GB1582378A - Method of preparing n-glycosyl derivatives of polyene macrolide and the salts thereof - Google Patents
Method of preparing n-glycosyl derivatives of polyene macrolide and the salts thereof Download PDFInfo
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Abstract
The amino group-containing polyene macrolide is reacted with a mono- or oligosaccharide of the aldose or ketose series in an organic solvent or an organic solvent mixture. In order to be able to use an inexpensive, non-flammable solvent, the N-glycosyl derivative produced is precipitated from the reaction medium by means of water or an aqueous solution of an inorganic salt, purified by crystallisation from a higher alcohol, and optionally converted into a salt.
Description
(54) THE METHOD OF PREPARING N-GLYCOSYL DERIVATIVES
OF POLYENE MACROLIDE AND THE SALTS THEREOF
(71) We, POLITECHNIKA GDANSKA, of ul. Majakowskiego 11/12, Gdansk,
Poland, and INSTYTUT PRZEMYSLU FARMACEUTYCZNEGO, of ul. Rydygiera 8,
Warsaw, Poland, both State enterprises organised and existing under the laws of Poland, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:
This invention relates to a method of preparing the N-methylglucamine salt of N-glycosyl derivatives of a polyene macrolide.
Known methods of preparation of N-glycosyl derivatives of polyene macrolides and their salts comprises treating polyene macrolides containing an amino group with an aldose or ketose mono- or oligosaccharide in a medium of organic solvent or mixture of solvents. The derivative thus obtained is precipitated together with unreacted sugar from the reaction medium with ethyl ether, washed with ethyl ether, dried under reduced pressure then separated from the sugar and optionally transformed into a salt.
However, the above described method required the use of costly and combustible solvents and also a series of additional operations is necessary to separate the product from the excess of an unreacted sugar.
In addition to these disadvantages the salts obtained by this process, however soluble in water, did not form clear solutions and this restricts their use.
According to the present invention there is provided a method of preparing the
N-methylglucamine salt of an N-glycosyl derivative of a polyene macrolide antibiotic comprising reacting a polyene macrolide antibiotic containing at least one amino group with a saccharide selected from aldose monosaccharides, ketose monosaccharides, aldose oligosaccharides and ketose oligosaccharides in an organic solvent to form an N-glycosyl derivative of the said antibiotic, precipitating the said N-glycosyl derivative by the addition of water or an aqueous solution of an inorganic salt; recovering the precipitate and reacting same with N-methylglucamine.
Preferably the N-methylglucamine salt is purified by recrystallization from an alkanol.
Advantageously the N-glycosyl derivative precipitate is purified by recrystallization from an alkanol also.
The most preferred alkanol is n-butanol.
Preferably the inorganic salt is ammonious sulphate.
The present invention provides N-methylglucamine salt of N-glycosyl derivative of polyene macrolides which like the polyene macrolides, their N-glycosyl derivatives and their already known salts. exhibit antifungal antibiotic activity.
The new N-methylglucamine salts exhibit the same antifungal spectrum as the parent antibiotics, or their complexes. for example the so-called fungizone, water soluble complex of amphotericin B with sodium desoxycholate, the only water soluble form of this antibiotic used in chemotherapy.
However. some of the new salts, for example N-methylglucamine salt of N-glycosyl derivative of polifungin, compared to the fungizone exhibit activity against Trichomonas vaginalis. The polifungin inhibits growth of Trichomonas vaginalis in the concentration of 837,7 mcg/ml, while the inhibiting concentration of N-methylglucamine salt of N-glycosyl derivative of polifungin is 268,4 mcg/ml.
Additionally, these salts, for example N-methylglucamine salt of N-glucosyl derivative of amphotericin B, exhibit enhanced antifungal properties in comparison with that of fungizone against many micro-organisms for instance Torula sp., Geotrichum candidum and Cryptococcus neoformans. The in vitro activities of N-methylglucamine salts of
N-glycosyl derivative of amphotericin B and fungizone against some fungi are compared in
Table 1.
TABLE 1
The minimal active concentration CElo (in mcg/ml)
Fungi N-methylglucamine salt of
N-glycosyl derivative of Fungizone
amphotericin B
Torula sp. 1.66 2.39
Geotrichum candidum 1.07 1.48
Cryptococcus neoformans 1.25 1.48
There is a different sensitivity of different strains, for example Candida sp. to
N-methylglucamine salt of N-glycosyl derivative of amphotericin B and fungizone.
Statistically, the amount of fungizone insensitive strains is much higher than the amount of
N-methylglucamine salt insensitive strains. This concerns especially Candida albicans strains ZM, HM, and 1/75, Candida tropicalis strains JD and 20/75 and Candida krusei strains TS and 16/75, which are insensitive to fungizone. but sensitive to N-methylglucamine salt of N-glycosyl derivative of amphotericin B.
The relative activity index representing the antibiotic activity in experimental chemotherapy of Candida albicans infected mice is much more advantageous for N-methylglucamine salts of N-glycosyl derivatives of polyene macrolides than for fungizone (Table 2).
TABLE 2
Antibiotic Relative activity index
in Candida albicans mice
infection
Fungizone
N-methylglucamine salt of
N-glycosyl derivative of:
- amphotericin B 2.35
- polifungin 5.08
- nystatin 2.41 On the intravenous administration of N-methylglucamine salts of polyene macrolide
N-glycosyl derivatives and fungizone to the rats the effect is much more advantageous for the salt, because its presence in the serum can be shown longer than in the case of fungizone (Table 3).
TABLE 3
Time of the presence of an
antibiotic in serum after 1/5
Antibiotic LD50 dose administration (in
minutes)
Fungizone 5
N-methylglucamine salt of
N-glycosyl derivative of:
- amphotericin B 15
- polifungin 60
- nystatin 30
The data representing the selective toxicity are also more advantageous for Nmethylglucamine salt of N-glycosyl derivatives of polyene macrolides than for fungizone.
The indices of selective toxicity EK50 and EH50 DK50 DK50 illustrating the ratio of the minimal antibiotic concentration causing 50% effluence of the potassium ions from erythrocytes of human blood (EK5(,) and the minimal concentration of antibiotic causing 50% hemolysis of erythrocytes (EHSo) to the minimal antibiotic concentration causing 50% effluence of the potassium ions from Saccaromyces cerevisiae cells (DK5()) are compared in Table 4.
TABLE 4
Selective toxicity index
Antibiotic EK5(, EH5(, DK50 DK5(, Fungizone 1.09 1.4 - 2.9
N-methylglucamine
salt of N-glycosyl
derivative of:
- amphotericin B 1.37 24
- polifungin 11.4 31
- nystatin 17.3 45
On intravenous administration in mice the acute toxicity LD5(, of N-methylglucamine salts of N-glycosyl derivatives of polyene macrolides is lower than that of fungizone (Table 5).
TABLE 5
LD50 for mice in mg/kg
Antibiotic weight body administered
intravenously
Fungizone 7.4 - 9.3
N-methylglucamine salt of
N-glycosyl derivative of:
- amphotericin B 12.1 - 14.3
- polifungin 13.8 - 16.4
- nystatin 19
The sodium, tris and imidazole salts of glycosyl derivative of polyene macrolides are described in British Patent No. 1 387 187. Tris and imidazole salts are not used as therapeutics because of their characteristics, whereas the application of sodium salts of
N-glycosyl derivatives of polyene macrolides in the form of injection solutions is difficult on account of the high pH values of this solution. Moreover the sodium salts of N-glycosyl derivatives of polyene macrolides in water solutions at so high values of pH are labile, the biological activity of the appropriate pharmaceutical preparations in comparison with the activity of the parent substance being reduced. In IR spectrum the significant degradation of the lactone ring was observed. Unlike sodium salts of N-glycosyl derivatives of polyene macrolides, N-methylglucamine salts are more water soluble and their water solutions are stable and show lower pH value (Table 6).
TABLE 6
Sodium salt of N-gly- N-methylglucamine
cosyl derivative of salt of N-glycosyl
polifungin derivative of poli
fungin
pH 1% water
solution 9.9 8.9
no absorption at no difference in
IR spectrum 1704 cm-' present comparison with
in polifungin the standard
Biological
activity in u/mg 1860 2365
Solubility
in water 4 - 10% > 15%.
N-methylglucamine salts of N-glycosyl derivatives of polyene macrolides may be used in the treatment of surface and systemic fungal infections, caused by fungi: Candida albicans,
Cryptococcus neoformans. Aspergillus, Geotrichum, Torulopsis and others, in well known pharmaceutical forms such as aerosols, solutions for infusion, vaginal tablets. compresses, drops and solutions for parenteral administration.
The present invention will now be described, by way of illustration, in the following
Examples, of which Examples l-VIII are illustrative of methods of obtaining the N-glycosyl derivative of various antibiotics and their salts, other than N-methylglucamine salts.
Example I
1 g of amphotericin B and 0.3g of anhydrous glucose were suspended in 15 ml of dimethyl formamide and allowed to stand at a temperature of 37"C for 16 hours. 200 ml of distilled water were added to this solution. the precipitate formed was centrifuged. washed twice with 50 ml of benzene and once with 50 ml of hexane, was dried under reduced pressure and extracted at a temperature of 50 C with 100 ml of methanol for 15 minutes. Insoluble precipitate was centrifuged and again extracted with the same volume of methanol.
Combined solutions were left overnight at a temperature of -5 C. Precipitate was separated by centrifugation, washed twice with 50 ml of benzene and once with 50 ml of hexane and dried under reduced pressure. 0.65 g of crystalline N-glycosyl derivative of amphotericin B, of Etg' = 1450 at 381 nm, IC5() = 0.04 mcg/ml were obtained. Original antibiotic: E' = 1580 at 381 nm, and IC5() = 0.03 mcg/ml.
lcrn Example II
10 g of polifungin and 2.4 g of glucose were dissolved in 50 ml of dimethyl formamide and allowed to stand at a temperature of 32 C for 16 hours. The derivative was precipitated with 11. of 0.1 N sodium chloride aqueous solution, centrifuged and washed with 100 ml of water. The product was extracted eight times, every time with 100 ml of methanol. 100 ml of n-butanol was added to combined extracts and the mixture was evaporated under reduced pressure to the 50 ml volume and left for crystallisation at the temperature of -5"C. The precipitate was centrifuged and washed twice with acetone and hexane and then dried. 7.2 g of N-glycosyl derivative of polifungin of E1cm1% = 710 at 304 nm, ICs" = 0.25 mcg/ml was obtained.
Example 111
5g of candicidin and 1.5g of glucose was suspended in 25 ml of dimethyl formamide and allowed to stand at a temperature of 37 C for 20 hours. The derivative was precipitated with 200 ml of 5% ammonium sulphate aqueous solution and was washed twice with 20 ml of water. Obtained in the reaction N-glycosyl derivative of candicidin was extracted with 200 ml of methanol at a temperature of 36 C, then with 200 ml of the methanol n-butanol mixture. Methanol and water with butanol were evaporated, then the derivative was crystallised from n-butanol. 1.14 g of N-glycosyl derivative of candicidin of E' /'m = 210 at 378 nm from the methanol fraction and 1.96 g of derivative of E' /m = 270 at 378 nm from the methanol-butanol fraction were obtained. IC" of N-glycosyl derivative of candicidin = 0.004 mcg/ml. Original antibiotic: E''C'm = 210 at 378 nm, IC" = 0.0025 mcg/ml.
Example IV
The reaction of condensation of 5g of aureofacin of E T /'m = 410 at 378 nm and 1.5 g of glucose was performed as described in Example III. 2.93 of N-glycosyl derivative of aureofacin of E'i).m = 290 at 378 nm from the methanol fraction and 1.82g of derivative of
E1cm1% = 320 at 378 nm from the methanol-n-butanol fraction were obtained. IC5" of
N-glycosyl derivative of aureofacin = O.OOX mcg/ml. IC50 of original antibiotic = 0.006 mcg/ml.
Example V
3 g of aureofacin and 0.9 g of glucose were condensed in 35 ml of dimethyl formamide.
Insoluble residue was centrifuged and the derivative was precipitated with 200 ml of 10% ammonium sulphate aqueous solution. The precipitate was filtered on Celite (Trade Mark), washed with 200 ml of water and 200 ml of acetone and the derivative was extracted with the mixture of chloroform-methanol-water (10:10:1). Chloroform, methanol and water as azeotropic mixture with n-butanol were evaporated and the residue was left in n-butanol to crystallise overnight at a temperature of -5"C. 1.85 g of N-glycosyl derivative of aureofacin of E'i)m = 320 at 378 nm and IC)) = 0.008 mcg/ml were obtained. lCs" of original antibiotic = 0.006 mcg/ml.
Example VI
1 g of amphotericin B and ().3 g of glucose were suspended in 15 ml of dimethyl formamide and were allowed to stand at a temperature of 37 C for 2() hours. N-glycosyl derivative was precipitated with 300 ml of 5% ammonium sulphate aqueous solution and washed with 5() ml of water. The precipitate was suspended in 50 ml of methanol and 40 ml of n-butanol. whereupon ().1 mM of sodium carbonate in 10 ml of water was added.
Methanol and water as azeotropic mixture with n-butanol were evaporated and the residue was allowed to crvstallise. 1.2 g of sodium salt of N-glycosyl derivative of amphotericin B of
E1cm1% = 12()() at 38() nm and lC5" = 0.05 mcg/ml were obtained.
Example VII
I g of amphotericin B and ().3 g of glucose was suspended in 15 ml of dimethyl formamide and allowed to stand for 2() hours at a temperature of 37 C. N-glycosyl derivative was precipitated with 3(3(3 ml of 5(4 ammonium sulphate aqueous solution. The precipitate was washed with 50 ml of water, dissolved in 50 ml of methanol and 1 mM of tris and 40 ml of n-butanol was added, then methanol and water as azeotropic mixture with n-butanol was distilled and the residue was left for crystallisation. The tris salt of N-glycosyl derivative of amphotericin B of El ''m = 1040 at 380 nm and ICso = 0.6 mcg/ml was obtained.
Example VILLI 3 g of polifungin was suspended in 15 ml of dimethylformamide, 0.9 g of glucose was added and allowed to stand at a temperature of 38"C for 24 hours. Insoluble residue was centrifuged and N-glycosyl derivative was precipitated from the filtrate with 11 of 5% ammonium sulphate aqueous solution. The precipitate was centrifuged and extracted three times with 40 ml of methanol at a temperature of 38"C. 3 mM tris was added to the solution, then 40 ml of n-butanol, whereupon methanol and water as azeotropic mixture with n-butanol was evaporated and the residue was left for crystallisation at a temperature of -5"C. 2.85 g of tris salt of N-glycosyl derivative of polifungin of Et / m = 570 at 304 nm and IC5 = 0.4 mcg/ml were obtained. Original antibiotic: El m = 660 at 304 nm, IC5)) = 0.15 mcg/ml.
Example IX
20 g of polifungin and 6g of glucose were dissolved in 100 ml of dimethyl formamide and allowed to stand at a temperature of 36"C for 18 hours. The resulting solution was filtered then 400 ml of 5% ammonium sulphate aqueous solution was added to the filtrate and allowed to stand at a temperature of +4"C for 2 hours. The precipitate was filtered and washed with water and then extracted three times using 800 ml of methanol for each portion. 6 g of N-methylglucamine was dissolved in 60 ml of water and added to the methanol extracts. 1000 ml of n-butanol was added to this solution whereupon the reaction mixture was evaporated at a temperature of 45"C under reduced pressure to remove methanol and water. The residue was allowed to stand at a temperature of +4"C for crystallisation. The precipitate was filtered and washed with n-butanol, then with petroleum ether and was dried at a room temperature. 16.5 g of the N-methylglucamine salt of
N-glycosyl derivative of polifungin in El /'m = 560 at 304 nm and ICSo = 0.42 mcg/ml was obtained. Original antibioic: E,'C'n, = 660 at 304 nm and ICs(, = 0.16 mcg/ml.
Example X
20 g of nystatin and 6g of glucose was dissolved in 100 ml of dimethyl formamide. Further procedure was carried out as given in Example IX. 18 g of N-methylglucamine salt of N-glycosyl derivative of nystatin of El ism = 560 at 304 nm and IC5 = 0.45 mcg/ml was obtained. Original antibiotic: E) 'm = 790 at 304 nm, IC5() = 0.18 mcg/ml.
Example XI
20 g of amphotericin B and 6 g of glucose was dissolved in 200 ml of dimethyl formamide and allowed to stand at a temperature of 35"C for 18 hours. The resulting solution was filtered and 500 ml of 5% ammonium sulphate aqueous solution was added to the filtrate then the mixture was allowed to stand at a temperature of + 4"C for 2 hours. The precipitate was filtered and washed with water. 1500 ml of methanol at a temperature of 50"C and 6g of N-methylglucamine salt dissolved in 60 ml of water was added to the precipitate whereupon the mixture was mixed for 30 minutes, then 1 1 of n-butanol was added. The obtained solution was evaporated at a temperature of 45"C under reduced pressure until the methanol and water were removed. The residue was allowed to stand at a temperature of +4 C for crystallisation. The sediment was filtered, washed with n-butanol then with petroleum ether and dried at the room tem, erature. 18 g of N-methylglucamine salt of N-glycosyl derivative of amphotericin B of Ei c?rn = 1140 at 380 nm and IC5(l = 0.1 mcg/ml were obtained.
WHAT WE CLAIM IS:- 1. A method of preparing the N-methylglucamine salt of an N-glycosyl derivative of a polyene macrolide antibiotic comprising reacting a polyene macrolide anitbiotic containing at least one amino group with a saccharide selected from aldose monosaccharides, ketose monosaccharides, aldose oligosaccharides and ketose oligosaccharides in an organic solvent to form an N-glycosyl derivative of the said antibiotic, precipitating the said N-glycosyl derivative by the addition of water or an aqueous solution in an inorganic salt; recovering the precipitate and reacting same with N-methylglucamine.
2. A method according to claim 1. in which the inorganic salt is ammonium sulphate.
3. A method according to claim I or claim 2 in which the N-methylglucamine salt of the
N-glycosyl derivative of the said antibiotic is recrystallized from an alkanol.
4. A method according to claim 1 or claim 2 in which the N-glycosyl derivatives precipitate is purified by recrystallization from an alkanol also.
**WARNING** end of DESC field may overlap start of CLMS **.
Claims (12)
- **WARNING** start of CLMS field may overlap end of DESC **.washed with 50 ml of water, dissolved in 50 ml of methanol and 1 mM of tris and 40 ml of n-butanol was added, then methanol and water as azeotropic mixture with n-butanol was distilled and the residue was left for crystallisation. The tris salt of N-glycosyl derivative of amphotericin B of El ''m = 1040 at 380 nm and ICso = 0.6 mcg/ml was obtained.Example VILLI3 g of polifungin was suspended in 15 ml of dimethylformamide, 0.9 g of glucose was added and allowed to stand at a temperature of 38"C for 24 hours. Insoluble residue was centrifuged and N-glycosyl derivative was precipitated from the filtrate with 11 of 5% ammonium sulphate aqueous solution. The precipitate was centrifuged and extracted three times with 40 ml of methanol at a temperature of 38"C. 3 mM tris was added to the solution, then 40 ml of n-butanol, whereupon methanol and water as azeotropic mixture with n-butanol was evaporated and the residue was left for crystallisation at a temperature of -5"C. 2.85 g of tris salt of N-glycosyl derivative of polifungin of Et / m = 570 at 304 nm and IC5 = 0.4 mcg/ml were obtained. Original antibiotic: El m = 660 at 304 nm, IC5)) = 0.15 mcg/ml.Example IX20 g of polifungin and 6g of glucose were dissolved in 100 ml of dimethyl formamide and allowed to stand at a temperature of 36"C for 18 hours. The resulting solution was filtered then 400 ml of 5% ammonium sulphate aqueous solution was added to the filtrate and allowed to stand at a temperature of +4"C for 2 hours. The precipitate was filtered and washed with water and then extracted three times using 800 ml of methanol for each portion. 6 g of N-methylglucamine was dissolved in 60 ml of water and added to the methanol extracts. 1000 ml of n-butanol was added to this solution whereupon the reaction mixture was evaporated at a temperature of 45"C under reduced pressure to remove methanol and water. The residue was allowed to stand at a temperature of +4"C for crystallisation. The precipitate was filtered and washed with n-butanol, then with petroleum ether and was dried at a room temperature. 16.5 g of the N-methylglucamine salt of N-glycosyl derivative of polifungin in El /'m = 560 at 304 nm and ICSo = 0.42 mcg/ml was obtained. Original antibioic: E,'C'n, = 660 at 304 nm and ICs(, = 0.16 mcg/ml.Example X20 g of nystatin and 6g of glucose was dissolved in 100 ml of dimethyl formamide. Further procedure was carried out as given in Example IX. 18 g of N-methylglucamine salt of N-glycosyl derivative of nystatin of El ism = 560 at 304 nm and IC5 = 0.45 mcg/ml was obtained. Original antibiotic: E) é'm = 790 at 304 nm, IC5() = 0.18 mcg/ml.Example XI20 g of amphotericin B and 6 g of glucose was dissolved in 200 ml of dimethyl formamide and allowed to stand at a temperature of 35"C for 18 hours. The resulting solution was filtered and 500 ml of 5% ammonium sulphate aqueous solution was added to the filtrate then the mixture was allowed to stand at a temperature of + 4"C for 2 hours. The precipitate was filtered and washed with water. 1500 ml of methanol at a temperature of 50"C and 6g of N-methylglucamine salt dissolved in 60 ml of water was added to the precipitate whereupon the mixture was mixed for 30 minutes, then 1 1 of n-butanol was added. The obtained solution was evaporated at a temperature of 45"C under reduced pressure until the methanol and water were removed. The residue was allowed to stand at a temperature of +4 C for crystallisation. The sediment was filtered, washed with n-butanol then with petroleum ether and dried at the room tem,çerature. 18 g of N-methylglucamine salt of N-glycosyl derivative of amphotericin B of Ei c?rn = 1140 at 380 nm and IC5(l = 0.1 mcg/ml were obtained.WHAT WE CLAIM IS:- 1. A method of preparing the N-methylglucamine salt of an N-glycosyl derivative of a polyene macrolide antibiotic comprising reacting a polyene macrolide anitbiotic containing at least one amino group with a saccharide selected from aldose monosaccharides, ketose monosaccharides, aldose oligosaccharides and ketose oligosaccharides in an organic solvent to form an N-glycosyl derivative of the said antibiotic, precipitating the said N-glycosyl derivative by the addition of water or an aqueous solution in an inorganic salt; recovering the precipitate and reacting same with N-methylglucamine.
- 2. A method according to claim 1. in which the inorganic salt is ammonium sulphate.
- 3. A method according to claim I or claim 2 in which the N-methylglucamine salt of the N-glycosyl derivative of the said antibiotic is recrystallized from an alkanol.
- 4. A method according to claim 1 or claim 2 in which the N-glycosyl derivatives precipitate is purified by recrystallization from an alkanol also.
- 5. A method according to claim 3 or claim 4 in which the alkanol is N-butanol.
- 6. A method of preparing an N-methylglucamine salt of an N-glycosyl derivative of a polyene macrolide according to any one of Examples IX to XI hereinbefore.
- 7. The N-glucamine salt of an N-glycosyl derivative of a polyene macrolide antibiotic whenever prepared by the method claimed in any one of claims 1 to 6.
- 8. The N-methylglucamine salt of N-glycosyl derivatives of polyene macrolides.
- 9. The N-methylglucamine salt of N-glycosyl derivative of amphotericin B.
- 10. The N-methylglucamine salt of N-glycosyl derivative of polifungin.
- 11. The N-methylglucamine salt of N-glycosyl derivative of nystatin.
- 12. Pharmaceutical preparations comprising an N-methylglucamine salt of an Nglycosyl derivative of a polyene macrolide and a pharmaceutical carrier.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PL1976188979A PL100966B1 (en) | 1976-04-22 | 1976-04-22 | METHOD OF OBTAINING N-GLYCOSYL DERIVATIVES OF POLYENUM MACROLIDES AND THEIR SALT, ESPECIALLY N-METHYL GLUCAMINE SALT |
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| Publication Number | Publication Date |
|---|---|
| GB1582378A true GB1582378A (en) | 1981-01-07 |
Family
ID=19976536
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB15058/77A Expired GB1582378A (en) | 1976-04-22 | 1977-04-12 | Method of preparing n-glycosyl derivatives of polyene macrolide and the salts thereof |
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| JP (1) | JPS52131594A (en) |
| AU (1) | AU513015B2 (en) |
| BE (1) | BE853893A (en) |
| BR (1) | BR7702505A (en) |
| CA (1) | CA1072088A (en) |
| CH (1) | CH631995A5 (en) |
| CS (1) | CS193092B2 (en) |
| DD (1) | DD129331A5 (en) |
| DE (1) | DE2717811C2 (en) |
| DK (1) | DK178077A (en) |
| ES (1) | ES458093A1 (en) |
| FR (1) | FR2361418A1 (en) |
| GB (1) | GB1582378A (en) |
| HU (1) | HU177885B (en) |
| IN (1) | IN144113B (en) |
| IT (1) | IT1080375B (en) |
| NL (1) | NL7704395A (en) |
| PL (1) | PL100966B1 (en) |
| RO (1) | RO71938A (en) |
| SE (1) | SE7704604L (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| PL122086B1 (en) * | 1979-04-09 | 1982-06-30 | Politechnika Gdanska | Process for preparing amides of antibiotics from the group of polyene macrolides and their derivativesvykh makrolidov i ikh proizvodnykh |
| GB2122892B (en) * | 1982-07-02 | 1986-01-29 | Squibb & Sons Inc | Nystantin pastille formulation |
| US9447136B2 (en) | 2012-03-09 | 2016-09-20 | Blirt S.A. | Semisynthetic derivatives of Nystatin A1 |
| BR112014031060A2 (en) | 2012-06-15 | 2017-06-27 | Blirt S A | compound of formula 1a; pharmaceutical composition; use of the compound; method for treating fungal infection in a patient; plant protection product; method for treating fungal infection in a plant; antifungal building treatment product; method for treating a building; and compound for use |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FI60877C (en) * | 1971-08-13 | 1982-04-13 | Politechnika Gdanska | PROTECTION OF THERAPEUTIC ACTIVITIES OF THERAPEUTIC ACTIVITIES WITH A DISPENSABLE POLYENMACROLIDANTIBIOTICS-N-GLYCOSYL DERIVATIVES |
| DE2417993C2 (en) * | 1974-04-11 | 1982-07-01 | Leningradskij naučno-issledovatel'skij institut antibiotikov, Leningrad | Polyene macrolide antibiotic complexes, processes for their preparation and pharmaceuticals containing these compounds |
-
1976
- 1976-04-22 PL PL1976188979A patent/PL100966B1/en unknown
-
1977
- 1977-04-06 CH CH433677A patent/CH631995A5/en not_active IP Right Cessation
- 1977-04-12 YU YU00966/77A patent/YU96677A/en unknown
- 1977-04-12 IN IN557/CAL/1977A patent/IN144113B/en unknown
- 1977-04-12 GB GB15058/77A patent/GB1582378A/en not_active Expired
- 1977-04-19 AU AU24418/77A patent/AU513015B2/en not_active Expired
- 1977-04-20 RO RO7790105A patent/RO71938A/en unknown
- 1977-04-20 DD DD7700198505A patent/DD129331A5/en unknown
- 1977-04-20 FR FR7711907A patent/FR2361418A1/en active Granted
- 1977-04-21 SE SE7704604A patent/SE7704604L/en not_active Application Discontinuation
- 1977-04-21 CS CS772666A patent/CS193092B2/en unknown
- 1977-04-21 DE DE2717811A patent/DE2717811C2/en not_active Expired
- 1977-04-21 IT IT22707/77A patent/IT1080375B/en active
- 1977-04-21 CA CA276,646A patent/CA1072088A/en not_active Expired
- 1977-04-22 ES ES458093A patent/ES458093A1/en not_active Expired
- 1977-04-22 DK DK178077A patent/DK178077A/en unknown
- 1977-04-22 JP JP4671377A patent/JPS52131594A/en active Granted
- 1977-04-22 HU HU77PO646A patent/HU177885B/en unknown
- 1977-04-22 NL NL7704395A patent/NL7704395A/en not_active Application Discontinuation
- 1977-04-22 BE BE176963A patent/BE853893A/en unknown
- 1977-05-27 BR BR7702505A patent/BR7702505A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| CH631995A5 (en) | 1982-09-15 |
| BR7702505A (en) | 1978-03-21 |
| DD129331A5 (en) | 1978-01-11 |
| ES458093A1 (en) | 1978-03-16 |
| PL100966B1 (en) | 1978-11-30 |
| JPS5721278B2 (en) | 1982-05-06 |
| YU96677A (en) | 1982-06-30 |
| HU177885B (en) | 1982-01-28 |
| IN144113B (en) | 1978-03-25 |
| AU2441877A (en) | 1978-10-26 |
| RO71938A (en) | 1981-11-04 |
| NL7704395A (en) | 1977-10-25 |
| DE2717811A1 (en) | 1977-10-27 |
| JPS52131594A (en) | 1977-11-04 |
| BE853893A (en) | 1977-08-16 |
| DK178077A (en) | 1977-10-23 |
| CS193092B2 (en) | 1979-09-17 |
| DE2717811C2 (en) | 1983-10-20 |
| FR2361418A1 (en) | 1978-03-10 |
| CA1072088A (en) | 1980-02-19 |
| SE7704604L (en) | 1977-10-23 |
| FR2361418B1 (en) | 1980-04-18 |
| AU513015B2 (en) | 1980-11-06 |
| IT1080375B (en) | 1985-05-16 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PS | Patent sealed [section 19, patents act 1949] | ||
| PCNP | Patent ceased through non-payment of renewal fee |