JP2544488B2 - 3'-hydroxybenzoxazinorifamycin derivative - Google Patents

Description

TECHNICAL FIELD The present invention relates to a novel rifamycin derivative or a salt thereof, a method for producing the same, and an antibacterial agent containing the same as an active ingredient. More specifically, the invention is of formula (I): {In the formula, R represents a hydrogen atom or an acetyl group, and A is [In the formula, R ¹ is an alkyl group having 4 to 8 carbon atoms, and 2 to 8 carbon atoms.
Alkenyl group, C2-C8 alkynyl group, C1-C4 aminoalkyl group, C2-C6 monoalkylaminoalkyl group, C3-C8 dialkylaminoalkyl group, C2-C2 8 alkoxyalkyl group, C3-8 alkoxyalkyloxyalkyl group, C2-6 thioalkoxyalkyl group, C3-8
Dialkoxy alkyl group, a halogenated alkyl group having 1 to 6 carbon atoms, an acyl group having 1 to 6 carbon atoms, the _{formula: - (CH 2) a -CONHR} 2 ( wherein, a represents an integer of 0 to 3 Further, R ² represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms), an alkoxy group having 1 to 3 carbon atoms, or: Represents a group represented by], a group represented by the formula: (In the formula, b represents an integer of 2 to 6) or a group represented by the formula: (In the formula, n represents an integer of 2 to 6, and R ³ is an amino group, a monoalkylamino group having 1 to 6 carbon atoms, or 2 to 2 carbon atoms.
Represents a dialkylamino group having 10 carbon atoms or an acylamino group having 1 to 6 carbon atoms), a novel rifamycin derivative or a salt thereof, a process for producing the same, and the rifamycin derivative or a pharmacological agent thereof. The present invention relates to an antibacterial agent containing an acceptable salt as an active ingredient.

[Prior Art / Problems to be Solved by the Invention] The rifamycin derivative according to the present invention is a novel compound not described in the literature.

In order to find new and superior antibacterial agents, we have to formula (I): A novel rifamycin derivative represented by the formula (wherein R and A are the same as above) was synthesized, and its antibacterial activity and pharmacological properties were investigated. As a result, they have found that the novel rifamycin derivative represented by the formula (I) has a strong antibacterial action and excellent pharmacological properties, and thus reached the present invention.

Means for Solving the Problems The present invention provides a compound of formula (I): {In the formula, R represents a hydrogen atom or an acetyl group, and A is [In the formula, R ¹ is an alkyl group having 4 to 8 carbon atoms, and 2 to 8 carbon atoms.
Alkenyl group, C2-C8 alkynyl group, C1-C4 aminoalkyl group, C2-C6 monoalkylaminoalkyl group, C3-C8 dialkylaminoalkyl group, C2-C2 8 alkoxyalkyl group, C3-8 alkoxyalkyloxyalkyl group, C2-6 thioalkoxyalkyl group, C3-8
Dialkoxy alkyl group, a halogenated alkyl group having 1 to 6 carbon atoms, an acyl group having 1 to 6 carbon atoms, the _{formula: - (CH 2) a -CONHR} 2 ( wherein, a represents an integer of 0 to 3 Further, R ² represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms), an alkoxy group having 1 to 3 carbon atoms, or Represents a group represented by], a group represented by the formula: (In the formula, b represents an integer of 2 to 6) or a group represented by the formula: (In the formula, n represents an integer of 2 to 6, and R ³ is an amino group, a monoalkylamino group having 1 to 6 carbon atoms, or 2 to 2 carbon atoms.
Represents a dialkylamino group having 10 carbon atoms or an acylamino group having 1 to 6 carbon atoms), and a novel rifamycin derivative represented by the formula (II): A rifamycin derivative represented by the formula (wherein R represents a hydrogen atom or an acetyl group) is reacted with an amine represented by the formula AH (in the formula, A is the same as above). And a method for producing a rifamycin derivative represented by the formula (1) or a salt thereof, and an antibacterial agent containing the rifamycin derivative represented by the formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient.

The novel rifamycin derivative represented by the above formula (I) according to the present invention includes many organic solvents, halogenated hydrocarbons such as chloroform; alcohols such as ethyl alcohol; esters such as ethyl acetate; aromatic compounds such as benzene. Hydrocarbons; soluble in ethers such as tetrahydrofuran.

Specific examples of the substituent A of the novel rifamycin derivative represented by the formula (I) according to the present invention are as follows.
That is, A The group represented by (R ¹ is the same as above) includes And so on.

A is the formula (Wherein b is the same as above) And so on.

A is the formula (In the formula, n and R ³ are the same as above) And so on.

The novel rifamycin derivative represented by the above formula (I) according to the present invention can form a salt with either a base or an acid. As the base or acid that can be used for forming a salt, any base or acid that can form a salt with the rifamycin derivative represented by the formula (I) can be selected. Specific salts with bases, for example, (1) metal salts, especially salts with alkali metals and alkaline earth metals, (2) ammonium salts, (3) amine salts, especially methylamine,
There are salts with ethylamine, diethylamine, triethylamine, pyrrolidine, morpholine, hexamethyleneimine and the like. Examples of salts with acids include (1) salts with mineral acids such as sulfuric acid and hydrochloric acid, (2) p-toluenesulfonic acid,
There are salts with organic salts such as trifluoroacetic acid and acetic acid.

The novel rifamycin derivative represented by the above formula (I) according to the present invention can be produced as follows.

That is, (A) Formula (II) synthesized by the method described in US Pat. No. 4,690,919: 3'-hydroxybenzoxazinorifamycin represented by
It is dissolved in an organic solvent such as N, N-dimethylformamide or dimethylsulfoxide, and the amine represented by the formula AH (in the formula, A is the same as above) is dissolved in an acid such as hydrochloric acid at a temperature from -20 ° C to the boiling point of the solvent. It can be obtained by reacting in the presence or absence of an oxidizing agent such as manganese dioxide in the presence or absence of coexistence with or without coexistence for 1 hour to 1 month.

The rifamycin derivative represented by the formula (II) is 1
Good results are obtained by using 0.5 to 10 moles, especially 1 to 3 moles, of the amine represented by the formula AH with respect to moles.

As the reaction solvent, methanol, ethanol, isopropyl alcohol, tetrahydrofuran, pyridine, acetone, ethyl acetate, chloroform, N, N-dimethylformamide, N, N-dimethylacetamide, hexamethylphosphoric triamide, N-methyl-2- Pyrrolidone, dimethylsulfoxide and the like can be used, but better results can be obtained by using pyridine, N, N-dimethylformamide, N, N-dimethylacetamide, hexamethylphosphoric triamide, dimethylsulfoxide and the like. As the reaction temperature, a temperature from -20 ° C to the boiling point of the solvent can be selected, but better results can be obtained by carrying out the reaction at -5 ° C to 50 ° C. The reaction time is about 1 hour to 1 month, but the optimum reaction time depends on the reaction conditions such as the type and amount of amine used in the reaction, the presence or absence of oxidizing agent, the type and amount, and the reaction temperature. Should be tracked and determined by thin layer chromatography. In the reaction carried out in the presence of an oxidant, as an oxidant that can be used, air, oxygen, manganese dioxide,
There are lead dioxide, silver oxide, potassium ferricyanide, hydrogen peroxide, etc., but better results can be obtained by selecting manganese dioxide, silver oxide, potassium ferricyanide, etc.

(B) The rifamycin derivative represented by the above formula (I) has the following formula (III) instead of the rifamycin derivative represented by the formula (II) used in the method described in (A): (Wherein R represents a hydrogen atom or an acetyl group, X represents a halogen atom, an alkoxy group having 1 to 6 carbon atoms or a nitro group), and a rifamycin derivative represented by the following method (A) is used. Can be synthesized.
The synthesis conditions such as reaction solvent and reaction temperature may be the same as those described in the synthesis method (A).

The rifamycin derivative represented by the formula (III), which is the starting material of this synthetic method, is the rifamycin S and the formula: It can be obtained by reacting a compound represented by the formula (wherein X is the same as above) according to the method for synthesizing 3'-hydroxybenzoxazinorifamycin described in U.S. Pat. No. 4,690,919.

The rifamycin derivative represented by the formula (I) in which R is hydrogen can also be obtained by hydrolyzing the rifamycin derivative represented by the formula (I) in which R is an acetyl group with an acid or a base. . Acids that can be used for hydrolysis include mineral acids such as sulfuric acid and hydrochloric acid, p-
There are organic acids such as toluenesulfonic acid and trifluoroacetic acid. Examples of bases that can be used in the same manner include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkaline earth metal hydroxides such as calcium hydroxide and barium hydroxide; 1,5-diazabicyclo [4.3.0]. ] There are organic bases such as non-5-ene, 1,8-diazabicyclo [5.4.0] undec-7-ene. Using alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, hydrous methanol,
Good results can be obtained by carrying out the reaction at room temperature using a solvent such as hydrous pyridine.

The rifamycin derivative represented by the formula (I) according to the present invention is a dark purple solid, but it is relatively easy to separate and purify it from the reaction product. That is, the amine represented by the above formula AH (in the formula, A is the same as above) used in the excess amount of the reaction,
The reaction solvent and the like are removed, and the obtained crude product is purified by crystallization, column chromatography and the like to obtain the intended rifamycin derivative.

The novel rifamycin derivative represented by the formula (I) is reduced by a reducing agent such as ascorbic acid or sodium hydrosulfite to give the formula (IV): It is also possible to convert to a rifamycin derivative represented by the formula (wherein R and A are the same as above). The rifamycin derivative represented by the formula (IV) is also novel and has a strong antibacterial action.

Representative examples of novel rifamycin derivatives according to the present invention are shown in Table 1. In Table 1, the infrared absorption spectrum was measured by the potassium bromide tablet method. Thin-layer chromatography was carried out using silica gel 60F ₂₅₄ manufactured by Merck & Co., Inc. using a thin-layer chromatography plate (20 cm × 20 cm).
The nuclear magnetic resonance spectrum was measured using tetramethylsilane as an internal standard and a deuterated chloroform solution of the sample.

The rifamycin derivative according to the present invention exhibits strong antibacterial activity against Gram-positive bacteria and mycobacteria.

The antibacterial activity of the novel rifamycin derivative according to the present invention is determined by the standard method of the Japanese Society of Chemotherapy [Journal of the Japanese Society of Chemotherapy, Vol.
Page 76 (1981)]. Table 2 shows a representative example. As is clear from Table 2, the novel rifamycin derivative according to the present invention has a strong antibacterial activity against Gram-positive bacteria and acid-fast bacteria. This means that the novel rifamycin derivative according to the present invention is
For example, it is effective against Staphylococcus, Streptococcus, Bacillus, etc., and is an effective antibacterial agent against antibacterial acid such as tubercle bacillus, atypical acid-fast bacterium, and Lepra bacillus. The derivative numbers in Table 2 correspond to the derivative numbers in Table 1.

The rifamycin derivative represented by the formula (I) according to the present invention exhibits a strong antibacterial action against Mycobacterium tuberculosis. Mycobacterium tuberculosis bacterium (Mycobacterium tu
berculosis H ₃₇ Rv strain) is cultivated in Dubos medium to prepare a 1 mg / ml bacterial solution, and a 10-fold diluted solution of 0.05 ml is added to 2 m.
l of 10% bovine serum was inoculated into Kirchner liquid medium. For determination, a multiple dilution series containing the test derivative was prepared according to a conventional method, and after culturing at 37 ° C. for 4 weeks, the concentration at which the growth of the bacteria was completely macroscopically inhibited was defined as the minimum inhibitory concentration. The results are shown in Tables 3 and 4. From the results shown here, it can be seen that the novel rifamycin derivative according to the present invention exhibits a strong antibacterial activity against Mycobacterium tuberculosis. The derivative numbers in Tables 3 and 4 correspond to the derivative numbers in Table 1.

The rifamycin derivative represented by the formula (I) according to the present invention shows an excellent therapeutic effect against experimental infectious diseases by oral administration. As an example, the therapeutic effect of tuberculosis using mice will be shown.

One group of 20 ddy male mice of 5 weeks old was used. Mycobacterium tuberculosis Mycobacterium tuberculosis cultivated in Dubos medium
H ₃₇ Rv strain) 0.2 ml of concentrated bacterial solution (the number of viable cells was 2.4 × 10 ⁸ ) was inoculated into the tail vein of the mouse for infection. From the day after infection, each test derivative was made into a 2.5% gum arabic suspension containing 0.2% Tween 80, and 0.2 ml each, that is, 200 μg / mouse was orally administered. As a control, a 2.5% gum arabic solution containing 0.2% Tween 80 containing no test compound was administered. The treatment was carried out once a day for 6 days a week, and the therapeutic effect was evaluated by prolonging the life of infected mice.

The results are shown in FIG. In the figure, a indicates the time of infection, and b indicates the start of treatment. From these results, no deaths were observed by the treatment with the derivative 2 according to the present invention until 38 days after the treatment, and the derivative 2 was rifampicin as a control drug and the derivative A having the following structure described in US Pat. No. 4,690,919. It can be seen that it shows an extremely superior therapeutic effect. In addition, derivative B having the following structure described in US Pat. No. 4,690,919 and derivative C having the following structure described in European Patent Application No. 0253340 have rifampicin therapeutic effects in therapeutic tests. It has been proved that it is not equal to.

Further, a test for treating Mycobacterium tuberculosis infection was carried out using 10 ddY male mice per group in the same system as above, and the survival rate 40 days after the start of the test was determined. The results are shown in Tables 5 and 6.

In the experiment shown in Table 5, the control group without drug administration was
The survival rate of 30%, the control drug rifampicin administration group
Derivative 2, according to the present invention, while having a survival rate of 80%,
No deaths were observed in the groups administered with 3, 5, 10, 12 or 29.

In the experiments shown in Table 6, all the control groups that did not receive the drug died, whereas the control group that received rifampicin had a survival rate of 40%, while the derivative 1, 4, 6 or 11 according to the present invention had a survival rate. No deaths were observed in the group treated with. This result shows that the rifamycin derivative according to the present invention is an extremely advantageous drug against tuberculosis.

The novel rifamycin derivative according to the present invention shown in Table 1 was orally administered to mice at a rate of 1000 mg / kg, but it did not show any toxicity, indicating that the novel rifamycin derivative according to the present invention has low toxicity. It was.

As the preparation of the antibacterial agent containing the novel rifamycin derivative according to the present invention as an active ingredient, any preparation prepared by oral, enteral or parenteral administration can be selected. Specific formulations include tablets, capsules, fine granules,
Examples include syrups, suppositories, ointments and the like.
As carriers for the formulation of the antibacterial agents according to the invention, organic or inorganic solid or liquid, usually inert pharmaceutical carrier materials suitable for oral, enteral or other parenteral administration are used. Specifically, for example, crystalline cellulose, gelatin, lactose, starch, magnesium stearate, talc, vegetable and animal fats and oils, gums,
There are polyalkylene glycols. The ratio of the antibacterial agent of the present invention to the carrier in the preparation can be varied from 0.2 to 100%. In addition, the antibacterial agent according to the present invention may include other antibacterial agents and other drugs compatible with the antibacterial agent. In this case, it goes without saying that the antibacterial agent according to the present invention does not have to be the main component in the preparation.

The antibacterial agent according to the invention is generally administered in a dose such that the desired effect is achieved without side effects. Although the specific value should be determined by the judgment of a doctor, it is usual to administer 10 mg to 10 g, preferably about 20 mg to 5 g per adult. The antibacterial agent of the present invention can be administered as an active ingredient as a pharmaceutical preparation in a unit of 1 mg to 5 g, preferably 3 mg to 1 g.

[Examples] Examples will be described below to make the understanding of the present invention clearer, but these are merely examples and do not limit the present invention. The derivative numbers in the examples correspond to the derivative numbers in Table 1.

Example 1 (Synthesis of Derivative 1) According to the method described in US Pat. No. 4,690,919.
3'-hydroxybenzoxazinorifamycin made
8.0 g of 80 ml of dimethyl sulfoxide (hereinafter referred to as DMSO
20 ml of 1-n-butylpiperazine 2.85 g.
Solution in DMSO was added. Manganese dioxide solution
Gun (9.0 g) was added and the reaction was allowed to stir at room temperature for 40 hours. In the reaction solution
Add 600 ml of ethyl acetate, dilute, and filter the manganese dioxide.
Separately removed. The filtrate was washed 3 times with saturated saline, and anhydrous sulfuric acid was used.
After dehydration with sodium, the solvent was distilled off under reduced pressure. Waco the residue
Gel Silica gel column chromatography using C-200
2 times with Raffy [Developing solvent: 1st chloroform-aceto
(4: 1), second time chloroform-methanol (50:
1)] After purification, crystallization from ethyl acetate-n-hexane system
Then, 3.58 g of the desired derivative 1 was obtained.

Example 2 (Synthesis of Derivative 2) 3'-hydroxybenzoxazinorifamycin 3.0 g
Dissolved in 30 ml of DMSO, 1.05 g of 1-isobutylpiperazine
Was added, and then 3.0 g of manganese dioxide was added at room temperature for 2 hours.
The reaction was carried out with stirring. Add ethyl acetate to the reaction mixture and
After filtering off the gangan, wash with water and saturated saline solution in that order.
It was dried over sodium acidate overnight and the solvent was evaporated under reduced pressure. The rest
Wako gel with residue Silica gel column using C-200
Romanography [Developing solvent: chloroform-acetone
(8: 2)] and then purified with ethyl acetate-n-hexane.
Crystallization from the system yielded 0.82 g of derivative 2.

Example 3 (Synthesis of Derivative 3) 6.0 g of 3'-hydroxybenzoxazinorifamycin
Is dissolved in 60 ml of DMSO and 1-cyclopropylmethylpipet
Add 2.13 g of azine, then add 6.0 g of manganese dioxide
The reaction was allowed to stir at room temperature for 30 hours. The reaction solution was the same as in Example 2.
After processing into the residue the Wako gel Using C-200
Rica gel column chromatography [Developing solvent: chloro
Form-acetone (8: 2)] and purified derivative 3 to 4.0
g got.

Example 4 (Synthesis of Derivative 4) 4.5 g of 3'-hydroxybenzoxazinorifamycin
Was dissolved in 45 ml of DMSO and 1-sec-butylpiperazine 1.56
g, and then 4.5 g of manganese dioxide at room temperature at 22:00
The reaction was carried out with stirring. After treating the reaction mixture as in Example 2,
Wako gel residue Silica gel column using C-200
Chromatography twice [developing solvent: first chloroform
Mu-acetone (8: 2), 2nd chloroform-methanone
(98: 2)] to obtain 3.9 g of the desired derivative 4.

Example 5 (Synthesis of Derivative 5) 8.0 g of 3'-hydroxybenzoxazinorifamycin
Was dissolved in 80 ml of DMSO and 3.13 g of 1-isoamylpiperazine
Was added to a solution of 20 ml in DMSO. Diacid in this solution
9.0 g of manganese iodide was added and the reaction was allowed to stir at room temperature for 40 hours. Anti
After treating the reaction solution in the same manner as in Example 1, the residue was treated with Wako gel.
Silica gel column chromatography using C-200
3 times [Developing solvent: 1st time chloroform-acetone (5:
1) Second time, chloroform-ethyl acetate (2: 1), third time
Chloroform-ethyl acetate-methanol (15: 10: 1)]
After purification, crystallized from a system of chloroform-n-hexane,
3.38 g of derivative 5 was obtained.

Example 6 (Synthesis of Derivative 6) 3'-Hydroxybenzoxazinorifamycin 4.38
g in DMSO 30 ml and 1-tert-butylpiperazine 3.
Add 10 g and 1.0 g manganese dioxide and stir for 21 hours at room temperature
Let Chloroform was added to the reaction solution to dilute it, and insoluble materials were filtered off.
Separately, the filtrate is washed successively with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate.
After dehydration with lithium, chloroform was distilled off under reduced pressure. The rest
Wako gel with residue Silica gel column using C-200
Romanography [Developing solvent: Chloroform-Methano]
(98: 2)] and then ethyl acetate-n-hexa
To give 2.97 g of the desired derivative 6.

Example 7 (Synthesis of Derivative 7) 3'-hydroxybenzoxazinorifamycin 4.38
g in 30 ml DMSO and 1-cyclobutylpiperazine 3.
Add 06g and 1.0g manganese dioxide and stir at room temperature for 17 hours.
Let Chloroform was added to the reaction solution to dilute it, and insoluble materials were filtered off.
Separately, the filtrate is washed successively with water and saturated brine, and dried over anhydrous sodium sulfate.
After dehydration with thorium, chloroform was distilled off under reduced pressure.
Wako gel residue Silica gel column using C-200
Chromatography [Developing solvent: chloroform-methano]
(99: 1)] and then chloroform-n-hexane.
Crystallization from xane gave 2.77 g of the desired derivative 7.

Example 8 (Synthesis of derivative 8) 2.6 g of 3'-hydroxybenzoxazinorifamycin
Was dissolved in 20 ml of DMSO and 1-neopentylpiperazine 2.04
g, then 0.5 g of manganese dioxide, and room temperature for 67 hours
The reaction was carried out with stirring. Add chloroform to the reaction mixture and
After removing the cancer, it is washed with water and saturated saline solution in that order and sulfuric acid is removed.
It was dried over sodium overnight and the solvent was distilled off under reduced pressure. The residue
Wako gel Silica gel column chroma using C-200
5 times by tography [Developing solvent: 1, 2 and 5 times
Loform: methanol (99: 1), 3rd chloroform:
Methanol (199: 1), 4th time Ethyl acetate: n-hexane
(1: 1)] Purification yielded 0.44 g of the desired derivative 8.

Example 9 (Synthesis of Derivative 9) 4.5 g of 3'-hydroxybenzoxazinorifamycin
Is dissolved in 45 ml of DMSO and 1-cyclopentylpiperazine 1.
Add 7g, then add 4.5g manganese dioxide at room temperature 19:00
The reaction was carried out with stirring. Add chloroform to the reaction mixture
After manganese is filtered off, it is washed with water and saturated saline, and anhydrous sulfuric acid is used.
It was dried over sodium overnight and the solvent was distilled off under reduced pressure. Residue
Wako gel Silica gel column chromatography using C-200
Matography [Developing solvent: chloroform-methanol
(98: 2)] followed by crystallization from ethanol to give derivative 9
2.8g was obtained.

Example 10 (Synthesis of Derivative 10) 3'-hydroxybenzoxazinorifamycin 4.5 g
Was dissolved in 40 ml of DMSO, and 1.39 g of 1-allylpiperazine was added.
Then, add 4.5 g of manganese dioxide and stir at room temperature for 25 hours
It was made to react. The reaction mixture was treated as in Example 8 and the residue
Wako gel with residue Silica gel column using C-200
Romanography [Developing solvent: Chloroform-Methano]
(95: 5)] four times to obtain derivative 10 (2.7 g).

Example 11 (Synthesis of Derivative 11) 3'-hydroxybenzoxazinorifamycin 4.5 g
Was dissolved in 45 ml DMSO and 1- (3-butenyl) piperazine was added.
Add 2.0g and then add 4.5g manganese dioxide at room temperature for 23.5
The reaction was allowed to stir for an hour. Add chloroform to the reaction mixture
After removing the manganese oxide by filtration, it was washed with water and saturated saline solution in that order and dried.
It was dried over sodium sulfate overnight and the solvent was distilled off under reduced pressure. The rest
Wako gel with residue Silica gel column using C-200
2 times by chromatography [Developing solvent: 1st time chloroform
-Acetone (8: 2), second time chloroform-methanol
(99: 1)] After purification from a system of chloroform-n-hexane
Crystallization gave 3.36 g of the desired derivative 11.

Example 12 (Synthesis of Derivative 12) 4.5 g of 3'-hydroxybenzoxazinorifamycin
Was dissolved in 45 ml of DMSO and 1- (3-methyl-2-buten
Lu) piperazine 1.69g, then manganese dioxide
4.5 g was added and the reaction was allowed to stir at room temperature for 28 hours. Conduct the reaction solution
After treatment as in Example 2, the residue is Wakogel Use C-200
2 times with silica gel column chromatography
Solvent: 1st time chloroform-methanol (98: 2), 2nd time
Ethyl acetate] purification, and further ethyl acetate-n-hexane
Crystallization by the system yielded 1.8 g of derivative 12.

Example 13 (Synthesis of Derivative 13) 3'-hydroxybenzoxazinorifamycin 4.5 g
Was dissolved in 45 ml DMSO and 1- (2-propynyl) piperazi
2.7g of manganese dioxide and then 4.5g of manganese dioxide at room temperature.
The reaction was allowed to stir for 3.5 hours. Add chloroform to the reaction mixture
After manganese dioxide was filtered off, it was washed successively with water and saturated saline.
Dry overnight with anhydrous sodium sulfate and evaporate the solvent under reduced pressure.
Was. Wako gel residue Silica gel filter using C-200
Lamb chromatography 4 times [Developing solvent: 1st to 3rd
Loloform-methanol (98: 2), 4th time chloroform
-Acetone (9: 1)] After purification Chloroform-n-hexa
The target derivative 13 was crystallized from the above system to obtain 1.57 g of the desired derivative 13.

Example 14 (Synthesis of Derivative 14) 4.5 g of 3'-hydroxybenzoxazinorifamycin
Was dissolved in 45 ml DMSO and 1- (2-fluoroethyl) pipet was added.
Add 1.0 g of ladin and then add 4.5 g of manganese dioxide at room temperature
The mixture was reacted with stirring for 96 hours. Add chloroform to the reaction mixture
After manganese dioxide was filtered off, it was washed successively with water and saturated saline.
Dry overnight with anhydrous sodium sulfate and evaporate the solvent under reduced pressure.
Was. Wako gel residue Silica gel filter using C-200
Lamb chromatography 4 times [Developing solvent: 1st to 3rd
Loloform-methanol (98: 2), 4th time chloroform
-Acetone (9: 1)] After purification Chloroform-n-hexa
The target derivative 14 was crystallized from the above system to obtain 0.48 g of the desired derivative 14.

Example 15 (Synthesis of Derivative 15) 3'-hydroxybenzoxazinorifamycin 2.0 g
Is dissolved in 20 ml of DMSO and 1- (3-chloropropyl) pi
Perazine dihydrochloride hemihydrate 1.22g
Then, add 2.8 ml of triethylamine and manga dioxide.
2.0 g of benzene was added and the reaction was allowed to stir at room temperature for 56 hours. Reaction liquid
After treating in the same manner as in Example 9, the residue is Wako gel. C-20
Silica gel column chromatography using 0 [development
Solvent: Chloroform-Acetone (8: 2)] three times purification
Then, it was crystallized from ethyl acetate to obtain 0.6 g of derivative 15.

Example 16 (Synthesis of Derivative 16) 3'-hydroxybenzoxazinorifamycin 2.7 g
Was dissolved in 27 ml of DMSO to dissolve 1- (2-dimethylaminoethyl).
Lu) 1.0 g of piperazine is added, and then 2.7 g of manganese dioxide is added.
The reaction was stirred at room temperature for 122 hours. Chloropho in the reaction solution
Rumm was added and manganese dioxide was filtered off, then washed with water and saturated saline.
Wash sequentially and dry with anhydrous sodium sulfate overnight to reduce the solvent.
It was distilled off. Wako gel residue Siri using C-200
4 times by Kagel column chromatography [Developing solvent: black
Loloform-methanol (9: 1)]
0.57 g of conductor 16 was obtained.

Example 17 (Synthesis of Derivative 17) 4.5 g of 3'-hydroxybenzoxazinorifamycin
Was dissolved in 45 ml DMSO and 1- (2-diethylaminoethyl) was added.
Le) Piperazine 2.0g, then manganese dioxide 4.5g
Was added and the reaction was allowed to stir at room temperature for 27 hours. Methanol in the reaction mixture
And manganese dioxide was filtered off and the solvent was distilled off under reduced pressure.
Wako gel residue Silica gel column using C-200
Chromatography 5 times [Developing solvent: chloroform-
Methanol (95: 5)] and refined the desired derivative 17 to 0.62
g got.

Example 18 (Synthesis of Derivative 18) 4.5 g of 3'-hydroxybenzoxazinorifamycin
Was dissolved in 45 ml DMSO and 1- (2-pyrimidyl) pipera
Add 2.6 g of gindihydrochloride and then triethyl
Manganese dioxide (4.5 g) was added to the amine (3.1 ml) at room temperature for 24 hours.
The reaction was carried out with stirring. Add chloroform to the reaction mixture and
After removing the cancer, it is washed with water and saturated saline solution in that order and sulfuric acid is removed.
It was dried over sodium overnight and the solvent was distilled off under reduced pressure. The residue
Wako gel Silica gel column chroma using C-200
3 times by tography [Developing solvent: chloroform-methano]
(49: 1)], after purification, chloroform-n-hexane
Crystallization from the system gave 2.65 g of the desired derivative 18.

Example 19 (Synthesis of Derivative 19) 3'-hydroxybenzoxazinorifamycin 4.5 g
Was dissolved in 45 ml of DMSO and 1- (2-methoxyethyl) pi
Add 1.59 g of perazine and then 4.5 g of manganese dioxide.
The reaction was allowed to stir at room temperature for 51 hours. The reaction solution was the same as in Example 2.
After processing, the residue is Wako gel Siri using C-200
Kagel column chromatography [Developing solvent: chloropho
Rum-methanol (98: 2)] and purified twice.
1.2 g of derivative 19 was obtained by crystallization from the system of m-n-hexane.
Was.

Example 20 (Synthesis of Derivative 20) 3'-hydroxybenzoxazinorifamycin 1.8 g
Was dissolved in 18 ml of DMSO and 1- (2-ethoxyethyl) pi
Add 1.4 g of perazine, then add 1.8 g of manganese dioxide.
Then, the mixture was reacted with stirring at room temperature for 120 hours. The reaction solution was used in Example 7.
After processing in the same manner as above, the residue is Wako gel Use C-200
Silica gel column chromatography [Developing solvent: black
The product was purified twice with [Rhoform-methanol (98: 2)] and then purified with ethyl acetate.
Crystallization from the chill-n-hexane system gave 0.5 g of derivative 20.
Was.

Example 21 (Synthesis of derivative 21) 4.5 g of 3'-hydroxybenzoxazinorifamycin
Was dissolved in 45 ml of DMSO and 1-[(2-methoxy) -2-e
Toxiethyl] piperazine 2.1 g was added, followed by
4.5 g of Ngan was added and the reaction was allowed to stir at room temperature for 28.5 hours. reaction
Chloroform was added to the solution and manganese dioxide was filtered off, then water,
Wash sequentially with saturated saline solution and dry overnight with anhydrous sodium sulfate.
Then, the solvent was distilled off under reduced pressure. Wako gel residue C-200
Twice by silica gel column chromatography using
[Developing solvent: chloroform-methanol (98: 2)] Purification
After that, it was crystallized from the system of chloroform-n-hexane to obtain the target.
0.72 g of derivative 21 was obtained.

Example 22 (Synthesis of derivative 22) 4.5 g of 3'-hydroxybenzoxazinorifamycin
Was dissolved in 45 ml of DMSO, and 1- (1,3-dioxolane-2-
I) Methylpiperazine 1.89 g was added, followed by
4.5 g of Ngan was added and the reaction was allowed to stir at room temperature for 26 hours. reaction
After treating the liquid in the same manner as in Example 9, the residue was treated with Wako gel. C-
Silica gel column chromatography using 200
Open solvent: chloroform-methanol (98: 2)] and refine twice.
After the production, it was crystallized from ethyl acetate to obtain 2.7 g of derivative 22.

Example 23 (Synthesis of Derivative 23) 1.8 g of 3'-hydroxybenzoxazinorifamycin
Was dissolved in 18 ml of DMSO and 0.5 g of 1-formylpiperazine was added.
Then, add 1.8 g of manganese dioxide and then at room temperature for 24 hours.
The reaction was carried out with stirring. The reaction mixture was treated as in Example 9.
After that, the residue is Wako gel Silica gel filter using C-200
Rum chromatography [Developing solvent: chloroform-me
Tanol (98: 2)] five times and then chloroform-n-
Crystallization from a hexane system yielded 0.9 g of derivative 23.

Example 24 (Synthesis of derivative 24) 4.5 g of 3'-hydroxybenzoxazinorifamycin
Is dissolved in 45 ml of DMSO and 1.4 g of 1-acetylpiperazine is added.
Then, add 4.5 g of manganese dioxide at room temperature for 22 hours.
The reaction was carried out with stirring. The reaction mixture was treated as in Example 9.
After that, the residue is Wako gel Silica gel filter using C-200
Rum chromatography [Developing solvent: chloroform-me
It was then purified with a tanol (98: 2)] to obtain 3.2 g of derivative 24.

Example 25 (Synthesis of derivative 25) 3.0 g of 3'-hydroxybenzoxazinorifamycin
Is dissolved in 30 ml of DMSO and 1-cyclopropanecarbonyl is dissolved.
Add 1.3 g piperazine, then add 2.0 g manganese dioxide.
The reaction was allowed to stir at room temperature for 22 hours. The reaction solution was used as in Example 9.
After the same treatment, the residue is Wako gel Using C-200
3 times by Rika gel column chromatography [Developing solvent: 1
2nd chloroform-methanol (99: 1), 2nd chloro
Form-methanol (98: 2), 3rd time chloroform-a
Cetone (95: 5)] to obtain 2.0 g of derivative 25.

Example 26 (Synthesis of derivative 26) 1.8 g of 3'-hydroxybenzoxazinorifamycin
Was dissolved in 18 ml of DMSO and N-isopropyl-1-pipera was dissolved.
Add 0.82 g of ginacetamide, then manganese dioxide
1.8 g was added and the mixture was reacted with stirring at room temperature for 27 hours. Conduct the reaction solution
After treating as in Example 9, the residue is wacogel. C-200
Silica gel column chromatography [development
Medium: Chloroform-methanol (98: 2)] and then vinegar
Crystallization from ethyl acetate gave 1.4 g of derivative 26.

Example 27 (Synthesis of Derivative 27) 4.5 g of 3'-hydroxybenzoxazinorifamycin
Dissolved in 45 ml DMSO and 1- (2-ethylthioethyl)
Add 1.9 g of piperazine, then add 4.5 g of manganese dioxide.
The reaction was allowed to stir at room temperature for 23 hours. Chloroform in the reaction solution
Was added and the manganese dioxide was filtered off, then sequentially with water and saturated saline.
Wash and dry overnight with anhydrous sodium sulfate, and depressurize the solvent.
Distilled off. Wako gel residue Silica using C-200
6 times by gel column chromatography [Developing solvent: 1-5
6th chloroform-methanol (98: 2), 6th chloro
Form-acetone (4: 1)] purified and the desired derivative 2
3.00 g of 7 was obtained.

Example 28 (Synthesis of derivative 28) 3'-hydroxybenzoxazinorifamycin 2.63
g was dissolved in DMSO 15 ml and 1-methoxypiperazine 0.76 g
And 1.0 g of manganese dioxide were added, and the mixture was stirred and reacted at room temperature for 3 days.
Was. 1-Methoxypiperazine used here is a product of US Pat.
1-Cyclopropylpiperazide described in 3,342,816
N, N-bis (β-chloroethyl)-
p-toluenesulfonamide and o-methylhydroxyl
Synthesized from amines. Add chloroform to the reaction mixture
Dilute, remove insoluble matter by filtration, and filterate sequentially with water and saturated saline.
After washing, chloroform was distilled off under reduced pressure. Waco the residue
Gel Silica gel column chromatography using C-200
2 times with Raffy [Developing solvent: 1st chloroform-aceto
Second (95: 5), second time chloroform-methanol (98:
2)] Purify and then precipitate from ethyl acetate-n-hexane
After precipitation, 1.71 g of the desired derivative 28 was obtained.

Example 29 (Synthesis of derivative 29) 1.8 g of 3'-hydroxybenzoxazinorifamycin
Is dissolved in 18 ml of DMSO, and the method of ME Freed et al. [Journal of Organic Chemistry (J.Org.Che
m.), 25, 2108, 1960], 1,4-
0.56 g of diazabicyclo (4,3,0) nonane was added, then 1.8 g of manganese dioxide was added, and the mixture was reacted with stirring at room temperature for 52 hours.

 After treating the reaction solution in the same manner as in Example 2, the residue was treated with Wako gel.
Silica gel column chromatography using C-200
-[Developing solvent: chloroform-methanol (98: 2)]
Purification 5 times yielded 0.3 g of derivative 29.

Example 30 (Synthesis of Derivative 30) 1.8 g of 3'-hydroxybenzoxazinorifamycin
Was dissolved in 18 ml of DMSO, and 3-dimethylaminopyrrolidine was dissolved.
1.0g, then 1.8g manganese dioxide at room temperature
The reaction was stirred for 140 hours. The reaction solution was treated in the same manner as in Example 7.
After processing, the residue is Wako gel Silica using C-200
Gel column chromatography [Developing solvent: chloroform
-Methanol (98: 2)] four times to give derivative 30
5g was obtained.

Example 31 (Synthesis of Derivative 31) 3'-Hydroxybenzoxazinorifamycin 1.8 g
Was dissolved in DMSO (18 ml) and 3-acetamidopyrrolidine (0.5) was added.
Add 6 g, then add 1.8 g manganese dioxide at room temperature to 47
The reaction was allowed to stir for an hour. The reaction mixture was treated as in Example 9.
After that, the residue is Wako gel Silica gel using C-200
Column chromatography [Developing solvent: chloroform-
Methanol (95: 5)] three times to obtain 0.8 g of derivative 31
Was.

Example 32 (Synthesis of derivative 32) A mixed solution of 90 ml of ethanol and 90 ml of water was cooled with ice water to dissolve 0.96 g of sodium hydroxide. 21.05 g of the derivative synthesized according to the method shown in Example 2 was added to the mixed solution, and the mixture was reacted with stirring at room temperature for 2 hours. 40 ml of cold water was added to the reaction solution, and 1N-
The mixture was neutralized with HCl, extracted three times with 40 ml of chloroform, and the solvent was distilled off under reduced pressure.

 Wako gel residue Silica gel color using C-200
Chromatography [Developing solvent: chloroform-meta
Nol (99: 1)] three times, and the desired derivative 32 is purified to 0.
70g was obtained.

[Effect of the Invention] The novel rifamycin derivative of the present invention has an effect of having a strong antibacterial action and excellent pharmacological properties.

[Brief description of drawings]

FIG. 1 is a graph showing the relationship between the survival rate of mice and the treatment days when the rifamycin derivative of the present invention and other test compounds are orally administered to mice with tuberculosis.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Kiyoshi Watanabe 5-15-41 Matsugaoka, Akashi City, Hyogo Prefecture

Claims (14)

(57) [Claims] 1. Formula (I): {In the formula, R represents a hydrogen atom or an acetyl group, and A is a formula. [In the formula, R ¹ is an alkyl group having 4 to 8 carbon atoms, and 2 to 8 carbon atoms.
Alkenyl group, C2-C8 alkynyl group, C1-C4 aminoalkyl group, C2-C6 monoalkylaminoalkyl group, C3-C8 dialkylaminoalkyl group, C2-C2 8 alkoxyalkyl group, C3-8 alkoxyalkyloxyalkyl group, C2-6 thioalkoxyalkyl group, C3-8
Dialkoxy alkyl group, a halogenated alkyl group having 1 to 6 carbon atoms, an acyl group having 1 to 6 carbon atoms, the _{formula: - (CH 2) a -CONHR} 2 ( wherein, a represents an integer of 0 to 3 , R ² represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms), an alkoxy group having 1 to 3 carbon atoms, or a formula: Represents a group represented by], a group represented by the formula: (In the formula, b represents an integer of 2 to 6) or a group represented by the formula: (In the formula, n represents an integer of 2 to 6, and R ³ is an amino group, a monoalkylamino group having 1 to 6 carbon atoms, or 2 to 2 carbon atoms.
A dialkylamino group having 10 carbon atoms or an acylamino group having 1 to 6 carbon atoms), or a salt thereof. 2. The rifamycin derivative or a salt thereof according to claim 1, wherein in the formula (I), R is an acetyl group. 3. The rifamycin derivative or a salt thereof according to claim 1, wherein in the formula (I), R is a hydrogen atom. 4. In the formula (I), R is an acetyl group and A is (In the formula, R ⁴ is an alkyl group having 4 to 8 carbon atoms or 2 carbon atoms.
Represents a alkenyl group of ~ 8) or a formula: The rifamycin derivative or a salt thereof according to claim 1, which is a group represented by the formula (b represents an integer of 2 to 6). 5. In the formula (I), R is an acetyl group and A is The rifamycin derivative or a salt thereof according to claim 1, which is a group represented by: 6. In the formula (I), R is an acetyl group and A is The rifamycin derivative or a salt thereof according to claim 1, which is a group represented by: 7. In the formula (I), R is an acetyl group and A is The rifamycin derivative or a salt thereof according to claim 1, which is a group represented by: 8. In the formula (I), R is an acetyl group and A is The rifamycin derivative or a salt thereof according to claim 1, which is a group represented by: 9. Formula (II): (Wherein R represents a hydrogen atom or an acetyl group), a rifamycin derivative represented by the formula AH [In the formula, R ¹ is an alkyl group having 4 to 8 carbon atoms, and 2 to 8 carbon atoms.
Alkenyl group, C2-C8 alkynyl group, C1-C4 aminoalkyl group, C2-C6 monoalkylaminoalkyl group, C3-C8 dialkylaminoalkyl group, C2-C2 8 alkoxyalkyl group, C3-8 alkoxyalkyloxyalkyl group, C2-6 thioalkoxyalkyl group, C3-8
Dialkoxy alkyl group, a halogenated alkyl group having 1 to 6 carbon atoms, an acyl group having 1 to 6 carbon atoms, the _{formula: - (CH 2) a -CONHR} 2 ( wherein, a represents an integer of 0 to 3 , R ² represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms), an alkoxy group having 1 to 3 carbon atoms, or a formula: Represents a group represented by], a group represented by the formula: (In the formula, b represents an integer of 2 to 6) or a group: (In the formula, n represents an integer of 2 to 6, and R ³ is an amino group, a monoalkylamino group having 1 to 6 carbon atoms, or 2 to 2 carbon atoms.
A dialkylamino group having 10 carbon atoms or an acylamino group having 1 to 6 carbon atoms) is represented by the formula (I): (In the formula, R and A are the same as above). 10. The process according to claim 9, wherein the rifamycin derivative represented by the formula (II) is reacted with an amine represented by the formula AH (A is the same as above) in the presence of an oxidizing agent. 11. The oxidant is manganese dioxide.
The manufacturing method described. 12. A process for producing a rifamycin derivative represented by the formula (I) wherein R is a hydrogen atom, characterized in that the rifamycin derivative represented by the formula (I) in which R is an acetyl group is hydrolyzed. 13. The method according to claim 12, wherein the reagent used for hydrolysis is an alkali metal hydroxide. 14. Formula (I): {In the formula, R represents a hydrogen atom or an acetyl group, and A is [In the formula, R ¹ is an alkyl group having 4 to 8 carbon atoms, and 2 to 8 carbon atoms.
Alkenyl group, C2-C8 alkynyl group, C1-C4 aminoalkyl group, C2-C6 monoalkylaminoalkyl group, C3-C8 dialkylaminoalkyl group, C2-C2 8 alkoxyalkyl group, C3-8 alkoxyalkyloxyalkyl group, C2-6 thioalkoxyalkyl group, C3-8
Dialkoxy alkyl group, a halogenated alkyl group having 1 to 6 carbon atoms, an acyl group having 1 to 6 carbon atoms, the _{formula: - (CH 2) a -CONHR} 2 ( wherein, a represents an integer of 0 to 3 , R ² represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms), an alkoxy group having 1 to 3 carbon atoms, or a formula: Represents a group represented by], a group represented by the formula: (In the formula, b represents an integer of 2 to 6) or a group represented by the formula: (In the formula, n represents an integer of 2 to 6, and R ³ is an amino group, a monoalkylamino group having 1 to 6 carbon atoms, or 2 to 2 carbon atoms.
And 10 represents a dialkylamino group or an acylamino group having 1 to 6 carbon atoms), or an pharmaceutically acceptable salt thereof as an active ingredient.