JP2780807B2 - Substituted benzoxazinolifamycin derivatives - Google Patents

Description

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 present invention provides a compound of formula (I): Ａwhere A is (Wherein R ¹ and R ² are the same or different and have 1 to 1 carbon atoms)
An alkylalkyl group having 3 to 3 carbon atoms, an aminoalkyl group having 2 to 6 carbon atoms, a monoalkylaminoalkyl group having 2 to 6 carbon atoms or a dialkylaminoalkyl group having 3 to 6 carbon atoms); (Where a represents an integer of 2 to 7, R ³ represents a hydrogen atom, an amino group, a monoalkylamino group having 1 to 4 carbon atoms or a dialkylamino group having 2 to 8 carbon atoms) Or (Where b and c are the same or different and represent an integer of 1 to 4, R ⁴ is a hydrogen atom, an alkyl having 1 to 6 carbon atoms which may be substituted by a cycloalkyl group having 3 to 5 carbon atoms) group, an alkenyl group having 2 to 7 carbon atoms, represents a group represented by a cycloalkyl group having an alkoxyalkyl group or a 3 to 5 carbon atoms having 2 to 6 carbon atoms), X ¹ is 3 'carbon atoms of positions 1 An alkoxy group having 2 to 6 carbon atoms or an alkenyloxy group having 2 to 6 carbon atoms, an alkoxy group having 2 to 6 carbon atoms at the 4'-position,
An alkylthio group having 1 to 6 carbon atoms, an acyl group having 1 to 6 carbon atoms, an acylalkyl group having 2 to 6 carbon atoms or an iodine atom, an alkoxy group having 1 to 6 carbon atoms at the 5'-position, or a carbon number at the 6'-position A rifamycin derivative or a salt thereof represented by｝, which represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, wherein X ² represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms; Related to antibacterial agents.

[Prior art / problem to be solved by the invention] The rifamycin derivative according to the present invention is a novel compound not described in any literature.

We have found that to find new and superior antimicrobial agents, the formula (I): (Wherein X ¹ , X ² and A are as defined above) were synthesized and their antibacterial activity and pharmacological properties were examined. As a result, the present inventors have found that the novel rifamycin derivative represented by the formula (I) has a strong antibacterial activity and has excellent pharmacological properties, and reached the present invention.

[Means for Solving the Problems] The present invention provides a compound of the formula (I): Ａwhere A is (Wherein R ¹ and R ² are the same or different and have 1 to 1 carbon atoms)
An alkylalkyl group having 3 to 3 carbon atoms, an aminoalkyl group having 2 to 6 carbon atoms, a monoalkylaminoalkyl group having 2 to 6 carbon atoms or a dialkylaminoalkyl group having 3 to 6 carbon atoms); (Where a represents an integer of 2 to 7, R ³ represents a hydrogen atom, an amino group, a monoalkylamino group having 1 to 4 carbon atoms or a dialkylamino group having 2 to 8 carbon atoms) Or (Where b and c are the same or different and represent an integer of 1 to 4, R ⁴ is a hydrogen atom, an alkyl having 1 to 6 carbon atoms which may be substituted by a cycloalkyl group having 3 to 5 carbon atoms) group, an alkenyl group having 2 to 7 carbon atoms, represents a group represented by a cycloalkyl group having an alkoxyalkyl group or a 3 to 5 carbon atoms having 2 to 6 carbon atoms), X ¹ is 3 'carbon atoms of positions 1 An alkoxy group having 2 to 6 carbon atoms or an alkenyloxy group having 2 to 6 carbon atoms, an alkoxy group having 2 to 6 carbon atoms at the 4'-position,
An alkylthio group having 1 to 6 carbon atoms, an acyl group having 1 to 6 carbon atoms, an acylalkyl group having 2 to 6 carbon atoms or an iodine atom, an alkoxy group having 1 to 6 carbon atoms at the 5'-position, or a carbon number at the 6'-position A rifamycin derivative represented by｝ or a salt thereof, wherein X ² represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, or a salt thereof; (Wherein X ³ is a hydrogen atom, an alkoxy group having 1 to 6 carbon atoms,
A halogen atom or a nitro group; X ⁴ represents a 3'-position alkoxy group having 1 to 6 carbon atoms or an alkenyloxy group having 2 to 6 carbon atoms; a 4'-position alkoxy group having 2 to 6 carbon atoms; 6 alkylthio group, an acyl group having 1 to 6 carbon atoms, an acyl group or an iodine atom or 6'-position alkoxy group or halogen atom having 1 to 6 carbon atoms of 2 to 6 carbon atoms, X ⁵ is hydrogen A rifamycin derivative represented by an atom or an alkyl group having 1 to 6 carbon atoms) reacted with an amine represented by the formula AH (where A is the same as defined above): (Wherein A, X ⁴ and X ⁵ are the same as described above), a method for producing a rifamycin derivative represented by the formula (IV): (Wherein X ⁶ is a hydrogen atom, an alkoxy group having 1 to 6 carbon atoms,
X ⁷ represents a halogen atom or a nitro group, X ⁷ represents a 4′-position alkoxy group having 2 to 6 carbon atoms, an alkylthio group having 1 to 6 carbon atoms, an acyl group having 1 to 6 carbon atoms, and an acylalkyl having 2 to 6 carbon atoms. Group or iodine atom, carbon number of 1 to 6 at 5'-position
Alkoxy or 6 'represents a position alkoxy group or halogen atom having 1 to 6 carbon atoms, X ⁸ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, 5' position X ⁷ or other than a hydrogen atom the rifamycin derivative represented by a is) a group representing the X ^8, wherein the formula AH (a is characterized by reacting an amine represented by the same) and the (V): Wherein A, X ⁷ and X ⁸ are the same as defined above, and a rifamycin derivative represented by the formula (I) or a physiologically acceptable salt thereof as an active ingredient Related to antibacterial agents.

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

Substituents A novel rifamycin derivative of the formula (I) according to the invention, to name a specific example of X ¹ and X ² are the following.

That is, A (Wherein R ¹ and R ² are the same as described above): And so on, Wherein a and R ³ are the same as defined above, And so on. Also, (Wherein b, c and R ⁴ are the same as defined above) And so on.

X ¹ of 3 'position of the methoxy group is the alkoxy group having 1 to 6 carbon atoms, an ethoxy group, a propoxy group, isopropoxy group, butoxy group, isobutoxy group, sec- butoxy group, t
ert-butoxy group, pentyloxy group, isopentyloxy group, neopentyloxy group, tert-pentyloxy group, hexyloxy group, isohexyloxy group, and the like. Group, allyloxy group, 2-methyl-2-propenyloxy group, 2-butenyloxy group, 3-methyl-
2-butenyloxy group, 2-pentenyloxy group, 4-
A pentenyloxy group and the like;
Ethoxy, propoxy, isopropoxy, butoxy, isobutoxy,
sec-butoxy group, tert-butoxy group, pentyloxy group, isopentyloxy group, neopentyloxy group, te
rt-pentyloxy group, hexyloxy group, isohexyloxy group and the like. Examples of the alkylthio group having 1 to 6 carbon atoms include methylthio group, ethylthio group, propiothio group, isopropiothio group, butylthio group, isobutylthio group, sec-butylthio group, tert-butylthio group, hexylthio group and the like.Examples of the acyl group having 1 to 6 carbon atoms include formyl group, acetyl group, propionyl group, butyryl group, isobutyryl group, and hexanoyl group. Examples of the acylalkyl group of Formulas 2 to 6 include formylmethyl, acetylmethyl, propionylmethyl, butyrylmethyl, isobutyrylmethyl, valerylmethyl, isovalerylmethyl, pivaloylmethyl, 1-formylethyl, 1 -Acetylethyl group, 1
-Propionylethyl group, 1-butyrylethyl group, 1-
Isobutyrylethyl group, 2-formylethyl group, 2-acetylethyl group, 2-propionylethyl group, 2-butyrylethyl group, 2-isobutyrylethyl group, 1-formylpropyl group, 1-acetylpropyl group, 1 -Propionylpropyl group, 2-formylpropyl group, 2-acetylpropyl group, 2-propionylpropyl group, 3-formylpropyl group, 3-acetylpropyl group, 3-propionylpropyl group, 1-formylbutyl group, 1-acetyl Butyl group, 2-formylbutyl group, 2-acetylbutyl group, 3-formylbutyl group, 3-acetylbutyl group,
4-formylbutyl group, 4-acetylbutyl group and the like, iodine atom as a 4′-substituted atom, and methoxy group and ethoxy group as a 5′-position alkoxy group having 1 to 6 carbon atoms. , Propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, t
an ert-butoxy group, a pentyloxy group, an isopentyloxy group, a neopentyloxy group, a tert-pentyloxy group, a hexyloxy group, an isohexyloxy group, and the like, and an alkoxy group having 1 to 6 carbon atoms at the 6'-position. As methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, tert-pentyloxy Hexyloxy group, isohexyloxy group and the like, and the halogen atom includes a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

Methyl group of an alkyl group having 1 to 6 carbon atoms X ^2, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec- butyl group, tert- butyl group, and hexyl groups.

The novel rifamycin derivative represented by the 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 the salt, any base or acid that can form a salt with the rifamycin derivative represented by the formula (I) can be selected. Specific examples of the salt with a base include (1) a metal salt, particularly a salt with an alkali metal or an alkaline earth metal, (2) an ammonium salt, (3) an amine salt, particularly 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 acids such as trifluoroacetic acid and acetic acid.

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

That is, (A) Rifamycin S and the formula: (Wherein X ¹ , X ² and A are the same as described above) and a compound represented by the method of W. Kump et al. (Helv. Chim. Acta, 56, 2348, 1973) )).

(B) Among the rifamycin derivatives represented by the formula (I), the derivative represented by the formula (III) in which A is at the 5′-position is:
Formula (II): (Wherein X ³ is a hydrogen atom, an alkoxy group having 1 to 6 carbon atoms,
A halogen atom or a nitro group; X ⁴ represents a 3'-position alkoxy group having 1 to 6 carbon atoms or an alkenyloxy group having 2 to 6 carbon atoms; a 4'-position alkoxy group having 2 to 6 carbon atoms; 6 alkylthio group, an acyl group having 1 to 6 carbon atoms, an acyl group or an iodine atom or 6'-position alkoxy group or halogen atom having 1 to 6 carbon atoms of 2 to 6 carbon atoms, X ⁵ is hydrogen Rifamycin derivative represented by an atom or an alkyl group having 1 to 6 carbon atoms) is dissolved in an organic solvent such as methanol, ethanol, tetrahydrofuran, N, N-dimethylformaluminide, N, N-dimethylacetamide and dimethylsulfoxide. At a temperature from −20 ° C. to the boiling point of the solvent, the formula AH
A is the same as defined above) by reacting the amine for 1 hour to 1 month in the presence or absence of an acid such as hydrochloric acid or in the presence or absence of an oxidizing agent such as manganese dioxide. . AH used for reaction
Good results can be obtained by using 0.5 to 10 mol, particularly 1 to 4 mol, of the amine represented by the formula (II) with respect to the rifamycin derivative represented by the formula (II). Reaction solvents include methanol, ethanol, isopropyl alcohol, tetrahydrofuran, pyridine, acetone,
Ethyl acetate, chloroform, N, N-dimethylformalumide, N, N-dimethylacetamide, dimethylsulfoxide and the like can be used, but pyridine, N, N-dimethylformalumide, N, N-dimethylacetamide,
Good results can be obtained by using dimethyl sulfoxide or the like. The reaction temperature can be selected from -20 ° C to the boiling point of the solvent, but good results can be obtained by reacting at -5 ° C to 50 ° C. The reaction time is about one hour to one 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 by thin layer chromatography or the like. In the reaction performed in the presence of the oxidizing agent, oxidizing agents that can be used include air, oxygen, manganese dioxide, lead dioxide, silver oxide, potassium ferricyanide, and hydrogen peroxide. Good results can be obtained by selecting potassium ferricyanide or the like.

The rifamycin derivative represented by the formula (II), which is a starting material of the present synthesis method, is obtained by adding a rifamycin S to the formula: (Wherein X ³ , X ⁴ and X ⁵ are as defined above) by the method of W. Kump et al. (Helv. Chim. Acta, 56, 2348, 1973) ) Can be synthesized.

(C) Among the rifamycin derivatives represented by the formula (I), the derivative represented by the formula (V) in which A is at the 3'-position can also be synthesized as follows. That is, according to the method of W. Kump et al. The following formula (IV) obtained by reacting a compound represented by the following formula: (Wherein X ⁶ , X ⁷ and X ⁸ are the same as those described above, and the 5′-position is a group representing X ⁷ or X ⁸ other than a hydrogen atom). , A is the same as defined above). The synthesis conditions such as the reaction solvent and the reaction temperature are the same as those described in the synthesis method (B).

Separation and purification of the rifamycin derivative represented by the formula (I) according to the present invention from the reaction product is relatively easy. That is, the amine represented by the AH (where A is the same as the above) used in the excess reaction, the reaction solvent, and the like are removed, and the obtained crude product is purified by crystallization, column chromatography, or the like, The desired rifamycin derivative can be obtained.

The novel rifamycin derivative represented by the formula (I) is reduced with a reducing agent such as ascorbic acid or sodium dithionite to give the following formula (IV): (Wherein X ¹ , X ² and A are the same as those described above). The rifamycin derivative represented by the formula (VI) is also novel and has a strong antibacterial action.

Table 1 shows representative examples of the novel rifamycin derivatives according to the present invention. In Table 1, the infrared absorption spectrum was measured by the potassium bromide tablet method. Thin layer chromatography was performed using Merck silica gel 60F _254, thin-layer chromatography plate (20cm × 20cm). 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 acid-fast bacteria.

The antimicrobial activity of the novel rifamycin derivative according to the present invention was determined by the standard method of the Japanese Society of Chemotherapy [Japanese Journal of Chemotherapy, Vol. 29,
76 (1981)]. Representative examples are shown in Table 2. 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. 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 has a strong antibacterial activity against Mycobacterium tuberculosis. Mycobacterium tuberculosis (Mycobacterium tuberculosis)
The tuberculosis H ₃₇ Rv strain)) were cultured in Deyubosu (Dubos) medium, to prepare a bacterial solution of 1 mg / ml, the 10-fold dilutions 0.05ml
Was inoculated into 2 ml of Kirchner liquid medium supplemented with 10% bovine serum. For the 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 inhibited macroscopically 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 has strong antibacterial activity against Mycobacterium tuberculosis. The derivative numbers in Tables 3 and 4 correspond to the derivative numbers in Table 1.

The rifamycin derivatives according to the invention of the formula (I) are absorbed orally and show high blood levels. dd
Derivatives 19 and 30 shown in Table 1 were orally administered to male Y mice (7 weeks old) at a rate of 20 mg / kg. In accordance with the usual method, the plasma concentration was determined by using Micrococcu luteus.
s luteus IFO 12708) as a test bacterium. As a result, Derivatives 19 and 30 were absorbed by oral administration and 1, 3, 5 and 8 hours after administration.
19 is 17.0 μg / ml, 13.3 μg / ml, 14.5 μg / ml and 4.2 μg
Derivative 30 shows 17.3 μg / ml, 16.2
It was found to show plasma concentrations of μg / ml, 13.8 μg / ml and 10.1 μg / ml.

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

 Male ddY mice, 5 weeks old, were used in a group of 20 mice. De
Mycobacterium tuberculosis cultured in Dubos medium
Mycobacterium tuberculos
is H₃₇Rv strain)) Concentrated bacterial solution 0.2 ml (viable bacterial unit number 2.4 × 10⁸)
Was inoculated into the tail vein of mice. From the day after infection,
The test derivative is 0.2% Tween (Tween 2.5% A including 80)
Make a rubia rubber suspension, 0.2 ml each, that is, 200 μg / mouse
Oral administration. Controls contain 0.2% tuner without test compound.
A 2.5% gum arabic solution containing Ine 80 was administered. Cure
The treatment is carried out once a day, 6 days a week, to
Was evaluated by the prolongation of life.

The result is shown in FIG. In the figure, a indicates the time of infection, and b indicates the time of starting treatment. From these results, no death was observed in the treatment with the derivative 24 according to the present invention until 38 days after the treatment, and the derivative 24 was used as a control drug, rifampicin, a derivative A having the following structure described in U.S. Patent No. 4,690,919. It can be seen that the treatment effect is extremely excellent. In addition, derivative B having the following structure described in U.S. Pat. No. 4,690,919 and derivative C having the following structure described in European Patent Application No. 0253340 were treated in the same therapeutic test. The effect is
It has been found to be inferior to rifampicin.

Furthermore, a treatment test for M. tuberculosis infection was performed using 10 ddY male mice per group using the same system as described above, and the survival rate 40 days after the start of the test was determined. The results are shown in Table 5.

The control group not receiving the drug had a 30% survival rate and the control group receiving rifampicin had a 80% survival rate, whereas the group receiving the derivative 19, 32 or 36 according to the present invention had no death. I was not able to admit. This result indicates that the rifamycin derivative according to the present invention is a very effective drug against tuberculosis.

The novel rifamycin derivative shown in Table 1 according to the present invention was orally administered to mice at a rate of 1000 mg / kg, but showed no toxicity, indicating that the novel rifamycin derivative according to the present invention has low toxicity. Was.

As the preparation of the antibacterial agent containing the novel rifamycin derivative according to the present invention as an active ingredient, any preparation by oral, enteral or parenteral administration can be selected. Specific formulations include tablets, capsules, fine granules,
Syrups, suppositories, ointments and the like can be mentioned.
As carriers for the formulation of the antimicrobial agents according to the invention, use is made of organic or inorganic solid or liquid, usually inert pharmaceutical carrier materials which are suitable for oral, enteral or parenteral administration. 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 antimicrobial agent of the present invention to the carrier in the preparation can be varied between 0.2 and 100%. Also, the antimicrobial agent according to the present invention may include other antimicrobial agents compatible with this and other pharmaceuticals. In this case, it goes without saying that the antibacterial agent according to the present invention may not be the main component in the preparation.

The antimicrobial agent according to the present invention is generally administered at a dose that achieves the desired effect without side effects. The specific value should be determined at the discretion of the physician, but will generally be about 10 mg to 10 g, preferably about 20 mg to 5 g per day for an adult. The antibacterial agent of the present invention can be administered as a pharmaceutical preparation in a unit of 1 mg to 5 g, preferably 3 mg to 1 g, as an active ingredient.

[Examples] Hereinafter, examples will be described in order to further clarify the understanding of the present invention. However, these are merely examples, and do not limit the present invention. Note that the derivative numbers in the examples correspond to the derivative numbers in Table 1.

Example 1 (3 ', 5'-dimethoxybenzoxazinolifamycin
Synthesis of 5.0 g of 3,5-dimethoxyphenol and 4 ml of acetic acid
Was stirred on ice and mixed with 2.75 ml of 61% nitric acid and 12 ml of acetic acid.
Add the mixture, gradually raise the temperature, then add 100 ml of water
The resulting precipitate was collected by filtration, washed with water and air-dried to
The product was obtained. This is Wakogel Using C-200
Ricagel column chromatography [Developing solvent: chloro
Form] to give 3,5-dimethoxy-2-nitro
0.61 g of phenol was obtained.

0.61 g of 3,5-dimethoxy-2-nitrophenol was added to water 25
suspension, add 1.5 g of sodium dithionite and add 80 ° C
And stirred. About 20 minutes later, 1.5 g of sodium dithionite was added and reacted for a total of 1 hour. The reaction solution was neutralized by adding sodium hydrogen carbonate, and extracted five times with ether. After the extract was dried over anhydrous sodium sulfate, the desiccant was filtered off, and the solvent was removed under reduced pressure to obtain 0.42 g of a crude 2-amino-3,5-dimethoxyphenol product.

 1.74 g of rifamycin S and 2-amino-3,5 obtained above
-Dimethoxyphenol crude product 0.42 g in toluene 30m
and stirred at 60 ° C. for 24 hours to react. Solvent
Remove under reduced pressure, dissolve the residue in 30 ml of ethanol and add diacid
Add 1.74 g of manganese oxide and react at room temperature with stirring for 27 hours.
Was. Using a filter aid, filter the manganese dioxide and remove the solvent.
Removed under reduced pressure. Wako gel for residue Using C-200
Silica gel column chromatography [Developing solvent:
Roloform-acetone (9: 1)]
3 ', 5'-dimethoxybenzoxazinorifamicis
1.04 g was obtained.

Thin layer chromatography RF = 0.26 purple spot [Carrier: silica gel, developing solution
Medium: chloroform-acetone (9: 1)] Example 2 (Synthesis of Derivative 1) 3 ′, 5′-di synthesized by the method described in Example 1
0.8 g of methoxybenzoxazinolifamycin in dimethyl
Dissolve in 8 ml of sulfoxide, add 0.18 ml of piperidine and
0.8 g of manganese was added, and the mixture was stirred and reacted at room temperature for 20 hours.
Then, ethyl acetate was added to the reaction solution to dilute the solution.
The manganese dioxide was filtered off using, and the filtrate was washed with water, 0.1
After washing with normal, hydrochloric acid, water and saturated saline,
Dried with um. Filter off the desiccant and remove the solvent under reduced pressure
And remove the residue from Wakogel Silica gel using C-200
3 times by column chromatography [Developing solvent: chloroform
M-methanol (98: 2), ethyl acetate-n-hexane
(7: 8), then chloroform-acetone (9: 1)]
Thus, 0.1 g of the desired derivative 1 was obtained.

Example 3 (Synthesis of Derivatives 2 and 13) 3 ′, 5′-Di synthesized by the method described in Example 1
2.0 g of methoxybenzoxazinolifamycin in dimethyl
Dissolve in 15 ml of sulfoxide and add N-isobutylpiperazine 0.
Add 67 g and 0.5 g of manganese dioxide and stir at room temperature for 28 hours
Reacted. Then, add ethyl acetate to the reaction solution and dilute
Manganese dioxide is filtered off using a filter aid and the filtrate is filtered.
Next, it was washed with water and saturated saline. Then remove the solvent under reduced pressure
Remove and remove residue from Wako gel Silica gel using C-200
Column chromatography [Developing solvent: chloroform-
Acetone (95: 5)].
1 g was obtained. The solvent was removed from the eluate containing derivative 2 under reduced pressure.
The residue was crystallized from ethyl acetate-n-hexane.
As a result, 0.7 g of a desired derivative 2 was obtained.

Example 4 (Synthesis of 3'-ethoxybenzoxazinorifamycin) 15.51 g of 2-nitroresorcinol was dissolved in 200 ml of acetone, 8.02 ml of ethyl iodide was added dropwise over 1 hour while adding 13.82 of potassium carbonate and heating under reflux. .

After the completion of the dropwise addition, the mixture was heated under reflux for 17 hours. The reaction solution was allowed to cool to room temperature, and insolubles were removed by filtration, and the filtrate was distilled off under reduced pressure. Water was added to the residue, and the mixture was extracted with methylene chloride, and the methylene chloride layer was separated. The methylene chloride was removed under reduced pressure to obtain 7.8 g of a crude product of 2-nitroresorcinol monoethyl ether.

Dissolve 7.8 g of 2-nitroresorcinol monoethyl ether crude product obtained in the above method in 100 ml of ethanol,
1.0 g of 10% palladium carbon was added and hydrogenated at a hydrogen pressure of 5 kg / cm ² at room temperature for 6 hours. The catalyst was filtered off from the reaction solution, and the filtrate was distilled off under reduced pressure to obtain 6.1 g of a crude product of 2-aminoresorcinol monoethyl ether.

27.7 g of rifamycin S and 6.1 g of a crude product of 2-aminoresorcinol monoethyl ether obtained by the above method are dissolved in 500 ml of toluene, stirred at room temperature for 15 hours, and then stirred at 50 ° C for 2 hours.
After stirring for an hour, the solvent was distilled off under reduced pressure, the residue was dissolved in 350 ml of ethanol, 10 g of manganese dioxide was added, and the mixture was stirred at room temperature for 1 hour.
The mixture was stirred and reacted for hours.

Hereinafter, the treatment and purification were performed in substantially the same manner as in Example 1,
12.34 g of 3'-ethoxybenzoxazinolifamycin were obtained.

Thin layer chromatography Rf = 0.28 Red-purple spot [Carrier: silica gel, developing solvent: chloroform-acetone (9: 1)] Example 5 (Synthesis of derivative 3) 3′-ethoxy synthesized by the method described in Example 4 Dissolve 2.0 g of benzoxazinorifamycin in 15 ml of dimethyl sulfoxide and add 0.62 g of N-isopropylpiperazine
And 2.1 g of manganese dioxide were added and reacted with stirring at room temperature for 30 minutes.

 Thereafter, the same treatment as in Example 2 was performed and the residue was subjected to Wakogel. C
For silica gel column chromatography using -200
4 times [Developing solvent: chloroform-acetone (8: 2)
Twice with ethyl acetate, ethyl acetate-methanol (9:
1)] After purification, preparative thin-layer chromatography
Ricagel 60F₂₅₄(Manufactured by Merck), developing solvent: ethyl acetate
-Methanol (9: 1)] twice to give ethyl acetate-n.
0.45 g of the desired derivative 3 which was crystallized from a hexane system
Obtained.

Example 6 (Synthesis of Derivative 4) 2.0 g of 3'-ethoxybenzoxazinolifamycin synthesized by the method described in Example 4 was dissolved in 15 ml of dimethyl sulfoxide, and 0.7 g of N-isobutylpiperazine and 0.7 g of manganese dioxide were added. The reaction was stirred at room temperature for 13 hours.

 Thereafter, the treatment was carried out in substantially the same manner as in Example 3, and the residue was washed with wax.
-Gel Silica gel chromatography using C-200
[Developing solvent: chloroform-acetone (9:
1), ethyl acetate-n-hexane (1: 1), ethyl acetate-
n-hexane (2: 1)] to give the desired derivative 4
0.6 g was obtained.

Example 7 (Synthesis of Derivative 5) Instead of 0.62 g of N-isopropylpiperazine of Example 5, 0.75 g of N-isoamylpiperazine was used, and the others were reacted, treated and purified in the same manner. By crystallizing, 0.12 g of the desired derivative 5 was obtained.

Example 8 (Synthesis of 3'-propoxybenzoxazinolifamycin) Propyl iodide was used in place of 8.04 ml of ethyl iodide of Example 4.
Using 9.71 ml, the reaction and treatment were carried out in the same manner as above, to obtain 6.7 g of a crude product of 2-nitroresorcinol monopropyl ether.

Dissolve 6.7 g of 2-nitroresorcinol monopropyl ether crude product obtained in the above method in 90 ml of ethanol,
0.8 g of 10% palladium carbon was added, and the reaction was carried out in substantially the same manner as in Example 4 to obtain 4.31 g of a crude product of 2-aminoresorcinol monopropyl ether.

17.7 g of rifamycin S and 4.31 g of a crude product of 2-aminoresorcinol monopropyl ether obtained by the above method were dissolved in 300 ml of toluene, and reacted by stirring at room temperature for 22 hours.
The reaction solution was distilled off under reduced pressure, the residue was dissolved in 250 ml of ethanol, 8 g of manganese dioxide was added, and the mixture was stirred and reacted at room temperature for 30 minutes. Thereafter, treatment and purification were carried out in substantially the same manner as in Example 1 to obtain 10.7 g of 3'-propoxybenzoxazininorifamycin.
I got

Thin layer chromatography Rf = 0.30 Red-purple spot [Carrier: silica gel, developing solvent: chloroform-acetone (9: 1)] Example 9 (Synthesis of derivative 6) 3′-propoxy synthesized by the method described in Example 8 1.7 g of benzoxazinolifamycin was dissolved in 10 ml of dimethyl sulfoxide, and 0.44 ml of N-isobutylpiperazine was dissolved.
g and 0.6 g of manganese dioxide were added and stirred at room temperature for 16 hours. Thereafter, treatment and purification were conducted in substantially the same manner as in Example 6 to obtain 0.65 g of the desired derivative 6.

Example 10 (Synthesis of 3'-allyloxybenzoxazinolifamycin) Instead of 8.04 ml of ethyl iodide of Example 4, allyl bromide was used.
The reaction and treatment were conducted in the same manner as in Example 4 except that 46 ml was used.
g of 2-nitroresorcinol monoallyl ether crude product was obtained.

25 g of sodium dithionite was added to a suspension of 12.2 g of a crude product of 2-nitroresorcinol monoallyl ether obtained in the above manner in 500 ml of water, and the mixture was stirred and reacted at 80 ° C. for 30 minutes. Sodium was added and the mixture was stirred and reacted at 80 ° C. for 1 hour. The reaction was allowed to cool, brought to room temperature, neutralized with sodium bicarbonate and extracted with chloroform. Chloroform was distilled off under reduced pressure to obtain 12.8 g of a crude product of 2-aminoresorcinol monoallyl ether.

27.0 g of rifamycin S and 12.8 g of a crude product of 2-aminoresorcinol monoallyl ether obtained by the above method were dissolved in 500 ml of toluene, and reacted by stirring at room temperature for 15 hours. The reaction solution was distilled off under reduced pressure, the residue was dissolved in 400 ml of ethanol, 10 g of manganese dioxide was added, and the mixture was stirred and reacted at room temperature for 40 minutes. Thereafter, treatment and purification were conducted in substantially the same manner as in Example 1 to obtain 4.1 g of 3'-allyloxybenzoxazininorifamycin.
I got

Thin layer chromatography Rf value = 0.27 Red-purple spot [Carrier: silica gel, developed
Solvent: chloroform-acetone (9: 1)] Example 11 (Synthesis of Derivative 7)
2.0 g of xybenzoxazinolifamycin in dimethyl sulf
Dissolved in 15 ml of hydroxide and 0.51 g of N-isobutylpiperazine
And 1.0 g of manganese dioxide were added and stirred at room temperature for 70 minutes.
I let you. Thereafter, the same treatment as in Example 3 was performed, and the residue was subjected to Wakogel.
2 by silica gel chromatography using C-200
Times [Developing solvent: ethyl acetate, ethyl acetate-n-hexane]
(2: 1)] purification, then ethyl acetate-n-hexane
The crystals were recrystallized to obtain 1.3 g of the desired derivative 7.

Example 12 (Synthesis of 4'-ethoxybenzoxazinolifamycin) Using 2.87 g of 4-ethoxy-2-nitrophenol,
By the same operation as in Example 1, 1.62 g of 2-amino-4-ethoxyphenol was obtained.

After adding 6.96 g of rifamycin S and 1.62 g of 2-amino-4-ethoxyphenol to 200 ml of toluene and stirring at 60 ° C. for 31 hours, the solvent was distilled off from the reaction mixture under reduced pressure.
Dissolve the residue in ethanol 200ml 6.96g manganese dioxide
Was added and stirred at room temperature for 4.5 hours. The reaction mixture was filtered to remove insolubles, the solvent was distilled off under reduced pressure, and the residue obtained was subjected to silica gel column chromatography twice (developing solvent:
Chloroform-acetone (9: 1) and then chloroform-acetone (19: 1)] were purified to obtain 1.34 g of the desired 4'-ethoxybenzoxazininorifamycin.

Thin layer chromatography Rf = 0.29 Dark red spot [carrier: silica gel, developing solvent: chloroform-acetone (9: 1)] Example 13 (Synthesis of derivative 8) 4′-ethoxybenzoxazinori obtained in Example 12 Famycin (0.60 g) was dissolved in dimethyl sulfoxide (5 ml), and pyrrolidine (0.12 ml) and manganese dioxide (0.60 g) were added, followed by stirring at room temperature for 14.5 hours. Next, 70 ml of ethyl acetate was added to the reaction mixture, and insolubles were filtered off. The filtrate was washed three times with a dilute saline solution and once with a saturated saline solution, and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was subjected to silica gel column chromatography [developing solvent: ethyl acetate-n-hexane (1: 1)], and then crystallized from ethyl acetate to obtain the desired derivative 8. 0.22 g was obtained.

Example 14 (Synthesis of Derivative 9) Except that 0.14 ml of piperidine was used in place of pyrrolidine of Example 13, treatment and purification were carried out in the same manner as in Example 13 to obtain 0.26 g of the desired derivative 9.

Example 15 (Synthesis of derivative 10) 4'-ethoxy synthesized by the method described in Example 12
0.37 g of cibenzoxazinolifamycin in 5 ml of ethanol
In 0.13 g of N-isobutylpiperazine and
0.38 g of gangane was added, and the mixture was stirred and reacted at room temperature for 24 hours.
Next, the same treatment as in Example 3 was carried out, and the residue was subjected to Wako gel. C
Silica gel column chromatography using -200
3 times [Developing solvent: chloroform-acetone (9: 1),
Roloform-methanol (98: 2), then chloroform
-Ethyl acetate (2: 3)] to give the desired derivative 10
0.26 g was obtained.

Example 16 (Synthesis of 4'-propoxybenzoxazinolifamycin) 15.0 g of potassium carbonate and 10 ml of propyl iodide were added to a solution of 10.0 g of 4-propoxyphenol in 100 ml of N, N-dimethylformamide and reacted at room temperature for 3 days. I let it. The insolubles were removed by filtration, and the filtrate was distilled off under reduced pressure. Water was added to the residue, and the resulting crystals were collected by filtration and washed sequentially with water, dilute aqueous sodium hydroxide solution, dilute hydrochloric acid and water. Crystallized from hot ethanol-water, 1,4
-10 g of dipropoxybenzene were obtained. 10 g of the obtained 1,4-dipropoxybenzene was dissolved in 25 ml of acetic acid, and
% Nitric acid was slowly added, and the temperature was gradually raised to room temperature, followed by further reaction at room temperature for 1 hour. The reaction solution was poured into ice water, extracted twice with chloroform, and the solvent was distilled off under reduced pressure to obtain a crude product of 1,4-dipropoxy-2-nitrobenzene. The resulting 1,4-dipropoxy-2-nitrobenzene is converted to toluene 3
The mixture was dissolved in 0 ml, and 2.7 g of aluminum chloride was added, followed by a reaction at room temperature for 6 hours. The reaction solution was poured into ice water, adjusted to pH 1 to 2 with hydrochloric acid, and transferred with ether. After adding a dilute aqueous sodium hydroxide solution and extracting the aqueous layer to remove the organic layer, the aqueous layer was adjusted to pH 3 with hydrochloric acid and extracted with ether. The extract was dried over sodium sulfate and the solvent was distilled off to obtain 5.4 g of 2-nitro-4-propoxyphenol. 5.0 g of the obtained 2-nitro-4-propoxyphenol was added to a solution prepared by dissolving 41.2 g of sodium dithionite in 300 ml of water, and the mixture was heated and stirred at 60 to 75 ° C. until the yellow color of the aqueous solution disappeared. Sodium was added.
The reaction solution was neutralized with sodium hydrogen carbonate, saturated with sodium chloride, and extracted with ether. The extract was dried over sodium sulfate, and the solvent was distilled off. 2.5 g of 2-amino-4-propoxyphenol
I got

 Dissolve 6.96 g of rifamycin S in 100 ml of toluene.
2-amino-4-propoxyphenol 1.67 obtained above
The reaction was performed at room temperature for 3 days. The solvent is distilled off under reduced pressure.
Add 100 ml of ethanol and 8.8 g of manganese dioxide and stir for 30 minutes
Thereafter, manganese dioxide was filtered off, and the solvent was distilled off under reduced pressure. Remaining
Wako gel residue Silica gel column using C-200
Chromatography [Developing solvent: chloroform-acetone
(9: 1)] and the desired 4'-propoxybenzo
0.34 g of xazinorifamycin was obtained.

Thin layer chromatography Rf = 0.32 Infrared spot [Carrier: silica gel, developing solution
Medium: chloroform-acetone (9: 1)] Example 17 (Synthesis of Derivative 11) 4′-propo synthesized according to the method described in Example 16
0.34 g of xybenzoxazinolifamycin in dimethyls
Dissolved in 5 ml of rufoxide and 230 mg of N-isobutylpiperazine
And manganese dioxide (0.35 g) were added and stirred at room temperature for 3 days.
I let you. Ethyl acetate was added to the reaction solution, and manganese dioxide was filtered off.
The filtrate is washed three times with a saturated saline solution, and the organic layer is washed with sodium sulfate.
And the solvent was distilled off under reduced pressure. Wako gel for residue
Silica gel column chromatography using C-200
[Developing solvent: chloroform-acetone (9: 1),
Chloroform-methanol (98: 2)]
Thin layer chromatography [silica gel 60 F₂₅₄(Mel
Developing solvent: chloroform-acetone (9:
1)] to obtain 0.05 g of the desired derivative 11.

Example 18 (Synthesis of 4'-butoxybenzoxazinolifamycin) In place of 10.0 g of 4-propoxyphenol in Example 16, 4
Using 10.0 g of butoxyphenol, 10 ml of butyl bromide instead of 10 ml of propyl iodide, and the other
This was treated to give 3.0 g of 2-amino-4-butoxyphenol. Then, 2-amino-4-propoxyphenol obtained above was replaced with 1.67 g of 2-amino-4-propoxyphenol in Example 16.
Using butoxyphenol (1.81 g), the other reaction, treatment and purification were carried out in the same manner to obtain 0.84 g of the desired 4'-butoxybenzoxazinolifamycin.

Thin layer chromatography Rf = 0.35 Red-purple spot [Carrier: silica gel, developing solvent: chloroform-acetone (9: 1)] Example 19 (Synthesis of Derivative 12) 4′-Propoxybenzoxazininorifamycin 0.34 of Example 17 4'-butoxybenzoxazinolinifamicin 0.84 synthesized by the method described in Example 18 in place of g
g, N-isobutylpiperazine and manganese dioxide were used in 0.56 g and 0.85 g, respectively, and the others were reacted, treated and purified in the same manner to obtain 0.03 g of the desired derivative 12.

Example 20 (Synthesis of 5'-ethoxybenzoxazinolifamycin
Dissolve 25.2 ml of 3-ethoxyphenol in 300 ml of ether
Thaw, add 150 ml of water and then add 20 ml of 61% nitric acid under ice-cooling.
The mixture was added slowly and reacted at room temperature for 1 hour. Take the organic layer
Wash with water, aqueous sodium bicarbonate and saturated saline nitric acid
It was dried over sodium and the solvent was distilled off. Wakoge residue
Le Silica gel column chromatography using C-200
Purification twice (developing solvent: chloroform)
10.1 g of xy-2-nitrophenol was obtained. 5 obtained
3.7 g of ethoxy-2-nitrophenol in methanol 20
Dissolve in 0 ml, add 0.3 g of 10% palladium on carbon, and add hydrogen pressure of 5 kg
/cm^TwoFor 2 hours. After filtering off the catalyst,
The solvent was distilled off to give 2-amino-5-ethoxyphenol.
0 g was obtained.

 Dissolve 13.9 g of rifamycin S in 200 ml of toluene.
3.0 g of 2-amino-5-ethoxyphenol obtained above was added.
The reaction was carried out at room temperature for 3 days. The solvent is distilled off under reduced pressure and the ethanol
Add 200 ml of ethanol and 17.5 g of manganese dioxide for 30 minutes at room temperature
After stirring, manganese dioxide was filtered off and the solvent was distilled off under reduced pressure.
Was. Wako gel for residue Silica gel using C-200
Two times by column chromatography [Developing solvent: chloroform
M-acetone (9: 1), chloroform-methanol (99:
1)] Purified 5'-ethoxybenzoxazino
1.6 g of rifamycin was obtained.

Thin layer chromatography Rf = 0.36 reddish brown spot [Carrier: silica gel, developing solution
Medium: chloroform-acetone (9: 1)] Example 21 (Synthesis of Derivative 14) 5′-ethoxy synthesized by the method described in Example 20
1.6 g of cibenzoxazinolifamycin in dimethyl sulfo
Dissolved in 10 ml of oxide and 0.28 g of N-isobutylpiperazine
1.7 g of manganese dioxide was added and reacted with stirring for one week. That
During this time, add 0.83 g of N-isobutylpiperazine in three
Added. Ethyl acetate was added to the reaction solution, and manganese dioxide was filtered off.
Separately, the filtrate was washed three times with saturated saline, and the organic layer was washed with sodium nitrate.
It was dried over lithium and the solvent was distilled off under reduced pressure. Waco the residue
-Gel Silica gel column chromatography using C-200
Raffy three times [Developing solvent: chloroform-ethyl acetate
(2: 1), (1: 1), (3: 2)], followed by YMC-Pack
 High speed preparative liquid using S-343 I-15ODS [Yamazen Co., Ltd.]
Chromatography twice [Developing solvent: methanol]
And crystallized from ether-n-hexane system.
Thus, 0.22 g of derivative 14 was obtained.

Example 22 Synthesis of (6'-methoxybenzoxazinolifamycin
1) 2-methoxyphenol 15.0g in ether-water two layers
Dissolve in the system, add 12.7 ml of 61% nitric acid dropwise, and stir at room temperature for 15 minutes.
The mixture was stirred and reacted. Separate the ether layer and dry with anhydrous sodium sulfate.
Dried. The drying agent is filtered off and the solvent is removed under reduced pressure.
Was. Wako gel for residue Silica gel using C-200
Ram chromatography [Developing solvent: chloroform-n
-Hexane (1: 1)] to give 2-methoxy-6.
4.72 g of nitrophenol were obtained.

4.72 g of 2-methoxy-6-nitrophenol in 100 m of water
l, 30 ml of methanol was suspended, 29.3 g of sodium dithionite was added, and the mixture was stirred at 60 ° C and reacted until a uniform colorless solution was obtained. Saturated saline was added to the reaction solution, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The drying agent was filtered off, the solvent was removed under reduced pressure, and 2-amino-6 was removed.
3.65 g of crude methoxyphenol product were obtained.

 Rifamycin S 18.65 g and the 2-amino obtained above
3.65 g of crude product of -6-methoxyphenol was dissolved in toluene 400
The mixture was dissolved in ml, stirred at room temperature for 12 days, and reacted. Unnecessary things
Was removed by filtration, and the solvent was removed from the filtrate under reduced pressure. Residue
Dissolve in 300 ml of ethanol and add 9.0 g of manganese dioxide
The reaction was stirred at room temperature for 7 hours. Using a filter aid, diacid
Manganese oxide was filtered off and the solvent was distilled off under reduced pressure. The residue
Kogel Silica gel column chromatography using C-200
[Development solvent: chloroform-methanol (9
9: 1)] and purify the desired 6'-methoxy
10.15 g of nnzoxazinorifamycin were obtained.

Thin layer chromatography Rf = 0.21 Dark brown spot [Carrier: silica gel, developing solution
Medium: chloroform-acetone (9: 1)] Example 23 (Synthesis of Derivative 15) 6′-Methoxy synthesized by the method described in Example 22
8.0 g of cibenzoxazinolifamycin in dimethyl sulfo
Dissolve in 30 ml of oxide, 0.46 ml of pyrrolidine and manganese dioxide
And 1.5 g of the reaction mixture was added, and the mixture was stirred and reacted at room temperature for 5 days. Then
Ethyl acetate was added to the reaction mixture to dilute it, and insolubles were removed by filtration.
The filtrate was washed successively with water and saturated saline, and dried over anhydrous sodium sulfate.
Dry with thorium. The drying agent is filtered off and the solvent is removed under reduced pressure.
Was removed. Wako gel for residue Silicate using C-200
Twice by Kagel column chromatography [Developing solvent: vinegar
Ethyl acid, then chloroform-methanol (99: 1)]
The product was purified and crystallized from ethyl acetate-n-hexane.
0.42 g of the target derivative 15 was obtained.

Example 24 (Synthesis of Derivative 16) 6.49 g of 6'-methoxybenzoxazinolifamycin synthesized by the method described in Example 22 was dissolved in 60 ml of dimethyl sulfoxide, and 3.0 g of manganese dioxide was added to 1.77 ml of N-methylpiperazine. Was added, and the mixture was stirred and reacted at room temperature for 24 hours. Thereafter, the same treatment as in Example 23 was carried out, purified twice by silica gel column chromatography [developing solvent: chloroform-methanol (95: 5)], and crystallized from a system of ethyl acetate-n-hexane. 0.56 g of derivative 16 was obtained.

Example 25 (Synthesis of Derivative 17) 5.0 g of 6'-methoxybenzoxazinorifamycin synthesized by the method described in Example 22 was dissolved in 50 ml of dimethyl sulfoxide, and 1.05 g of N-isobutylpiperazine was dissolved.
Was added with 2.5 g of manganese dioxide, and the mixture was stirred and reacted at room temperature for 4 days. Hereinafter, the same treatment, purification and crystallization as in Example 23,
0.70 g of the desired derivative 17 was obtained.

Example 26 (Synthesis of 6'-ethoxybenzoxazinolifamycin) Using 25.8 g of 2-ethoxyphenol, nitration was carried out in the same manner as in Example 22, and reduced to give 2-amino-6-aminophenol.
10.9 g of a crude product of ethoxyphenol was obtained.

Rifamycin S (49.5 g) and 2-amino-6 obtained above
10.9 g of a crude product of ethoxyphenol was dissolved in toluene 1 and reacted with stirring at room temperature for 18 days. The insolubles were removed by filtration, and the solvent was removed under reduced pressure. 300 ml of ethanol residue
And 15.0 g of manganese dioxide was added, followed by stirring at room temperature for 24 hours. Using a filter aid, manganese dioxide was filtered off, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: chloroform-methanol (99: 1)). Crystallization from the n-hexane system gave 35.6 g of the desired 6'-ethoxybenzoxazininorifamycin.

Thin layer chromatography Rf = 0.52 g dark red spot [Carrier: silica gel, developing solvent: chloroform-acetone (7: 3)] Example 27 (Synthesis of derivative 18) 6′-ethoxybenzoxazinori obtained in Example 26 Dissolve 5.0 g of famycin in 50 ml of dimethyl sulfoxide, 0.92 ml of trimethylethylenediamine and 2.5 g of manganese dioxide
Was added and the mixture was stirred and reacted at room temperature for 2 days. Hereinafter, Example 24
Treatment, purification and crystallization were performed in the same manner as described above.
40 g were obtained.

Example 28 (Synthesis of Derivative 19) 3.24 g of 6'-ethoxybenzoxazinorifamycin obtained in Example 26 was dissolved in 30 ml of dimethyl sulfoxide.
0.65 ml of pyrrolidine and 1.5 g of manganese dioxide were added and reacted at room temperature with stirring for 24 hours. Thereafter, the same treatment as in Example 23 was carried out to obtain 0.89 g of the desired derivative 19.

Example 29 (Synthesis of Derivative 20) 5.0 g of 6′-ethoxybenzoxazinolifamycin obtained in Example 26 was dissolved in 50 ml of dimethyl sulfoxide, and
-0.76 g of dimethylaminopyrrolidine and manganese dioxide were added, and the mixture was stirred and reacted at room temperature for 24 hours. Hereinafter, Example 24
The same treatment, purification, and crystallization were performed to obtain the desired derivative 20 in 0.
60 g was obtained.

Example 30 (Synthesis of Derivative 21) 3.0 g of 6'-ethoxybenzoxazinolinifamycin obtained in Example 26 was dissolved in 30 ml of dimethyl sulfoxide,
-Methylpiperazine (0.48 ml) and manganese dioxide (1.5 g) were added, and the mixture was stirred and reacted at room temperature for 24 hours. Hereinafter, the same treatment as in Example 24, purification, crystallization, 0.51 g of the desired derivative 21
I got

Example 31 (Synthesis of derivative 22) 5.0 g of 6'-ethoxybenzoxazinolifamycin obtained in Example 26 was dissolved in 50 ml of dimethyl sulfoxide, and
-Ethyl piperazine (0.84 ml) and manganese dioxide (2.5 g) were added, and the mixture was stirred and reacted at room temperature for 24 hours. Thereafter, the same treatment as in Example 23 was carried out, and the mixture was subjected to silica gel column chromatography for 2 hours.
[Developing solvent: chloroform-methanol (98: 2)], and crystallized from ethyl acetate-n-hexane to give 1.40 g of the desired derivative 22.

Example 32 (Synthesis of derivative 23) 4.0 g of 6'-ethoxybenzoxazinolifamycin obtained in Example 26 was dissolved in 40 ml of dimethyl sulfoxide, and
-0.72 g of isopropyl piperazine and 2.0 g of manganese dioxide
Was added and the mixture was stirred and reacted at room temperature for 6 days. Hereinafter, Example 23
And developed by silica gel column chromatography three times [eluent: chloroform-methanol (97:
3)] Purification and crystallization from an ethyl acetate-n-hexane system gave 0.17 g of the desired derivative 23.

Example 33 (Synthesis of Derivative 24) 5.0 g of 6'-ethoxybenzoxazinolifamycin obtained in Example 26 was dissolved in 50 ml of dimethyl sulfoxide, and
1.0 g of isobutylpiperazine and 2.5 g of manganese dioxide were added, and the mixture was stirred and reacted at room temperature for 3 hours. Thereafter, the same treatment as in Example 23 was carried out to obtain 0.74 g of the target derivative 24.

Example 34 (Synthesis of Derivative 25) 3.26 g of 6'-ethoxybenzoxazinorifamycin obtained in Example 26 was dissolved in 30 ml of dimethyl sulfoxide.
0.66 g of N-cyclopropylmethylpiperazine and 1.6 g of manganese dioxide were added, and the mixture was stirred and reacted at room temperature for 3 days. Thereafter, the same treatment, purification and crystallization as in Example 31 were performed to obtain 0.50 g of the desired derivative 25.

Example 35 (Synthesis of Derivative 26) 5.0 g of 6'-ethoxybenzoxazinolifamycin obtained in Example 26 was dissolved in 50 ml of dimethyl sulfoxide,
1.11 g of-(3-methyl-2-butenyl) piperazine and 2.5 g of manganese dioxide were added, and the mixture was stirred and reacted at room temperature for 24 hours. Thereafter, treatment, purification and crystallization were carried out in the same manner as in Example 31 to obtain 1.08 g of the desired derivative 26.

Example 36 (Synthesis of Derivative 27) 5.0 g of 6'-ethoxybenzoxazinolinifamicin obtained in Example 26 was dissolved in 50 ml of dimethyl sulfoxide, and N
1.04 g of-(2-methoxyethyl) piperazine and 2.5 g of manganese dioxide were added, and the mixture was stirred and reacted at room temperature for 3 days.
Thereafter, treatment, purification and crystallization were carried out in the same manner as in Example 31 to obtain 0.85 g of the desired derivative 27.

Example 37 (Synthesis of 6'-n-propoxybenzoxazinolifamycin) Example 2 was carried out using 20.0 g of 2-n-propoxyphenol.
Nitration and reduction were carried out in the same manner as in 2, to obtain 10.6 g of crude 2-amino-6-n-propoxyphenol.

Rifamycin S (44.2 g) and 2-amino-6 obtained above.
10.6 g of a crude product of -n-propoxyphenol was dissolved in 800 ml of toluene, and reacted at room temperature with stirring for 12 days.
The insolubles were removed by filtration, and the solvent was removed under reduced pressure. The residue was dissolved in ethanol (500 ml), manganese dioxide (20.0 g) was added, and the mixture was stirred at room temperature for 24 hours. Using a filter aid, manganese dioxide was filtered off, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [eluent: chloroform-methanol (99: 1)].
Crystallization from the -hexane system gave 22.1 g of the desired 6'-n-propoxybenzoxazinolinifamicin.

Thin layer chromatography Rf = 0.50 Dark red spot [Carrier: silica gel, developing solvent: chloroform-acetone (7: 3)] Example 38 (Synthesis of derivative 28) 6′-n-propoxybenzoxa obtained in Example 37 5.0 g of dinorifamycin was dissolved in 50 ml of dimethyl sulfoxide, 0.74 ml of pyrrolidine and 2.5 g of manganese dioxide were added, and the mixture was stirred and reacted at room temperature for 3 days. Thereafter, the same treatment, purification and crystallization as in Example 23 were carried out to obtain 1.19 g of the desired derivative 28.

Example 39 (Synthesis of Derivative 29) 5.0 g of 6'-n-propoxybenzoxazinorifamycin obtained in Example 37 was dissolved in 50 ml of dimethyl sulfoxide, and 1.01 g of N-isobutylpiperazine and manganese dioxide were dissolved.
2.5 g was added, and the mixture was stirred and reacted at room temperature for 24 hours. Hereinafter, the same treatment, purification and crystallization as in Example 23, the desired derivative
0.97 g of 29 was obtained.

Example 40 (Synthesis of 6'-isopropoxybenzoxazinolifamycin) Example 2 was carried out using 24.8 g of 2-isopropoxyphenol.
Nitration and reduction were carried out in the same manner as in 2, to obtain 16.0 g of crude 2-amino-6-isopropoxyphenol.

66.7 g of rifamycin S and 2-amino-6 obtained above
16.0 g of crude isopropoxyphenol was added to toluene 1
And reacted with stirring at room temperature for 13 days. The insolubles were removed by filtration, and the solvent was removed under reduced pressure. Residue is 700m ethanol
The mixture was dissolved in l, manganese dioxide (30 g) was added, and the mixture was stirred at room temperature for 24 hours. Using a filter aid, filter manganese dioxide,
The solvent was distilled off under reduced pressure. The residue was purified twice by silica gel column chromatography [developing solvent: chloroform-methanol (99: 1)] to obtain 25.9 g of the desired 6'-isopropoxybenzoxazininorifamycin.

Thin layer chromatography Rf = 0.49 Dark red spot [Carrier: silica gel, developing solvent: chloroform-acetone (7: 3)] Example 41 (Synthesis of Derivative 30) 6′-Isopropoxybenzoxazinori obtained in Example 40 Dissolve 5.0 g of famycin in 50 ml of dimethyl sulfoxide, add 0.59 ml of pyrrolidine and 2.5 g of manganese dioxide,
The mixture was stirred and reacted at room temperature for 24 hours. Thereafter, treatment, purification and crystallization were carried out in the same manner as in Example 23 to obtain 1.68 g of the desired derivative 30.

Example 42 (Synthesis of derivative 31) 5.0 g of 6'-isopropoxybenzoxazinolifamycin obtained in Example 40 was dissolved in 50 ml of dimethyl sulfoxide, and 0.90 ml of N-ethylpiperazine and 2.5 g of manganese dioxide were dissolved.
Was added and the mixture was stirred and reacted at room temperature for 2 days. Examples below
Process, purify and crystallize in the same manner as 32 to obtain the desired derivative 31
1.57 g was obtained.

Example 43 (Synthesis of Derivative 32) 5.0 g of 6'-isopropoxybenzoxazinolinifamycin obtained in Example 40 was dissolved in 50 ml of dimethyl sulfoxide, and 1.01 g of N-isobutylpiperazine and 2.5 g of manganese dioxide were added. The mixture was stirred and reacted at room temperature for 7 hours. Less than,
The same treatment, purification and crystallization as in Example 23 were performed to obtain 1.29 g of the desired derivative 32.

Example 44 (Synthesis of 6'-isobutoxybenzoxazinolifamycin) Example 1 was carried out using 20.0 g of 2-isobutoxyphenol.
Nitrate and reduce 2-amino-
7.5 g of crude 6-isobutoxyphenol was obtained.

29.3 g of rifamycin S and 2-amino-6 obtained above
7.5 g of crude isobutoxyphenol product in 600 ml of toluene
And reacted at room temperature with stirring for 7 days. The insolubles were removed by filtration, and the solvent was removed under reduced pressure. Residue is 300m ethanol
Then, 15.0 g of manganese dioxide was added, and the mixture was stirred at room temperature for 24 hours. Using a filter aid, filter manganese dioxide,
The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [eluent: chloroform-methanol (99: 1)] to give 9.88 g of the desired 6'-isobutoxybenzoxazinolifamycin.

Thin layer chromatography Rf = 0.59 dark red spot [carrier: silica gel, developing solvent: ethyl acetate] Example 45 (Synthesis of derivative 33) 6'-isobutoxybenzoxazininorifamycin synthesized by the method described in Example 44 5.0 g was dissolved in 50 ml of dimethyl sulfoxide, and N-isobutylpiperazine 1.
0 g and manganese dioxide (2.5 g) were added, and the mixture was stirred and reacted at room temperature for 2 days. Thereafter, treatment, purification and crystallization were carried out in the same manner as in Example 23 to obtain 0.84 g of the desired derivative 33.

Example 46 (Synthesis of 6'-methoxy-3'-methylbenzoxazinolifamycin) Using 10.0 g of 2-methoxy-5-methylphenol,
Nitration and reduction were performed in the same manner as in Example 22 to give 2
-Amino-3-methyl-6-methylphenol crude product
2.6 g were obtained.

Rifamycin S (11.8 g) and 2-amino-3- obtained above
2.6 g of a crude product of methyl-6-methoxyphenol was dissolved in 250 ml of toluene, and stirred and reacted at room temperature for 14 days. The insoluble material was separated by filtration, and the solvent was removed under reduced pressure. The residue was dissolved in ethanol (250 ml), manganese dioxide (6.0 g) was added, and the mixture was stirred at room temperature for 1 hour. Manganese dioxide was filtered off using a filter aid, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [developing solvent: chloroform-methanol (99: 1)], and 6.3 g of desired 6'-methoxy-3'-methylbenzoxazinolifamycin was obtained.
I got

Thin layer chromatography Rf = 0.50 dark red spot [carrier: silica gel, developing solvent: chloroform-acetone (7: 3)] Example 47 (Synthesis of derivative 34) 6′-methoxy-3′- obtained in Example 46 3.0 g of methylbenzoxazinolifamycin in dimethyl sulfoxide 30
Then, 0.6 ml of pyrrolidine and 1.5 g of manganese dioxide were added, and the mixture was stirred and reacted at room temperature for 5.5 hours. Hereinafter, Example 23
The same treatment, purification and crystallization as in were carried out to obtain 0.56 g of the desired derivative 34.

Example 48 (Synthesis of Derivative 35) 3.0 g of 6'-methoxy-3'-methylbenzoxazinolifamycin obtained in Example 46 was added to dimethyl sulfoxide 30.
Then, 0.80 ml of N-methylpiperazine and 1.5 g of manganese dioxide were added, and the mixture was stirred and reacted at room temperature for 7 hours. Thereafter, the same treatment, purification and crystallization as in Example 24 were carried out to obtain 1.21 g of the desired derivative 35.

Example 49 (Synthesis of Derivative 36) 4.0 g of 6'-methoxy-3'-methylbenzoxazinolifamycin obtained in Example 46 was added to dimethyl sulfoxide 40.
Then, 1.37 g of N-isobutylpiperazine and 2.0 g of manganese dioxide were added, and the mixture was stirred and reacted at room temperature for 6 hours.
Thereafter, treatment, purification and crystallization were carried out in the same manner as in Example 23 to obtain 2.37 g of the desired derivative 36.

Example 50 (Synthesis of 6'-methoxy-4'-methylbenzoxazinolifamycin) Using 10.0 g of 2-methoxy-4-methylphenol,
Nitration and reduction as in Example 22 gave 2-amino-
5.9 g of crude 4-methyl-6-methoxyphenol was obtained.

26.8 g of rifamycin S and 2-amino-4 obtained above
5.9 g of a crude product of -methyl-6-methoxyphenol was dissolved in 550 ml of toluene, and reacted at room temperature for 6 days with stirring.
The insoluble material was separated by filtration, and the solvent was removed under reduced pressure. The residue was dissolved in 300 ml of ethanol, 13.0 g of manganese dioxide was added, and the mixture was stirred at room temperature for 7 hours. Using a filter aid, manganese dioxide was filtered off, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (developing solvent: chloroform-methanol (99: 1)) to obtain the desired 6 '
7.8 g of -methoxy-4'-methylbenzoxazinolifamycin were obtained.

Thin layer chromatography Rf = 0.49 Dark brown spot [carrier: silica gel, developing solvent: chloroform-acetone (7: 3)] Example 51 (Synthesis of Derivative 37) 6′-Methoxy-4′- obtained in Example 46 3.0 g of methylbenzoxazinolifamycin in dimethyl sulfoxide 30
Then, 0.6 ml of pyrrolidine and 1.5 g of manganese dioxide were added, and the mixture was stirred and reacted at room temperature for 2 days. Hereinafter, Example 23
In the same manner as above, 0.15 g of the desired derivative 37 was obtained.

Example 52 (Synthesis of 4′-methylthiobenzoxazinolifamycin) 1.7 g of 2-amino-4- (methylthio) phenol was obtained in the same manner as in Example 1 using 2.75 g of 4-methylthio-2-nitrophenol. Obtained.

 5.57 g of rifamycin and 2-amino acid in 100 ml of toluene
Add 1.24 g of -4- (methylthio) phenol and add room temperature
For 70 hours. The solvent is distilled off from the reaction mixture under reduced pressure.
After removal, the residue is dissolved in 60 ml of ethanol and
Stir for 12 hours. Then, the solvent was distilled off under reduced pressure, and the residue was washed with water.
Kogel Silica gel column chromatography using C-200
[Development solvent: chloroform-acetone (9:
1)] and then crystallized from ethyl acetate-n-hexane.
4'-Methylthiobenzoxazinolinif
2.8 g of crude amycin product was obtained.

Thin layer chromatography Rf = 0.34 dark brown spot [carrier: silica gel, developing solvent: chloroform-acetone (9: 1)] Example 53 (Synthesis of derivative 38) 4′-methylthio synthesized by the method described in Example 52 0.40 g of a crude product of benzoxazinolifamycin was dissolved in 4 ml of ethanol, and 0.08 ml of pyrrolidine and 0.4 g of manganese dioxide were added thereto, and the mixture was stirred and reacted at room temperature for 25 hours. Thereafter, the same treatment as in Example 23 was carried out to obtain 0.22 g of the desired derivative 38.

Example 54 (Synthesis of derivative 39) 4'-methyl synthesized by the method described in Example 52
2.77 g of crude product of thiobenzoxazinolifamycin
Dissolve in ethanol (15 ml) and add N-isobutylpiperazine (0.1%).
Add 95 g and 2.9 g of manganese dioxide and stir at room temperature for 70 hours.
I responded. Next, the same treatment as in Example 3 was performed, and the residue was washed with wax.
-Gel Silica gel column chromatography using C-200
4 times with Raffy [Developing solvent: chloroform-acetone
(9: 1), chloroform-methanol (98: 2), chloro
Form-ethyl acetate (2: 3), then chloroform-vinegar
Ethyl acid-methanol (15: 10: 1)]
Crystallization from roloform-n-hexane and desired induction
0.96 g of body 39 was obtained.

Example 55 Synthesis of (4'-ethylthiobenzoxazinolifamycin
1) 4-hydroxythiophenol in methylene chloride
Dissolve in 0 ml, and iodide with 20 ml of triethylamine under ice-cooling
Ethyl (11 ml) was added and reacted at room temperature overnight. Concentrate the reaction solution
Then, ether was added and the resulting insolubles were filtered off and the solvent was distilled off.
did. Wako gel for residue Silica gel using C-200
Column chromatography [Developing solvent: chloroform]
Then, 11 g of 4- (ethylthio) phenol was obtained.
6.2 g of the obtained 4- (ethylthio) phenol was etherified
Dissolve in 200 ml, add 60 ml of water, then slowly add 3.9 ml of 61% nitric acid
Added to each. After stirring at room temperature for 1 hour, the aqueous layer was saturated with sodium chloride.
The organic layer was separated. Dry the organic layer over sodium sulfate and dissolve
The medium was distilled off. Wako gel for residue Using C-200
Ricagel column chromatography [Developing solvent: chloro
Form) and purified with 4-ethylthio-2-nitrophenol.
I got This 4-ethylthio-2-nitrophenol
1.3 g was dissolved in 30 ml of methanol, and 10% palladium on carbon 10
Add 0ml and hydrogen pressure 4kg / cm^TwoHydrogenation reaction for 3 days
Was. The catalyst was filtered off and the solvent was distilled off under reduced pressure to give 2-amino-
1.1 g of 4- (ethylthio) phenol were obtained.

 To a solution of rifamycin S4.1 g in 50 ml of triene
2-amino-4- (ethylthio) pheno thus obtained
1.0 was added and the mixture was stirred and reacted at room temperature for 2 days. Reduce solvent
Evaporate under reduced pressure, add 100 ml of ethanol and stir at room temperature for 2 days.
Stirred. The solvent is distilled off under reduced pressure, and the residue is C
Silica gel column chromatography using -200
Purified with [Developing solvent: chloroform-acetone (10: 1)]
4'-Methylthiobenzoxazino lipama
2.3 g of isin was obtained.

Thin layer chromatography Rf = 0.29 brown spot [Carrier: silica gel, developing solution
Medium: chloroform-acetone (10: 1)] Example 56 (Synthesis of Derivative 40) 4′-ethyl synthesized by the method described in Example 55
2.3 g of thiobenzoxazinolifamycin in dimethyl sulf
Dissolved in 15 ml of hydroxide and N-isobutylpiperazine 0.77
g and 2.4 g of manganese dioxide were added and reacted for 3 days. Less than
Treated in the same manner as in Example 2 below, and the residue was C-20
3 times with silica gel column chromatography using 0
[Developing solvent: chloroform-acetone (9: 1) twice,
Chloroform-methanol (99: 1)] purified and ethyl acetate
Derivative 40 which is crystallized from -n-hexane system
0.44 g was obtained.

Example 57 (Synthesis of 4'-acetylbenzoxazinolifamycin) 5.08 g of p-hydroxyacetophenone was dissolved in 40 ml of acetic acid, cooled with ice, and added with 5.7 ml of 61% nitric acid (specific gravity 1.38).
Stirred for minutes. Then, the mixture was returned to room temperature and further stirred for 50 minutes, and 200 ml of water was added. The resulting precipitate was collected by filtration and washed with water.
The precipitate was recrystallized twice from ethanol to obtain 2.59 g of 4-hydroxy-3-nitroacetophenone.

This 4-hydroxy-3-nitroacetophenone 1.15
g in 100 ml of ethanol and 5% palladium on carbon 0.05
6 g was added, and hydrogen was bubbled at normal temperature and normal pressure for 11 hours. The reaction mixture was filtered, the solvent was distilled off from the filtrate under reduced pressure, and the obtained residue was crystallized from water to obtain 0.73 g of 3-amino-4-hydroxyacetophenone.

2.78 g of rifamycin S and 0.56 g of 3-amino-4-hydroxyacetophenone were added to 80 ml of toluene, and
Stirred at C for 3 hours. After the solvent was distilled off from the reaction mixture under reduced pressure, the residue was dissolved in 80 ml of ethanol, 2.78 g of manganese dioxide was added, and the mixture was stirred at room temperature for 2 days. The reaction mixture was filtered to remove insolubles, and the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography [developing solvent:
Chloroform-acetone (9: 1)] to purify the desired 4'-acetylbenzoxazinolifamycin 2.
01g was obtained.

Thin layer chromatography Rf = 0.39 Red-purple spot [Carrier: silica gel, developing solvent: butyl acetate] Example 58 (Synthesis of Derivative 41) 4'-acetylbenzoxazininorifamicin 1.00 synthesized by the method described in Example 57 g was dissolved in 10 ml of dimethyl sulfoxide, 0.4 ml of pyrrolidine and 1.00 g of manganese dioxide were added, and the mixture was stirred and reacted at room temperature for 53 hours. Thereafter, the same treatment as in Example 23 was carried out to obtain 0.02 g of the desired derivative 41.

Example 59 (Synthesis of 4 '-(3-oxobutyl) benzoxazinolifamycin) 1- (p-hydroxyphenyl) -3-butanone 10.0 was suspended in 50 ml of water, and 9.1 ml of 61% nitric acid was cooled on ice. Was added dropwise, and the mixture was returned to room temperature and stirred and reacted for 2 hours. The reaction solution was extracted with 200 ml of ethyl acetate, washed with water and saturated saline, and dried over anhydrous sodium sulfate. The desiccant is filtered off,
The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [developing solvent: chloroform].
8.09 g of 1- (4-hydroxy-3-nitrophenyl) -3-butanone was obtained.

1- (4-hydroxy-3-nitrophenyl) -3-
8.09 g of butanone was dissolved in 320 ml of ethanol, 0.8 g of 10% palladium carbon was added, and hydrogen was introduced at normal pressure and room temperature for 5 hours. The catalyst was filtered off using a filter aid, and the solvent was distilled off under reduced pressure to give 1- (3-amino-4-hydroxyphenyl) -3.
7.01 g of crude butanone were obtained.

22.95 g of rifamycin S and crude 1- (3-amino-4-hydroxyphenyl) -3-butanone obtained above
7.01 g was dissolved in 450 ml of toluene, and stirred and reacted at room temperature for 24 hours. Thereafter, the same treatment as in Example 4 was carried out to obtain 5.11 g of the objective 4 '-(3-oxobutyl) benzoxazinolifamycin.

Thin layer chromatography Rf = 0.39 Red-purple spot [Carrier: silica gel, developing solvent: chloroform-acetone (9: 1)] Example 60 (Synthesis of Derivative 42) 4 ′-(Synthesized according to the method described in Example 59) 3
-Oxobutyl) benzoxazinolifamycin (1.0 g) was dissolved in dimethyl sulfoxide (10 ml), and pyrrolidine (0.20 ml) was dissolved.
And 1.0 g of manganese dioxide were added and reacted at room temperature for 4 hours with stirring. Thereafter, the same treatment and purification were carried out as in Example 23 to obtain 0.07 g of the desired derivative 42.

Example 61 Synthesis of (6′-fluorobenzoxazinolifamycin
2) 2-Fluorophenol 25.2g ether-water bilayer
Dissolve in the system, add 20.5 ml of 61% nitric acid, and stir at room temperature for 2.5 hours.
The mixture was stirred and reacted. Separate the ether layer and add anhydrous sodium nitrate.
Dried. The drying agent is filtered off and the solvent is removed under reduced pressure.
Was. Wako gel for residue Silica gel using C-200
Ram chromatography [Developing solvent: chloroform-n
-Hexane (1: 1)] to give 2-fluoro-6
13.7 g of nitrophenol were obtained.

13.7 g of 2-fluoro-6-nitrophenol in 200 m of water
l, suspended in a mixture of 100 ml of ethanol, added with 60.7 g of sodium dithionite, stirred at 60 ° C, and reacted with stirring until a uniform colorless solution was obtained. Saturated saline was added to the reaction solution, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The drying agent was separated by filtration, and the solvent was removed under reduced pressure to obtain 8.6 g of a crude product of 2-amino-6-fluorophenol.

Rifamycin S (47.2 g) and 2-amino-6 obtained above
8.6 g of crude fluorophenol was dissolved in toluene 1 and stirred at room temperature for 6 days to react. The insolubles were removed by filtration, and the solvent was removed from the filtrate under reduced pressure. The residue was dissolved in 400 ml of ethanol, 20.0 g of manganese dioxide was added, and the mixture was stirred and reacted at room temperature for 24 hours. Using a filter aid, manganese dioxide was filtered off, insolubles were eluted with acetone, and the solvent was distilled off from the combined filtrate under reduced pressure. Crystallization from ethanol yielded 26.7 g of the desired 6'-fluorobenzoxazinolifamycin.

Thin layer chromatography Rf = 0.52 red spot [Carrier: silica gel, developing solution
Medium: ethyl acetate] Example 62 (Synthesis of Derivative 43) 6′-Fluoro synthesized by the method described in Example 61
5.0 g of robenzoxazinolifamycin in dimethyl sulfo
Dissolved in 50 ml of oxide and 1.1 g of N-isobutylpiperazine.
Add 2.5 g of manganese dioxide, and stir at room temperature for 24 hours.
I let you. Then, the reaction solution was diluted by adding ethyl acetate,
The solution was filtered off, and the filtrate was washed successively with water and saturated saline.
The organic layer was dried with anhydrous sodium sulfate. Filtration of desiccant
Then, the solvent was removed under reduced pressure. Wako gel for residue C-
Silica gel column chromatography using 200
Times [Developing solvent: chloroform-methanol (99: 1)]
And crystallized from ethyl acetate-n-hexane.
3.43 g of the derivative 43 was obtained.

Example 63 (Synthesis of 6'-chlorobenzoxazinorifamycin) 2.78 g of 2-chloro-6-nitrophenol and 6.00 g of sodium dithionite were added to 100 ml of water, and the mixture was stirred at 90 ° C for 30 minutes. Add 6.00 g of sodium dithionite and add 90
After stirring at 40 ° C. for another 40 minutes, the mixture was cooled to room temperature and neutralized with sodium hydrogen carbonate. The reaction mixture was extracted four times with ether (300 ml in total), the extract was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give 2-amino-6.
0.95 g of crude chlorophenol product was obtained.

Dissolve in 4.3 g of rifamycin S, 0.9 g of crude 2-amino-6-chlorophenol product and 70 ml of toluene, and add
The mixture was stirred and reacted for 9.5 hours. The reaction solvent is removed under reduced pressure,
The residue was dissolved in 70 ml of ethanol, 4.3 g of manganese dioxide was added, and the mixture was stirred and reacted at room temperature for 120 hours. Manganese dioxide was filtered off using a filter aid and the solvent was removed under reduced pressure.
Thereafter, the same treatment as in Example 52 was carried out to obtain 3.23 g of the desired 6'-chlorobenzoxazinolifamycin.

Thin layer chromatography Rf = 0.56 red-purple spot [carrier: silica gel, developing solvent: chloroform-acetone (7: 3)] Example 64 (Synthesis of derivative 44) 6′-chloro synthesized by the method described in Example 63 Dissolve 1.0 g of benzoxazinolifamycin in 10 ml of dimethyl sulfoxide, 0.2 ml of pyrrolidine and manganese dioxide
1.0 g, and the mixture was stirred and reacted at room temperature for 21 hours. Thereafter, the same treatment as in Example 23 was carried out to obtain 0.28 g of the desired derivative 44.

Example 65 (Synthesis of 4'-iodobenzoxazinolifamycin) 8.50 g of p-iodophenol was added to 50 ml of acetic acid, and 3.3 ml of 61% nitric acid (specific gravity 1.38) was added with stirring under ice-cooling. Stirred for minutes. A precipitate formed by adding 20 ml of water thereto was collected by filtration, washed with water, and air-dried. The obtained crude product was crystallized from carbon tetrachloride to give 4-iodo-2-nitrophenol 3.
00g was obtained. This was added to a mixture of 70 ml of water and 20 ml of ethanol, and 4.24 g of sodium dithionite was added.
Stirred for minutes. After adding 4.24 g of sodium dithionite, the mixture was further stirred at 80 ° C. for 40 minutes, cooled to room temperature, and neutralized by adding sodium hydrogen carbonate. The reaction mixture was extracted five times with ethyl acetate (250 ml in total), and the extract was dried over anhydrous sodium sulfate. The solvent of the extract was distilled off under reduced pressure to give a crude product of 2-amino-4-iodophenol 0.82.
g was obtained.

This 2-amino-4-iodophenol crude product 0.82
g and rifamycin S2.43 g are added to 70 ml of toluene to give 60
Stirred at 2 ° C. for 24.5 hours. After the solvent was distilled off from the reaction mixture under reduced pressure, the residue was dissolved in 70 ml of methanol, 2.43 g of manganese dioxide was added, and the mixture was stirred at room temperature overnight. The insoluble material was separated by filtration from the reaction mixture, and the residue obtained by evaporating the solvent under reduced pressure was purified twice by silica gel column chromatography [developing solvent: chloroform-acetone (9: 1),
Then, ethyl acetate-n-hexane (1: 1)] was carried out to give the desired 4'-iodobenzoxazino rifamycin.
0.71 g was obtained.

Thin layer chromatography Rf = 0.43 purple spot [carrier: silica gel, developing solvent: ethyl acetate-n-hexane (1: 1)] Example 66 (Synthesis of derivative 45) 4′-iodobenzoxa obtained in Example 65 Dinorifamycin 0.39 g, pyrrolidine 0.07 ml, manganese dioxide 0.39 g
And 5 ml of dimethyl sulfoxide, and
By the same operation as described above, 0.21 g of the desired derivative 45 was obtained.

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

[Brief description of the drawings]

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

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁶ Identification code FI C07D 307: 00) (72) Inventor Kazunori Hosoe 3- 8-5 Nishihata, Takasago City, Hyogo Prefecture (72) Inventor Fumiyuki Kuze Kyoto, Kyoto Prefecture 467-1 Shimogamo-Takagicho, Sakyo-ku, City 803 Jyo Shimogamo 803 (72) Inventor Kiyoshi Watanabe 5-15-41, Matsugaoka, Akashi-shi, Hyogo (56) References JP-A-64-6279 (JP, A) 64-6281 (JP, A) JP-A-63-30490 (JP, A) (58) Fields investigated (Int. Cl. ⁶ , DB name) C07D 498/18 A61K 31/535 CA (STN) REGISTRY (STN )

Claims (12)

(57) [Claims] (1) Formula (I): Ａwhere A is (Wherein R ¹ and R ² are the same or different and have 1 to 1 carbon atoms)
An alkylalkyl group having 3 to 3 carbon atoms, an aminoalkyl group having 2 to 6 carbon atoms, a monoalkylaminoalkyl group having 2 to 6 carbon atoms or a dialkylaminoalkyl group having 3 to 6 carbon atoms); (Where a represents an integer of 2 to 7, R ³ represents a hydrogen atom, an amino group, a monoalkylamino group having 1 to 4 carbon atoms or a dialkylamino group having 2 to 8 carbon atoms) Or (Where b and c are the same or different and represent an integer of 1 to 4, R ⁴ is a hydrogen atom, an alkyl having 1 to 6 carbon atoms which may be substituted by a cycloalkyl group having 3 to 5 carbon atoms) group, an alkenyl group having 2 to 7 carbon atoms, represents a group represented by a cycloalkyl group having an alkoxyalkyl group or a 3 to 5 carbon atoms having 2 to 6 carbon atoms), X ¹ is 3 'carbon atoms of positions 1 An alkoxy group having 2 to 6 carbon atoms or an alkenyloxy group having 2 to 6 carbon atoms, an alkoxy group having 2 to 6 carbon atoms at the 4'-position,
An alkylthio group having 1 to 6 carbon atoms, an acyl group having 1 to 6 carbon atoms, an acylalkyl group having 2 to 6 carbon atoms or an iodine atom, an alkoxy group having 1 to 6 carbon atoms at the 5'-position, or a carbon number at the 6'-position A rifamycin derivative represented by｝, which represents an alkoxy group having 1 to 6 atoms or a halogen atom, and X ² represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, or a salt thereof. 2. In the above formula (I), A is Wherein a and R ³ are the same as defined above, or (Wherein, b, c, and R ⁴ are as defined above) rifamycin derivative or a salt thereof according to claim 1, wherein the group represented by. 3. The rifamycin derivative or a salt thereof according to claim 1, wherein in the formula (I), X ¹ is an alkoxy group having 1 to 6 carbon atoms at the 6′-position. 4. In the above formula (I), A is Wherein a and R ³ are the same as defined above, or Wherein b, c and R ⁴ are the same as defined above, wherein X ¹ is a 6'-position alkoxy group having 1 to 6 carbon atoms, and X ² is a hydrogen atom or a carbon atom having 1 to 6 carbon atoms. The rifamycin derivative or a salt thereof according to claim 1, which is an alkyl group of 6. 5. In the above formula (I), A is the 5'-position. Wherein a and R ³ are the same as defined above, or (Wherein b, c and R ⁴ are the same as defined above), X ¹ is a 6′-position alkoxy group having 1 to 6 carbon atoms, and X ² is a hydrogen atom or a 3′-position The rifamycin derivative or a salt thereof according to claim 1, which is an alkyl group having 1 to 6 carbon atoms. 6. In the above formula (I), A is the 5′-position. The rifamycin derivative or a salt thereof according to claim 1, wherein X ¹ is a 6′-OC ₂ H ₅ group, and X ² is a hydrogen atom. 7. In the above formula (I), A is the 5'-position. The rifamycin derivative or a salt thereof according to claim 1, wherein X ¹ is a 6′-OC ₂ H ₅ group, and X ² is a hydrogen atom. 8. In the above formula (I), A is the 5′-position. The rifamycin derivative or a salt thereof according to claim 1, wherein X ¹ is a 6′-OCH (CH ₃ ) ₂ group, and X ² is a hydrogen atom. 9. In the above formula (I), A is the 5'-position. X ¹ is a 6′-OCH ₃ group, and X ² is a 3′-CH _{3 group.}
The rifamycin derivative or a salt thereof according to claim 1, which is a group. 10. The formula (II): (Wherein X ³ is a hydrogen atom, an alkoxy group having 1 to 6 carbon atoms,
A halogen atom or a nitro group; X ⁴ represents a 3′-position alkoxy group having 1 to 6 carbon atoms or an alkenyloxy group having 2 to 6 carbon atoms; a 4′-position alkoxy group having 2 to 6 carbon atoms; 6 alkylthio group, an acyl group having 1 to 6 carbon atoms, an acyl group or an iodine atom or 6'-position alkoxy group or halogen atom having 1 to 6 carbon atoms of 2 to 6 carbon atoms, X ⁵ is hydrogen Wherein A represents an atom or an alkyl group having 1 to 6 carbon atoms), wherein A is (Wherein R ¹ and R ² are the same or different and have 1 to 1 carbon atoms)
An alkylalkyl group having 3 to 3 carbon atoms, an aminoalkyl group having 2 to 6 carbon atoms, a monoalkylaminoalkyl group having 2 to 6 carbon atoms or a dialkylaminoalkyl group having 3 to 6 carbon atoms); (Where a represents an integer of 2 to 7, R ³ represents a hydrogen atom, an amino group, a monoalkylamino group having 1 to 4 carbon atoms or a dialkylamino group having 2 to 8 carbon atoms) Or (Where b and c are the same or different and represent an integer of 1 to 4, R ⁴ is a hydrogen atom, an alkyl having 1 to 6 carbon atoms which may be substituted by a cycloalkyl group having 3 to 5 carbon atoms) A alkenyl group having 2 to 7 carbon atoms, an alkoxyalkyl group having 2 to 6 carbon atoms or a cycloalkyl group having 3 to 5 carbon atoms). Equation (III): (Wherein A, X ⁴ and X ⁵ are the same as described above). 11. The formula (IV): (Wherein X ⁶ is a hydrogen atom, an alkoxy group having 1 to 6 carbon atoms,
X ⁷ represents a halogen atom or a nitro group, X ⁷ represents a 4′-position alkoxy group having 2 to 6 carbon atoms, an alkylthio group having 1 to 6 carbon atoms, an acyl group having 1 to 6 carbon atoms, and an acylalkyl having 2 to 6 carbon atoms. Group or iodine atom, carbon number of 1 to 6 at 5'-position
Represents an alkoxy group having 1 to 6 carbon atoms or a halogen atom at the 6′-position, X ⁸ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and the 5′-position represents X ⁷ other than a hydrogen atom or the rifamycin derivative represented by a group) representing the X ^8, wherein AH {wherein, a is (Wherein R ¹ and R ² are the same or different and have 1 to 1 carbon atoms)
An alkylalkyl group having 3 to 3 carbon atoms, an aminoalkyl group having 2 to 6 carbon atoms, a monoalkylaminoalkyl group having 2 to 6 carbon atoms or a dialkylaminoalkyl group having 3 to 6 carbon atoms); (Where a represents an integer of 2 to 7, R ³ represents a hydrogen atom, an amino group, a monoalkylamino group having 1 to 4 carbon atoms or a dialkylamino group having 2 to 8 carbon atoms) Or (Where b and c are the same or different and represent an integer of 1 to 4, R ⁴ is a hydrogen atom, an alkyl having 1 to 6 carbon atoms which may be substituted by a cycloalkyl group having 3 to 5 carbon atoms) Represents an alkenyl group having 2 to 7 carbon atoms, an alkoxyalkyl group having 2 to 6 carbon atoms or a cycloalkyl group having 3 to 5 carbon atoms). Equation (V): (Wherein A, X ⁷ and X ⁸ are the same as described above). 12. An antibacterial agent comprising the rifamycin derivative according to claim 1 or a salt thereof as an active ingredient.