ALKYL-SUBSTITUTED BENZOXAZINORIFAMYCIN DERIVATIVE, PROCESS FOR PREPARING THE SAME AND ANTIBACTERIAL AGENT CONTAINING THE SAME

Abstract: A novel rifamycin derivative having the formula (I): wherein X¹ is an alkyl group with l to 6 carbon atoms or a cycloalkyl group with 3 to 8 carbon atoms; X² is a hydrogen atom or an alkyl group with l to 4 carbon atoms; R¹ is hydrogen atom or acetyl group; A is a group represented by the formula: wherein R² is an alkyl group with l to 4 carbon atoms or an alkoxyalkyl group with 2 to 6 carbon atoms and R³ is an alkyl group with l to 6 carbon atoms or an alkoxyalkyl group with 2 to 6 carbon atoms, or a group represented by the formula: wherein is a 3 to 9 membered cyclic amino group with 2 to 8 carbon atoms, R⁴ is a hydrogen atom or an alkyl group having l to 4 carbon atoms, or salts thereof, a process for preparing the same and antibacterial agents containing the same as an effective ingredient. The rifamycin derivative of the present invention having the formula (I) shows a strong antibacterial activity against the Gram-positive bacteria and the acid-fast bacteria.

Description: The present invention relates to a novel rifamycin derivative or salts thereof, a process for preparing the same and antibacterial agents containing the same as an effective ingredient More particularly, the present invention relates to a novel rifamycin derivative having the formula (I): wherein X¹ is an alkyl group with 1 to 3 carbon atoms; X² is a hydrogen atom or an alkyl group with 1 to 3 carbon atoms; R¹ is hydrogen atom or acetyl group; A is a group represented by the formula: wherein R² is an alkyl group with 1 to 3 carbon atoms or an alkoxyalkyl group with 2 to 6 carbon atoms and R³ is an alkyl group with 1 to 6 carbon atoms or an alkoxyalkyl group with 2 to 6 carbon atoms, or a 3 to 8 membered cyclic amino group with 2 to 7 carbon atoms represented by the formula: or salts thereof, a process for preparing the same and antibacterial agents containing the same as an effective ingredient. In the present invention, a 3 to 8 membered cylic amino group with 2 to 7 carbon atoms represented by the formula: means a group represented by the formula: The rifamycin derivative of the present invention is a novel compound which has not yet been reported in the literature. Rifamycin derivatives are already described in GB-A-1 081 757 and EP-A-0 190 709. GB-A-1 081 757 discloses benzoxazinorifamycin derivatives and other derivatives of rifamycin O and S. EP-A-0 190 709 refers to alkyl-substituted benzoxazinorifamycin derivatives and anti-bacterial agents containing them. In accordance with the present invention, there is provided a novel rifamycin derivative having the formula (I): wherein X¹ is an alkyl group with 1 to 3 carbon atoms; X² is a hydrogen atom or an alkyl group with 1 to 3 carbon atoms; R¹ is hydrogen atom or acetyl group; A is a group represented by the formula: wherein R² is an alkyl group with 1 to 3 carbon atoms or an alkoxyalkyl group with 2 to 6 carbon atoms and R³ is an alkyl group with 1 to 6 carbon atoms or an alkoxyalkyl group with 2 to 6 carbon atoms, or a 3 to 8 membered cyclic amino group with 2 to 7 carbon atoms represented by the formula: or salts thereof, a process for preparing the same and antibacterial agents containing the same as an effective ingredient. As the result of the present inventors' study, it has been found that a rifamycin derivative having the formula (I): wherein X¹, X², R¹ and A are as defined above, could be prepared by reacting a rifamycin derivative having the formula (II): wherein X¹, X² and R¹ are as defined above, with an amine having the formula: AH, wherein A is as defined above and the obtained rifamycin derivative having the formula (I) shows a strong antibucterial activity. The rifamycin derivative having the formula (I) is soluble in various kinds of organic solvents, e.g. halogenated hydrocarbons such as chloroform, alcohols such as ethanol, esters such as ethyl acetate, aromatic hydrocarbons such as benzene and ethers such as tetrahydrofuran. Examples of substituents X¹ and X² in the novel rifamycin derivative of the present invention having the formula (I) are listed below. An example of an alkyl group with 1 to 3 carbon atoms for X¹ is methyl group, ethyl group, propyl group or isopropyl group. An example of an alkyl group with 1 to 3 carbon atoms for X² is methyl group, ethyl group, propyl group or isopropyl group. The rifamycin derivative of the present invention having the formula (I) can form a salt with either a base or an acid. Any base or acid which can form a salt with the rifamycin derivative having the formula (I) can be employed. Examples of the salt with base are (1) a metallic salt, especially an alkali metal salt or an alkaline earth metal salt, (2) an ammonium salt and (3) an amine salt, especially a salt with methylamine, ethylamine, diethylamine, triethylamine, pyrrolidine, morpholine or hexamethyleneimine. Examples of the salt with an acid are (1) a salt with mineral acid such as sulfuric acid or hydrochloric acid and (2) a salt with an organic acid such as p-toluenesulfonic acid, trifluoroacetic acid or acetic acid. The rifamycin derivative of the present invention having the formula (I) can be prepared by means of the following process. (a) The rifamycin derivative of the present invention can be prepared by reacting the rifamycin derivative having the formula (II) dissolved in an organic solvent such as methanol, ethanol, tetrahydrofuran, N,N-dimethylformamide or dimethylsulfoxide with the amine having the formula: AH, wherein A is as defined above, in the presence or absence of an acid such as hydrochloric acid at a temperature ranging from -20°C to a boiling point of the solvent for 1 hour to 1 month and in the presence or absence of an oxidizing agents such as manganese dioxide. The rifamycin derivative having the formula (II), which is a starting material, can be prepared by rifamycin S with a compound represented by the formula: wherein X¹ and X² are as defined above, in accordance with the method disclosed by W. Kump et al [Helv. Chim. Acta, 56 , 2348 (1978)]. Examples of the reaction solvent employed in the above process are, for instance, methanol, ethanol, isopropyl alcohol, tetrahydrofuran, pyridine, acetone, ethyl acetate, chloroform, N,N-dimethylformamide or dimethylsulfoxide. Among them, pyridine, N,N-dimethylformamide or dimethylsulfoxide is preferably employed in the above process with an excellent result. The reaction is carried out at a temperature ranging from -20°C to a boiling point of the solvent, preferably from -50 to 50°C. Though the reaction may be carried out for a duration of around 1 hour to around 1 month, the optimum reaction time should be determined depending on the proceeding of the reaction, the proceeding can be shown by thin layer chromatography since it varies depending on the kind and amount of the amine employed in the above process, the presence or absence of an oxidizing agent, the kind and amount thereof when present, or the reaction temperature. When the reaction is carried out in the presence of the oxidizing agent, air, oxygen, manganese dioxide, lead dioxide, silver oxide, potassium ferricyanide or hydrogen peroxide are employed as the oxidizing agent. Among them, manganese dioxide, silver oxides or potassium ferricyanide is preferably employed in the above process with an excellent result. (b) The rifamycin derivative of the present invention having the formula (I) can also be prepared by using the rifamycin derivative having the formula (III): wherein R¹, X¹ and X² are as defined above and X³ is a halogen atom, a lower alkoxy group or nitro group, in place of the rifamycin derivative having the formula (II) in the above (a) and in accordance with the procedures described in the above (a) except for the starting material. The rifamycin derivative having the formula (III), which is a starting material, can be prepared by reacting rifamycin S with a compound represented by the formula : wherein X¹, X² and X³ are as defined above, in accordance with the method disclosed by W. Kump et al [Helv. Chim. Acta, 56 , 2348 (1978)]. (c) The rifamycin derivative having the formula (I), wherein R¹ is hydrogen atom, can be also prepared by hydrolyzing the rifamycin derivative having the formula (I), wherein R¹ is acetyl group, with an acid or a base. Examles of the acid employed for hydrolysis are, for instance, (1) a mineral acid such as sulfuric acid or hydrochloric acid and (2) an organic acid such as p -toluenesulfonic acid or trifluoroacetic acid. Examples of the base employed for hydrolysis are, for instance, (1) an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide, (2) an alkaline earth metal hydroxide such as calcium hydroxide or barium hydroxide, and (3) an organic base such as 1,5-diazabicyclo[4.3.0]non-5-ene or 1,8-diazabicyclo[5.4.0]undec-7-ene. Preferably the hydrolysis reaction is carried out at room temperature employing an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide and employing a solvent such as water-containing methanol or water-containing pyridine. The rifamycin derivative of the present invention having the formula (I), which is a dark purple solid, can be separated and purified from the reaction products in a relatively easy manner. That is, an excess amount of the amine having the formula: AH, wherein A is as defined above and the reaction solvent are removed from the reaction system to give a crude product, which is then purified by crystallization or column-chromatography. The rifamycin derivative of the present invention having the formula (I) can be also converted into the rifamycin derivative having the formula (IV): wherein X¹, X², R¹ and A are as defined above, by reducing the rifamycin derivative having the formula (I) with a reducing agent such as ascorbic acid or sodium hydrosulfite. The rifamycin derivative having the formula (IV) is also a novel compound and shows a strong antibacterial activity. Typical examples of the rifamycin derivative of the present invention are shown in Table 1. In Table 1, infrared absorption spectrum was measured according to the potassium bromide tablet method. Thin layer chromatography was carried out using silica gel 60 F₂₅₄ plate for thin layer chromatography (20 cm x 20 cm, made by E. Merck Co.). Nuclear magnetic resonance spectrum was measured using tetramethylsilane as an internal standard and deuterated chloroform solution. The rifamycin derivative of the present invention shows a strong antibacterial activity against the Gram-positive bacteria and the acid-fast bacteria. The antibacterial activity of the rifamycin derivative of the present invention was tested by the method according to the standard method of Japan Society of Chemotherapy [Chemotherapy (Tokyo), 29 , 76 (1981)]. The results obtained from the typical compounds are shown in Table 2. As shown in Table 2, it is clear that the rifamycin derivative of the present invention shows a strong antibacterial activity against the Gram-positive bacteria and the acid-fast bacteria. In Table 2, test compound No. corresponds to derivative No. in Table 1. It has been also found that the rifamycin derivative of the present invention had a low toxicity since toxicity was never exhibited by oral administration of 1000 mg/kg weight of the rifamycin derivative of the present invention shown in Table 1 to mice. The rifamycin derivative of the present invention having the formula (I) is absorbed by oral administration to show a high blood level. Typical compounds were tested employing Wister Strain male rats (10 to 15 weeks) and the results obtained are shown in Table 3. The derivative No. in Table 3 corresponds to the derivative No. in Table 1. Blood levels were measured, according to the usual method, by means of bioassay employing Micrococcus luteus IFO 12708 as an assay bacteria. Derivative No. Dose (mg/kg) Concentration in plasma (mcg/ml) 1 hr. 3 hrs. 5 hrs. 13 20 8.0 26.4 20.0 18 20 10.4 23.0 14.6 19 20 4.2 21.5 25.8 22 20 7.3 18.3 11.5 23 20 6.3 12.0 5.5 24 20 3.9 11.5 5.9 28 20 4.7 12.2 10.6 35 20 13.5 22.0 12.5 Benzoxazinorifamycin (known compound) 100 0.05> 0.05> 0.05> Antibacterial agents containing the rifamycin derivative of the present invention as an effective ingredient can be in any dosage form for an oral, rectal, topical or parenteral administration. Examples of the dosage form are, for instance, tablets, capsules, granules, syrups, suppositories or ointments. Carriers usually used in the dosage form of the antibacterial agents of the present invention are an inactive pharmaceutical carriers of organic or inorganic solid or liquid suitable for oral, rectal, or other parenteral administration. An example of the carrier is crystalline cellulose, gelatin, lactose, starch, magnesium sterate, talc, vegetable or animal fat or oil, gum or polyalkylene glycol. The ratio of the antibacterial agent of the present invention to the carrier in the dosage form can vary from 0.2 to 100 % by weight. The antibacterial agent of the present invention can contain another pharmaceutical ingredient such as another antibacterial agent compatible with the antibacterial agent of the present invention. In this case, the antibacterial agent of the present invention is not necessarily the main ingredient of the dosage form. The antibacterial agent of the present invention is administered with such a dose that the desired activity is achieved without any side-effect. Though the actual dose should be determined according to the judgment of the doctor, around 10 mg to around 10 g, preferably around 20 mg to around 5 g per day of the antibacterial agent of the present invention may be usually administered for adults. The antibacterial agent of the present invention can be administered in a pharmaceutical dosage unit containing 1 mg to 5 g, preferably 3 mg to 1 g of an effective ingredient. The present invention is more particularly described and explained by the following Examples. However, it should be understood that the present invention is not limited to such Examples and various changes and modifications can be made without departing from the scope and spirit of the present invention. In the following Examples, infrared adsorption spectrum was measured according to the potassium bromide tablet method. Nuclear magnetic resonance spectrum was measured using tetramethylsilane as an internal standard and deuterated chloroform solution. Example 1 [Synthesis of 3'-methylbenzoxazinorifamycin] A solution of 5.0 g of 3-methyl-2-nitrophenol in 100 mℓ of ethanol was mixed with, 0.5 g of 10 % palladium carbon. Hydrogen was introduced into the solution with stirring at room temperature for 4 hours. Palladium carbon was filtered off from the reaction mixture by using a filter aid and the solvent was distilled away under reduced pressure to give 4.44 g of a crude product of 2-amino-3-methylphenol. A solution of 16.7 g of rifamycin S and 4.44 g of the crude product of 2-amino-3-methylphenol in 200 mℓ of toluene was stirred at room temperature for a day. To the reaction mixture was added 500 mℓ of toluene, which was washed with a 5 % aqueous solution of a sodium hydrogencarbonate, water and a brine successively and dried with anhydrous sodium sulfate. After the drying agent was filtered off, toluene was replaced with 300 mℓ of ethanol. To the above solution of ethanol was added 16.7 g of manganese dioxide and the mixture was reacted at room temperature for a day. Manganese dioxide was filtered off by using a filter aid and the solvent was distilled away under reduced pressure. The residue was purified by subjecting to silica-gel column-chromatography by employing Wakogel® C=200 [eluent: chloroform-acetone (95 : 5)] to give 9.99 g of desired 3'-methylbenzoxazinorifamycin. Thin layer chromatography Rf = 0.28, purplish red spot [carrier: silica-gel, solvent system: chloroform-acetone (9 : 1)] Example 2 [Synthesis of derivative No. 1] To a solution of 1.0 g of 3'-methylbenzoxazinorifamycin synthesized according to the procedure of Example 1 in 10 mℓ of dimethyl sulfoxide were added 0.2 g of dimethylamine hydrochloride, 0.35 mℓ of triethylamine and 1.0 g of manganese dioxide, and the mixture was reacted with stirring at room temperature for 3 days. The reaction mixture was diluted by addition of ethyl acetate and insoluble substances were filtered off. Then, the filtrate was washed successively with water, diluted hydrochloric acid, water and a brine and ethyl acetate was distilled away under reduced pressure. The residue was purified by subjecting to silica-gel column-chromatography by employing Wakogel® C-200 twice [eluent: ethyl acetate] and the obtained residue was dissolved in ethyl acetate-n-hexane to crystallize 0.09 g of the desired derivative No. 1. Example 3 [Synthesis of derivative No. 2] To a solution of 1.0 g of 3'-methylbenzoxazinorifamycin synthesized according to the procedure of Example 1 in 10 mℓ of dimethyl sulfoxide were added 0.27 mℓ of N-methylisobutylamine and 1.0 g of manganese dioxide, and the mixture was reacted with stirring at room temperature for 8 hours. The reaction mixture was treated in the same manner as in Example 2 to give 0.12 g of the desired derivative No. 2. Example 4 [Synthesis of derivative No. 3] The procedure of Example 3 was repeated except that 0.4 g of bis(2-ethoxyethyl)amine was used instead of N-methylisobutylamine and that the reaction was carried out for 9 days instead of 8 hours to give 0.15 g of the desired derivative No. 3. Example 5 [Synthesis of derivative No. 41 The procedure of Example 3 was repeated except that 0.21 mℓ of pyrrolidine was used instead of N-methylisobutylamine and that the reaction was carried out for 5 hours instead of 8 hours to give 0.20 g of the desired derivative No. 4. Example 6 [Synthesis of derivative No. 5] The procedure of Example 3 was repeated except that 0.25 mℓ of piperidine was used instead of N-methylisobutylamine and that the reaction was carried out for 5 hours instead of 8 hours to give 0.54 g of the desired derivative No. 5. Example 7 [Synthesis of derivative No. 6] A solution of 1.0 g of 4'-methylbenzoxazinorifamycin, which was prepared according to the method described in Helv. Chim. Acta, 56 , 2348 (1973), in 10 mℓ of dimethyl sulfoxide was mixed with 0.2 g of dimethylamine hydrochloride, 0.34 mℓ of triethylamine and 1.0 g of manganese dioxide, and the mixture was reacted with stirring at room temperature for 8 hours. Then, the reaction mixture was treated in the same manner as in Example 2 to give 0.61 g of the desired derivative No. 6. Example 8 [Synthesis of derivative No. 7] The procedure of Example 7 was repeated except that 0.22 mℓ of methylethylamine was used instead of dimethylamine hydrochloride and triethylamine and that the reaction was carried out for 5 hours instead of 8 hours to give 0.53 g of the desired derivative No. 7. Example 9 [Synthesis of derivative No. 8] The procedure of Example 7 was repeated except that 0.26 mℓ of diethylamine was used instead of dimethylamine hydrochloride and triethylamine and that the reaction was carried out for a day instead of 8 hours to give 0.38 g of the desired derivative No. 8. Example 10 [Synthesis of derivative No. 9] The procedure of Example 7 was repeated except that 0.30 mℓ of N-methylisobutylamine was used instead of dimethylamine hydrochloride and triethylamine and that the reaction was carried out for 3 hours instead of 8 hours to give 0.48 g of the desired derivative No. 9. Example 11 [Synthesis of derivative No. 10] The procedure of Example 7 was repeated except that 0.40 g of bis(2-ethoxyethyl)amine was used except that dimethylamine hydrochloride and triethylamine and that the reaction was carried out for 2 days instead of 8 hours to give 0.30 g of the desired derivative No. 10. Example 12 [Synthesis of derivative No. 11] The procedure of Example 7 was repeated except that 0.18 mℓ of propylene imine was used instead of dimethylamine hydrochloride and triethylamine and that the reaction was carried out for 2 days instead of 8 hours to give 0.15 g of the desired derivative No. 11. Example 13 [Synthesis of derivative No. 12] The procedure of Example 7 was repeated except that 0.17 mℓ of azetidine was used instead of dimethylamine hydrochloride and triethylamine and that the reaction was carried out for 2 hours instead of 8 hours to give 0.43 g of the desired derivative No. 12. Infrared absorption spectrum ν (cm⁻¹): 3450, 2970, 2940, 2890, 1719, 1648, 1610, 1475, 1399, 1375, 1302, 1258, 1220, 1167, 1140, 1068, 1042, 980, 918, 809, 772, 680, 591 and 418 ¹H-nuclear magnetic resonance spectrum δ (ppm): 0.48, 0.78, 0.94 (CHC H ₃), 1.80, 1.91, 2.00, 2.21, 2.38, 3.05 (CH₃), 4.36 (CH₂NCH₂), 6.13, 7.56 (protons of aromatic ring) and 15.17 (phenolic proton) Elementary analysis (C₄₇H₅₅N₃O₁₂) Calcd.(%): C 66.10, H 6.49, N 4.92 Found (%): C 65.95, H 6.36, N 5.10 Example 14 [Synthesis of derivative No. 13] The procedure of Example 7 was repeated except that 0.20 mℓ of pyrrolidine was used instead of dimethylamine hydrochloride and triethylamine and that the reaction was carried out for 1 hour instead of 8 hours to give 0.61 g of the desired derivative No. 13. Infrared absorption spectrum ν (cm⁻¹): 3550, 2960, 2920, 2870, 1712, 1650, 1599, 1460, 1388, 1360, 1342, 1320, 1284, 1251, 1206, 1160, 1130, 1180, 1160, 1140, 974, 943, 916, 842, 810, 764, 684, 660, 582 and 576 ¹H-nuclear magnetic resonance spectrum δ (ppm): 0.50, 0.77, 0.93 (CHC H ₃), 1.80, 2.00, 2.10, 2.19, 2.54, 3.04 (CH₃), 3.63 (CH₂NCH₂), 6.50, 7.60 (protons of aromatic ring) and 15.20 (phenolic proton) Elementary analysis (C₄₈H₅₇N₃O₁₂) Calcd.(%): C 66.42, H 6.62, N 4.84 Found (%): C 66.55, H 6.58, N 4.72 Example 15 [Synthesis of derivative No. 14] The procedure of Example 7 was repeated except that 0.24 mℓ of piperidine was used instead of dimethylamine hydrochloride and triethylamine and that the reaction was carried out for 4 hours instead of 8 hours to give 0.50 g of the desired derivative No. 14. Infrared absorption spectrum ν (cm⁻¹): 3460, 2945, 2830, 1720, 1660, 1602, 1584, 1502, 1460, 1421, 1380, 1360, 1320, 1305, 1246, 1200, 1180, 1136, 1105, 1086, 1056, 1043, 996, 962, 940, 908, 878, 830, 803, 784, 742, 704, 676, 644 and 600 ¹H-nuclear magnetic resonance spectrum δ (ppm): 1.47, 1.80, 1.98 (CHC H ₃), 1.72 (protons of piperidine ring), 1.80, 2.03, 2.13, 2.20, 2,40 3.03 (CH₃), 6.51, 7.77 (protons of aromatic ring) and 14.67 (phenolic proton) Elementary analysis (C₄₉H₅₉N₃O₁₂) Calcd.(%): C 66.73, H 6.74, N 4.76 Found (%): C 66.83, H 6.67, N 4.64 Example 16 [Synthesis of derivative No. 15] The procedure of Example 7 was repeated except that 0.28 mℓ of hexamethyleneimine was used instead of dimethylamine hydrochloride and triethylamine and that the reaction was carried out for 5 hours instead of 8 hours to give 0.73 g of the desired derivative No. 15. Example 17 [Synthesis of derivative No. 16] A solution of 1.0 g of 6'-methylbenzoxazinorifamycin, which was prepared according to the method described in Helv. Chim. Acta. 56 , 2348 (1973), in 10 mℓ of dimethyl sulfoxide was mixed with 0.17 mℓ of azetidine and 1.0 g of manganese dioxide and the mixture was reacted with stirring at room temperature for 31 hours. Then, the reaction mixture was treated in the same manner as in Example 2 to give 0.41 g of the desired derivative No. 16. Example 18 [Synthesis of derivative No. 17] The procedure of Example 17 was repeated except that 0.21 mℓ of pyrrolidine was used instead of azetidine and that the reaction was carried out for 4 hours instead of 31 hours to give 0.54 g of the desired derivative No. 17. Infrared absorption spectrum ν (cm⁻¹): 3460, 2980, 2940, 2880, 1720, 1646, 1600, 1470, 1420, 1398, 1360, 1322, 1262, 1164, 1140, 1098, 1070, 980, 952, 920, 817, 772, 698, 646, 570, 540 and 438 ¹H-nuclear magnetic resonance spectrum δ (ppm): -0.16, 0.33, 0.80, 0.97 (CHC H ₃), 1.81, 1.99, 2.07, 2.23, 2.37, 3.00 (CH₃), 3.57 (CH₂NCH₂), 6.77, 7.61 (protons of aromatic ring) and 15.07 (phenolic proton) Elementary analysis (C₄₈H₅₇N₃O₁₂) Calcd.(%): C 66.42, H 6.62, N 4.84 Found (%): C 66.62, H 6.43, N 4.97 Example 19 [Synthesis of 4'-ethylbenzoxazinorifamycin] To a stirred mixture of 130 mℓ of water, 130 mℓ of ether, 7.66 g of sodium nitrate and 10.0 g of 4-ethylphenol was added 13 mℓ of concentrated hydrochloric acid, and the reaction was continued at room temperature for 3 days. To the reaction mixture was added 300 mℓ of water and the mixture was extracted with 500 mℓ of ether. The extract was washed with water, then a brine and dried with anhydrous sodium sulfate. The drying agent was filtered off and the solvent was distilled away under reduced pressure to give 13.0 g of 4-ethyl-2-nitrophenol. To a solution of 13.0 g of 4-ethyl-2-nitrophenol in 260 mℓ of ethanol was added 1.3 g of 10 % palladium carbon, to which hydrogen was introduced with stirring at room temperature for 4 hours. Palladium carbon was filtered off from the mixture and the solvent was distilled away under reduced pressure to give 10.68 g of a crude product of 2-amino-4-ethylphenol. A solution of 20.0 g of rifamycin S and 4.73 g of the obtained crude product of 2-amino-4-ethylphenol in 400 mℓ of toluene was stirred for a day. The reaction mixture was treated and purified in the same manner as in Example 1 to give 14.2 g of desired 4'-ethylbenzoxazinorifamycin. Thin layer chromatography Rf = 0.28, purplish red spot [carrier: silica-gel, solvent system: chloroform-acetone (9 : 1)] Example 20 [Synthesis of derivative No. 18] To a solution of 1.0 g of 4'-ethylbenzoxazinorifamycin synthesized according to the procedure of Example 19 in 10 mℓ of dimethyl sulfoxide were added 0.17 mℓ of azetidine and 1.0 g of manganese dioxide, and the reaction was continued with stirring at room temperature for 7 hours. The reaction mixture was treated in the same manner as in Example 2 to give 0.27 g of the desired derivative No. 18. Infrared absorption spectrum ν (cm⁻¹): 3460, 2970, 2940, 2880, 1718, 1658, 1605, 1505, 1470, 1398, 1375, 1290, 1260, 1217, 1166, 1068, 980, 940, 920, 815, 770, 680, 550 and 418 ¹H-nuclear magnetic resonance spectrum δ (ppm): 0.54, 0.77, 0.95 (CHC H ₃), 1.28, 2.70 (CH₂CH₃), 1.80, 2.02, 2.10, 2.21, 3.06 (CH₃), 4.34 (CH₂NCH₂), 6.21, 7.63 (protons of aromatic-ring) and 15.17 (phenolic proton) Elementary analysis (C₄₈H₅₇N₃O₁₂) Calcd.(%): C 66.42, H 6.62, N 4.84 Found (%): C 66.24, H 6.71, N 5.03 Example 21 [Synthesis of derivative No. 19] The procedure of Example 20 was repeated except that 0.21 mℓ of pyrrolidine was used instead of azetidine and that the reaction was carried out for 3 hours instead of 7 hours to give 0.48 g of the desired derivative No. 19. Infrared absorption spectrum ν (cm⁻¹): 3450, 2970, 2930, 2870, 1718, 1644, 1602, 1505, 1460, 1363, 1350, 1290, 1256, 1218, 1162, 1135, 1062, 978, 943, 915, 815, 768, 663, 590, 545 and 410 ¹H-nuclear magnetic resonance spectrum δ (ppm): 0.55, 0.75, 0.93 (CHC H ₃), 1.29, 2.90 (CH₂CH₃), 1.82, 1.98, 2.00, 2.17, 3.07 (CH₃), 3.60 (CH₂NCH₂), 6.60, 7.68 (protons of aromatic ring) and 15.15 (phenolic proton) Elementary analysis (C₄₉H₅₉N₃O₁₂) Calcd.(%): C 66.73, H 6.74, N 4.76 Found (%): C 66.49, H 6.97, N 4.86 Example 22 [Synthesis of derivative No. 20] The prcedure of Example 20 was repeated except that 0.24 mℓ of piperidine was used instead of azetidine and that the reaction was carried out for 5 hours instead of 7 hours to give 0.36 g of the desired derivative No. 20. Example 23 [Synthesis of 6'-ethylbenzoxazinorifamycin] To a stirred mixture of 130 mℓ of ether, 130 mℓ of water and 10.0 g of 2-ethylphenol was added dropwise 6.7 mℓ of 61 % nitric acid, and the reaction was continued with stirring at room temperature for 4 hours. The reaction mixture was extracted with 300 mℓ of ethyl acetate and washed with a brine, and then dried with anhydrous sodium sulfate. The drying agent was filtered off and the solvent was distilled away under reduced pressure. The residue was purified by subjecting to silica-gel column-chromatography [eluent: chloroform] to give 5.75 g of 6-ethyl-2-nitrophenol. To a solution of 4.96 g of 6-ethyl-2-nitrophenol in 200 mℓ of ethanol was added 0.5 g of 10 % palladium carbon, to which hydrogen was introduced with stirring at room temperature for 4.5 hours. Palladium carbon was filtered off from the mixture and the solvent was distilled away under reduced pressure to give 4.86 g of a crude product of 2-amino-6-ethylphenol. A solution of 15.0 g of rifamycin S and 3.25 g of the crude product of 2-amino-6-ethylphenol in 300 mℓ of toluene was stirred at room temperature for a day. Then, the reaction mixture was treated and subjected to purification in the same manner as in Example 1 to give 3.15 g of desired 6'-ethylbenzoxazinorifamycin. Thin layer chromatography Rf = 0.27, purplish red spot [carrier: silica-gel, solvent system: chloroform-acetone (9 : 1)] Example 24 [Synthesis of derivative No. 21] A solution of 1.0 g of 6'-ethylbenzoxazinorifamycin synthesized according to the procedure of Example 23 in 10 mℓ of dimethyl sulfoxide, were added 0.15 mℓ of azetidine and 1.0 g of manganese dioxide, and the reaction was continued with stirring at room temperature for a day. Then, the reaction mixture was treated in the same manner as in Example 2 to give 0.36 g of the desired derivative No. 21. Infrared absorption spectrum ν (cm⁻¹): 3460, 2975, 2940, 2880, 1725, 1648, 1608, 1474, 1399, 1378, 1318, 1265, 1174, 1140, 1073, 1050, 982, 950, 818, 770, 702 and 440 ¹H-nuclear magnetic resonance spectrum δ (ppm): -0.20, 0.39, 0.83, 1.01 (CHC H ₃), 1.84, 2.00, 2.05, 2.28, 3.03 (CH₃), 1.16, 2.75 (CH₂CH₃), 4.36, (CH₂NCH₂), 6.46, 7.72 (protons of aromatic ring) and 15.15 (phenolic proton) Elementary analysis (C₄₈H₅₇N₃O₁₂) Calcd. (%): C 66.42, H 6.62, N 4.84 Found (%): C 66.22, H 6.80, N 4.75 Example 25 [Synthesis of derivative No. 22] The procedure of Example 24 was repeated except that 0.21 mℓ of pyrrolidine was used instead of azetidine and that the reaction was carried out for 2 days instead of a day to give 0.40 g of the desired derivative No. 22. Infrared absorption spectrum ν (cm⁻¹): 3450, 2970, 2940, 2875, 1718, 1640, 1596, 1465, 1410, 1358, 1342, 1314, 1258, 1158, 1132, 1100, 1062, 1040, 975, 946, 810, 770, 684, 598 and 430 ¹H-nuclear magnetic resonance spectrum δ (ppm): -0.17, 0.42, 0.82, 0.99 (CHC H ₃), 1.84, 1.98, 2.04, 2.25, 3.02 (CH₃), 1.19, 2.94 (CH₂CH₃), 3.61 (CH₂NCH₂), 6.87, 7.71 (protons of aromatic ring) and 15.04 (phenolic proton) Elementary analysis (C₄₉H₅₉N₃O₁₂) Calcd.(%): C 66.73, H 6.74, N 4.76 Found (%): C 66.96, H 6.54, N 4.83 Example 26 [Synthesis of 4'-n-propylbenzoxazinorifamycin] To a suspension of 10.0 g of 4-n-propylphenol in 50 mℓ of water was added dropwise 11.0 mℓ of 61 % nitric acid while cooling with ice, the temperature of mixture was raised to room temperature and the reaction was carried out for 2 hours. The reaction mixture was extracted with 300 mℓ of ethyl acetate, washed with a brine and dried with anhydrous sodium sulfate. The drying agent was filtered off and the solvent was distilled away under reduced pressure. The residue was purified by subjecting to silica-gel column-chromatography [eluent: chloroform] to give 8.69 g of 4-n-propyl-2-nitrophenol. To a solution of 8.69 g of 4-n-propyl-2-nitrophenol in 350 mℓ of ethanol was added 0.8 g of 10 % palladium carbon, to which hydrogen was introduced with stirring at room temperature for 3.5 hours. Palladium carbon was filtered off and the solvent was distilled away under reduced pressure to give 7.78 g of a crude product of 2-amino-4-n-propylphenol. A solution of 20.0 g of rifamycin S and 4.35 g of the crude product of 2-amino-4-n-propylphenol in 400 mℓ of toluene was stirred at room temperature for a day. Then, the reaction mixture was treated and subjected to purification in the same manner as in Example 1 to give 10.86 g of desired 4'-n-propylbenzoxazinorifamycin. Thin layer chromatography Rf = 0.36, purplish red spot [carrier: silica-gel, solvent system: chloroform-acetone (9 : 1)] Example 27 [Synthesis of derivative No. 23] To a solution of 1.0 g of 4'-n-propylbenzoxazinorifamycin synthesized according to the procedure of Example 26 in 10 mℓ of dimethyl sulfoxide were added 0.16 mℓ of azetidine and 1.0 g of manganese dioxide, and the reaction was continued with stirring at room temperature for 4 hours. Then, the reaction mixture was treated in the same manner as in Example 2 to give 0.29 g of the desired derivative No. 23. Infrared absorption spectrum ν (cm⁻¹): 3450, 2955, 2925, 2865, 1717, 1645, 1600, 1500, 1462, 1384, 1364, 1290, 1250, 1206, 1159, 1132, 1084, 1065, 976, 943, 915, 818, 772, 684 and 595 ¹H-nuclear magnetic resonance spectrum δ (ppm): 0.55, 0.79, 0.95 (CHC H ₃), 1.03 (CH₂CH₂C H ₃), 1.81, 1.90, 2.02, 2.21, 3.07 (CH₃), 4.33 (CH₂NCH₂), 6.18, 7.61 (protons of aromatic ring) and 15.16 (phenolic proton) Elementary analysis (C₄₉H₅₉N₃O₁₂) Calcd.(%): C 66.73, H 6.74, N 4.76 Found (%): C 66.57, H 6.88, N 4.91 Example 28 [Synthesis of derivative No. 24] The procedure of Example 27 was repeated except that 0.20 mℓ of pyrrolidine was used instead of azetidine and that the reaction was carried out for 2.5 hours instead of 4 hours to give 0.51 g of the desired derivative No. 24. Infrared absorption spectrum ν (cm⁻¹): 3450, 2955, 2925, 2875, 1715, 1645, 1596, 1498, 1458, 1395, 1357, 1340, 1282, 1250, 1200, 1152, 1124, 1075, 1060, 1032, 972, 948, 908, 814, 766, 660, 592 and 500 ¹H-nuclear magnetic resonance spectrum δ (ppm): 0.55, 0.78, 0.95 (CHC H ₃), 1.01 (CH₂CH₂C H ₃), 1.81, 1.91, 2.02, 2.19, 3.07 (CH₃), 3.58 (CH₂NCH₂), 6.62, 7.71 (protons of aromatic ring) and 15.16 (phenolic proton) Elementary analysis (C₅₀H₆₁N₃O₁₃) Calcd.(%): C 67.02, H 6.86, N 4.69 Found (%): C 67.29, H 6.98, N 4.42 Example 29 [Synthesis of 6'-n-propylbenzoxazinorifamycin] To a stirred mixture of 100 mℓ of water, 100 mℓ of ether and 10.0 g of 2-n-propylphenol was added dropwise 11.0 mℓ of 61 % nitric acid and the reaction was carried out with stirring at room temperature for 12 days. The reaction mixture was extracted with 200 mℓ of ethyl acetate and dried with anhydrous sodium sulfate. The drying agent was filtered off and the solvent was distilled away under reduced pressure. The residue was purified by subjecting to silica-gel column-chromatography [eluent: chloroform-n-hexane (1 : 1)] to give 3.76 g of 6-n-propyl-2-nitrophenol. To a suspension of 3.76 g of 6-n-propyl-2-nitrophenol in 20 mℓ of water was added 21.6 g of sodium hydrosulfite and the reaction was continued with stirring at 60°C for 1 hour. After the reacton mixture was neutralized by adding sodium hydrogencarbonate, the mixture was extracted with 200 mℓ of ethyl acetate and dried with anhydrous sodium sulfate. The drying agent was filtered off and the solvent was distilled away under reduced pressure to give 2.93 g of a crude product of 2-amino-6-n-propylphenol. A solution of 13.5 g of rifamycin S and 2.93 g of the crude product of 2-amino-6-n-propylphenol in 270 mℓ of toluene was stirred at room temperature for a day. Then, the reaction mixture was treated and subjected to purification in the same manner as in Example 1 to give 8.21 g of desired 6'-n-propylbenzoxazinorifamycin. Thin layer chromatography Rf = 0.23, purplish red spot [carrier: silica-gel, solvent system: chloroform-acetone (9 : 1)] Example 30 [Synthesis of derivative No. 25] To a solution of 2.0 g of 6'-n-propylbenzoxazinorifamycin synthesized according to the procedure of Example 29 in 20 mℓ of dimethyl sulfoxide were added 0.33 mℓ of azetidine and 2.0 g of manganese dioxide, and the mixture was reacted with stirring at room temperature for 8.5 hours. Then, the reaction mixture was treated in the same manner as in Example 2 to give 0.58 g of the desired derivative No. 25. Example 31 [Synthesis of derivative No. 26] The procedure of Example 30 was repeated except that 0.4 mℓ of pyrrolidine was used instead of azetidine and that the reaction was carried out for 4 hours instead of 8.5 hours to give 0.75 g of the derivative No. 26. Example 32 [Synthesis of 4'-isopropylbenzoxazinorifamycin] To a suspension of 5.0 g of 4-hydroxycumene in 14 mℓ of water was added dropwise 4.0 mℓ of 70 % nitric acid while cooling with ice and the temperature of mixture was raised to room temperature and the reaction was carried out for 40 minutes. After 500 mℓ of water was added thereto, the reaction mixture was extracted with 500 mℓ of ethyl acetate, washed with water and a brine successively, and dried with anhydrous sodium sulfate. The drying agent was filtered off and the solvent was distilled away under reduced pressure. The residue was purified by subjecting silica-gel column-chromatography [eluent: ethyl acetate] to give 5.07 g of 4-isopropyl-2-nitrophenol. To a solution of 5.07 g of 4-isopropyl-2-nitrophenol in 150 mℓ of ethanol was added 0.5 g of 10 % palladium carbon, to which hydrogen was introduced with stirring at room temperature for 4 hours. Palladium carbon was filtered off and the solvent was distilled away under a reduced pressure to give 4.87 g of a crude product of 2-amino-isopropylphenol. A solution of 10.0 g of rifamycin S and 3.26 g of the crude product of 2-amino-4-isopropylphenol in 200 mℓ of toluene was stirred at room temperature for a day. Then, the reaction mixture was treated and subjected to purification in the same manner as in Example 1 to give 4.24 g of desired 4'-isopropylbenzoxazinorifamycin. Thin layer chromatography Rf = 0.29, purplish red spot [carrier: slica-gel, solvent system: chloroform-aceton (9 : 1)] Example 33 [Synthesis of derivative No. 27] To a solution of 1.0 g of 4'-isopropylbenzoxazinorifamycin synthesized according to the procedure of Example 32 in 10 mℓ of dimethyl sulfoxide were added 0.17 mℓ of azetidine and 1.0 g of manganese dioxide, and the mixture was reacted with stirring at room temperature for 19 hours. Then, the reaction mixture was treated in the same manner as in Example 2 to give 0.21 g of the desired derivative No. 27. Example 34 [Synthesis of derivative No. 28] The procedure of Example 33 was repeated except that 0.20 mℓ of pyrrolidine was used instead of azetidine and that the reaction was carried out for 3 days instead of for 19 hours to give 0.39 g of the desired derivative No. 28. Infrared absorption spectrum ν (cm⁻¹): 3450, 2970, 2940, 2870, 1720, 1654, 1598, 1500, 1464, 1405, 1372, 1290, 1260, 1218, 1170, 1148, 1092, 1070, 980, 950, 918, 815, 769, 660, 596, 558 and 420 ¹H-nuclear magnetic resonance spectrum δ (ppm): 0.59, 0.76, 0.92 (CHC H ₃), 1.35 (C H ₃CHC H ₃), 1.82, 2.00, 2.10, 3.05 (CH₃), 3.53 (CH₂NCH₂), 6.64, 7.77 (protons of aromatic ring) and 15.05 (phenolic proton) Elementary analysis (C₅₀H₆₁N₃O₁₂) Calcd.(%): C 67.02, H 6.86, N 4.69 Found (%): C 67.23, H 6.98, N 4.49 Example 35 [Synthesis of derivative No. 29] The procedure of Example 33 was repeated except that 0.24 mℓ of piperidine was used instead of azetidine and that the reaction was carried out for a day instead of for 3 days to give 0.45 g of the desired derivative No. 29. Example 36 [Synthesis of 6'-isopropylbenzoxazinorifamycin] To a stirred mixture of 200 mℓ of water, 200 mℓ of ether and 20.0 g of 2-isopropylphenol was added dropwise 22.0 mℓ of 61 % nitric acid, and then the mixture was reacted with stirring at room temperature for 2 days. The reaction mixture was extracted with 200 mℓ of ethyl acetate and dried with anhydrous sodium sulfate. After, the drying agent was filtered off and the solvent was distilled away under reduced pressure. The residue was purified by subjecting to silica-gel column-chromatography [eluent: chloroform-n-hexane (1 : 1)] to give 7.69 g of 6-isopropyl-2-nitrophenol. To a solution of 7.69 g of 6-isopropyl-2-nitrophenol in 200 mℓ of ethanol was added 0.77 g of. 10 % palladium carbon, to which hydrogen was introduced with stirring at room temperature for 4 hours. Palladium carbon was filtered off and the solvent was distilled away under reduced pressure to give 6.39 g of a crude product of 2-amino-6-isopropylphenol. A solution of 26.9 g of rifamycin S and 6.39 g of the crude product of 2-amino-6-isopropylphenol in 500 mℓ of toluene was stirred at room temperature for a day. Then, the reaction mixture was treated and subjected to purification in the same manner as in Example 1 to give 5.30 g of desired 6'-isopropylbenzoxazinorifamycin. Thin layer chromatography Rf = 0.28, purplish red spot [carrier: silica-gel, solvent system: chloroform-acetone (9 : 1)] Example 37 [Synthesis of derivative No. 30] To a solution of 1.0 g of 6'-isopropylbenzoxazinorifamycin in 10 mℓ of dimethyl sulfoxide were added 0.16 mℓ of azetidine and 1.0 g of manganese dioxide, and the mixture was reacted with stirring at room temperature for 2 days. Then, the reaction mixture was treated in the same manner as in Example 2 to give 0.07 g of the desired derivative No. 30. Example 38 [Synthesis of 3',4'-dimethylbenzoxazinorifamycin] To a solution of 12.2 g of 3,4-xylenol in 100 mℓ of acetic acid was added a solution of 7.48 mℓ of 61 % nitric acid in 50 mℓ of acetic acid while keeping the reaction temperature at 20°C. Then the mixture was reacted with stirring at room temperature for two hours. To the reaction mixture was added 200 mℓ of ethyl acetate and the mixture was washed successively with water, an aqueous solution of sodium hydrogencarbonate, water and a brine, and then, ethyl acetate was distilled away under reduced pressure. The residue was purified by subjecting to silica-gel column-chromatography [eluent: chloroform] to give 0.69 g of 3,4-dimethyl-2-nitrophenol. To a solution of 0.69 g of 3,4-dimethyl-2-nitrophenol in 20 mℓ of ethanol was added 0.1 g of 10 % palladium carbon, to which was introduced hydrogen with stirring at room temperature for 3.5 hours. Palladium carbon was filtered off and the solvent was distilled away under reduced pressure to give 0.56 g of a crude product of 3,4-dimethyl-2-aminophenol. A solution of 2.69 g of rifamycin S and 0.53 g of the crude product of 3,4-dimethyl-2-aminophenol in 70 mℓ of toluene was stirred at room temperature for 5 days. Then, the reaction mixture was treated and subjected to purification in the same manner as in Example 1 to give 1.74 g of desired 3',4'-dimethylbenzoxazinorifamycin. Thin layer chromatography Rf = 0.29, purplish red spot [carrier: silica-gel, solvent system: chloroform-acetone (9 : 1)] Example 39 [Synthesis of derivative No. 31] To a solution of 0.8 g of 3',4'-dimethylbenzoxazinorifamycin synthesized according to the procedure of Example 38 in 5 mℓ of dimethyl sulfoxide were added 0.17 mℓ of pyrrolidine and 0.8 g of manganese dioxide and the mixture was stirred at room temperature for 22 hours. Then, the reaction mixture was treated in the same manner as in Example 2 to give 0.26 g of the desired derivative No. 31. Example 40 [Synthesis of 3',6'-dimethylbenzoxazinorifamycin] To a stirred mixture of 130 mℓ of water, 130 mℓ of ether and 10.0 g of 2,5-dimethylphenol was added dropwise 5.2 mℓ of 70 % nitric acid while cooling with ice. The temperature of the mixture was raised to room temperature and the reaction was continued for a day. After 500 mℓ of water was added, the reaction mixture was extracted with 500 mℓ of ethyl acetate, washed with water and a brine successively, and dried with anhydrous sodium sulfate. The drying agent was filtered off and the solvent was distilled away under reduced pressure. The residue was purified by subjecting to silica-gel column-chromatography [eluent: chloroform] to give 3.83 g of 3,6-dimethyl-2-nitrophenol. To a solution of 3.83 g of 3,6-dimethyl-2-nitrophenol in 150 mℓ of ethanol was added 0.4 g of 10 % palladium carbon, to which was introduced hydrogen with stirring at room temperature for 4 hours. Palladium carbon was filtered off and the solvent was distilled away under reduced pressure to give 2.2 g of a crude product of 2-amino-3,6-dimethylphenol. A solution of 11.19 g of rifamycin S and 2.2 g of the crude product of 2-amino-3,6-dimethylphenol in 200 mℓ of toluene was stirred at room temperature for a day. The reaction mixture was treated and subjected to purification in the same manner as in Example 1 to give 5.52 g of desired 3',6'-dimethylbenzoxazinorifamycin. Thin layer chromatography Rf = 0.15, purplish red spot [carrier: silica-gel, solvent system: chloroform-aceton (9 : 1)] Example 41 [Synthesis of derivative No. 32] To a solution of 1.0 g of 3',6'-dimethylbenzoxazinorifamycin synthesized according to the procedure of Example 40 in 10 mℓ of dimethyl sulfoxide were added 0.17 mℓ of azetidine and 1.0 g of manganese dioxide, and the mixture was reacted with stirring at room temperature for 2 hours. Then, the reaction mixture was treated in the same manner as in Example 2 to give 0.51 g of the desired derivative No. 32. Example 42 [Synthesis of derivative No. 33] The procedure of Example 41 was repeated except that 0.2 mℓ of pyrrolidine was used instead of azetidine and that the reaction was carried out for 4 hours instead of for 2 hours to give 0.62 g of the desired derivative No. 33. Example 43 [Synthesis of derivative No. 34] The procedure of Example 41 was repeated except that 0.24 mℓ of piperidine was used instead of azetidine and that the reaction was carried out for 7 hours instead of for 2 hours to give 0.86 g of the desired derivative No. 34. Example 44 [Synthesis of 4',6'-dimethylbenzoxazinorifamycin] A solution of 10 g of rifamycin S in 200 mℓ of toluene was mixed with 2.37 g of 6-amino-2,4-xylenol and the mixture was stirred at room temperature for 43 hours. Insoluble substances were filtered off and the filtrate was washed successively with a 5 % aqueous solution of sodium hydrogencarbonate, water and a brine, and then, toluene was distilled away under reduced pressure. The residue was dissolved in 200 mℓ of methanol, to which was added 10 g of manganese dioxide, and the mixture was stirred at room temperature for 6.5 hours. Insoluble substances were filtered off and the filtrate was evaporated to dryness under reduced pressure. The residue was subjected to silica-gel column-chromatography by using Wakogel® C-200 [eluent: chroroform-acetone (95 : 5)] to give 4.68 g of the desired derivative. Thin layer chromatography Rf = 0.25, purplish red spot [carrier: silica-gel, solvent system: ethyl acetate] Example 45 [Synthesis of derivative No. 35] To a solution of 1.0 g of 4',6'-dimethylbenzoxazinorifamycin synthesized according the procedure of Example 44 in 10 mℓ of dimethyl sulfoxide were added 0.12 mℓ of azetidine and 1.0 g of manganese dioxide, and the mixture was stirred at room temperature for a day. Then, the reaction mixture was treated in the same manner as in Example 2 to give 0.14 g of the desired derivative No. 35. Infrared absorption spectrum ν (cm⁻¹): 3440, 2970, 2925, 2875, 1718, 1640, 1597, 1464, 1384, 1357, 1306, 1280, 1257, 1207, 1160, 1140, 1100, 1068, 1036, 972, 945, 914, 818, 760 and 692 ¹H-nuclear magnetic resonance spectrum δ (ppm): -0.17, 0.33, 0.81, 0.98 (CHC H ₃), 1.83, 1.90, 1.98, 2.10, 2.28, 2.41, 3.01 (CH₃), 4.60 (CH₂NCH₂), 7.45 (proton of aromatic ring) and 15.26 (phenolic proton) Elementary analysis (C₄₈H₅₇N₃O₁₂) Calcd.(%): C 66.42, H 6.62, N 4.84 Found (%): C 66.20, H 6.51, N 5.03 Example 46 [Synthesis of derivative No. 36] The procedure of Example 45 was repeated except that 0.20 mℓ of pyrrolidine was used instead of azetidine and that the reaction was carried out for 3.5 hours instead of a day to give 0.17 g of the desired derivative No. 36. Example 47 [Synthesis of 3'-methyl-6'-isopropylbenzoxazinorifamycin] To a solution of 10.16 g of thymol in 100 mℓ of acetic acid was added 50 mℓ of a solution of acetic acid in which 5.06 mℓ of 61 % nitric acid was dissolved while keeping the reaction temperature not more than 20°C and the reaction was further continued with stirring at room temperature for 2 hours. After 200 mℓ of ethyl acetate was added, the reaction mixture was successively washed with water, an aqueous solution of sodium hydrogencarbonate, water and a brine and ethyl acetate was distilled away under reduced pressure. The residue was purified by subjecting to silica-gel column-chromatography [eluent: chloroform-n-hexane (1 : 1)] to give 2.85 g of 2-nitrothymol. To a solution of 2.85 g of 2-nitrothymol in 50 mℓ of ethanol was added 0.28 g of 10 % palladium carbon, to which was introduced hydrogen with stirring at room temperature for 4 hours. Palladium carbon was filtered off and the solvent was distilled away under reduced pressure to give 2.41 g of a crude product of 2-aminothymol. A solution of 8.46 g of rifamycin S and 2.41 g of the crude product of 2-aminothymol in 200 mℓ of toluene and the mixture was stirred at 50°C for 14 hours. Then, the reaction mixture was treated and subjected to purification in the same manner as in Example 1 to give 4.0 g of desired 3'-methyl-6'-isopropylbenzoxazinorifamycin. Thin layer chromatography Rf = 0.25, purplish red spot [carier: silica-gel, solvent system: chloroform-acetone (9 : 1)] Example 48 [Synthesis of derivative No. 37] To a solution of 1.0 g of 3'-methyl-6'-isopropylbenzoxazinorifamycin in 5 mℓ of dimethyl sulfoxide were added 0.17 mℓ of azetidine and 1.0 g of manganese dioxide, and the mixture was stirred at room temperature for 4 days. The reaction mixture was treated in the same manner as in Example 2 to give 0.23 g of the desired derivative No. 37. Example 49 [Synthesis of derivative No. 38] The procedure of Example 48 was repeated except that 0.52 mℓ of pyrrolidine was used instead of azetidine and that the reaction was carried out for 2 days instead of 4 days to give 0.22 g of the desired derivative No. 38. Example 50 [Synthesis of 3'-isopropyl-6'-methylbenzoxazinorifamycin] To a solution of 9.96 g of carvacrol in 100 mℓ of acetic acid was added 50 mℓ of a solution of acetic acid in which 4.96 mℓ of 61 % nitric acid was dissolved while keeping the reaction temperature not more than 20°C and the reaction was further continued with stirring at room temperature for 5 hours. After 300 mℓ of ethyl acetate was added, the reaction mixture was washed successively with water, an aqueous solution of sodium hydrogencarbonate, water and a brine, and ethyl acetate was distilled away under reduced pressure. The residue was purified by subjecting to silica-gel column-chromatography [eluent: chloroform-n-hexane (1 : 2)] to give 4.4 g of 2-nitrocarvacrol. To a solution of 4.4 g of 2-nitrocarbacrol in 80 mℓ of ethanol was added 0.44 g of 10 % palladium carbon, to which was introduced hydrogen with stirring at room temperature for 5 hours. Palladium carbon was filtered off and the solvent was distilled away under a reduced pressure to give 2.8 g of a crude product of 2-aminocarvacrol. A solution of 9.82 g of rifamycin S and 2.8 g of the crude product of 2-aminocarvacrol in 300 mℓ of toluene and the mixture was stirred at 50°C for 12 hours. Then, the reaction mixture was treated and subjected to purification in the same manner as in Example 1 to give 6.53 g of desired 3'-isopropyl-6'-methylbenzoxazinorifamycin. Thin layer chromatography Rf = 0.15, purplish red spot [carrier: silica-gel, solvent system: chloroform-acetone (9 : 1)] Example 51 [Synthesis of derivative No. 39] To a solution of 1.0 g of 3'-isopropyl-6'-methylbenzoxazinorifamycin synthesized according to the procedure of Example 50 in 5 mℓ of dimethyl sulfoxide were added 0.17 mℓ of azetidine and 1.0 g of manganese dioxide, and the mixture was stirred at room temperature for 3 days. Then, the reaction mixture was treated in the same manner as in Example 2 to give 0.18 g of the desired derivative No. 39. Example 52 [Synthesis of derivative No. 40] The procedure of Example 51 was repeated except that 0.21 mℓ of pyrrolidine was used instead of azetidine to give 0.30 g of the desired derivative No. 40. Example 53 [Synthesis of derivative No. 41] The procedure of Example 51 was repeated except that 0.60 mℓ of piperidine was used instead of azetidine and that the reaction was carried out for 24 hours instead of for 3 days to give 0.57 g of the desired derivative No. 41. Example 54 [Synthesis of derivative No. 42] To a solution of 1.0 g of the derivative No. 13 in 35 mℓ of ethanol was added 15 mℓ of a 10 % aqueous solution of sodium hydroxide, and the mixture was stirred at room temperature for 1 hour. After 300 mℓ of water was added, the reaction mixture was extracted with 500 mℓ of chloroform and dried with anhydrous sodium sulfate. The drying agent was filtered off and the solvent was distilled away under reduced pressure. The residue was purified by subjecting to silica-gel column-chromatography [eluent: ethyl acetate] and crystallized from ethyl acetate/n-hexane to give 0.57 g of the derivative No. 42. Example 55 [Synthesis of derivative No. 43] The procedure of Example 54 was repeated except that 0.85 g of derivative No. 18 was used instead of the derivative No. 13 to give 0.31 g of the derivative No. 43. Example 56 [Synthesis of derivative No. 44] The procedure of Example 54 was repeated except that 1.0 g of the derivative No. 19 was used instead of the derivative No. 13 to give 0.19 g of the desired derivative No. 44. Example 57 [Synthesis of derivative No. 45] The procedure of Example 54 was repeated except that 1.73 g of the derivative No. 22 was used instead of the derivative No. 13 to give 1.02 g of the desired derivative No. 45. Example 58 [Synthesis of derivative No. 46] The procedure of Example 54 was repeated except that 0.75 g of the derivative No. 28 was used instead of the derivative No. 13 to give 0.17 g of the desired derivative No. 46. In addition to the ingredients used in the Examples, other ingredients can be used in the Examples as set forth in the specification to obtain substantially the same results.

Claims: A rifamycin derivative having the formula (I): wherein X¹ is an alkyl group with 1 to 3 carbon atoms; X² is a hydrogen atom or an alkyl group with 1 to 3 carbon atoms; R¹ is hydrogen atom or acetyl group; A is a group represented by the formula: wherein R² is an alkyl group with 1 to 3 carbon atoms or an alkoxyalkyl group with 2 to 6 carbon atoms and R³ is an alkyl group with 1 to 6 carbon atoms or an alkoxyalkyl group with 2 to 6 carbon atoms, or a 3 to 8 membered cyclic amino group with 2 to 7 carbon represented by the formula: or salts thereof. The rifamycin derivative or salts thereof of Claim 1, wherein R¹ is a hydrogen atom in the formula (I). The rifamycin derivative or salts thereof of Claim 1, wherein R¹ is an acetyl group in the formula (I). The rifamycin derivative or salts thereof of Claim 1, wherein X¹ is an alkyl group with 1 to 3 carbon atoms in the formula (I). The rifamycin derivative or salts thereof of Claim 1, wherein X² is a hydrogen atom or an alkyl group with 1 to 3 carbon atoms in the formula (I). The rifamycin derivative or salts thereof of Claim 1, wherein A is a group represented by the formula: wherein R² is an alkyl group with 1 to 3 carbon atoms or an alkoxyalkyl group with 2 to 6 carbon atoms and R³ is an alkyl group with 1 to 6 carbon atoms or an alkoxyalkyl group with 2 to 6 carbon atoms, or a group represented by the formula: which is a 3 to 8 membered cyclic amino group with 2 to 7 carbon atoms in the formula (I). The rifamycin derivative or salts thereof of Claim 1, wherein A is a group represented by the formula: wherein R² is an alkyl group with 1 to 3 carbon atoms and R³ is an alkyl group with 1 to 6 carbon atoms in the formula (I). The rifamycin derivative or salts thereof of Claim 1, wherein A is a 3 to 8 membered cyclic amino group with 2 to 7 carbon atoms represented by the formula: in the formula (I). The rifamycin derivative or salts thereof of Claim 1, wherein methyl group is substituted at the C4'-position of phenylene ring, R¹ is acetyl group and A is a group represented by the formula: in the formula (I). The rifamycin derivative or salts thereof of Claim 1, wherein methyl group is substituted at the C4'-position of phenylene ring, R¹ is acetyl group and A is a group represented by the formula: in the formula (I). The rifamycin derivative or salts thereof of Claim 1, wherein methyl group is substituted at the C4'-position of phenylene ring, R¹ is acetyl group and A is a group represented by the formula: in the formula (I). The rifamycin derivative or salts thereof of Claim 1, wherein methyl group is substituted at the C6'-position of phenylene ring, R¹ is acetyl group and A is a group represented by the formula: in the formula (I). The rifamycin derivative or salts thereof of Claim 1, wherein ethyl group is substituted at the C4'-position of phenylene ring, R¹ is acetyl group and A is a group represented by the formula: in the formula (I). The rifamycin derivative or salts thereof of Claim 1, wherein ethyl group is substituted at the C4'-position of phenylene ring, R¹ is acetyl group and A is a group represented by the formula: in the formula (I). The rifamycin derivative or salts thereof of Claim 1, wherein ethyl group is substituted at the C6'-position of phenylene ring, R¹ is acetyl group and A is a group represented by the formula: in the formula (I). The rifamycin derivative or salts thereof of Claim 1, wherein ethyl group is substituted at the C6'-position of phenylene ring, R¹ is acetyl group and A is a group represented by the formula: in the formula (I). The rifamycin derivative or salts thereof of Claim 1, wherein n-propyl group is substituted at the C4'-position of phenylene ring, R¹ is acetyl group and A is a group represented by the formula: in the formula (I). The rifamycin derivative or salts thereof of Claim 1, wherein n-propyl group is substituted at the C4'-position of phenylene ring, R¹ is acetyl group and A is a group represented by the formula: in the formula (I). The rifamycin derivative or salts thereof of Claim 1, wherein isopropyl group is substituted at the C4'-position of phenylene ring, R¹ is acetyl group and A is a group represented by the formula: in the formula (I). The rifamycin derivative or salts thereof of Claim 1, wherein n-butyl group is substituted at the C4'-position of phenylene ring, R¹ is acetyl group and A is a group represented by the formula: in the formula (I). The rifamycin derivative or salts thereof of Claim 1, wherein sec-butyl group is substituted at the C4'-position of phenylene ring, R¹ is acetyl group and A is a group represented by the formula: in the formula (I). The rifamycin derivative or salts thereof of Claim 1, wherein methyl groups are substituted at the C4'-position and C6'-position of phenylene ring, R¹ is acetyl group and A is a group represented by the formula: in the formula (I). Process for preparing a rifamycin derivative of claim 1, characterized by the process comprising reacting a rifamycin derivative having the formula (II): wherein X¹, X² and R¹ are as defined above, with an amine having the general formula: AH, wherein A is as defined above. The process of Claim 23, wherein the rifamycin derivative having the formula (II) is reacted with the amine having the formula: AH in the presence of an oxydizing agent. The process of Claim 24, wherein the oxydizing agent is manganese dioxide. Antibacterial agents containing a rifamycin derivative of claim 1 or pharmaceutically acceptable salts thereof.

Inventors: HOSOE, KAZUNORI, KANO, FUMIHIKO, WATANABE, KIYOSHI, YAMANE TAKEHIKO, YAMASHITA, KATSUJI
Applicants: KANEGAFUCHI KAGAKU KOGYO KABUSHIKI KAISHA
Application year: 1987
Main classification: C07D498
IPC codes: A61K31, C07D498, A61P31