GB2102409A - Rifamycin derivatives - Google Patents
Rifamycin derivatives Download PDFInfo
- Publication number
- GB2102409A GB2102409A GB08207717A GB8207717A GB2102409A GB 2102409 A GB2102409 A GB 2102409A GB 08207717 A GB08207717 A GB 08207717A GB 8207717 A GB8207717 A GB 8207717A GB 2102409 A GB2102409 A GB 2102409A
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- GB
- United Kingdom
- Prior art keywords
- rifamycin
- acetonide
- hydroxy
- formyloxy
- derivative
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 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)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
<IMAGE> Rifamycin derivatives I (R1=R2=OH or R1+R2=acetonide; R3=OH, HCOO or CH3COO) are prepared from 3-bromo- rifamycin S (I, R1=R2=OH, R3=Br) or from 3-bromo-21,23-acetonide, rifamycin S (I, R1+R2=acetonide, R3=Br) by reaction with an alkali metal or triethylammonium formate or acetate in a dipolar aprotic solvent at from ambient temperature to 60 DEG C to give the rifamycin derivatives in which R3=HCOO or CH3COO; optionally followed by hydrolysing the formyloxy conditions to give compounds I in which R3 is OH. The rifamycin derivatives I other than 3-hydroxy-rifamycin S (I, R1=R2=R3=OH) are novel compounds and are claimed both per se and in or acetoxy group in mild alkaline pharmaceutical compositions containing them. They have antibiotic activity.
Description
SPECIFICATION
Rifamycin derivatives
The invention relates to certain rifamycin derivatives to a method for their preparation of those rifamycin derivatives and one other, and to pharmaceutical compositions containing them.
European Patent Specification No. 0014181 discloses, inter alia, 3-hydroxy-rifamycin S which has the formula I below, Ri, R2 and R3 all being hydroxy groups. This compound has interesting antibiotic activity, and may be obtained by fermentation of the strain Nocardia mediterranei. We have sought and found a chemical route to this compound, using inexpensive starting materials commonly available on the market. It was also found that other rifamycin derivatives could be prepared by the route found.
The invention provides a method for the preparation of a rifamycin derivative of the general formula I
wherein R1 and R2 both represent hydroxy groups or together represent an acetonide group and R3 represents a hydroxy, formyloxy or acetoxy group, the method comprising reacting a rifamycin derivative of the general formula I wherein R1 and R2 are as above defined and R3 represents a bromine atom with an alkali metal or triethylammonium formate or acetate in a dipolar aprotic solvent at from abient temperature to 600C and, if the desired rifamycin derivative is one in which R3 represents a hydroxy group, subjecting the resultant 3-formyloxy or acetoxy-rifamycin S or 21,23 acetonide derivative thereof to mild alkaline hydrolysis.By an acetonide group, we mean a group of the formula
With the exception of 3-hydroxy-rifamycin S, the compounds prepared according to the invention are novel, and the invention accordingly further provides a rifamycin derivative of the general formula I wherein R1 and R2 both represent hydroxy groups or together represent an acetonide group, and R3 represents a hydroxy, formyloxy or acetoxy group, with the proviso that P1, R2 and R3 do not simultaneously represent hydroxy groups.
The invention also provides a pharmaceutical composition comprising a rifamycin derivative having the general formula I as defined in the last preceding sentence or a rifamycin derivative prepared according to the invention in admixture with a pharmaceutically acceptable diluent or carrier.
One of the starting materials used in the method according to the invention, 3-bromo-rifamycin S (I, R,=R2=OH, R3=Br) is a known compound, see German Offenlegungsschriften Nos. 2548128 and 2851312. The other, 3-bromo-21 ,23-acetonide-rifamycin S (I, R1+R2=acetonide, R3=Br) is a novel compound. It may be prepared from 21 23-acetonide-rifamycin S, see Helvetica Chemica Acta, 56, 2343 (1973), by the bromination methods described in the German Offenlegungsschriften supra.
The invention is illustrated by the following Examples, in which the thin layer chromatography measurements were obtained on silica gel 60 F254 Merck plates, using toluene:ethyl acetate:methanol 11:4:4 by volume as eluent.
EXAMPLE 1 3-Formyloxy-rifamycin S
7 g of 3-bromo-rifamycin S was dissolved in 50 ml of dimethylformamide and 2.5 g of potassium formate were added at room temperature. The solution was warmed to 500C, stirred for 6 hours and then diluted with 200 ml of ethyl acetate. After washing with water, the organic phase was treated with dilute hydrochloric acid and washed again with distilled water, The ethyl acetate solution was dried on anhydrous sodium sulphate, filtered and evaporated to dryness. The residue was dissolved in chloroform and allowed to crystallize.
Yield: 5.7 g of a compound of the general formula I wherein
R1=R2=OH and R3=H.COO
MS = 739 (M+)
Rf = 0.30
EXAMPLE 2 3-Hydroxy-rifamycin S
5.7 g of 3-formyloxy-rifamycin S, prepared as described in Example 1 , was dissolved in 50 ml of methanol and mixed with 100 ml of 1% aqueous sodium bicarbonate solution. The solution was stirred for 4 hours at 500C, and then 1 50 ml of chloroform was added to it. The organic layer was washed with dilute hydrochloric acid and then with distilled water. After drying on anhydrous sodium sulphate the chloroform solution was filtered and evaporated to dryness.
Yield: 5.2 g of a compound of the general formula I wherein R,=R2=R3=OH.
The P.M.R. spectrum is superimposable on that reported in European Patent Specification No.
0014181.
Rf = 0.35
The same compound can be obtained from 3-hydroxy-2 1 ,23-acetonide-rifamycin S (Example 4) by hydrolyzing the acetonide group according to the procedure described in Helv. Chim. Acta 56, 2347 (1973).
EXAMPLE 3 3-Bromo-2 1,23-acetonide-rifamycin S
7.5 g of 21 23-acetonide-rifamycin S was brominated according to well known techniques (German Patent Applications Nos. 2851312 and 2548128).
Yield: 7 g of the title compound.
Br%: 9.8%
Rf = 0.49
EXAMPLE 4 3-Hydroxy-2 1,23-acetonide-rifamycin S
7 g of 3-bromo-21,23-acetonide-rifamycin S was reacted with potassium formate according to the procedure described with potassium formate according to the procedure described in Example 1 and the crude 3-formyloxy-2 1 23-acetonide-rifamycin S thus obtained yielded 4.8 g of the title compound following hydrolysis according to the procedure described in Example 2.
MS = 751 (M+)
Rf = 0.46
The antibacterial activity of some of the compounds according to the present invention was tested by serial twofold technique in nutrient medium and the results obtained are set out in the following table (in which they are compared with the activity of rifampicin):
|; Compound of Compound of Bacteria Rifampicin Example 2 Example 1 Staphylococcus aureus 0.0005 0.018 0.022 Streptococcus pyogenes 0.6 25 20 Streptococcus fecal is 0.3 25 20 Sarcina lutea 0.0045 0.09 0.004 Escherichia coli 5 12.5 10 Klebsiellapneumoniae 5 25 20 Proteus vulgaris 5 25 20 Pseudomonas aeruginosa 5 50 20 Salmonellaabortivoequina 2.5 25 20 Mycobacterium tuberculosis H37 Rv 0.01 0.025 0.01 The numerical values written in the Table represent the MIC and are determined as mcg/ml.
The compound of Example 2, although less active than Rifampicin, retains a significative inhibiting action especially 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 (7)
1. A method for the preparation of a rifamycin derivative of the general formula I
wherein R, and R2 both represent hydroxy groups or together represent an acetonide group and R3 represents a hydroxy, formyloxy or acetoxy group, the method comprising reacting a rifamycin derivative of the general formula I wherein R and R2 are as above defined and R3 represents a bromine atom with an alkali metal or triethylammonium formate or acetate in a dipolar aprotic solvent at from ambient temperature to 600C and, if the desired rifamycin derivative is one in which R3 represents a hydroxy group, subjecting the resultant 3-formyloxy or acetoxy-rifamycin S or 21,23 acetonide derivative thereof to mild alkaline hydrolysis.
2. A method according to claim 1, the method being substantially as described herein with reference to Example 1, 2 or 4.
3. A rifamycin derivative of the general formula I
wherein R1 and R2 both represent hydroxy groups or together represent an acetonide group, and R3 represents a hydroxy, formyloxy or acetoxy group, with the proviso that R1, R2 and R3 do not all simultaneously represent hydroxy groups.
4. 3-Formyloxy-rifamycin S.
5. 3-Formyloxy-2 1 2 3-acetonide-rifa myci n S.
6. 3-Hydroxy-21 ,23-acetonide-rifamycin S.
7. A pharmaceutical composition comprising a rifamycin derivative according to any of claims 3 to 6 or a rifamycin derivative prepared according to claim 1 or claim 2 in admixture with a pharmaceutically acceptable diluent or carrier.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB08207717A GB2102409B (en) | 1981-07-21 | 1982-03-17 | Rifamycin derivatives |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB8122417 | 1981-07-21 | ||
GB08207717A GB2102409B (en) | 1981-07-21 | 1982-03-17 | Rifamycin derivatives |
Publications (2)
Publication Number | Publication Date |
---|---|
GB2102409A true GB2102409A (en) | 1983-02-02 |
GB2102409B GB2102409B (en) | 1985-01-16 |
Family
ID=26280197
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GB08207717A Expired GB2102409B (en) | 1981-07-21 | 1982-03-17 | Rifamycin derivatives |
Country Status (1)
Country | Link |
---|---|
GB (1) | GB2102409B (en) |
-
1982
- 1982-03-17 GB GB08207717A patent/GB2102409B/en not_active Expired
Also Published As
Publication number | Publication date |
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GB2102409B (en) | 1985-01-16 |
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Date | Code | Title | Description |
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PCNP | Patent ceased through non-payment of renewal fee |