JPS62240688A - Aminobenzoxazino-and aminobenzothiazinorifamycin derivative having hydroxymethyl group - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I {X<1> represents O or S; R<1> represents formula II [R<2> represents H, 1-3C alkyl or CH2CH2OH; R<3> represents H, 1-3C alkyl or -(CH2)lX<2>(l is 1-4; X<2> represents OH, COOH, -CHOHCH2OH, etc.), etc.], formula III [m and n represent 1-3; X<3> represents O or NR<8> (R<8> represents H, 1-4C alkyl, CH2CH2OH, etc.)], etc.] and salt thereof. USE:An antibacterial agent. PREPARATION:A rifamycin derivative expressed by formula IV is reacted with a compound expressed by the formula R<1>H in a solvent such as methanol, THF, pyridine, DMF, etc., in the presence of an acid such as hydrochloric acid, etc., as necessary, and further in the presence of an oxidizing agent if necessary.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Application 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 relates to the formula Cll 0H8cuB ((wherein, XI represents an oxygen atom or an i yellow atom, an alkyl group of 8 alkyl group t
Taha (CH2)z
In Table C! ON
A group represented by H, an aminomethyl group or 000R7
(R7 represents an alkyl group having 1 to 4 carbon atoms)] or 1 to 5, x
s is an oxygen atom or NR8 (R8 is a hydrogen atom, carbon number 1
-4 alkyl group, group represented by OR20Hg OH, group represented by (300R9 (R9 represents an alkyl group having 1 to 4 carbon atoms), C0R (R is a hydrogen atom or an alkyl group having 1 to 8 carbon atoms) ) or 0
112 (representing a group represented by 3ON O)) or a salt thereof, and an antibacterial agent containing the same as an active ingredient It is.

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

(Means for solving the problem and production effect) In order to develop new antibacterial agents, the present inventors synthesized various rifamycin derivatives and investigated their antibacterial activity. As a result, the above formula (
We have discovered that the novel rifamycin derivative represented by I) has excellent antibacterial activity, and have arrived at the present invention.

The novel rifamycin derivative represented by the above formula CI according to the present invention can be used in many organic solvents, halogenated hydrocarbons such as chloroform and methylene chloride; alcohols such as methyl alcohol and ethyl alcohol; methyl formate,
It is soluble in esters such as ethyl acetate; aromatic hydrocarbons such as Hensen and toluene; and ethers such as tetofhydrofuran and dioxane.

The novel rifamycin derivative represented by the formula [I] according to the present invention can form a salt with a base or an acid. As the base or acid that can be used to form a salt, any base or acid that can form a salt with the rifamycin derivative represented by formula [I] can be selected. Specific examples of salts with bases include (1) metal salts, especially alkali metal salts, salts with alkaline earth metals, (2) ammonium salts, <5) phosphorus salts, especially methylamine, ethylamine, diethylamine. , triethylamine, pyrrolidine,
There are salts with morpholine, hexamethyleneimine, etc., and examples of salts with acids are (1) salts with mineral acids such as i-acid and hydrochloric acid, (2) p-toluenesulfonic acid, trifluoroacetic acid, and acetic acid. There are salts with organic acids, etc.

The novel rifamycin derivative represented by the formula [I] according to the present invention can be produced as follows.

A rifamycin derivative represented by the formula [nl OH80H8 (Xl is as described above) is dissolved in a solvent, and then dissolved in the presence or absence of an acid such as hydrochloric acid, and further in the presence or absence of an oxidizing agent. 1
It can be synthesized by reacting with a compound represented by the formula [■] IH[IO3 (R1 is as described above). Methanol and ethanol are used as reaction solvents.

It is possible to use organic solvents such as tetofhydrofuran, pyridine, N,N-dimethyl formalde, dimethyl sulfoxide or the reaction reagent RIH (R1 is as described above) itself. The reaction temperature can be selected from -20°C to the boiling point of the solvent, but usually about 10°C to 40°C. The reaction time is about 1 hour to 1 week, but the optimal reaction time varies depending on the type and amount of the compound represented by RIH (R1 is as described above) used in the reaction9, the reaction temperature, the presence or absence of an oxidizing agent, etc. Therefore, the optimal reaction time should be determined by monitoring the progress of the reaction using layered chromatography or the like. In addition, as oxidizing agents that can coexist,
Air, oxygen, manganese dioxide.

Examples include lead dioxide, silver oxide, and potassium ferricyanide.

A novel rifamycin derivative represented by the formula [CI] can be synthesized with the formula [■MA] CM, CH by a redundant agent such as ascorbic acid.
It is also possible to use a derivative represented by I (xl and Rs are as described above). Sofamycin derivatives represented by the formula CIT also have strong antibacterial activity.

The rifamycin derivative represented by formula (I) according to the present invention can be separated from the reaction product MfM relatively easily.That is, by removing excess amounts of the reagents and reaction solvent used in the reaction, The desired rifamycin derivative can be obtained by purifying the crude product by crystallization, column chromatography, etc.

Representative examples of the novel rifamycin derivatives represented by formula [1] according to the present invention are shown in Table 1.

In Table 1, thin layer chromatography was performed using a silica gel 60F254 thin layer chromatography plate (: 20 x 20 cm) manufactured by Merck. Nuclear magnetic resonance spectra were measured using tetotsumethylsifun as an internal standard and as a deuterated chloroform solution, unless otherwise specified.

(Me2,47 white) The rifamycin derivative according to the present invention exhibits strong antibacterial activity against Gram-positive bacteria and acid-fast bacteria.The antibacterial activity of the new rifamycin derivative according to the present invention was evaluated using the Japanese Society of Chemotherapy standard method Journal of Therapeutic Society.

Vol. 29, p. 76 (1981)]. Representative examples are shown in Table 2. As is clear from Table 2, 1
It can be seen that the novel rifamycin derivative according to the present invention exhibits strong antibacterial activity against Gram-positive bacteria and acid-fast bacteria. Note that the derivative numbers in the table correspond to the derivative numbers in Table 1.

100010 novel rifamycin derivatives according to the present invention
The new rifamycin derivative of the present invention was found to have low toxicity when administered orally to mice at a concentration of 0.0 O, but did not show any toxicity.

The antibacterial agent formulation containing the novel rifamycin derivative of the present invention as an active ingredient may be a formulation for oral, enteral or parenteral administration.

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

Antimicrobial agents according to the invention are generally administered at dosages that achieve the desired effect without side effects. The specific value should be determined by a doctor's judgment, but in general, it is 10 mJ7 to 10 I per day for adults, preferably 20 mJ, 9
It would normally be administered at about ~51. The antibacterial agent of the present invention can be administered as a pharmaceutical preparation containing 1 m17 to 5Ii, preferably amg to II, of the active ingredient.

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

Example 1 Synthesis of derivative A 4-chloro-8-nitrobenzaldehyde 50I in a sooml aqueous solution of Na28j 9H20194,11
After adding i and heating under reflux for 8 hours, the mixture was allowed to cool, and the reaction solution was extracted and washed with ether. Sodium chloride was added to the aqueous layer to saturate it, and the resulting precipitate of 2-amino-4-formylthiophenol sodium salt was separated and dried to obtain a residue of 8B and Bl. The obtained residue was dissolved in 600 m/ml of water, insoluble materials were separated, and a concentrated aqueous solution of zinc chloride was gradually added to the P solution under water cooling. The resulting yellow precipitate was separated, washed with water and methanol, and then dried to obtain 29.1% of 2-amino-4-formylthiophenol zinc salt.

Finely crush 24.8 ji of the obtained 2-amino-4-formylthiophenol zinc salt, and add 800 ml of ethanol!
8-Bromolyfamycin S (Japanese Patent Application Laid-Open No. 1989-1998)
-95599) was added and stirred at room temperature for 8 hours.

Insoluble matter was separated, the solvent of Solution F was distilled off under hydraulic pressure, and the residue was dissolved in chloroform and washed with water. The chloroform in the chloroform layer was distilled off under reduced pressure, and the resulting residue was subjected to silica gel strength chromatography using Wa-Gel ■C-200 as a carrier (eluent: chloroform-acetone 95:5).
) K I) Made of Si, 59.8. A rifamycin derivative in which XI is a sulfur atom and 4 is a formyl group in the formula [I] of F was obtained.

Rifamycin L%6 ao obtained by the above method
y to 210 [111! of ethanol and cooled with ice water. To this was added 0.27 Ii of sodium borohydride dissolved in 11 m7 of ethanol, and the mixture was stirred for 80 minutes. The reaction solution was dried over a wire, and the resulting residue was purified by silica gel column chromatography (eluent: chloroform-acetone 95:5) to obtain 28.8,9
A derivative was obtained in which xl is a sulfur atom, the 4'-position is a hydroxymethyl group, and the 5-position is a hydrogen atom in the formula [I].

Example 2 Synthesis of Derivative 1 Derivative A415my synthesized according to the method of Example 1 was added to 5 ml of methanol! Methylamine hydrochloride sg dissolved in
gmy and triethylamine 0.56 ml! Add and
The reaction was stirred at room temperature for 22 hours. The reaction solution was diluted with ethyl acetate, washed sequentially with water, 0.1N hydrochloric acid, and saturated saline, and the organic layer was separated, concentrated to dryness, and purified with preparative thin-layer chromatography using silica gel as a carrier ( The developing solution was purified by repeating chloroform-acetone (9:1) and 80 m
, the desired derivative 1 of p was obtained.

Examples 8-28 Synthesis of Derivatives 2-9 and 11-28 Derivatives 2-9 and 11-28 were synthesized using the reagents shown in Table 8 and in the same manner as in Example 2.

(Carbohydrate-F Fattening Example 24 Synthesis of Derivative 10 88.5 J' of 4-hydroxy-8-nitrobenzaldehyde and 40 J' of sodium borohydride in ethanol 2/2.
After adding F and heating under reflux for 6 hours, the reaction mixture was poured into a large amount of water. Add 10% hydrochloric acid to it to make it acidic.
Extraction was performed using ethyl acetate. The extract was dehydrated using anhydrous sodium sulfate, and then the solvent was distilled off. The obtained residue was purified by column chromatography using silica gel as a carrier (eluent: chloroform-acetone = 95:5).85.5. 4-hydroxy-8-nitrobenzyl alcohol of p was obtained.

4-Hydroxy-8-nitrobenzyl alcohol was dissolved in ethanol 11 and added with Padilla carbon (5%).
8.5j1 was added and hydrogenated at room temperature and pressure for 8 hours. After removing the catalyst by filtration, the solvent was distilled off to obtain 16.0.9 of 8-amino-4-hydroxybenzyl alcohol.

Obtained 3-amino-4-hydroxybenzyl alcohol 13.91. Rifamycin 869.58I and benzene 2I for F! The mixture was heated and stirred at 50°C for 18.5 hours, and then concentrated with methanol (11!). and manganese dioxide 1
89.16F and stirred overnight at room temperature. The reaction mixture was filtered, the solvent was distilled off, and the resulting residue was subjected to column chromatography using silica gel as a carrier twice (each eluate was chloroform-acetone 95:5-7:
8 and ethyl acetate-n-hexane 1:5-8:2)
purified, xl is an oxygen atom, 4 is a hydroxymethyl group, 5
Derivative B represented by formula [I] in which the position is a hydrogen atom
10.8.9 was obtained.

Derivative B0.81511 in dimethyl sulfoxide 15m
/ dissolved in 0.197 ml of piperidine! and 0.815 JF of manganese dioxide were added and stirred at room temperature for 18 hours. Thereafter, the same treatment as in Example 2 was carried out to obtain the desired derivatives io, sat, and p.

Patent applicant Makoto Asano, agent of Kanebuchi Chemical Industry Co., Ltd., patent attorney - Voluntary procedure amendment dated August 2, 1985, 1986 Patent Application No. 84846 Relationship to patent applicant address Nakanoshima, Kita-ku, Osaka Representative of 3-chome 2-4
New recruit 4, Agent name (6932) Patent attorney Makoto Asano - [Stock] 5, Date of amendment order 6, Number of inventions increased by amendment (2) Detailed description of invention column in specification Amendment 1) Formula [I] is corrected on page 8 of the specification. CFI 2 state 2) In the second line of page 9 of the specification cylinder, ``hydroxyl group 1.'' is corrected to ``1'' means hydroxyl group and carboxyl group 9.

3) Page 9 of the specification, line 7, “R6 is a hydroxyl group 9.” “R6 is a hydrogen atom, a hydroxyl group 1. Correct to.

4) Page 11 of the specification, 5th line from the bottom “Organic acids such as acetic acid,” “Organic acids such as acetic acid.”

Correct to.

5) Specification page 12, formula [n] H20H H20H Correct to.

6) Second line from the bottom of page 12 of the specification “Formalde” is corrected to 1 formamide.

7) Statement tube page 13, line 4 “Correct the 10-40°C force to 110°-40°C7.

8) Page 14 of the specification, line 8 from the bottom, 6 sofamycin derivatives, 0 rifamycin derivatives,
Correct to.

9) Add "Unit: μda/ml" to the right side of Table 2 on page 20 of the specification.

10) The second line from the bottom of page 22 of the specification ° residual method was obtained. The obtained residue 7 is corrected to "obtained solid substance. Obtained solid substance 9."

Above (Attachment) Claims (1) A rifamycin derivative represented by the following formula [I] and a salt thereof.

H20H ((wherein, XI represents an oxygen atom or a sulfur atom with a prime number of 1 to 3
represents an alkyl group or a group represented by CH2CH20H, R3 is a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, or -(CH2)lX [, # represents 1 to 4, X2 is a hydroxyl group, a carboxyl group, -CHoHC ) a group represented by T20H or an atom or an alkyl group having 1 to 3 carbon atoms; R6 represents a hydrogen atom, a hydroxyl group, a group represented by CONH2, an aminomethyl group, or a group represented by C00R7 (R7 represents an alkyl group having 1 to 4 carbon atoms) (m and n are the same or different 1 to 5 and X3 is an oxygen atom or NR8 [
R8 is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, CH2C
A group represented by H20H, C00R9 (R9 has 1 carbon number
~4 alkyl group), COR'' (
(2) In formula [I], Xl is oxygen The rifamycin derivative and its salt according to claim 1, which is an atom.

(3) The rifamycin derivative and its salt according to claim 1, wherein in formula [I], Xl is a sulfur atom.

(4) The rifamycin derivative represented by the following formula [1] C (where Xl represents an oxygen atom or a sulfur atom) is added with the formula [n1lR'
H[II[] represents an alkyl group having 1 to 3 carbon atoms or a group represented by -CH2CH20H, R3 is a hydrogen atom, an alkyl group having 1 to 3 carbon atoms or -(CH2)11X2 [l represents 1 to 4] X2 is a hydroxyl group, a carboxyl group, -CH0HCH
a group represented by 20H or an atom or an alkyl group having 1 to 3 carbon atoms; R6 is a hydrogen atom, a hydroxyl group, a group represented by CONH2, an aminomethyl group, or C00R7 (R7 has 1 carbon number
-4 alkyl group)] or different 1 to 5, X3 is an oxygen atom or NR8[R
8 is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, CHCHO
A group represented by H, a group represented by COOR9 (R9 represents an alkyl group having 1 to 4 carbon atoms), a group represented by COR'' (R10
represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms; or a group represented by CH2C0N5J; )) The formula [
I] A method for producing a rifamycin derivative represented by the formula H20H C, in which Xl and R1 are as described above.

((In the formula, Xl represents an oxygen atom or a sulfur atom having 1 to 1 carbon atoms.
3 represents an alkyl group or a group represented by CH2CH20H, R3 is a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, or -(CH2)lX2 [a represents 1 to 4, X2 is a hydroxyl group, a carboxyl group, -CH0HCH20H (also represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms) represents a 3- to 8-membered cyclic amino group having 2 to 7 carbon atoms, R6 represents a hydrogen atom, a hydroxyl group, a group represented by CONH2, an aminomethyl group or a group represented by COOR7 (R7 represents an alkyl group having 1 to 4 carbon atoms), or a group represented by 1 to 5 different from 1 to 5; X3 is an oxygen atom or NR8[R
8 is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, CH2CH
A group represented by 20H, C00R9 (R9 has 1 to 1 carbon atoms)
4), COR10 (represents an alkyl group of
R" represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms) or a group represented by cH2cozo))) rifamycin Antibacterial agents containing derivatives or their salts as active ingredients.

Claims (5)

[Claims] (1) A rifamycin derivative represented by the following formula [I] and a salt thereof. ▲There are mathematical formulas, chemical formulas, tables, etc.▼[I] {{In the formula, X^1 represents an oxygen atom or a sulfur atom,
R^1 has ▲numeric formulas, chemical formulas, tables, etc.▼{R^2 is a hydrogen atom, an alkyl group with 1 to 8 carbon atoms, or CH_2CH_2OH
Indicates a group represented by, R^8 is a hydrogen atom, and has 1 to 1 carbon atoms.
3 alkyl group or -(CH_2)_1 5 represents the same or different hydrogen atoms or alkyl groups having 1 to 3 carbon atoms) } represents a group represented by }, ▲Numerical formula,
There are chemical formulas, tables, etc. ▼ [▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ indicates a 3- to 8-membered cyclic amino group with 2 to 7 carbon atoms, R^6 is a hydroxyl group, a group represented by CONH_2,
Aminomethyl group or COOR^7 (R^7 is 1 carbon number
There are groups represented by ▲ mathematical formulas, chemical formulas, tables, etc. ▼ {m, n are the same or different 1 to 5, X^8 is Oxygen atom or NR^8 [R^8 is hydrogen atom, carbon number 1
-4 alkyl group, group represented by CH_2CH_2OH, group represented by COOR^9 (R^9 represents an alkyl group having 1 to 4 carbon atoms), COR^1^0 (R^1^0 is a hydrogen atom or carbon number 1
3 represents an alkyl group) or ▲There are numerical formulas, chemical formulas, tables, etc. ▼ represents a group represented by]] represents a group represented by }. (2) The rifamycin derivative and its salt according to claim 1, wherein in formula [I], X^1 is an oxygen atom. (3) The rifamycin derivative and its salt according to claim 1, wherein in formula [I], X^1 is a sulfur atom. (4) The following formula [II] ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [II] (In the formula, X^1 represents an oxygen atom or a sulfur atom) The rifamycin derivative represented by the formula }} [III ] R^1H [III] {{In the formula, R^1 is ▲There are mathematical formulas, chemical formulas, tables, etc.▼
{R^2 is a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, or C
Indicates a group represented by H_2CH_2OH, where R^3 is a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, or -(CH_2
)_lX^2 [l represents 1 to 4, X^2 is a hydroxyl group, a group represented by -CHOHCH_2OH or ▲mathematical formula,
There are chemical formulas, tables, etc. ▼ (R^4, R^5 are the same or different hydrogen atoms or alkyl groups having 1 to 3 carbon atoms))]
There are groups represented by ▲mathematical formulas, chemical formulas, tables, etc.▼
▲There are mathematical formulas, chemical formulas, tables, etc. ▼ indicates a 3- to 8-membered cyclic amino group with 2 to 7 carbon atoms, and R^6 is a hydroxyl group, a group represented by CONH_2, an aminomethyl group, or a COOR^7 (R ^7 indicates an alkyl group having 1 to 4 carbon atoms)) or ▲ Numerical formula, chemical formula, table, etc. ▼ {m, n indicate the same or different 1 to 5 , X^3 is an oxygen atom or NR^
8 [R^8 is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, C
A group represented by H_2CH_2OH, COOR^9(R
^9 represents an alkyl group having 1 to 4 carbon atoms), a group represented by COR^1^0 (R^1^0 represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms), or ▲
There are mathematical formulas, chemical formulas, tables, etc. ▼ represents a group] represents a group represented by } represents a group. }} A formula characterized by reacting a compound represented by [
I 〕 ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [ I 〕 A method for producing a rifamycin derivative represented by (in the formula, X^1 and R^1 are as described above). (5) Formula [I] ▲There are mathematical formulas, chemical formulas, tables, etc.▼ {{In the formula, X^1 represents an oxygen atom or a sulfur atom,
R^1 has ▲numerical formulas, chemical formulas, tables, etc.▼{R^2 is a hydrogen atom, an alkyl group with 1 to 3 carbon atoms, or CH_2C
Indicates a group represented by H_2OH, R^3 is a hydrogen atom,
Alkyl group having 1 to 3 carbon atoms or -(CH_2)_lX
^2 [l indicates 1 to 4, X^2 is a hydroxyl group, a group represented by -CHOHCH_2OH or ▲ mathematical formula,
There are chemical formulas, tables, etc. ▼ (R^4, R^5 are the same or different hydrogen atoms or alkyl groups having 1 to 3 carbon atoms))]
There are groups represented by ▲mathematical formulas, chemical formulas, tables, etc.▼
▲There are mathematical formulas, chemical formulas, tables, etc.▼ means 3 with 2 to 7 carbon atoms.
Represents a cyclic amino group with 8 to 8 members, R^6 is a hydroxyl group, CO
Group represented by NH_2, aminomethyl group or COO
a group represented by R^7 (R^7 represents an alkyl group having 1 to 4 carbon atoms)] or a group represented by the formula ▲,
There are chemical formulas, tables, etc. ▼ {m, n are the same or different 1 to 5, X^3 is an oxygen atom or NR^8 [R^8 is a hydrogen atom, carbon number 1
-4 alkyl group, group represented by CH_2CH_2OH, group represented by COOR^9 (R^9 represents an alkyl group having 1 to 4 carbon atoms), COR^1^0 (R^1^0 is a hydrogen atom or carbon number 1
- 3 represents an alkyl group) or ▲There are mathematical formulas, chemical formulas, tables, etc. ▼ represents a group represented by ] represents a group represented by) and antibacterial agents containing its salts as active ingredients.