JPH0197A - 16-membered ring macrolide compound - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION [Foreground of the Invention] Technical Field The present invention relates to a novel 16-membered ring macrolade compound. More specifically, the present invention relates to a novel derivative of 16i (ring macrolade compound), which is known as an antibiotic, and has excellent in vivo antibacterial activity.

Prior Art A 16-membered ring macrolade compound is a substance already known as an antibiotic.

As a known 16-membered ring macrolade compound, the formula ([1
There is a compound shown by

(In the formula, A is HO-10- or R represents OCH or CH, R2 is HR represents CH, R3 is H%CH3, CH20H or R is CH3 or C2H5, R5 is H1C0CH
or represents COC2H5, R6 is H or COC2H5
, R7 is HlCOCHCOC2H5, C0C3
Examples of antibiotics comprising the compound represented by formula (n) (representing H7 or 3'C0CHCH(CH3) 2) include the following.

2,7/ Antibiotic A Rt R2R3 Diyosamycin HO-OCH3HH Leucomycin A HO-0CR3HHTMS-19-Q
HO-OCH3HH midecamycin
HO-0CR3HHC )CH3 RR6R7 R45 CH3HHC0C3H7 CH3HC0C2H3COC3H7 CHCOCHHCOC2H5 CH3I HH CHHHH These are already widely used as antibacterial agents in humans and animals. Therefore, macrolade-based compounds can be used as pharmaceuticals (
It can be said that it occupies an important position as an antibacterial agent. In general, the physiological activity of a chemical substance largely depends on its chemical structure, and there is a constant demand for macrolade compounds that differ from existing ones in the type or substituents of their aglycone moieties and sugar moieties. There is.

[Summary of the invention]

Summary The present inventors focused on the aldehyde moiety at position 18 of 16M-ring macrolade compounds, and as a result of repeated studies to provide a derivative with excellent in vivo antibacterial activity, the present inventors discovered that a 5- or 6-B ring lactone containing S The present invention was completed based on the discovery that a derivative in which the compound has been formed exhibits an extremely high infection treatment effect (in vivo antibacterial activity) when administered orally, compared to the starting antibiotic.

That is, the 16-membered ring macrolade compound according to the present invention is represented by the following formula [I] or an acid addition salt thereof.

(In the formula, n is 0 or 1, Ro represents H or a linear or branched alkyl group, A represents HO-1R represents OCH or CH3, R2 represents H or CH3, R3 represents H% CH3, H2
0H R represents CH3 or C2H5, R5 is H2C0CH
or COC2H5, R6 represents H or COCH, and R7 represents H1 COCHCOCHC0C3H7 or 3ゝ 2 5ゝC0CHCH(CH3) 2) Effect As described above, the 16-membered ring macrolade compound according to the present invention has the following effects: It has greater in vivo antibacterial activity upon oral administration than the parent compound.

[Detailed description of the invention]

Compound The compound provided by the present invention is represented by the above formula [I]. It is preferable that n is 0. Also, R is
Lower alkyl (about 01 to C6) is preferred. Me is a methyl group.

An example of the compound of the present invention represented by formula (13) is as follows.

(m) (JM-2MP) (IVI (TL-2MP) These compounds have a basic amino group in their molecules, so they exist in the form of acid addition salts.

Acids that can be used to form such acid addition salts include, for example, inorganic acids such as hydrochloric acid, sulfuric acid, and phosphoric acid, or organic acids such as acetic acid, tartaric acid, propionic acid, citric acid, and succinic acid. Ru.

Preparation of Compound The compound of formula [1] above can be prepared by any method suitable for introducing the substituent and forming a bonded chain. A typical method consists of converting the formyl group attached to the 17-position of the known compound of formula (II) into a sulfur-containing lactone ring. Specifically, for example, the compound of formula (CI) of the present invention can be produced by condensing the compound of formula (II) with a mercaptocarboxylic acid. That is, compound (n) is prepared in an organic solvent having no active hydrogen atom in the presence of 1,3-dicyclohexylcarbodiimide (hereinafter abbreviated as DCC) and optionally a base, H R-CH(CH2), A mercaptocarboxylic acid represented by C0OH (in the formula, n1Ro has the same meaning as above), and -
React at 25-60°C for 1-6 hours. Here, examples of organic solvents without active hydrogen atoms include chloroform, dichloromethane, dichloroethane, benzene, toluene,
Examples include acetone, ethyl acetate, tetrahydrofuran, dimethylformamide, and pyridine, among which chloroform or dichloromethane is preferred. Bases include tertiary amines such as pyridine, dimethylaminopyridine, quinoline, triethylamine, tribenzylamine, and inorganic bases such as sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, etc. Dimethylaminopyridine is most preferable in terms of width. Examples of mercaptocarboxylic acids include mercaptoacetic acid, 2-mercaptopropionic acid, 3-mercaptopropionic acid, 2-mercaptobutanoic acid, 3-mercaptobutanoic acid, and the like. The reaction product can be purified using silica gel column chromatography.

The compound of formula (1) produced as described above can be produced by a method known per se, such as hydrochloric acid, phosphoric acid, sulfuric acid,
It can be converted into an acid addition salt by treatment with succinic acid, propionic acid, citric acid, etc.

The compound of formula (n) is a known compound, and can be obtained by culturing a known compound (n)-producing bacterium, followed by isolation and purification. An example of producing bacteria is as follows. All of these microorganisms are easily available to those skilled in the art.

Usefulness of the Compound The compound of formula (1) and its salt provided by the present invention are substances that exhibit strong antibacterial activity and excellent bioavailability against pathogenic microorganisms such as various Gram-positive bacteria and mycoplasma. . Its high activity is evidenced by the following tests.

In vitro antibacterial activity The compound of the formula (1) according to the present invention is a substance that exhibits antibacterial activity against various microorganisms, and the minimum growth inhibitory concentration (MIC 1 μg/ml) was determined by the agar plate dilution method. It is as shown in Table 1. In addition, as a control,
The MICs of josamycin and tylosin are also shown. Further, the names and structures of the compounds are as in the above specific examples.

The MIC was determined by preparing a cell suspension between assays at 10 6 cells/ml, inoculating it with a microblunter, and determining the presence or absence of growth after culturing. Muter-Hinton agar/pH 7,
3/37℃/20 hours.

An example of an experiment on the therapeutic effect of an in vIvo antibacterial active compound [l] on experimental infections in mice is shown.

〔Method〕

Animals: ICR male-neutral mice ± Ig.

Test RA: 6 animals per group: Ministaphylococcus ureus Smith inoculation amount: 1 to 3 x 105 CFU/mouse The pre-cultured test bacteria were suspended in 5% gastric mucin, and
), the prescribed amount was inoculated.

Drug administration: Each drug was suspended in 196 Tveen 80 and orally administered 1 hour after inoculation.

Calculation method of ED5o value: Mice were observed for 7 days after infection, and EDso was determined by the 5Bchrons-Kacrbcr method.
The value (1 g/mouse) was calculated.

〔result〕

It is as shown in Table 2. As a control, the EDso values of josamycin and tylosin are also shown. Further, the names and structures of the compounds are as in the above specific examples.

Compound III (JM-2MP) 4.6 Diyosamycin 4.4 Compound IV
(TL-2MP) 1. 6 Tylosin
5.2 Toxicity Compound of the present invention (JM-2MP or TL-2MP)
When a dose of 400 mg/kg of the drug was orally administered to mice, the mice survived on the gold side for 70 days.

Uses of the Compound The novel compound (I) provided by the present invention has excellent antibacterial activity and can be used as an active ingredient of antibacterial agents for the prevention and treatment of infectious diseases caused by various bacteria.

When used as a drug for the prevention and treatment of infectious diseases, compound (1) and its salts can be used in various media commonly used as formulations, such as water, salt solutions, alcohol, vegetable oils, polyethylene glycols, gelatin, Using lactose, amylose, magnesium stearate, talc, silylic acid, paraffin, Yoshitani oil, fatty acid monoglyceride, diglyceride, hydroxymethylcellulose, etc., capsules, tablets, powders, syrups, ointments,
It can be administered in the form of a skewer or injection. Dosages can generally be lower than those known for the known parent compounds.

Compound (I) is also a useful substance as a synthetic intermediate for new pharmaceuticals.

Experimental example The following examples are intended to illustrate the invention.

Example 1 (Synthesis of compound m (JM-2MP)) 1.00 g of josamycin was dissolved in 10 ml of dichloromethane and cooled on ice. Separately, DCC623ag was dissolved in 10 ml of dichloromethane, 536 μl of 2-mercaptopropionic acid was added dropwise under water cooling, and the mixture was stirred at 0° C. for 30 minutes, and then 100 mg of dimethylaminopyridine was added and further stirred. This solution was gradually added to the previous josamycin solution under water cooling, and the mixture was stirred at room temperature for 3 days. The reaction mixture was diluted with chloroform, shaken with saturated aqueous sodium bicarbonate solution, and the chloroform layer was separated. The aqueous layer was further extracted twice with chloroform, the chloroform layers were combined and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography using chloroform-methanol (100:1) as the eluent system, and then precipitated with hexane to obtain the target compound as a colorless powder (
0.34 g) was obtained. The analytical values of the obtained compound are as follows: 6 (a) FD-MS (m/z): 917 ([M+1]'').

(b) 'H-NMR (500 MHz, CDC13ゝ internal standard TMS) δppm: 0, 98.1.01, 1.13.1, 14.1, 27.
1.29.1. 57.2. 13.2, 31.2.5
2.2.73.3.30.3, 55.3. 89.4
．． 19.4.45.4, 63.5. 08.5.4
9.5.64.6, 06.6.58° Example 2 (Synthesis of Compound IV (TL-2MP)) Tylosin 1. oo was dissolved in 10 ml of dichloromethane and cooled on ice. Separately, DCC675a+g was dissolved in 10 ml of dichloromethane, 484 μl of 2:mercaptopropionic acid was added dropwise under water cooling, and the mixture was stirred at 0° C. for 30 minutes, followed by adding 100 mg of dimethylaminopyridine and further stirring. This solution was gradually added to the above tylosin solution while cooling with water, and the mixture was stirred for 3 days at room temperature. The reaction mixture was diluted with chloroform, shaken with saturated aqueous sodium bicarbonate,
The chloroform layer was separated. The aqueous layer was further extracted twice with chloroform, the chloroform layers were combined and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was mixed with chloroform-methanol-80:1-50:
After purification by silica gel column chromatography using 1 as the elution solvent, the desired compound (0.48 g) was obtained as a colorless powder by hexane precipitation. The analytical values of the obtained compound are as follows.

(a) FD-MS (m/z): 1004 ((M+1)).

(0) 'H-NMR (500 MHz, CDC13ゝ internal standard TMS) δppIl: 0.94.1.01.1.20.1.22.1.24.
1.26.1.29.1, 58.1.79.2, 49.
3.48.3.49.3.62.4, 30.4.56.
4.98.5.08.5.55.5.92.6.25.
7.33゜Applicant's agent Mr. Sato

Claims (1)

[Scope of Claims] A 16-membered ring macrolade compound represented by the following formula [I] or an acid addition salt thereof. ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [I] (In the formula, n is 0 or 1, R_0 represents H or a straight chain or branched alkyl group, A is HO-, O= or ▲Mathical formula, There are chemical formulas, tables, etc. Represents ▼, R_1 represents OCH_3 or CH_3, R_2 represents H
or represents CH_3, R_3 is H, CH_3CH_2
OH or ▲There are mathematical formulas, chemical formulas, tables, etc.▼, R_4 represents CH_3 or C_2H_5, R_5 represents H, COCH_3 or COC_2H_5, R_
6 represents H or COC_2H_5, R_7 represents H, C
OCH_3, COC_2H_5, COC_3H_7 or COCH_2CH(CH_3)_2)