JPS6335578A - Benzoxazino or benzothiazinorifamycin derivative - Google Patents

Abstract

NEW MATERIAL:The compound of formula I (n is 1-5; X is O or S; R<1> and R<2> are H, 1-4C alkyl or 1-4C hydroxyalkyl) and its salt. USE:A medicine. An antibacterial agent. It is a solid having dark red color, soluble in a number of organic solvents, exhibiting strong antibacterial activity against Gram-positive bacteria and acid-fast bacteria and having low toxicity. It can be used as a production raw material for novel rifamycin derivative of formula II having strong antibacterial activity. It is administered at a rate of 10mg-10g of the active component daily for adult. PREPARATION:The compound of formula I can be produced by reacting a rifamycin derivative of formula III with an amine of formula IV in an organic solvent such as methanol in the presence of a reducing agent such as sodium cyanoborohydride at room temperature for 30min - about 1 month, thereby effecting reductive amination reaction.

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) Bi-N(CH2)11 (wherein, n represents 1 to 5, X represents an oxygen atom or a sulfur atom, and R1 and R2 are the same or different hydrogen atoms) This invention relates to a novel rifamycin derivative or its salt represented by an atom, an alkyl group having 1 to 4 carbon atoms, or a hydroxyalkyl group having 1 to 4 carbon atoms, a method for producing the same, and an antibacterial agent containing the same as an active ingredient. be.

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

(Means and Effects for Solving the Problems) The present inventors have developed a rifamycin derivative represented by the general formula (n) (X represents an oxygen atom or a sulfur atom) using the formula R'NH (CIi2). n
A compound represented by NH 2 (n represents 1 to 5, R1 2 represents the same or different hydrogen atom, an alkyl group having 1 to 4 carbon atoms, or a hydroxyalkyl group having 1 to 4 carbon atoms) It has been found that a novel rifamycin derivative represented by the above general formula (I) can be obtained by subjecting it to the reductive amination reaction used. The inventors have discovered that the obtained derivative has a strong antibacterial effect and is useful as an antibacterial agent, leading to 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, alcohols such as ethyl alcohol, esters such as ethyl acetate, and aromatic substances such as benzene. It is soluble in group hydrocarbons and ethers such as tetrahydrofuran.

The novel rifamycin derivative represented by the general 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 to form a salt, any base or acid that can form a salt with the rifamycin derivative represented by the general formula (I) can be selected. Examples of specific salts with bases are (1)
metal salts, especially salts with alkali metals, alkaline earth metals,
(2) ammonium salts, (3) amine salts, especially salts with methylamine, ethylamine, diethylamine, triethylamine, pyrrolidine, morpholine, hexamethyleneimine, etc. Further, examples of salts with acids include (1) salts with expanded 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.

That is, the rifamycin derivative represented by the general formula (n) is dissolved in an organic solvent such as methanol, ethanol, tetrahydrofuran, or dioxane, and then dissolved in the presence of hydrogen and a hydrogenation catalyst or a reducing agent such as sodium cyanoborate hydride. It can be synthesized by carrying out a reductive amination reaction using a compound represented by the general formula %.

Hydrogenation catalysts that can be used here include platinum,
Examples include Raney nickel.

Reducing agents that can be used include sodium cyanoborohydride, zinc and acid, sodium borohydride, dimethylamine-borane complex, sodium amalgam, and the like.

The reaction temperature can be selected from -20°C to the boiling point of the solvent, but it can usually be carried out at room temperature. The reaction time is about 30 minutes to 1 month, but the optimal reaction time varies depending on the type of amine used in the reaction, the type of hydrogenation catalyst or reducing agent, the reaction temperature, etc. The progress should be followed and determined by thin layer chromatography.

The rifamycin derivative represented by the general 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 general formula NH(CH
2) Remove the amine, catalyst, reaction solvent, etc. represented by nNT (n, 几1.几2 are as described above), and purify the obtained crude product by crystallization, column chromatography, etc. By this, the desired rifamycin derivative can be obtained.

By reducing the novel rifamycin derivative represented by the general formula (I) with a reducing agent such as ascorbic acid or sodium hydrosulfide, the new rifamycin derivative represented by the general formula (III)
) (where n+x+1.R2 is as described above). The rifamycin derivative represented by general formula (III) 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 the table, thin layer chromatography is performed using Merck's silica gel 60F25.
4. Plate for thin layer chromatography (20cm x 2
0α).

Nuclear magnetic resonance spectra were measured using tetramethylcycne as an internal standard as a deuterated chloroform solution.

The rifamycin derivative according to the present invention exhibits strong antibacterial activity against Durham-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.

The novel rifamycin derivative according to the present invention was prepared at 10100O
,"e was orally administered to mice, but 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 in general, it is iom, y ~ 1011 per day for an adult, preferably 20 m, 9
It would normally be administered at about ~51. The antibacterial agent of the present invention can be administered as a pharmaceutical preparation with an active ingredient of 1 my to 511, preferably 3 my to II.

(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 l Na2S ・9H20194, 1g of 800ml! 50 g of 4-chloro-3-nitrobenzaldehyde in aqueous solution
was added and heated under reflux for 8 hours, then allowed to cool, and the reaction solution was extracted and washed with ether. The aqueous layer was saturated with 1-IJium chloride, and the resulting precipitate of 2-amino-4-formylthiophenol sodium salt was separated and dried to obtain residues of aa and ag. Pour the resulting residue into 600ml of water! After dissolving the insoluble matter in the p-liquid, a concentrated aqueous solution of zinc chloride was gradually added to the p-liquid while cooling with water. The resulting yellow precipitate was collected, washed with water and methanol, and dried to give 29.1% of the 2-amino-4-formylthiophenol zinc salt. I got it.

Obtained 2-amino-4-formylthiophenol zinc salt 24.3. Finely crush p.
iooy (synthesized according to the method described in No. 599) was added thereto, and the mixture was stirred at room temperature for 3 hours.

Insoluble matters were separated, the solvent of the p solution was distilled off under reduced pressure, and the residue was dissolved in chloroform and washed with water. The chloroform in the chloroform layer was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography using Wakogel ■C-200 as a carrier [developing solvent: chloroform-acetone (95
:5):l to obtain a rifamycin derivative A of formula [■] of 59.8,9 in which X is a sulfur atom.

Example 2 Synthesis of Derivative 1 0.4 ethylenediamine was added to a 10 mj' methanol solution of rifamycin derivative A1, Oy synthesized in Example 1.
8ml! , 12N hydrochloric acid 0.2 mA' and sodium cyanoborohydride 0.058. Add F and 1 at room temperature.
Stir for hours. Add chloroform to the reaction solution, add water twice,
The mixture was washed once with saturated brine, chloroform was distilled off under reduced pressure, the residue was dissolved again in chloroform, 0.5.9% of manganese dioxide was added, and the mixture was stirred at room temperature for 1 hour. Insoluble matter was separated, chloroform was distilled off under reduced pressure, and the residue was used with Wakogel ■C-200. Silica gel column chromatography CR Opening solvent: Chloroform: Methanol (9:
1)] and then purified by preparative thin layer chromatography [developing solvent: chloroform:methanol (9:1)] using Merck's Silica Gel 60 Plate F254 20X20α Size 5717, and 0.02 g of the target and Derivative 1 was obtained.

Example 3 Synthesis of Derivative 2 In place of ethylenediamine in Example 2, 0.64 mr of N-methylethylenediamine was added, and the mixture was stirred at room temperature for 2 hours. Thereafter, the same operation was performed to obtain the desired derivative 2 of o and aay.

Example 4 Synthesis of Derivative 3 In place of ethylenediamine in Example 2, 0.76 mf of N-ethylethylenediamine was processed and stirred at room temperature for 1 hour. Thereafter, the same operation was performed to obtain 0.06 g of the desired derivative 3.

Example 5 Synthesis of Derivative 4 0.78 ml of 2-(2-aminoethylamino)ethanol was added to the ethylenediamine of Example 2, and the mixture was stirred at room temperature for 1.5 hours. From here on, operate in the same way and get 0.05!
The desired derivative 4 of 1 was obtained.

Example 6 Synthesis of Derivative 5 83.5 g of 4-hydroxy-3-nitrobenzaldehyde and 40 g of sodium borohydride were added to 2 J of ethanol, and after heating under reflux for 6 hours, the reaction mixture was poured into 1 large cup of water. The mixture was made acidic by adding 10% hydrochloric acid, and extracted with ethyl acetate. The extract was dehydrated using anhydrous sodium sulfate, and then the solvent was distilled off. The obtained residue was purified by column chromatography using silica gel as a carrier [developing solvent: chloroform-acetone (95:5):l to obtain 4-hydroxy-3-nitrobenzyl alcohol of 35.5,9. .

4-Hydroxy-3-nitrobenzyl alcohol was dissolved in ethanol 11 and palladium on carbon (5%) was added.
3.5 and 9 were added and hydrogenated at room temperature and pressure for 8 hours. After removing the catalyst by filtration, the solvent was distilled off to obtain 3-amino-4-hydroxybenzyl alcohol with a T of 16.0.9.

Rifamycin 869.58I and benzene 21 were added to the obtained 3-amino-4-hydroxybenzyl alcohol 13.911, and the mixture was heated and stirred at 50°C for 18.5 hours.
Then, after concentration, methanol 11! and manganese dioxide 18
9.16. p and stirred overnight at room temperature. The reaction mixture was filtered, and the residue obtained by distilling off the solvent was subjected to column chromatography using silica gel as a carrier twice [Developing solvent: chloroform-acetone (95:5 to 7:3)]
and ethyl acetate-n-hexane (l:5-8:2):
A rifamycin derivative B having the general formula CI[] in which X is an oxygen atom is purified with 14.45. I got F.

Rifamycin derivative B1.0 (l and N,N-dimethylethylenediamine o, ta, y were mixed in 35 ml of methanol.
The solution was dissolved in water and left overnight at room temperature. After neutralizing by adding hydrochloric acid-methanol reagent 10 (manufactured by Tokyo Kasei), sodium cyanogen borohydride 0.064.9 was added and
Stir for hours. Add 150 mj' of chloroform to the reaction mixture.
When I added it and washed it with water, multiple insoluble substances were formed, so I separated them and added 50ml of methanol! and dried over anhydrous sodium sulfate. Moreover, the chloroform layer was similarly dried with anhydrous sodium sulfate. 1.36 g of manganese dioxide was added to the mixture, and the mixture was stirred at room temperature for 1.5 hours. Then, it was filtered and the P solution was concentrated to obtain 0.91 g of residue.

This residue was subjected to column chromatography using silica gel as a carrier [developing solvent: chloroform-methanol (95%
:5)] was repeated twice to obtain 0.12.9% of the desired derivative 5.

Example 7 Synthesis of Derivative 6 Instead of ethylenediamine in Example 2, 0.58 mJ of N,N'-dimethylethylenediamine was processed and stirred at room temperature for 30 minutes. The same procedure was followed to obtain 0.07jp of the desired derivative 6.

Example 8 Synthesis of Derivative 7 Ethylenediamine of Example 2 was processed with N,N-diethylethylenediamine toamz and stirred at room temperature for 1 hour. Repeat the same operation below, starting at 0.02. ! ; The desired derivative 7 of I was obtained.

Example 9 Synthesis of derivative 8 0.94 mJ of N,N'-diethyl-1,3-propanediamine was added to the ethylenediamine of Example 2,
Stirred at room temperature for 3 hours. Follow the same procedure, and 0.02g
The desired derivative 8 was obtained.

Claims (6)

[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, n represents 1 to 5, X represents an oxygen atom or a sulfur atom, R^1, R^2 are the same or different hydrogen atoms, Alkyl group having 1 to 4 carbon atoms or 1 to 4 carbon atoms
(represents a hydroxyalkyl group) (2) The rifamycin derivative and its salt according to claim 1, wherein in the general formula (I), X is an oxygen atom. (3) The rifamycin derivative and its salt according to claim 1, wherein in the general formula (I), X is a sulfur atom. (4) General formula (II) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (II) The rifamycin derivative represented by (X represents an oxygen atom or a sulfur atom) is expressed by the general formula R^1NH (CH_2
)_nNHR^2 (n represents 1 to 5, R^1, R^
2 represents the same or different hydrogen atoms, alkyl groups having 1 to 4 carbon atoms, or hydroxyalkyl groups having 1 to 4 carbon atoms. Formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) A method for producing a rifamycin derivative represented by (n, X, R^1, R^2 are as described above). (5) The method for producing a rifamycin derivative according to claim 4, wherein the reducing agent used in the reductive amination reaction is sodium cyanoborohydride. (6) 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, n represents 1 to 5, X represents an oxygen atom or a sulfur atom, R^1, R^2 are the same or different hydrogen atoms, Alkyl group having 1 to 4 carbon atoms or 1 to 4 carbon atoms
(represents a hydroxyalkyl group)