Patent AT343734B successfully refreshed from Google Patents.
Patent EP0056291A2 successfully refreshed from Google Patents.
EP0056291A2
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EP
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Novel semisynthetic macrolidic antibiotics, microbiological processes for their preparation and related microorganism, novel intermediate compounds for their preparation and related pharmaceutical compositions containing them
Assignee: Pfizer Italia SRL
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Filing: 1982-01-08
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Granted: —
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Expires: 2002-01-08
Abstract
Abstract From the fermentation carried out with mutants blocked in the synthesis respectively of erythromycin and of oleandomycin, namely Streptomyces erythreus ATCC 31772 and Streptomyces antibioticus ATCC 31771, using as the substrate a derivative of erythronolide A, namely (8S)-8-fluoroerythronolide A, a derivative of erythronolide B, namely (8S)-8-fluoroeryth-ronolide B, or a derivative of 3-0-mycarosyl-erythronolide B, namely 3-0-mycarosyl-(8S)-fluoroerythronolide B, the corresponding (8S)-8-fluoro derivatives of the erythromycins A, B, C and D, as well as 3-0-oleandrosyl-5-deosaminyl-(8S)-8-fluoro-erythronolide A and 3-0-oleandrosyl-5-0-desosaminyl-(8S)-8-fluoroerythronolide B, all belonging to the class of the macrolide antibiotics are obtained. The preparation of the aforesaid substrate comprises the convention of erythronolide A, erythronolide B or 3-0-mycaro-syl-erythronolide B into the corresponding hemiacetal, the reaction of the latter with a compound capable of generating electrophilic fluorine and the opening of the resulting acetal with aqueous acid.
Inventors
- 👤 Luciano Toscano
- 👤 Leonardo M. Cappelletti
Bibliographic Details
Application Number
—
Jurisdiction
EP
Data Source
google_patents
Last Synchronized
2026-11-07 15:18
CPC Classifications
C; C07; C07D; C07D493/00; C07D493/02; C07D493/08; C07D313/00; C07H; C07H17/00; C07H17/04; C07H17/08; C12; C12N; C12N1/00; C12N1/20; C12N1/205; C12P; C12P19/00; C12P19/44; C12P19/60; C12P19/62; C12R; C12R2001/00; C12R2001/01; C12R2001/465; C12R2001/48; Y; Y10; Y10S; Y10S435/00; Y10S435/8215; Y10S435/822; Y10S435/886; Y10S435/888
Claims Analysis
Total Claims: 55
Claim 1
Independent Claim
22 words
(8S)-8-fluoroerythromycin A, having the formula: and the esters, salt-esters and salts thereof with organic and inorganic, non toxic and pharmaceutically acceptable, acids.
Claim 2
Dependent Claim
22 words
(8S)-8-fluoroerythromycin A, having the formula: and the esters, salt-esters and salts thereof with organic and inorganic, non toxic and pharmaceutically acceptable, acids.
Claim 3
Dependent Claim
22 words
(8S)-8-fluoroerythromycin B, having the formula: and the esters, salt-esters and salts thereof with organic and inorganic, non toxic and pharmaceutically acceptable, acids.
Claim 4
Dependent Claim
22 words
(8S)-8-fluoroerythromycin B, having the formula: and the esters, salt-esters and salts thereof with organic and inorganic, non toxic and pharmaceutically acceptable, acids.
Claim 5
Dependent Claim
22 words
(8S)-8-fluoroerythromycin C, having the formula: and the esters, salt-esters and salts thereof with organic and inorganic, non toxic and pharmaceutically acceptable acids.
Claim 6
Dependent Claim
22 words
(8S)-8-fluoroerythromycin C, having the formula: and the esters, salt-esters and salts thereof with organic and inorganic, non toxic and pharmaceutically acceptable acids.
Claim 7
Dependent Claim
22 words
(8S)-8-fluoroerythromycin D, having the formula: and the esters, salt-esters and slats thereof with organic and inorganic, non toxico and pharmaceutically acceptable acids.
Claim 8
Dependent Claim
22 words
(8S)-8-fluoroerythromycin D, having the formula: and the esters, salt-esters and slats thereof with organic and inorganic, non toxico and pharmaceutically acceptable acids.
Claim 9
Dependent Claim
22 words
3-0-oleandrosyl-5-0-desosaminyl-(8S)-8-fluoroerythronolide A, having the formula: and the esters, salt-esters and salts thereof with organic and inorganic, non toxic and pharmaceutically acceptable acids.
Claim 10
Dependent Claim
22 words
3-0-oleandrosyl-5-0-desosaminyl-(8S)-8-fluoroerythronolide A, having the formula: and the esters, salt-esters and salts thereof with organic and inorganic, non toxic and pharmaceutically acceptable acids.
Claim 11
Dependent Claim
22 words
3-0-oleandrosyl-5-0-desosaminyl-(8S)-8-fluoroerythronolide B, having the formula: and the esters, salt-esters and salts thereof with organic and inorganic, non toxic and pharmaceutically acceptable acids.
Claim 12
Dependent Claim
22 words
3-0-oleandrosyl-5-0-desosaminyl-(8S)-8-fluoroerythronolide B, having the formula: and the esters, salt-esters and salts thereof with organic and inorganic, non toxic and pharmaceutically acceptable acids.
Claim 13
Dependent Claim
12 words
Carbonate-derivatives of the antibiotics according to the claims 1, 3 and 5.
Claim 14
Dependent Claim
19 words
Streptomyces erythreus ATCC 31772, useful for microbiological processes for the preparation of antibiotics and blocked in the erythromycin synthesis.
Claim 15
Dependent Claim
19 words
Streptomyces erythreus ATCC 31772, useful for microbiological processes for the preparation of antibiotics and blocked in the erythromycin synthesis.
Claim 16
Dependent Claim
62 words
A process for the preparation of Streptomyces erythreus ATCC 31772, characterized in that a stock of Streptomyces erythreus producer of erythromycin is subjected to mutagenesis such as to kill at least 99% of the spores, and the surviving spores are analized and selected on the basis of their capacity of recognizing and converting (8S)-8-fluoroerythronolide B as the substrate in a fermentation process.
Claim 17
Dependent Claim
62 words
A process for the preparation of Streptomyces erythreus ATCC 31772, characterized in that a stock of Streptomyces erythreus producer of erythromycin is subjected to mutagenesis such as to kill at least 99% of the spores, and the surviving spores are analized and selected on the basis of their capacity of recognizing and converting (8S)-8-fluoroerythronolide B as the substrate in a fermentation process.
Claim 18
Dependent Claim
34 words
A process according to claim 9, characterized in that said irradiation with U. V. rays is carried out with rays having an emission maximum at 254 nm and with a dosage of 3000 erg/sq.cm.
Claim 19
Dependent Claim
45 words
A process for the prpearation of the compounds according to the claims 1 and 3, characterized in that a fermentation is carried out in a per se known manner using Streptomyces erythreus ATCC 31772 as the biosynthesis micro-organism and (85)-8-fluoroerythronolide A as the fermentation substrate.
Claim 20
Dependent Claim
42 words
A process for the preparation of the compound according to claim 5, characterized in that a fermentation is carried out, in a per se known manner, using Streptomyces antibioticus ATCC 31771 as the biosynthesis micro-organism and (8S)-8-fluoroerythro-nolide A as the fermentation substrate.
Claim 21
Dependent Claim
52 words
A process for the preparation of the compounds according to the claims 2 and 4, characterized in that a fermentation is carried out, in a per se known mannner, using Streptomyces erythreus ATCC 31772, as the biosynthesis micro-organism and a compound selected among (8S)-8-fluoroerythronolide B and 3-0-mycarosyl-(8S)-fluoroe-rythronolide B as the fermentation substrate.
Claim 22
Dependent Claim
47 words
A process for the preparation of the ocmpound of claims 6, characterized in that a fermentation is carried out,in a per se known manner, using Streptomyces antibioticus ATCC 31771 as the biosynthesis micro-organism and a compound selected among (85)-8-fluroerythronolide B and 3-0-mycarosyl-(8S)-8-fluoroerythronolide B as the fermentation substrate.
Claim 23
Dependent Claim
40 words
A process according to the claims 11 to 14, characterized in that the fermentation is continued up to a substantial disappearance of the substrate and, after a control with chromatographic and/or bioautographic methods the desired compounds are isolated and purified.
Claim 24
Dependent Claim
17 words
A process accoridng to claim 15, characterized in that the isolation is carried out by solvent extraction.
Claim 25
Dependent Claim
17 words
A process according to claim 15, characterized in that the purification is carried out by column chromatography.
Claim 26
Dependent Claim
5 words
(8S)-8-fluoroerythronolide A, having the formula:
Claim 27
Dependent Claim
5 words
(8S)-8-fluoroerythronolide A, having the formula:
Claim 28
Dependent Claim
6 words
(8S)-8-fluoroerythronolide A-6,9; 9,11-acetal, having the formula:
Claim 29
Dependent Claim
6 words
(8S)-8-fluoroerythronolide A-6,9; 9,11-acetal, having the formula:
Claim 30
Dependent Claim
6 words
8,9-anhydroerythronolide A 6,9-hemiacetal, having the formula:
Claim 31
Dependent Claim
6 words
8,9-anhydroerythronolide A 6,9-hemiacetal, having the formula:
Claim 32
Dependent Claim
5 words
(8S)-8-fluoroerythronolide B, having the formula:
Claim 33
Dependent Claim
5 words
(8S)-8-fluoroerythronolide B, having the formula:
Claim 34
Dependent Claim
6 words
(8S)-8-fluoroerythronolide B-6,9; 9,11-acetal, having the formula:
Claim 35
Dependent Claim
6 words
(8S)-8-fluoroerythronolide B-6,9; 9,11-acetal, having the formula:
Claim 36
Dependent Claim
5 words
3-0-mycarosyl-(8S)-8-fluoroerythronolide B, having the formula:
Claim 37
Dependent Claim
5 words
3-0-mycarosyl-(8S)-8-fluoroerythronolide B, having the formula:
Claim 38
Dependent Claim
6 words
3-0-mycarosyl-(8S)-8-fluoroerythrnolide B-6,9; 9,11-acetal having the formula:
Claim 39
Dependent Claim
6 words
3-0-mycarosyl-(8S)-8-fluoroerythrnolide B-6,9; 9,11-acetal having the formula:
Claim 40
Dependent Claim
5 words
3-0-mycarosyl-8,9-anhydroerythronolide B-6,9-hemiacetal having the formula:
Claim 41
Dependent Claim
5 words
3-0-mycarosyl-8,9-anhydroerythronolide B-6,9-hemiacetal having the formula:
Claim 42
Dependent Claim
82 words
A process for the preparation of the compounds of the claims 18, 21 and 23, characterized by the steps of: a) reaction of a compound selected among 8,9-anhydroerythronolide A-6,9-hemiacetal, 8,9-anhydroerythronolide B-6,9-hemiacetal and 3-0-mycarosyl-8,9-anhydroerythronolide B-6,9-hemiacetal with a compound capable of generating electrophilic fluorine in the presence of an organic inert solvent and at low temperature to form the corresponding (85)-8-fluoro acetalic derivative in admixture with the related (8S)-8-fluoro derivative, and b) reaction of (8S)-8-fluoro acetalic derivative with an acid and in aqueous solution.
Claim 43
Dependent Claim
24 words
A process according to claim 26, characeterized in that said reagent capable of generating electrophilic fluorine is selected in the class of the fluoroxy-perfluoro-alkanes.
Claim 44
Dependent Claim
17 words
28, A process according to claim 27, characterized in that said reagent generating electrophilic fluorine is fluoroxy-trifluoromethane.
Claim 45
Dependent Claim
17 words
A process according to claim 26, characterized in that said reagent generating electrophilic fluorine is perchloryl fluoride.
Claim 46
Dependent Claim
26 words
A process according to claim 26, characterized in that said reagent capable of generating electrophilic fluorine is selected among fluoroxy-sulphur-pentafluoride, molecular fluorine and lead tetraacetate-hydrogen fluoride.
Claim 47
Dependent Claim
20 words
A process according to claim 26, characterized in that said solvent is selected among chlorinated hydrocarbons, tetrahydrofuran and their mixtures.
Claim 48
Dependent Claim
19 words
A process according to claim 31, characterized in that said solvent is selected among trichlorofluoromethane, chloroform and methylene chloride.
Claim 49
Dependent Claim
18 words
A process according oto claim 26, characterized in that the reaction temperature is of between -75 and -85°C.
Claim 50
Dependent Claim
19 words
A process according to claim 26, characterized in that said acid is selected among acetic acid and hydrochloric acid.
Claim 51
Dependent Claim
25 words
A process according to claim 26, characterized in that said reaction with the acid is carried out at a temperature of between 30°C and 150°C.
Claim 52
Dependent Claim
27 words
Pharmaceutical composition, characterized by containing as the active ingredient, an antibiotic according to any of the lciam 1,2,3,4,5 and 6 together with the common excipients, vehicles, fillers.
Claim 53
Dependent Claim
27 words
Pharmaceutical composition, characterized by containing as the active ingredient, an antibiotic according to any of the lciam 1,2,3,4,5 and 6 together with the common excipients, vehicles, fillers.
Claim 54
Dependent Claim
15 words
Pharmaceutical compositon according to claim 36, characterized by being in form suitable for oral administration.
Claim 55
Dependent Claim
21 words
Pharmaceutical composition according to claim 36, characterized by containing an unitary dose of between 10 and 100 mg of active ingredient.
References Cited (Backward Citations)
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