FR2510116A1 - PROCESS FOR THE PRODUCTION OF RIFAMYCIN DERIVATIVES AND NOVEL RIFAMYCIN DERIVATIVES OBTAINED USING THE SAME - Google Patents
PROCESS FOR THE PRODUCTION OF RIFAMYCIN DERIVATIVES AND NOVEL RIFAMYCIN DERIVATIVES OBTAINED USING THE SAME Download PDFInfo
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- FR2510116A1 FR2510116A1 FR8206006A FR8206006A FR2510116A1 FR 2510116 A1 FR2510116 A1 FR 2510116A1 FR 8206006 A FR8206006 A FR 8206006A FR 8206006 A FR8206006 A FR 8206006A FR 2510116 A1 FR2510116 A1 FR 2510116A1
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- rifamycin
- formula
- compound
- rifamycin derivatives
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- 0 CC*(C(C(C1C)O*)[C@](/C=C/*C(C)(C(c2c3C(C(*)=C4*5C)=O)=O)Oc2c(*)c(N)c3C4=O)OC)=*C1C(C)C(*)C(*)C=CC=C(C)C5=* Chemical compound CC*(C(C(C1C)O*)[C@](/C=C/*C(C)(C(c2c3C(C(*)=C4*5C)=O)=O)Oc2c(*)c(N)c3C4=O)OC)=*C1C(C)C(*)C(*)C=CC=C(C)C5=* 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/08—Bridged systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D498/18—Bridged systems
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Procédé de fabrication de dérivés de la rifamycine et nouveaux dérivés de la rifamycine obtenus au moyen dudit procédé.Process for the manufacture of rifamycin derivatives and novel rifamycin derivatives obtained by the process
L'invention se rapporte à un procédé de fabrication de dérivés de la rifamycine.The invention relates to a process for the manufacture of rifamycin derivatives.
La demande de brevet européen NO 0014181 décrit de nouveaux dérivés de la rifamycine, parmi lesquels la 3-hydroxyrifamycine S, de formule
ayant une activité antibiotique intéressante.European Patent Application No. 0014181 discloses novel rifamycin derivatives, including 3-hydroxyrifamycin S, of the formula
having an interesting antibiotic activity.
Selon ladite demande de brevet européen, la 3-hydroxyrifamycine S est obtenue par fermentation de la souche Nocardia mediterranei. According to said European patent application, 3-hydroxyrifamycin S is obtained by fermentation of the strain Nocardia mediterranei.
L'invention a pour objet un procédé au moyen duquel on peut obtenir la 3-hydroxy-rifamycine S par voie chimique avec emploi de matières premières bon marché facilement disponibles sur le marché.The subject of the invention is a process by which 3-hydroxy-rifamycin S can be obtained chemically using cheap raw materials readily available on the market.
On a trouvé en outre que ledit procédé convenait à la production, non seulement de la 3-hydroxy-rifamycine S, mais également d'autres composés intéressants de la rifamycine.It has further been found that said method is suitable for the production not only of 3-hydroxy-rifamycin S but also of other compounds of interest to rifamycin.
Plus particulièrement, le procédé suivant l'invention est approprié à la fabrication de dérivés de la rifamycine de formule
dans laquelle R1 et R2 sont chacun -OH, ou R1 et R2 pris ensemble sont
et R3 est pris dans le groupe composé de
et est caractérisé en ce que l'on fait réagir un composé de formule I, dans laquelle R1 t R2 sont tels que définis cidessus et R3 est -Br, avec un sel de sodium, de potassium, ou de triéthylamine, d'acide formique ou acétique dans un solvant aprotique bipolaire à une température comprise entre la température ambiante et + 600C.More particularly, the process according to the invention is suitable for the manufacture of rifamycin derivatives of formula
wherein R1 and R2 are each -OH, or R1 and R2 taken together are
and R3 is taken from the group consisting of
and is characterized in that a compound of formula I, wherein R 1 t R 2 is as defined above and R 3 is -Br, with a sodium, potassium, or triethylamine, formic acid salt is reacted; or acetic acid in a bipolar aprotic solvent at a temperature between room temperature and + 600C.
Certains des dérivés de la rifamycine produits au moyen du procédé ci-dessus se sont révélés être nouveaux.
Plus précisément, ces dits dérivés de la rifamycine (qui font également partie de l'invention) ont la formule générale < I) ci-dessus, dans laquelle R1 et R2 pris ensemble sont
et R3 est pris dans le groupe composé de
et -Br. Le composé dans lequel R3 est -Br est un composé intermédiaire qui sert à produire les autres dérivés de la rifamicyne, dans lesquels R3 est
en le faisant réagir avec un sel de sodium, de potassium ou de triéthylamine d'acide formique ou acétique, dans un solvant aprotique bipolaire, à une température comprise entre la température ambiante et +60 C. Some of the rifamycin derivatives produced by the above method have been found to be novel.
More specifically, these so-called rifamycin derivatives (which are also part of the invention) have the general formula (I) above, wherein R1 and R2 taken together are
and R3 is taken from the group consisting of
and -Br. The compound wherein R3 is -Br is an intermediate compound which serves to produce the other rifamicyne derivatives, wherein R3 is
by reacting it with a salt of sodium, potassium or triethylamine of formic or acetic acid, in a bipolar aprotic solvent, at a temperature between room temperature and +60 C.
Le composé de formule (I), dans laquelle R1 et R2 pris ensemble sont
et R3 est -Br, peut être facilement obtenu, en partant d'un composé de la rifamycine ayant la même formule, mais dans laquelle R3 est -H 3un tel composé est bien connu en soi et décrit dans dans Helvetica Chimica Acta, 56, 2343 (1973)j7, en suivant les procédés décrits dans les demandes de brevet d'Allemagne de l'Ouest publiées DOS 2548128 et DOS 2851312 : ces deux demandes de brevet concernant la préparation d'un composé de formule (I) dans laquelle R1 = R2 = -OH et R3 = -Br.The compound of formula (I) in which R1 and R2 taken together are
and R3 is -Br, can be easily obtained starting from a rifamycin compound having the same formula, but wherein R3 is -H3a such compound is well known per se and described in Helvetica Chimica Acta, 56, 2343 (1973), following the methods described in West German patent applications DOS 2548128 and DOS 2851312: these two patent applications relating to the preparation of a compound of formula (I) wherein R1 = R2 = -OH and R3 = -Br.
Ce dernier composé est également (de façon connue en soi) un composé intermédiaire qui peut être utilisé pour la mise en oeuvre du procédé de l'invention.The latter compound is also (in a manner known per se) an intermediate compound which can be used for carrying out the process of the invention.
L'invention sera mieux comprise à l'aide d'un certain nombre d'exemples non limitatifs donnés ci-après, dans lesquels des chromatographies en couche mince ônt été effectuées sur des plaques de Merck à gel de silice 60 F254 en utilisant comme éluant : toluène ; acétate d'éthyle ; méthanol 11 ; 4 ; 4.The invention will be better understood with the aid of a number of non-limiting examples given below, in which thin layer chromatography has been carried out on Merck silica gel 60 F254 plates using as eluent : toluene; ethyl acetate ; methanol 11; 4; 4.
Exemple 1 3-Formyloxy-rifamycine S
On dissout 7 g. de 3-bromo-rifamycine S dans 50 ml de diméthyl-formamide et on ajoute 2,5 g de formiate de potassium à la température ambiante. On réchauffe la solution jusqu'à 500C ; on l'agite pendant 6 heures et on la dilue avec 200 ml d'acétate d'éthyle. Après lavage à. l'eau, la phase organique est traitée avec de l'acide chlorhydrique dilué et lavée de nouveau à l'eau distillée.Example 1 3-Formyloxy-rifamycin S
7 g are dissolved. of 3-bromo-rifamycin S in 50 ml of dimethylformamide and 2.5 g of potassium formate are added at room temperature. The solution is heated to 500C; it is stirred for 6 hours and diluted with 200 ml of ethyl acetate. After washing at. water, the organic phase is treated with dilute hydrochloric acid and washed again with distilled water.
La solution d'acétate d'éthyle est séchée sur du sulfate de soude anhydre, filtrée et évaporée jusqu'à l'état sec. Le résidu est dissous dans du chloroforme et on le laisse cristalliser.The ethyl acetate solution is dried over anhydrous sodium sulphate, filtered and evaporated to dryness. The residue is dissolved in chloroform and allowed to crystallize.
Rendement : 5,7-9 d'un composé ayant la formule générale (I) dans laquelle R1 = R2 = -OH et
MS = 739 (M+)
Rf = 0,30
Exemple 2 3-Hydroxy-rifamycine S
On dissout 5,7 g; de 3-formyloxyrifamycine S dans 50 ml de méthanol et on mélange avec 100 ml d'une solution aqueuse à 1% de bicarbonate de soude.MS = 739 (M +)
Rf = 0.30
Example 2 3-Hydroxy-rifamycin S
5.7 g are dissolved; of 3-formyloxyrifamycin S in 50 ml of methanol and mixed with 100 ml of a 1% aqueous solution of sodium bicarbonate.
La solution obtenue est agitée pendant 4 heures à 500C puis on y ajoute 150 ml de chloroforme. La couche organique est lavée avec de l'acide chlorhydrique dilué, puis à l'eau distillée. The solution obtained is stirred for 4 hours at 500 ° C. and then 150 ml of chloroform are added thereto. The organic layer is washed with dilute hydrochloric acid and then with distilled water.
Après séchage sur du sulfate de soude anhydre, la solution de chloroforme est filtrée et évaporée jusqu'à l'état sec.After drying over anhydrous sodium sulphate, the chloroform solution is filtered and evaporated to dryness.
Rendement : 5,2 g d'un composé de formule générale (I), dans laquelle R1 = R2 = R3 = -OH. Yield: 5.2 g of a compound of general formula (I), wherein R 1 = R 2 = R 3 = -OH.
Le spectre P.M.R. est superposable à celui mentionné dans le demande de brevet européen N 0014181.The spectrum P.M.R. is superimposable to that mentioned in the European patent application N 0014181.
Rf = 0,35
Le même composé peut être obtenu à partir de 3-hydroxy21,23-acétonide-rifamycine S (exemple 4) en hydrolysant le groupe acétonide selon la procédure décrite dans Helv. Chim.Rf = 0.35
The same compound can be obtained from 3-hydroxy-21,23-acetonide-rifamycin S (Example 4) by hydrolyzing the acetonide group according to the procedure described in Helv. Chim.
Acta 56, 2347 (1973).Acta 56, 2347 (1973).
Exemple 3 3-Bromo-21,23-acétonide-rifamycine S
On effectue la bromation de 7,5 g de 21,23-acétoniderifamycine S selon des techniques bien connues (Demandes de brevet d'Allemagne de l'Ouest NO 2851312 et 2548128). Example 3 3-Bromo-21,23-acetonide-rifamycin S
The bromination of 7.5 g of 21,23-acetoniderifamycin S is carried out according to well-known techniques (West German Patent Applications Nos. 2851312 and 2548128).
Rendement : 7 g du dérivé 3-bromo correspondant.Yield: 7 g of the corresponding 3-bromo derivative.
Br% : 9,8%
Rf = 0,49
Exemple 4 3-Hydroxy-21,23-acétonide-rifamycine S
On fait réagir 7 g de 3-bromo-21,23-acétonide-rifamycine S avec du formiate de potassium selon le même procédé que celui décrit dans l'exemple 1 et la 3-formyloxy-21,23acétonide-rifamycine S brute ainsi obtenue produit 4,8 g du composé mentionné en titre, en suivant le procédé décrit dans l'exemple 2.Br%: 9.8%
Rf = 0.49
Example 4 3-Hydroxy-21,23-acetonide-rifamycin S
7 g of 3-bromo-21,23-acetonide-rifamycin S are reacted with potassium formate according to the same process as that described in Example 1 and the crude 3-formyloxy-21,23 -acetonide-rifamycin S thus obtained produced 4.8 g of the title compound, following the procedure described in Example 2.
MS = 751 (M+)
Rf = 0,46
L'activité antibactérienne de certains des composés suivant l'invention a été essayée en utilisant la technique série double dans un milieu nutritif et les résultats obtenus sont indiqués dans le tableau ci-dessous < dans lequel ils sont comparés avec l'activité de la rifampicine)
Rf = 0.46
The antibacterial activity of some of the compounds according to the invention was tested using the double series technique in a nutrient medium and the results obtained are shown in the table below in which they are compared with the activity of rifampicin. )
<tb> Bactéries <SEP> Rifampicine <SEP> Composé <SEP> de <SEP> Composé <SEP> de
<tb> <SEP> l'Exemple <SEP> 2 <SEP> l'-Exemple <SEP> 1
<tb> Staphylococcus
<tb> aureus <SEP> 0,0005 <SEP> -0,018 <SEP> 0,022
<tb> Streptococcus
<tb> pyogenes <SEP> 0,6 <SEP> - <SEP> 25 <SEP> 20
<tb> Streptococcus
<tb> faecalis <SEP> 0,3 <SEP> 25 <SEP> 20
<tb> Sarcina <SEP> lutea <SEP> 0,0045 <SEP> 0,09 <SEP> 0,004
<tb> Escherichia <SEP> coli <SEP> 5 <SEP> 12,5 <SEP> 10
<tb> Klebsiella
<tb> pneumoniae <SEP> 5 <SEP> 25 <SEP> 20
<tb> Proteus
<tb> vulgaris <SEP> 5 <SEP> 25 <SEP> 20
<tb> pseudomonas
<tb> aeruginosa <SEP> 5 <SEP> 50 <SEP> 20
<tb> Salmonella <SEP>
<tb> abortivoequina <SEP> 2,5 <SEP> -25 <SEP> 20
<tb> Mycobacter <SEP> ium <SEP>
<tb> tuberculosis
<tb> H37 <SEP> Rv <SEP> 0,01 <SEP> 0,25 <SEP> 0,01
<tb>
Les valeurs numériques inscrites au tableau représentent le concentration inhibitrice minimale et sont déterminées en pg/ml. <tb> Bacteria <SEP> Rifampicin <SEP> Compound <SEP> of <SEP> Compound <SEP> of
<tb><SEP> Example <SEP> 2 <SEP> the Example <SEP> 1
<tb> Staphylococcus
<tb> aureus <SEP> 0.0005 <SEP> -0.018 <SEP> 0.022
<tb> Streptococcus
<tb> pyogenes <SEP> 0.6 <SEP> - <SEP> 25 <SEP> 20
<tb> Streptococcus
<tb> faecalis <SEP> 0.3 <SEP> 25 <SEP> 20
<tb> Sarcina <SEP> lutea <SEP> 0.0045 <SEP> 0.09 <SEP> 0.004
<tb> Escherichia <SEP> coli <SEP> 5 <SEP> 12.5 <SEP> 10
<tb> Klebsiella
<tb> pneumoniae <SEP> 5 <SEP> 25 <SEP> 20
<tb> Proteus
<tb> vulgaris <SEP> 5 <SEP> 25 <SEP> 20
<tb> pseudomonas
<tb> aeruginosa <SEP> 5 <SEP> 50 <SEP> 20
<tb> Salmonella <SEP>
<tb> abortivoequina <SEP> 2,5 <SEP> -25 <SEP> 20
<tb> Mycobacter <SEP> ium <SEP>
<tb> tuberculosis
<tb> H37 <SEP> Rv <SEP> 0.01 <SEP> 0.25 <SEP> 0.01
<Tb>
Numerical values in the table represent the minimum inhibitory concentration and are determined in μg / ml.
Le composé de l'exemple 2, bien que moins actif que la rifampic-ine, conserve une action inhibitrice significative, en particulier contre les bactéries Gram-positives et le
Mycobacterium tuberculosis. L'activité du dérivé obtenu selon l'exemple 1 est améliorée et, de façon intéressante, elle atteint celle de la rifampicine sur le Mycobacterium tuberculos is. The compound of Example 2, although less active than rifampicin, retains a significant inhibitory action, in particular against Gram-positive bacteria and
Mycobacterium tuberculosis. The activity of the derivative obtained according to Example 1 is improved and, interestingly, it reaches that of rifampicin on Mycobacterium tuberculosis.
Claims (4)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB8122417 | 1981-07-21 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| FR2510116A1 true FR2510116A1 (en) | 1983-01-28 |
Family
ID=10523383
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| FR8206006A Pending FR2510116A1 (en) | 1981-07-21 | 1982-04-02 | PROCESS FOR THE PRODUCTION OF RIFAMYCIN DERIVATIVES AND NOVEL RIFAMYCIN DERIVATIVES OBTAINED USING THE SAME |
Country Status (8)
| Country | Link |
|---|---|
| JP (1) | JPS5824588A (en) |
| BE (1) | BE893873A (en) |
| CH (1) | CH651046A5 (en) |
| DE (1) | DE3209109A1 (en) |
| DK (1) | DK318182A (en) |
| FR (1) | FR2510116A1 (en) |
| IT (1) | IT1210479B (en) |
| NL (1) | NL8202378A (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0014181A2 (en) * | 1979-01-25 | 1980-08-06 | Ciba-Geigy Ag | Compounds with antibiotic activity, their manufacture by fermentation and pharmaceutical preparations containing them |
| EP0023885A1 (en) * | 1979-07-20 | 1981-02-11 | Ciba-Geigy Ag | Method for the introduction of an oxygen-containing functional group into ansamycines, compounds thus obtained, and pharmaceutical compositions containing them |
-
1982
- 1982-03-12 DE DE19823209109 patent/DE3209109A1/en not_active Withdrawn
- 1982-04-02 FR FR8206006A patent/FR2510116A1/en active Pending
- 1982-05-27 IT IT8221518A patent/IT1210479B/en active
- 1982-05-28 CH CH3308/82A patent/CH651046A5/en not_active IP Right Cessation
- 1982-06-11 NL NL8202378A patent/NL8202378A/en not_active Application Discontinuation
- 1982-07-15 DK DK318182A patent/DK318182A/en not_active Application Discontinuation
- 1982-07-19 BE BE0/208621A patent/BE893873A/en not_active IP Right Cessation
- 1982-07-19 JP JP57124538A patent/JPS5824588A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0014181A2 (en) * | 1979-01-25 | 1980-08-06 | Ciba-Geigy Ag | Compounds with antibiotic activity, their manufacture by fermentation and pharmaceutical preparations containing them |
| EP0023885A1 (en) * | 1979-07-20 | 1981-02-11 | Ciba-Geigy Ag | Method for the introduction of an oxygen-containing functional group into ansamycines, compounds thus obtained, and pharmaceutical compositions containing them |
Also Published As
| Publication number | Publication date |
|---|---|
| DK318182A (en) | 1983-01-22 |
| CH651046A5 (en) | 1985-08-30 |
| IT1210479B (en) | 1989-09-14 |
| JPS5824588A (en) | 1983-02-14 |
| DE3209109A1 (en) | 1983-02-10 |
| NL8202378A (en) | 1983-02-16 |
| BE893873A (en) | 1982-11-16 |
| IT8221518A0 (en) | 1982-05-27 |
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