JPS6335579A - Sulfur-containing benzoxazinorifamycin derivative - Google Patents

Abstract

NEW MATERIAL:The compound of formula I {a is 0-2; b is 0-4; R<1> is 1-4C monohydroxyalkyl, dihydroxyalkyl, group of formula II (R<2> and R<3> are 1-4C alkyl) or formula III [c and d are 1-4; X is O or N-R<4> (R<4> is H or 1-3C alkyl)]}. USE:A medicine. An antibacterial agent. It is soluble in a number of solvents, exhibits strong antibacterial activity against Gram-positive bacteria and acid-fast bacteria and has low toxicity. It can be used as a production raw material for a novel rifamycin derivative of formula IV having strong antibacterial activity. It is administered daily for adults at a rate of 10mg-10g of the active component. PREPARATION:The compound of formula I can be produced by reacting rifamycin O or S with an o-aminophenol compound of formula V in an organic solvent such as benzene to obtain an intermediate, substituting the solvent with another organic solvent such as methanol and reacting the intermediate in the presence of an oxidizing agent such as MnO2.

Description

DETAILED DESCRIPTION OF THE INVENTION (Field of Industrial Application) 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 present invention relates to the general formula (I
) (In the formula, a represents 0 to 2, b represents O to 4, and R
1 represents a monohydroxyalkyl group or dihydroxyalkyl group having 1 to 4 carbon atoms, a group represented by a 1 to 4 alkyl group), and 1 represents a different group from 1 to 4, and X represents an oxygen atom or N-Il4 (R' represents a group represented by (represents hydrogen or an alkyl group having 1 to 3 carbon atoms) a new rifamycin derivative represented by (represents a group represented by ) or a salt thereof, and a method for producing the same, and uses the same as an active ingredient It concerns antibacterial agents.

(Prior Art) The rifamycin derivative according to the present invention is a novel compound that has not been described in any literature.

(Means for Solving the Problems and Effects) The present inventors have discovered that a novel rifamycin derivative represented by the general formula (I) can be obtained by the method described below. The obtained derivative has strong antibacterial activity,
They found that it is useful as an antibacterial agent and completed the present invention.

The novel rifamycin derivative represented by the general formula (I) according to the present invention can be used in many organic solvents, halogenated hydrocarbons such as chloroform and methylene chloride, alcohols such as methyl alcohol and ethyl alcohol, methyl acetate,
It is soluble in esters such as ethyl acetate, aromatic hydrocarbons such as benzene and toluene, and ethers such as tetrahydrofuran and dioxane.

The novel rifamycin derivative represented by the general formula (I) according to the present invention can form a salt with a base. Furthermore, among the derivatives represented by the general formula (Il), derivatives having a basic group can form salts with acids. As bases or acids that can be used to form salts, general Any compound capable of forming a salt with the rifamycin derivative represented by formula (I) can be selected.

Specific examples of salts with bases include (1) metal salts, especially salts with alkali metals and alkaline earth metals, (2) ammonium salts, (3) amine salts, especially methylamine, ethylamine, diethylamine, There are salts with triethylamine, pyrrolidine, morpholine, hexamethyleneimine, etc. Examples of salts with acids include (1) salts with mineral acids such as sulfuric acid and hydrochloric acid, and (2) salts with organic acids such as p-)luenesulfonic acid, trifluoroacetic acid and acetic acid.

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

(1) Rifamycin O or S is added with the general formula (II
) (wherein a represents θ~2, b represents O~4
R1 is a monohydroxyalkyl group or dihydroxyalkyl group having 1 to 4 carbon atoms, or a group represented by 1 to 4 carbon atoms; or an alkyl group having 1 to 3 carbon atoms);

As disclosed in U.S. Pat. No. 3,338,888, this synthetic method is based on the combination of rifamycin O or S and 0 expressed by the general formula (rI) (wherein a, b, and R' are as described above). -Amine phenols are reacted in an organic solvent such as benzene to obtain an intermediate, and then the reaction solvent is replaced with an organic solvent such as methanol and the reaction is carried out again.

Solvents that can be used in the first stage reaction of this synthesis method include halogenated hydrocarbons such as chloroform, methylene chloride, and carbon tetrachloride; aromatic hydrocarbons such as benzene and toluene; diethyl ether, tetrahydrofuran, etc. ethers, and carbon disulfide. Among them, particularly good results can be obtained by using aromatic hydrocarbons such as benzene and toluene.

Solvents that can be used in the second stage of the reaction of this synthesis method include alcohols such as methanol, dimethyl sulfoxide, polar aprotic solvents such as N,N-dimethylformamide, and nitrogen-containing solvents such as pyridine and lutidine. Heterocyclic compounds; ethers such as tetrahydrofuran and dioxane. When alcohols such as methanol and ethanol are used, post-treatment after the reaction is completed can be easily carried out.

The second stage reaction consists of manganese dioxide, lead dioxide, silver oxide,
By carrying out the reaction in the coexistence of an oxidizing agent such as potassium ferricyanide, it is possible to shorten the reaction time and reduce the amount of side reaction products.

(11) Among the rifamycin derivatives represented by general formula (I), the derivative represented by formula (2) (e represents 1 to 4, and 1 is as described above) can also be synthesized as follows. be able to. That is, the method of Kump and H. Bickel [Helvetian force, Kimi force, Acta (I (elv, Chim.

Acta), 56, 244 (1973)), the benzoxazinorifamycin represented by the formula (IV) was synthesized according to the general formula R
It can be synthesized by reacting a compound represented by 1(CH2)esI-I (e and R' are as described above). Reaction solvents that can be used in this reaction include polar aprotic solvents such as dimethyl sulfoxide and N,N-dimethylformamide; nitrogen-containing heterocyclic compounds such as pyridine and lutidine; ethers such as tetrahydrofuran; methanol, ethanol, etc. alcohols can be used. When carrying out the reaction 1,
5-Diazabicyclo[4,3,0]non-5-ene (D
B N ), ■, 8-diazabicyclo[5,4,0]
Good results can be obtained by carrying out the reaction in the presence of an organic base such as undec-7-ene (DBU) or a base such as sodium carbonate or potassium carbonate. Particularly good results are obtained using organic bases such as DBN and DBU.

Separation and purification of the rifamycin derivative represented by general formula (I) according to the present invention from the reaction product is relatively easy. That is, the desired rifamycin derivative can be obtained by removing excess amounts of reagents, reaction solvents, etc. used in the reaction, and purifying the resulting crude product by crystallization, column chromatography, etc.

The new rifamycin derivative represented by the general formula (I) can be transformed into the novel rifamycin derivative represented by the following general formula (■) (a, b, and R1 are as described above) by reducing with a reducing agent such as ascorbic acid or sodium hydrosulfide. It is also possible to convert into rifamycin derivatives.

The rifamycin derivative represented by the general formula ff> is also new and has strong antibacterial activity.

Representative examples of the novel rifamycin derivatives represented by general formula (I) according to the present invention are shown in Table 1. In Table 1, thin layer chromatography was performed using silica gel 60 F2 manufactured by Merck.
54, MJNI chromatography plate (20
CII! It was carried out using ×20 CII. Nuclear magnetic resonance spectra were measured using tetramethylsilane as an internal standard as a deuterated chloroform solution.

The rifamycin derivative according to the present invention exhibits strong antibacterial activity against Durum-positive bacteria and acid-fast bacteria.

The antibacterial activity of the novel rifamycin derivative according to the present invention was evaluated using the standard method of the Japanese Society of Chemotherapy [Journal of the Japanese Society of Chemotherapy, Vol. 29,
76 (1981)). Representative examples are shown in Table 2. As is clear from Table 2, the novel rifamycin derivatives of the present invention exhibit strong antibacterial activity against Durham-positive bacteria and acid-fast bacteria. Note that the derivative numbers in the table correspond to the derivative numbers in Table 1.

100011 novel rifamycin derivatives according to the present invention
When administered orally to mice at a ratio of 9/kq, it did not show any toxicity, indicating that the novel rifamycin derivative according to the present invention has low toxicity.

As for the preparation of the antibacterial agent containing the novel rifamycin derivative according to the present invention as an active ingredient, any of the preparations for oral, enteral or parenteral administration can be selected.

Specific formulations include tablets, capsules, fine granules, syrups, crude drugs, and ointments. As carriers for the antimicrobial formulations according to the invention, organic or inorganic solid or liquid, usually inert, pharmaceutical carrier materials suitable for oral, rectal or other parenteral administration are used. Specific examples include crystalline cellulose, gelatin, lactose, starch, magnesium stearate, talc, vegetable and animal fats and oils, gums, polyalkylene glycols. The proportion of antimicrobial agent of the invention to carrier in the formulation can vary between 0.2 and 100%. The antimicrobial agent according to the invention may also include other antimicrobial agents and other pharmaceutical agents that are compatible therewith. in this case,
It goes without saying that the antibacterial agent according to the invention does not have to be the main ingredient in the formulation.

Antimicrobial agents according to the invention are generally administered at dosages that achieve the desired effect without side effects. The specific value should be determined by a doctor's judgment, but it is generally 10 to 10 f per day for adults.

Preferably, it will usually be administered at about 20+fff to 5 Da. The antibacterial agent of the present invention contains 1 as an active ingredient.
It can be administered as a pharmaceutical preparation of ~5g, preferably 3q~1!7 units.

(Examples) In order to further clarify the understanding of the present invention, examples will be given and explained, but these are merely illustrative and do not limit the present invention.

Example 1 Synthesis of Derivative 1 0.78' of benzoxazinorifamycin was dissolved in 5 gt of tetrahydrofuran (TI(F), and DBUO15
txl was added and stirred. To this solution, 0.35++t of 2-mercaptoethanol was gradually added at room temperature and stirred for 10 minutes, and then 0.789 g of manganese dioxide was added and stirred for 30 minutes. Subsequently, the same operation was performed twice using a reagent equal to or less than 2-mercaptoethanol. After the reaction is complete,
The mixture was diluted with methanol, the manganese dioxide was taken out separately, diluted with water, neutralized with dilute hydrochloric acid, and extracted three times with ethyl acetate. The ethyl acetate of the extract was distilled off under reduced pressure, and the residual liquid was purified by silica gel column chromatography [developing solvent: acetone-chloroform (1:9)] to obtain the desired derivative 1. The obtained derivative 1 was purified by preparative thin layer chromatography using silica gel as a carrier [developing solvent: acetone-chloroform (1:4)], and crystallized from ethyl acetate to obtain the desired derivative 1 at a concentration of 0.251 Obtained.

Example 2 Synthesis of derivative 2 In place of 0.35xt of 2-mercaptoethanol in Example 1, 0.4 x 3-mercapto-1,2-propanediol
A similar operation was performed using 2xt to obtain a crude product containing the desired derivative 2.

The crude product was purified by silica gel column chromatography [developing solvent: acetone-chloroform (9), then acetone-chloroform (1:4)], and then preparative thin layer chromatography using silica gel as a carrier [developing solvent: acetone-chloroform (1:1)] to obtain 0.381 of the desired derivative 2.

Example 3 Synthesis of derivative 3 Benzoxazinorifamycin 0.78f was synthesized with TI (F5
ml, and 0.5 ml of DBU was added and stirred. To this solution, 0.709 liters of 2-dimethylaminoethanethiol hydrochloride and 1.6 liters of triethylamine were added in TH.
F dissolved in 5 ml was gradually added at room temperature. 30 minutes after the addition was completed, 0.789 g of manganese dioxide was added, stirred for 30 minutes, and 2-dimethylaminoethanethiol hydrochloride o
, 'toy and 1.6 units of triethylamine TTI F
5 xl solution was added slowly. 30 minutes after the addition was completed, 0.78 fl of manganese dioxide was added and stirred for 30 minutes.
U 0.5 ytl was added, and the following reagents including 2-dimethylaminoethanethiol hydrochloride were further added and the same operation was performed. After the reaction was completed, the mixture was diluted with methanol, the manganese dioxide was taken out, diluted with water, neutralized with dilute hydrochloric acid, and extracted three times with ethyl acetate.

The ethyl acetate of the extract was distilled off under reduced pressure, and the residual liquid was purified by silica gel column chromatography [developing solvent: acetone-chloroform (1:9), then methanol-chloroform (5:95)]. Target derivative 3
I got it. The obtained derivative 3 was purified by preparative thin layer chromatography using silica gel as a carrier [developing solvent: acetone-chloroform (1:1)], and the desired derivative 3 of high purity was purified to a concentration of 0.171%. Obtained.

Example 4 Synthesis of derivative 4 2-dimethylaminoethanethiol hydrochloride of Example 1 0
．． In place of 70f, 2-diethylaminoethanethiol 0
．． The same operation was carried out using 85f to obtain 0.391 of the desired derivative 4.

Example 5 Synthesis of Derivative 5 61gt of dilorsulfonic acid was added with 25gt of 2-benzoxacillinone. Of was added in small portions over 30 minutes with stirring. Meanwhile, the reaction vessel was cooled with water so that the reaction temperature was 15°C. Next, stir at 60°C for 2 hours and leave to cool.
Pour carefully into 00rxl of ice water little by little. Then,
The white precipitate formed was filtered and washed with water. The resulting cake was dissolved in THF40 (1+t), dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain 82.6f of 5-chlorosulfonyl-2-benzoxacillinone.

5-Chlorsulfonyl-2-benzoxasolinone2.
269 T I (F solution 40ml) and diethylamine 2.
19 f/T HF solution Lost was added under stirring.

The residue obtained by distilling off the solvent was suspended in water, passed through, and washed with water.
After drying, 1.14 g of compound A represented by the following formula was obtained.

6 t of IN sodium hydroxide aqueous solution to 0.59 g of compound A
ttl was added and kept at 90'C overnight. After cooling, water 3
The mixture was neutralized by adding IN hydrochloric acid. The generated precipitate was collected, washed with water, and dried to obtain 0.301 of Compound B represented by the following formula.

0H 20 tsl of benzene, 80.70 g of rifamycin and 0.30 of compound B! f and stirred at 60°C for 26 hours. Then, the solvent was distilled off and methanol 201111
After adding 0.68 g of manganese dioxide and stirring at room temperature overnight, the mixture was filtered. The residue obtained by concentrating the F solution was subjected to column chromatography using silica gel as a carrier [developing solvent:
acetone-chloroform (5:95)] to obtain the desired derivative 5 with a weight of 0.149.

Example 6 Synthesis of derivative 6 5-chlorosulfonyl-
2-Benzoxacillinone 2.261 and morpholine 2.
61! The compound C represented by the following formula is converted to 1 using
．． I got 96f.

Compound C1,2Of and IN aqueous sodium hydroxide solution 10
From tsl, the compound represented by the following formula is 0.743
I got f.

0.82 da of the desired derivative 6 was obtained from 0.74 g of compound D and 1.80 f of rifamycin S by the same method.

Example 7 Synthesis of derivative 7 5-chlorosulfonyl-
Compound E represented by the following formula was obtained in an amount of 2.15 f/by using 2.261 2-benzoxacillinone and N-methylpiperazine s,ooy.

Compound E1.209 and IN sodium hydroxide aqueous solution 1
0.90f of compound F represented by the following formula was obtained from 0M1.

The desired o, soy derivative 7 was obtained from 0.90 g of compound F and 82.299 rifamycin in the same manner.

Claims (8)

[Claims] (1) A rifamycin derivative represented by the following general formula (I) and a salt thereof. ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) {In the formula, a represents 0 to 2, b represents 0 to 4, and R
^1 is a monohydroxyalkyl group or dihydroxyalkyl group with 1 to 4 carbon atoms, ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (R^2 and R^3 are the same or different carbon atoms 1
~ 4 alkyl group), or ▲ mathematical formula, chemical formula, table, etc. ▼ [c, d are the same or different 1 to 4, X is an oxygen atom or N-R^4 (
R^4 represents hydrogen or an alkyl group having 1 to 3 carbon atoms)
represents a group represented by } represents a group represented by } (2) The rifamycin derivative and its salt according to claim 1, wherein in the general formula (I), a is 0. (3) The rifamycin derivative and its salt according to claim 1, wherein a is 2 in the general formula (I). (4) In general formula (I), R^1 has 1 to 4 carbon atoms
The rifamycin derivative and its salt according to claim 1, which is a monohydroxyalkyl group or a dihydroxyalkyl group. (5) In the general formula (I), R^1 is represented by ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (R^2 and R^3 are the same or different alkyl groups having 1 to 4 carbon atoms) The rifamycin derivative and salt thereof according to claim 1, which is a group represented by (6) In the general formula (I), R^1 is ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [c and d are the same or different 1
~4, and X represents an oxygen atom or a group represented by N-R^4 (R^4 represents hydrogen or an alkyl group having 1 to 3 carbon atoms). The rifamycin derivative and its salt according to item 1. (7) Rifamycin O or S has the general formula (II) ▲ Numerical formula, chemical formula, table, etc. ▼ (II) {In the formula, a represents 0 to 2, b represents 0 to 4, and R
^1 is a monohydroxyalkyl group or dihydroxyalkyl group with 1 to 4 carbon atoms, ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (R^2 and R^3 are the same or different carbon atoms 1
~ 4 alkyl group), or ▲ mathematical formula, chemical formula, table, etc. ▼ [c, d are the same or different 1 to 4, X is an oxygen atom or N-R^4 (
R^4 represents hydrogen or an alkyl group having 1 to 3 carbon atoms)
General formula (I) ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (I) (a , b, and R^1 are as described above). (8) An antibacterial agent containing a rifamycin derivative represented by the following general formula (I) or a salt thereof as an active ingredient. ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) {In the formula, a represents 0 to 2, b represents 0 to 4, and R
^1 is a monohydroxyalkyl group or dihydroxyalkyl group with 1 to 4 carbon atoms, ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (R^2 and R^3 are the same or different carbon atoms 1
~ 4 alkyl group), or ▲ mathematical formula, chemical formula, table, etc. ▼ [c, d are the same or different 1 to 4, X is an oxygen atom or N-R^4 (
R^4 represents hydrogen or an alkyl group having 1 to 3 carbon atoms)
represents a group represented by } represents a group represented by }