1) preparation 1-azido--2,3,4,6-four-
O-ethanoyl-
β-D-glucopyranoside (4a)
With acetylizad glucose
3a(10 g, 25.62 mmol) and 4A molecular sieve 10 g place 250 mL eggplant-shape bottles, vacuumize, and argon shield adds anhydrous methylene chloride 100 mL under the condition of ice bath, stir 10 min after, dropwise add trimethyl azide silane (TMSN
3, 8.5 mL, 64.05 mmol), after continuing to stir 30 min, dropwise add BFEE (BF
3.Et
2O, 8.0 mL, 64.05 mmol), after continuing to stir 1 h, remove ice bath, after stirring at room is reacted 8 h, TLC (sherwood oil: inspection ETHYLE ACETATE=1: 1), react complete, so suction filtration, filter cake is used washed with dichloromethane, pours filtrating into saturated NaHCO then
3In, be stirred to and do not produce till the bubble, tell organic layer, organic layer is used saturated NaHCO again
3Respectively wash once anhydrous Na with saturated NaCl
2SO
4Drying behind the concentrating under reduced pressure, is crossed purification by silica gel column chromatography, and developping agent is sherwood oil and ETHYLE ACETATE, gets midbody 4a behind the purifying, is the white powder solid, weighs 7.6 g, yield 79%.
(2) preparation 1-azido--2,3,4,6-four-
O-ethanoyl-
β-D-galactopyranoside (4b)
With acetylizad semi-lactosi
3b(10 g, 25.62 mmol) and 4A molecular sieve 10 g place 250 mL eggplant-shape bottles, vacuumize, and argon shield adds anhydrous methylene chloride 100 mL under the condition of ice bath, stir 10 min after, dropwise add trimethyl azide silane (TMSN
3, 8.5 mL, 64.05 mmol), after continuing to stir 30 min, dropwise add BFEE (BF
3Et
2O, 8.0 mL, 64.05 mmol), after continuing to stir 1 h, remove ice bath, after stirring at room is reacted 8 h, TLC (sherwood oil: inspection ETHYLE ACETATE=1: 1), react complete, so suction filtration, filter cake is used washed with dichloromethane, pours filtrating into saturated NaHCO then
3In, be stirred to and do not produce till the bubble, tell organic layer, organic layer is used saturated NaHCO again
3Respectively wash once anhydrous Na with saturated NaCl
2SO
4Drying behind the concentrating under reduced pressure, is crossed purification by silica gel column chromatography, and developping agent is sherwood oil and ETHYLE ACETATE, gets midbody 4b behind the purifying, is the white powder solid, weighs 7.8 g, yield 82 %.
(3) preparation 1-azido--2,3,4-three-
O-ethanoyl-
β-D-xylopyranoside (4c)
With acetylizad wood sugar
3c(8 g, 25.62 mmol) and 4A molecular sieve 10 g place 250 mL eggplant-shape bottles, vacuumize, and argon shield adds anhydrous methylene chloride 100 mL under the condition of ice bath, stir 10 min after, dropwise add trimethyl azide silane (TMSN
3, 8.5 mL, 64.05 mmol), after continuing to stir 30 min, dropwise add BFEE (BF
3.Et
2O, 8.0 mL, 64.05 mmol), after continuing to stir 1 h, remove ice bath, after stirring at room is reacted 8 h, TLC (sherwood oil: inspection ETHYLE ACETATE=1: 1), react complete, so suction filtration, filter cake is used washed with dichloromethane, pours filtrating into saturated NaHCO then
3In, be stirred to and do not produce till the bubble, tell organic layer, organic layer is used saturated NaHCO again
3Respectively wash once anhydrous Na with saturated NaCl
2SO
4Drying behind the concentrating under reduced pressure, is crossed purification by silica gel column chromatography, and developping agent is sherwood oil and ETHYLE ACETATE, gets midbody 4c behind the purifying, is the white powder solid, weighs 5.9 g, yield 77 %.
(4) preparation 1-azido--2,3,4-three-
O-ethanoyl-
β-D-pyrans rhamnoside (4d)
With acetylizad rhamnosyl
3d(8.5 g, 25.62 mmol) and 4A molecular sieve 10 g place 250 mL eggplant-shape bottles, vacuumize, and argon shield adds anhydrous methylene chloride 100 mL under the condition of ice bath, stir 10 min after, dropwise add trimethyl azide silane (TMSN
3, 8.5 mL, 64.05 mmol), after continuing to stir 30 min, dropwise add BFEE (BF
3Et
2O, 8.0 mL, 64.05 mmol), after continuing to stir 1 h, remove ice bath, after stirring at room is reacted 8 h, TLC (sherwood oil: inspection ETHYLE ACETATE=1: 1), react complete, so suction filtration, filter cake is used washed with dichloromethane, pours filtrating into saturated NaHCO then
3In, be stirred to and do not produce till the bubble, tell organic layer, organic layer is used saturated NaHCO again
3Respectively wash once anhydrous Na with saturated NaCl
2SO
4Drying behind the concentrating under reduced pressure, is crossed purification by silica gel column chromatography, and developping agent is sherwood oil and ETHYLE ACETATE, gets midbody 4d behind the purifying, is the white powder solid, weighs 6.3 g, yield 78 %.
(5) preparation 1-azido--2,3,4,6-four-
O-ethanoyl-
β-D-glucopyranosyl-(1-4)-2,3,6-three-
O-ethanoyl-
β-D-glucopyranoside (4e)
With acetylizad SANMALT-S
3e(17.5 g, 25.62 mmol) and 4A molecular sieve 10 g place 250 mL eggplant-shape bottles, vacuumize, and argon shield adds anhydrous methylene chloride 100 mL under the condition of ice bath, stir 10 min after, dropwise add trimethyl azide silane (TMSN
3, 8.5 mL, 64.05 mmol), after continuing to stir 30 min, dropwise add BFEE (BF
3Et
2O, 8.0 mL, 64.05 mmol), after continuing to stir 1 h, remove ice bath, after stirring at room is reacted 8 h, TLC (sherwood oil: inspection ETHYLE ACETATE=1: 1), react complete, so suction filtration, filter cake is used washed with dichloromethane, pours filtrating into saturated NaHCO then
3In, be stirred to and do not produce till the bubble, tell organic layer, organic layer is used saturated NaHCO again
3Respectively wash once anhydrous Na with saturated NaCl
2SO
4Drying behind the concentrating under reduced pressure, is crossed purification by silica gel column chromatography, and developping agent is sherwood oil and ETHYLE ACETATE, gets midbody 4e behind the purifying, is the white powder solid, weighs 13.7 g, yield 81 %.
(6) preparation 1-azido--2,3,4,6-four-
O-ethanoyl-
β-D-galactopyranose base-(1-4)-2,3,6-three-
O-ethanoyl-
β-D-glucopyranoside (4f)
With acetylizad lactose
3f(17.5 g, 25.62 mmol) and 4A molecular sieve 10 g place 250 mL eggplant-shape bottles, vacuumize, and argon shield adds anhydrous methylene chloride 100 mL under the condition of ice bath, stir 10 min after, dropwise add trimethyl azide silane (TMSN
3, 8.5 mL, 64.05 mmol), after continuing to stir 30 min, dropwise add BFEE (BF
3Et
2O, 8.0 mL, 64.05 mmol), after continuing to stir 1 h, remove ice bath, after stirring at room is reacted 8 h, TLC (sherwood oil: inspection ETHYLE ACETATE=1: 1), react complete, so suction filtration, filter cake is used washed with dichloromethane, pours filtrating into saturated NaHCO then
3In, be stirred to and do not produce till the bubble, tell organic layer, organic layer is used saturated NaHCO again
3Respectively wash once anhydrous Na with saturated NaCl
2SO
4Drying behind the concentrating under reduced pressure, is crossed purification by silica gel column chromatography, and developping agent is sherwood oil and ETHYLE ACETATE, gets midbody 4f behind the purifying, is the white powder solid, weighs 13.1 g, yield 77 %.
Three, preparation midbody 1-glycyl glucosides (5a-f)
(1) preparation 1-amino-2,3,4,6-four-
O-ethanoyl-
β-D-glucopyranoside (5a)
The nitrine acetyl glucosamine that drying is good
4a(3.0 g, 8.04 mmol) put in the 100 mL eggplant-shape bottles, after adding anhydrous methylene chloride 6 mL make it to dissolve fully, add 10% Pd-C (450 mg again; W/w=15%) and methyl alcohol 30 mL, vacuumize, charge into hydrogen; Behind stirring at room 1 h, and TLC (sherwood oil: inspection ETHYLE ACETATE=1: 1), react complete; So suction filtration after filtrating concentrates, gets the bullion midbody
5a, not purified, directly carry out next step reaction.
(2) preparation 1-amino-2,3,4,6-four-
O-ethanoyl-
β-D-galactopyranoside (5b)
The nitrine acetyl semi-lactosi that drying is good
4b(3.0 g, 8.04 mmol) put in the 100 mL eggplant-shape bottles, after adding anhydrous methylene chloride 6 mL make it to dissolve fully, add 10% Pd-C (450 mg again; W/w=15%) and methyl alcohol 30 mL, vacuumize, charge into hydrogen; Behind the stirring at room 1h, and TLC (sherwood oil: inspection ETHYLE ACETATE=1: 1), react complete; So suction filtration after filtrating concentrates, gets the bullion midbody
5b, not purified, directly carry out next step reaction.
(3) preparation 1-amino-2,3,4-three-
O-ethanoyl-
β-D-xylopyranoside (5c)
The nitrine acetyl wood sugar that drying is good
4c(3.0 g, 9.96 mmol) put in the 100 mL eggplant-shape bottles, after adding anhydrous methylene chloride 6 mL make it to dissolve fully, add 10% Pd-C (450 mg again; W/w=15%) and methyl alcohol 30 mL, vacuumize, charge into hydrogen; Behind stirring at room 1 h, and TLC (sherwood oil: inspection ETHYLE ACETATE=1: 1), react complete; So suction filtration after filtrating concentrates, gets the bullion midbody
5c, not purified, directly carry out next step reaction.
(4) preparation 1-amino-2,3,4 ,-three-
O-ethanoyl-
β-D-pyrans rhamnoside (5d)
The nitrine acetyl rhamnosyl that drying is good
4d(3.0 g, 9.52 mmol) put in the 100 mL eggplant-shape bottles, after adding anhydrous methylene chloride 6 mL make it to dissolve fully, add 10% Pd-C (450 mg again; W/w=15%) and methyl alcohol 30 mL, vacuumize, charge into hydrogen; Behind stirring at room 1 h, and TLC (sherwood oil: inspection ETHYLE ACETATE=1: 1), react complete; So suction filtration after filtrating concentrates, gets the bullion midbody
5d, not purified, directly carry out next step reaction.
(5) preparation 1-amino-2,3,4,6-four-
O-ethanoyl-
β-D-glucopyranosyl-(1-4)-2,3,6-three-
O-ethanoyl-
β-D-glucopyranoside (5e)
The nitrine acetyl SANMALT-S that drying is good
4e(3.0 g, 4.53 mmol) put in the 100 mL eggplant-shape bottles, after adding anhydrous methylene chloride 6 mL make it to dissolve fully, add 10% Pd-C (450 mg again; W/w=15%) and methyl alcohol 30 mL, vacuumize, charge into hydrogen; Behind stirring at room 1 h, and TLC (sherwood oil: inspection ETHYLE ACETATE=1: 1), react complete; So suction filtration after filtrating concentrates, gets the bullion midbody
5e, not purified, directly carry out next step reaction.
(6) preparation 1-amino-2,3,4,6-four-
O-ethanoyl-
β-D-galactopyranose base-(1-4)-2,3,6-three-
O-ethanoyl-
β-D-glucopyranoside (5f)
The nitrine acetyl lactose that drying is good
4f(3.0 g, 4.53 mmol) put in the 100 mL eggplant-shape bottles, after adding anhydrous methylene chloride 6 mL make it to dissolve fully, add 10% Pd-C (450 mg again; W/w=15%) and methyl alcohol 30 mL, vacuumize, charge into hydrogen; Behind stirring at room 1 h, and TLC (sherwood oil: inspection ETHYLE ACETATE=1: 1), react complete; So suction filtration after filtrating concentrates, gets the bullion midbody
5f, not purified, directly carry out next step reaction.
Four, preparation midbody glycosyl acid (6a-f)
(1) preparation midbody glycosyl acid (6a)
With the dry good bullion glycyl glucose of step 3
5aWith the 4-of catalytic amount (
N,
N-dimethylamino) (DMAP 0.050g) puts in the 100 mL eggplant-shape bottles pyridine, after adding anhydrous methylene chloride 12 mL make it dissolving; Add anhydrous pyridine 3 mL again, behind stirring 10 min, add Pyroglutaric acid under the condition of ice bath; Continue to stir 1 h recession deicing and bathe, after stirring at room is reacted 3 h, TLC (methylene dichloride: inspection methyl alcohol=10: 1); React complete, then in reaction solution, add methylene dichloride 60 mL, with the HCl solution washing of 30 mL 5%; Anhydrous magnesium sulfate drying concentrates the back and uses re-crystallizing in ethyl acetate, gets midbody
6a,Be a white powder, heavy 1.68g, two step total recovery 45 %.
(2) preparation midbody glycosyl acid (6b)
With the dry good bullion glycyl glucose of step 3
5bWith the 4-of catalytic amount (
N,
N-dimethylamino) (DMAP 0.050g) puts in the 100 mL eggplant-shape bottles pyridine, after adding anhydrous methylene chloride 12 mL make it dissolving; Add anhydrous pyridine 3 mL again, behind stirring 10 min, add Pyroglutaric acid under the condition of ice bath; Continue to stir 1 h recession deicing and bathe, after stirring at room is reacted 3 h, TLC (methylene dichloride: inspection methyl alcohol=10: 1); React complete, then in reaction solution, add methylene dichloride 60 mL, with the HCl solution washing of 30 mL 5%; Anhydrous magnesium sulfate drying concentrates the back and uses re-crystallizing in ethyl acetate, gets midbody
6b,Be a white powder, weigh 1.81 g, two step total recovery 49 %.
(3) preparation midbody glycosyl acid (6c)
With the dry good bullion glycyl glucose of step 3
5cWith the 4-of catalytic amount (
N,
N-dimethylamino) (DMAP 0.050g) puts in the 100 mL eggplant-shape bottles pyridine, after adding anhydrous methylene chloride 12 mL make it dissolving; Add anhydrous pyridine 3 mL again, behind stirring 10 min, add Pyroglutaric acid under the condition of ice bath; Continue to stir 1 h recession deicing and bathe, after stirring at room is reacted 3 h, TLC (methylene dichloride: inspection methyl alcohol=10: 1); React complete, then in reaction solution, add methylene dichloride 60 mL, with the HCl solution washing of 30 mL 5%; Anhydrous magnesium sulfate drying concentrates the back and uses re-crystallizing in ethyl acetate, gets midbody
6c,Be a white powder, weigh 1.82 g, yield 47 %.
(4) preparation midbody glycosyl acid (6d)
With the dry good bullion glycyl glucose of step 3
5dWith the 4-of catalytic amount (
N,
N-dimethylamino) (DMAP 0.050g) puts in the 100 mL eggplant-shape bottles pyridine, after adding anhydrous methylene chloride 12 mL make it dissolving; Add anhydrous pyridine 3 mL again, behind stirring 10 min, add Pyroglutaric acid under the condition of ice bath; Continue to stir 1 h recession deicing and bathe, after stirring at room is reacted 3 h, TLC (methylene dichloride: inspection methyl alcohol=10: 1); React complete, then in reaction solution, add methylene dichloride 60 mL, with the HCl solution washing of 30 mL 5%; Anhydrous magnesium sulfate drying concentrates the back and uses re-crystallizing in ethyl acetate, gets midbody
6d,Be a white powder, weigh 1.77 g, yield 46 %.
(5) preparation midbody glycosyl acid (6e)
With the dry good bullion glycyl glucose of step 3
5eWith the 4-of catalytic amount (
N,
N-dimethylamino) (DMAP 0.050g) puts in the 100 mL eggplant-shape bottles pyridine, after adding anhydrous methylene chloride 12 mL make it dissolving; Add anhydrous pyridine 3 mL again, behind stirring 10 min, add Pyroglutaric acid under the condition of ice bath; Continue to stir 1 h recession deicing and bathe, after stirring at room is reacted 3 h, TLC (methylene dichloride: inspection methyl alcohol=10: 1); React complete, then in reaction solution, add methylene dichloride 60 mL, with the HCl solution washing of 30 mL 5%; Anhydrous magnesium sulfate drying concentrates the back and uses re-crystallizing in ethyl acetate, gets midbody
6e,Be a white powder, heavy 1.70g, yield 50 %.
(6) preparation midbody glycosyl acid (6f)
With the dry good bullion glycyl glucose of step 3
5fWith the 4-of catalytic amount (
N,
N-dimethylamino) (DMAP 0.050g) puts in the 100 mL eggplant-shape bottles pyridine, after adding anhydrous methylene chloride 12 mL make it dissolving; Add anhydrous pyridine 3 mL again, behind stirring 10 min, add Pyroglutaric acid under the condition of ice bath; Continue to stir 1 h recession deicing and bathe, after stirring at room is reacted 3 h, TLC (methylene dichloride: inspection methyl alcohol=10: 1); React complete, then in reaction solution, add methylene dichloride 60 mL, with the HCl solution washing of 30 mL 5%; Anhydrous magnesium sulfate drying concentrates the back and uses re-crystallizing in ethyl acetate, gets midbody
6f,Be a white powder, weigh 1.66 g, yield 49 %.
Five, preparation key intermediate glycosyl Acibenzolar (7a-f)
(1) preparation key intermediate glycosyl Acibenzolar (7a)
With the acid of midbody glycosyl
6a(500 mg, 1.084 mmol) and N-maloyl imines (HOSU, 150 mg, 1.303 mmol) and N; N-NSC 57182 (DCC, 206 mg, 1.301 mmol) places 25 mL eggplant-shape bottles, adds methylene dichloride 10 mL and makes it to dissolve fully; Stirring at room, the adularescent solid is separated out behind 10 min, (the methylene dichloride: inspection methyl alcohol=10: 1) of TLC behind 30 min; React complete,, get bullion after filtrating concentrates so filter
7a, not purified, directly carry out next step reaction.
(2) preparation key intermediate glycosyl Acibenzolar (7b)
With the acid of midbody glycosyl
6b(500 mg, 1.084 mmol) and N-maloyl imines (HOSU, 150 mg, 1.303 mmol) and N; N-NSC 57182 (DCC, 206 mg, 1.301 mmol) places 25 mL eggplant-shape bottles, adds methylene dichloride 10 mL and makes it to dissolve fully; Stirring at room, the adularescent solid is separated out behind 10 min, (the methylene dichloride: inspection methyl alcohol=10: 1) of TLC behind 30 min; React complete,, get bullion after filtrating concentrates so filter
7b, not purified, directly carry out next step reaction.
(3) preparation key intermediate glycosyl Acibenzolar (7c)
With the acid of midbody glycosyl
6c(422 mg, 1.084 mmol) and N-maloyl imines (HOSU, 150 mg, 1.303 mmol) and N; N-NSC 57182 (DCC, 206 mg, 1.301 mmol) places 25 mL eggplant-shape bottles, adds methylene dichloride 10 mL and makes it to dissolve fully; Stirring at room, the adularescent solid is separated out behind 10 min, (the methylene dichloride: inspection methyl alcohol=10: 1) of TLC behind 30 min; React complete,, get bullion after filtrating concentrates so filter
7c, not purified, directly carry out next step reaction.
(4) preparation key intermediate glycosyl Acibenzolar (7d)
With the acid of midbody glycosyl
6a(437 mg, 1.084 mmol) and N-maloyl imines (HOSU, 150 mg, 1.303 mmol) and N; N-NSC 57182 (DCC, 206 mg, 1.301 mmol) places 25 mL eggplant-shape bottles, adds methylene dichloride 10 mL and makes it to dissolve fully; Stirring at room, the adularescent solid is separated out behind 10 min, (the methylene dichloride: inspection methyl alcohol=10: 1) of TLC behind 30 min; React complete,, get bullion after filtrating concentrates so filter
7d, not purified, directly carry out next step reaction.
(5) preparation key intermediate glycosyl Acibenzolar (7e)
With the acid of midbody glycosyl
6e(812 mg, 1.084 mmol) and N-maloyl imines (HOSU, 150 mg, 1.303 mmol) and N; N-NSC 57182 (DCC, 206 mg, 1.301 mmol) places 25 mL eggplant-shape bottles, adds methylene dichloride 10 mL and makes it to dissolve fully; Stirring at room, the adularescent solid is separated out behind 10 min, (the methylene dichloride: inspection methyl alcohol=10: 1) of TLC behind 30 min; React complete,, get bullion after filtrating concentrates so filter
7e, not purified, directly carry out next step reaction.
(6) preparation key intermediate glycosyl Acibenzolar (7f)
With the acid of midbody glycosyl
6f(812 mg, 1.084 mmol) and N-maloyl imines (HOSU, 150 mg, 1.303 mmol) and N; N-NSC 57182 (DCC, 206 mg, 1.301 mmol) places 25 mL eggplant-shape bottles, adds methylene dichloride 10 mL and makes it to dissolve fully; Stirring at room, the adularescent solid is separated out behind 10 min, (the methylene dichloride: inspection methyl alcohol=10: 1) of TLC behind 30 min; React complete,, get bullion after filtrating concentrates so filter
7f, not purified, directly carry out next step reaction.
Six, preparation midbody (9a-f)
(1) preparation midbody (9a)
With commercially available Caspofungin acetate
8(50 mg; 0.0412 mmol) place 25 mL eggplant-shape bottles, add each 2 mL of entry and dioxane and make it to dissolve fully, drip triethylamine (0.03 mL under the stirring at room; 0.206 mmol), drip the key intermediate glycosyl Acibenzolar that is dissolved in dioxane behind 10 min again
7a(by 90% purity meter, 60 mg, 0.0989 mmol), a complete back room temperature continues to stir 6 h, and the ESI-MS detection reaction is complete, so with getting bullion behind the reaction solution cryoconcentration
9a, directly carry out next step reaction.
(2) preparation midbody (9b)
With commercially available Caspofungin acetate
8(50 mg; 0.0412 mmol) place 25 mL eggplant-shape bottles, add each 2 mL of entry and dioxane and make it to dissolve fully, drip triethylamine (0.03 mL under the stirring at room; 0.206 mmol), drip the key intermediate glycosyl Acibenzolar that is dissolved in dioxane behind 10 min again
7b(by 90% purity meter, 60 mg, 0.0989 mmol), a complete back room temperature continues to stir 6 h, and the ESI-MS detection reaction is complete, so with getting bullion behind the reaction solution cryoconcentration
9b, directly carry out next step reaction.
(3) preparation midbody (9c)
With commercially available Caspofungin acetate
8(50 mg; 0.0412 mmol) place 25 mL eggplant-shape bottles, add each 2 mL of entry and dioxane and make it to dissolve fully, drip triethylamine (0.03 mL under the stirring at room; 0.206 mmol), drip the key intermediate glycosyl Acibenzolar that is dissolved in dioxane behind 10 min again
7c(by 90% purity meter, 48 mg, 0.0989 mmol), a complete back room temperature continues to stir 6 h, and the ESI-MS detection reaction is complete, so with getting bullion behind the reaction solution cryoconcentration
9c, directly carry out next step reaction.
(4) preparation midbody (9d)
With commercially available Caspofungin acetate
8(50 mg; 0.0412 mmol) place 25 mL eggplant-shape bottles, add each 2 mL of entry and dioxane and make it to dissolve fully, drip triethylamine (0.03 mL under the stirring at room; 0.206 mmol), drip the key intermediate glycosyl Acibenzolar that is dissolved in dioxane behind 10 min again
7d(by 90% purity meter, 50 mg, 0.0989 mmol), a complete back room temperature continues to stir 6 h, and the ESI-MS detection reaction is complete, so with getting bullion behind the reaction solution cryoconcentration
9d, directly carry out next step reaction.
(5) preparation midbody (9e)
With commercially available Caspofungin acetate
8(50 mg; 0.0412 mmol) place 25 mL eggplant-shape bottles, add each 2 mL of entry and dioxane and make it to dissolve fully, drip triethylamine (0.03 mL under the stirring at room; 0.206 mmol), drip the key intermediate glycosyl Acibenzolar that is dissolved in dioxane behind 10 min again
7e(by 90% purity meter, 84 mg, 0.0989 mmol), a complete back room temperature continues to stir 6 h, and the ESI-MS detection reaction is complete, so with getting bullion behind the reaction solution cryoconcentration
9e, directly carry out next step reaction.
(6) preparation midbody (9f)
With commercially available Caspofungin acetate
8(50 mg; 0.0412 mmol) place 25 mL eggplant-shape bottles, add each 2 mL of entry and dioxane and make it to dissolve fully, drip triethylamine (0.03 mL under the stirring at room; 0.206 mmol), drip the key intermediate glycosyl Acibenzolar that is dissolved in dioxane behind 10 min again
7f(by 90% purity meter, 84 mg, 0.0989 mmol), a complete back room temperature continues to stir 6 h, and the ESI-MS detection reaction is complete, so with getting bullion behind the reaction solution cryoconcentration
9f, directly carry out next step reaction.
Seven, preparation target compound (1a-f)
(1) preparation target compound (1a), i.e. compound 1a in the table 1
With step 6 gained bullion
9aPlace 25 mL eggplant-shape bottles, add the CH of pH=8
3ONa/CH
3OH solution, stirred overnight at room temperature, next day, ESI-MS detected; React complete, so transfer pH=7 with acetic acid, concentrate under reduced pressure at low temperature; Gained oily matter is crossed preparation HPLC purifying after revolving acetic acid with the toluene band; Moving phase is acetonitrile and water (0.1% trifluoroacetic acid, v/v=20:80 ~ 80:20), get white powder after the lyophilize
1a, weighing 50 mg, two step total recoverys are 73 %.
(2) preparation target compound (1b), i.e. compound 1b in the table 1
With step 6 gained bullion
9bPlace 25 mL eggplant-shape bottles, add the CH of pH=8
3ONa/CH
3OH solution, stirred overnight at room temperature, next day, ESI-MS detected; React complete, so transfer pH=7 with acetic acid, concentrate under reduced pressure at low temperature; Gained oily matter is crossed preparation HPLC purifying after revolving acetic acid with the toluene band; Moving phase is acetonitrile and water (0.1% trifluoroacetic acid, v/v=20:80 ~ 80:20), get white powder after the lyophilize
1b, weighing 51 mg, two step total recoverys are 75 %.
(3) preparation target compound (1c), i.e. compound 1c in the table 1
With step 6 gained bullion
9cPlace 25 mL eggplant-shape bottles, add the CH of pH=8
3ONa/CH
3OH solution, stirred overnight at room temperature, next day, ESI-MS detected; React complete, so transfer pH=7 with acetic acid, concentrate under reduced pressure at low temperature; Gained oily matter is crossed preparation HPLC purifying after revolving acetic acid with the toluene band; Moving phase is acetonitrile and water (0.1% trifluoroacetic acid, v/v=20:80 ~ 80:20), get white powder after the lyophilize
1c, weighing 46 mg, two step total recoverys are 71 %.
(4) preparation target compound (1d), i.e. compound 1d in the table 1
With step 6 gained bullion
9dPlace 25 mL eggplant-shape bottles, add the CH of pH=8
3ONa/CH
3OH solution, stirred overnight at room temperature, next day, ESI-MS detected; React complete, so transfer pH=7 with acetic acid, concentrate under reduced pressure at low temperature; Gained oily matter is crossed preparation HPLC purifying after revolving acetic acid with the toluene band; Moving phase is acetonitrile and water (0.1% trifluoroacetic acid, v/v=20:80 ~ 80:20), get white powder after the lyophilize
1d, weighing 49 mg, two step total recoverys are 74 %.
(5) preparation target compound (1e), i.e. compound 1e in the table 1
With step 6 gained bullion
9ePlace 25 mL eggplant-shape bottles, add the CH of pH=8
3ONa/CH
3OH solution, stirred overnight at room temperature, next day, ESI-MS detected; React complete, so transfer pH=7 with acetic acid, concentrate under reduced pressure at low temperature; Gained oily matter is crossed preparation HPLC purifying after revolving acetic acid with the toluene band; Moving phase is acetonitrile and water (0.1% trifluoroacetic acid, v/v=20:80 ~ 80:20), get white powder after the lyophilize
1e, weighing 57 mg, two step total recoverys are 71 %.
(6) preparation target compound (1f), i.e. compound 1f in the table 1
With step 6 gained bullion
9fPlace 25 mL eggplant-shape bottles, add the CH of pH=8
3ONa/CH
3OH solution, stirred overnight at room temperature, next day, ESI-MS detected; React complete, so transfer pH=7 with acetic acid, concentrate under reduced pressure at low temperature; Gained oily matter is crossed preparation HPLC purifying after revolving acetic acid with the toluene band; Moving phase is acetonitrile and water (0.1% trifluoroacetic acid, v/v=20:80 ~ 80:20), get white powder after the lyophilize
1f, weighing 58 mg, two step total recoverys are 71 %.
Need to prove that when all the other target compounds prepare, like n=1 or, adopt the sugar of corresponding R group at 2 o'clock, corresponding side chain is as raw material, method is the same.Agents useful for same is commercially available analytical pure among the embodiment, and preparation liquid phase solvent for use is a chromatographically pure, all purchases the chemical reagents corporation in Shanghai.
The pharmacological evaluation of embodiment 3 The compounds of this invention
(1) experimental technique: adopt Association for Standardization of U.S. clinical labororatory (Clinical and Laboratory Standards Institute, CLSI) CLSI-M27A3 and the M38-A2 file micro-liquid base dilution method of being recommended.
(1) experimental strain
This experiment has selected for use the common human body cause illness's standard fungal bacterial strain of following 6 kind of 7 strain as screening object:
Two strain ATCC type strains:
Candida albicans (
Candida albicans) SC5314
Cryptococcus neoformans (
Cryptococcus neoformans) 32609
Five strain clinical strains:
The Candida glabrata bacterium (
Candida krusei) 537
Candida parapsilosis (
Candida parapsilosis) 22019
Trichophyton (
Trichophyton rubrum) Cmccftla
Gypsum shape sporidiole bacteria (
Microsporum gypseum) Cmccfmza
Candida albicans (
Candida albicans) Y0109
(2) TP
The bacteria suspension preparation: above-mentioned candidiasis was cultivated 24 hours for 35 ℃ through the SDA substratum, and filamentous fungus was through PDA substratum activation 7 days, and twice activation is with the blood cell counting plate counting, with RPMI 1640 liquid nutrient mediums adjustment bacteria concentration to 1 * 10
3-2 * 10
4Individual/mL.
Soup preparation: get testing compound of the present invention and be dissolved in methyl-sulphoxide, be made into the medicine storage liquid of 6.4 mmol/L ,-70 ℃ of preservations.Be diluted to 640 μ mol/L with RPMI 1640 substratum before the experiment.
Inoculation: No. 1 hole of 96 orifice plates adds RPMI 1,640 200 μ L and makes blank; The 3-12 hole respectively adds RPMI 1,640 100 μ L; No. 2 the hole adds RPMI 1,640 180 μ L and 640 μ mol/L soups, 20 μ L, 10 grades of doubling dilutions of the drug level in 2-11 hole, and each hole drug level is respectively 64,32,16,8,4,2,1,0.5,0.25,0.125 μ mol/L; No. 12 the hole does not add soup, makes positive control.The medicine contrast is fluconazole (FCZ.).The bacteria suspension for preparing is seeded to the 2nd ~ No. 12 hole of 96 orifice plates with multichannel pipettor with 100 μ L bacterium liquid, and final inoculum density is 0.5 * 10
3-2.5 * 10
3CFU/mL; Last row of 96 orifice plates is Quality Control bacterial strain Candida parapsilosis ATCC22019.
Cultivate and detect: 96 orifice plates that will inoculate leave standstill cultivation after 1-7 days, observations in 35 ℃.If positive control hole OD value (OD value) is 100%, being lower than 80% lowest drug concentration with OD value than positive control hole is minimal inhibitory concentration value (MIC
80).
(2) experimental result
External bacteriostatic experiment result sees table 2.
Table 2 compound of the present invention
1a-fExternal antimycotic experimental result
Annotate: CAS is contrast medicine Caspofungin.
Visible by last table, The compounds of this invention has the selected fungi of major part and suppresses active, though the glycosyl derivatives molecular weight increases, it is active to the vitro inhibition of part bacterial strain that institute's synthetic target compound has kept basically, some compound as
1a,
1bThe isoreactivity comparison is according to medicine Caspofungin better effects if, so The compounds of this invention can be used for preparing new antifungal drug.
The stability experiment of embodiment 4 The compounds of this invention
The improvement situation of the relative Caspofungin stability of synthetic glycosyl derivatives is chosen target compound in order to investigate
1aWith
1e, and it has been carried out high humidity and thimble test.
(1) experimental technique
High wet test: in a moisture eliminator, place saturated sodium nitrite solution, keep its interior relative humidity, will fill compound then 75%
1a,
1eWith contrast medicine Caspofungin
1Sample bottle place wherein, room temperature was observed 10 days.Pick and place the sample of having put 0 day, 5 days and 10 days respectively and with performance liquid HPLC it is carried out content analysis through analyzing.
High temperature test: will fill compound
1a,
1eWith contrast medicine Caspofungin
1Sample bottle be positioned over a temperature maintenance in 60 ℃ thermostat container, observed 10 days.Pick and place the sample of having put 0 day, 5 days and 10 days respectively and with performance liquid HPLC it is carried out content analysis through analyzing.
(2) experimental result
The stability experiment result sees Fig. 2.From figure
2ACan find out compound
1a,
1eWith contrast medicine Caspofungin
1After 5 days, HPLC analyzes demonstration, compound in this super-humid conditions held
1aWith
1eAlmost not influence of content, and contrast medicine Caspofungin
1Content but descended about 2%; After 10 days, compound
1aWith
1eContent descended about 0.5% and 3.5% respectively, and contrast medicine Caspofungin
1Content but descended approximately 6.5%, be respectively compound
1aWith
1e13 times and 2 times.Above result shows that the glycosyl derivatives of Caspofungin is than guide's thing Caspofungin
1Be difficult for the moisture absorption.From figure
2BCan find out compound
1a,
1eWith contrast medicine Caspofungin
1All unstable under this hot conditions, but compound
1aWith
1eThan guide's thing Caspofungin
1Stable, for example, in this hot conditions held after 10 days, compound
1aWith
1eContent descended about 40%, and contrast medicine Caspofungin
1Content but descended up to 70% more than.
The formulation preparation of embodiment 10 The compounds of this invention
One, prepare tablet according to methods known in the art, every contains following compositions: compound
1a50mg, lactose 70mg, Magnesium Stearate 3mg, Vinylpyrrolidone polymer 7mg adds up to 130mg.
Two,Prepare tablet according to methods known in the art, every contains following compositions: compound
1e50mg, lactose 70mg, Magnesium Stearate 3mg, Vinylpyrrolidone polymer 7mg adds up to 130mg.
Three,Prepare capsule according to methods known in the art, contain following compositions in each capsule: compound
1a50mg, lactose 70mg, W-Gum 25mg, Magnesium Stearate 1mg, Vinylpyrrolidone polymer 4mg adds up to 150mg.
Four,Prepare capsule according to methods known in the art, contain following compositions in each capsule: compound
1e50mg, lactose 70mg, W-Gum 25mg, Magnesium Stearate 1mg, Vinylpyrrolidone polymer 4mg adds up to 150mg.
The above only is a preferred implementation of the present invention; Should be pointed out that for those skilled in the art, under the prerequisite that does not break away from the inventive method; Can also make some improvement and replenish, these improvement and replenish and also should be regarded as protection scope of the present invention.
Claims (7)
1. glycopeptide class antifungal compound and pharmacy acceptable salt thereof is characterized in that described glycopeptide class antifungal compound general structure is following:
Wherein, n equals 1,2 or 3;
R is monose or disaccharides;
Described monose is glucose, semi-lactosi, wood sugar, rhamnosyl, seminose, ribose, GS or acetylglucosamine;
Described disaccharides is SANMALT-S or lactose.
2. glycopeptide class antifungal compound according to claim 1 and pharmacy acceptable salt thereof is characterized in that described n equals 3.
3. glycopeptide class antifungal compound according to claim 2 and pharmacy acceptable salt thereof is characterized in that, described R is glucose or SANMALT-S.
4. glycopeptide class antifungal compound according to claim 1 and pharmacy acceptable salt thereof; It is characterized in that described pharmacy acceptable salt class is hydrochloride, vitriol, hydrosulfate, hydrobromate, acetate, oxalate, Citrate trianion or mesylate.
5. a pharmaceutical composition is characterized in that, it contains arbitrary described glycopeptide class antifungal compound of claim 1-4 and pharmacy acceptable salt thereof, and contains conventional pharmaceutical carrier.
6. the preparation method like arbitrary described glycopeptide class antifungal compound of claim 1-4 and pharmacy acceptable salt thereof is characterized in that this method comprises the following steps:
A) preparation key intermediate glycosyl Acibenzolar: with the glycosyl is starting raw material, obtains the glycosyl of full acetyl protection with sodium-acetate back flow reaction in acetic anhydride; Under the condition that trimethyl azide silane and BFEE exist substitution reaction takes place, the acetoxyl group of 1-position is become azido-then; Azido-generates amino back through 10% Pd-C catalytic hydrogenation and under the condition that 4-(N, N-dimethylamino) pyridine exists, is condensed into acid amides with corresponding acid anhydrides; The carboxyl that exposes out with N, generate corresponding glycosyl Acibenzolar with N-maloyl imines generation ester condensation under the condition that the N-NSC 57182 exists;
B) preparation target compound Caspofungin glycosyl derivatives: the Caspofungin glycosyl compound that condensation generates full acetyl protection takes place in the key intermediate glycosyl Acibenzolar and the Caspofungin acetate of step a) preparation under the triethylamine alkaline condition, the deacetylate protection promptly gets target compound Caspofungin glycosyl derivatives in sodium methylate/methanol solution then.
7. like arbitrary described glycopeptide class antifungal compound of claim 1-4 and the application of pharmacy acceptable salt in preparation treatment fungi infestation medicine thereof.
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| CN103897042A (en) * | 2014-03-13 | 2014-07-02 | 中国人民解放军第二军医大学 | Glycosylated derivative of cyclic peptide compounds and preparation method and application thereof |
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| CN109232691A (en) * | 2018-09-10 | 2019-01-18 | 南方医科大学南方医院 | A kind of gala sugar analogue of acetyl protection and preparation method thereof |
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