JPH09176091A - New compound f-12436s - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the above new active substance as an antimicrobial compound existing in a culture product of a strain belonging to the genus Dasyscypella, useful as a preventive and a therapeutic agent for bacteriosis, etc. SOLUTION: F-12436A of formula I, F-12436B of formula II, F-12426C of formula III, their salts and compounds in which their carboxyl groups are protected. These active substances are obtained from a culture product of Dasyscypella nivea SANK 26995 strain (FERM BP-5323), as a fungus belonging to the genus Dasyscypella, capable of producing F-12436A, F-12436B and/or F-12426C.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to F-12436A, F-12436B and / or F-12436C, salts thereof or compounds having protected carboxyl groups thereof, which are useful as antibacterial agents.

[0002]

As a compound having a decalin skeleton and a 6-membered ring α, β-unsaturated ketone or epoxide ring, for example, macrophorin (Macrophori) produced by a microorganism of the genus Macroforma is known.
n) A, B, C and D are known (Agric.
Biol. Chem. , 47, 187-189 (1
983), 48: 1923-1925 (198).
4 years)). However, no antibacterial action has been observed for these compounds.

[0003] In addition, dasifera nivea belonging to the genus Dasifera of the disk fungus
No compound has yet been produced from ea).

[0004]

DISCLOSURE OF INVENTION Problems to be Solved by the Invention As a result of years of intensive research on compounds having antibacterial activity, the inventors of the present invention have found that dasciella nivea (dasyspyella).
The present invention has been completed based on the finding that a compound having antibacterial activity is present in the culture of a strain belonging to Nivea).

[0005]

The present invention provides (1) Formula (I)

[0006]

Embedded image

F-12436A having a salt or a compound protected with a carboxyl group thereof, (2) Formula (II)

[0008]

Embedded image

F-12436B having, a salt thereof or a compound having a protected carboxyl group, and (3)
Formula (III)

[0010]

[Chemical 6]

F-12436C, a salt thereof or a compound protected with a carboxyl group thereof.

In addition, the present invention provides (4) dicifera (d)
F-12436 belonging to the genus asyspypella)
A, F-12436B and / or F-12436C
The producing bacterium is cultivated, and from the culture, F-12436A, F
F-12436A, F-12436B consisting of harvesting -12436B and / or F-12436C
And / or a method of making F-12436C.

More specifically, the present invention provides (5) that the F-12436A, F-12436B and / or F-12436C-producing strains belonging to the genus Dasifera are Dascipyla nivea S.
The production method according to (6), which is the ANK 26995 strain.

The present invention also provides (6) F-12436.
A, F-12436B and / or F-12436
A pharmaceutical agent comprising C, a salt thereof or a compound having a protected carboxyl group thereof.

More specifically, the present invention provides (7) F-1
2436A, F-12436B and / or F-12
436C, a salt thereof, or a compound having a protected carboxyl group thereof as an active ingredient, relates to a preventive or therapeutic agent for bacterial infections.

The F-12436A of the present invention has the following physicochemical properties.

(1) Properties of substance: Acid fat-soluble powder.

(2) Molecular formula: C ₂₈ H ₄₀ O ₈ (3) Molecular weight: 504 (measured by high resolution FAB-MS method) (4) Elemental analysis value: (%) C ₂₈ H ₄₀ O ₈ .H ₂ O Measured value: C 64.62, H 7.88 Calculated value: C 64.35, H 8.10 (5) Specific optical rotation: [α] _D ²⁵ -67.7 ° (C 1.
06, methanol) (6) Ultraviolet absorption spectrum (λ _max nm (ε)): The ultraviolet absorption spectrum measured in methanol is as shown below.

237 (6400) (7) Infrared absorption spectrum: ν _max cm ^-1 potassium bromide (KBr) The infrared absorption spectrum measured by the tablet method is as shown below.

3466, 2948, 1736, 1674, 1631, 1458, 1442, 1
391, 1205, 1185, 1095, 1001, 974, 904.

(8) ¹ H-nuclear magnetic resonance spectrum:
(Δ, ppm) Nuclear magnetic resonance spectrum (360MHz) measured using tetramethylsilane as an internal standard in deuterated methanol is
It is as follows.

6.90 (1H, s), 4.96 (2H, s), 3.08 (1H, d), 2.79 (2H, q),
2.65 (2H, q), 2.38 (1H, q), 2.17 (1H, m), 1.84 (1H, m),
1.0-1.7 (11H, m), 1.39 (3H, s), 0.96 (3H, s), 0.94 (3
H, s), 0.82 (3H, s), 0.77 (3H, s).

(9) ¹³ C-nuclear magnetic resonance spectrum:
(Δ, ppm) The nuclear magnetic resonance spectrum (90 MHz) measured by using tetramethylsilane as an internal standard in deuterated methanol is as shown below.

201.5 (s), 198.9 (s), 174.7 (s), 171.7 (s), 148.8
(s), 139.2 (d), 88.3 (s), 70.7 (s), 62.6 (d), 6
0.9 (d), 60.7 (t), 51.2 (s), 50.4 (d), 45.9 (t),
45.9 (t), 44.2 (t), 43.5 (t), 37.9 (s), 34.5 (s),
33.2 (q), 30.7 (q), 27.8 (q), 25.8 (t), 25.
3 (t), 21.7 (q), 19.7 (t), 19.3 (t), 16.5 (q).

(10) High Performance Liquid Chromatography: Separation Column: Senshu Pack ODS H-2151 (column φ6 × 150 mm, manufactured by Senshu Scientific Co., Ltd.) Mobile phase: acetonitrile-0.2% trifluoroacetic acid water = 7: 3 flow Speed: 1.5 ml / min Retention time: 6.8 minutes.

F-12436B of the present invention has the following physicochemical properties. (1) Properties of substance: Acid fat-soluble powder.

(2) Molecular formula: C ₂₈ H ₄₂ O ₈ (3) Molecular weight: 506 (measured by high resolution FAB-MS method) (4) Specific rotation: [α] _D ²⁵ −0.5 ° (C 1 .3
(5) Methanol) (5) Ultraviolet absorption spectrum (λ _max nm (ε)): The ultraviolet absorption spectrum measured in methanol is end absorption only.

(6) ¹ H-nuclear magnetic resonance spectrum:
(Δ, ppm) Nuclear magnetic resonance spectrum (360MHz) measured using tetramethylsilane as an internal standard in deuterated methanol is
It is as follows.

5.71 (1H, d), 4.81 (2H, m), 4.79 (1H, q), 4.75 (1H, s),
4.55 (1H, s), 4.15 (1H, d), 3.26 (1H, d), 2.75 (2H, q),
2.65 (2H, q), 2.40 (1H, d), 2.20 (1H, q), 2.04 (1H, d)
t), 1.95 (1H, d), 1.0-1.8 (10H, m), 1.45 (3H, s), 0.90
(3H, s), 0.83 (3H, s), 0.72 (3H, s).

(7) ¹³ C-nuclear magnetic resonance spectrum:
The nuclear magnetic resonance spectrum (90 MHz) measured using tetramethylsilane as an internal standard in (δ, ppm) deuterated methanol is as shown below.

174.8 (s), 172.3 (s), 151.1 (s), 133.9 (s), 126.7
(d), 107.3 (t), 70.7 (s), 67.2 (d), 66.1 (d), 6
5.3 (t), 62.9 (s), 61.5 (d), 56.9 (d), 52.6 (d),
46.2 (t), 45.9 (t), 43.3 (t), 40.5 (s), 40.2 (t),
39.1 (t), 34.6 (s), 34.2 (q), 27.8 (q), 25.
5 (t), 24.9 (t), 22.2 (q), 20.4 (t), 15.2 (q).

(8) High-performance liquid chromatography: Separation column: Senshupack ODS H-2151 (column φ6 × 150 mm, manufactured by Senshu Kagaku Co., Ltd.) Mobile layer: Acetonitrile-0.2% trifluoroacetic acid water = 7: 3 flow Speed: 1.5 ml / min Retention time: 4.0 minutes.

F-12436C of the present invention has the following physicochemical properties. (1) Properties of substance: Acid fat-soluble powder.

(2) Molecular formula: C ₂₈ H ₄₂ O ₈ (3) Molecular weight: 506 (measured by high resolution FAB-MS method) (4) Ultraviolet absorption spectrum (λ _max nm (ε)): measured in methanol The ultraviolet absorption spectrum is as shown below.

228 (5000) (5) ¹ H-nuclear magnetic resonance spectrum: (δ, ppm) The nuclear magnetic resonance spectrum (360 MHz) measured by using tetramethylsilane as an internal standard in deuterated methanol is:
It is as follows.

6.79 (1H, d), 4.76 (2H, s), 4.64 (1H, d), 2.80 (1H, q),
2.71 (2H, s), 2.64 (2H, s), 2.09 (1H, m), 1.94 (1H, m),
1.78 (1H, m), 1.70 (1H, m), 1.2-1.7 (10H, m), 1.37 (3
H, s), 1.04 (3H, s), 0.92 (3H, s), 0.90 (3H, s), 0.86 (3
H, s).

(6) ¹³ C-nuclear magnetic resonance spectrum:
(Δ, ppm) The nuclear magnetic resonance spectrum (90 MHz) measured by using tetramethylsilane as an internal standard in deuterated methanol is as shown below.

201.9 (s), 174.7 (s), 172.1 (s), 149.7 (d), 134.8
(s), 85.7 (s), 70.6 (s), 65.7 (d), 63.4 (d), 61.
6 (t), 52.1 (d), 51.5 (d), 50.9 (s), 46.1 (t), 4
5.8 (t), 44.3 (t), 43.5 (t), 38.1 (s), 34.1 (s),
33.9 (q), 32.3 (t), 30.8 (q), 28.3 (t), 27.7
(q), 22.3 (q), 20.9 (t), 19.9 (t), 17.0 (q).

(7) High-performance liquid chromatography: Separation column: Senshupack ODS H-2151 (column φ6 × 150 mm, manufactured by Senshu Kagaku Co., Ltd.) Mobile layer: Acetonitrile-0.2% trifluoroacetic acid water = 7: 3 flow Speed: 1.5 ml / min Retention time: 4.8 min.

F-12436A and F-124 of the present invention
36B and / or F-12436C (hereinafter, "F-
12436 ”. ) Can be converted into a salt according to a conventional method. Examples of salts of F-12436 include F-1
There is no particular limitation as long as it is medically used and pharmacologically acceptable as compared with 2436s, that is, it does not reduce the activity and does not increase the toxicity. It should be noted that there is no limitation when used for purposes other than medicine, for example, when used as an intermediate. Such salts are preferably sodium salts,
Alkali metal salts such as potassium salts, lithium salts; alkaline earth metal salts such as calcium salts, magnesium salts; metal salts such as aluminum salts, iron salts, zinc salts, copper salts, nickel salts, cobalt salts; Ammonium salt; t-octylamine salt, dibenzylamine salt, morpholine salt, glucosamine salt, phenylglycine alkyl ester salt,
Ethylenediamine salt, N-methylglucamine salt, guanidine salt, diethylamine salt, triethylamine salt, dicyclohexylamine salt, N, N'-dibenzylethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzyl-phenethylamine salt, Examples thereof include amine salts such as piperazine salts, tetramethylammonium salts, and organic salts such as tris (hydroxymethyl) aminomethane salts. Preferably, it is a pharmacologically acceptable salt.

The carboxyl-protecting group means a protecting group in the reaction (when used as a so-called intermediate) and a protecting group for forming a prodrug when administered to a living body, and examples thereof include methyl, ethyl, propyl, Isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl,
"Lower alkyl group" such as hexyl: 2,2,2-trichloroethyl, 2-bromoethyl, 2-chloroethyl, 2-fluoroethyl, 2,2-
“Halogeno lower alkyl group” such as dibromoethyl: benzyl, phenethyl, 3-phenylpropyl, α
A lower alkyl group substituted with 1 to 3 aryl groups such as naphthylmethyl, β-naphthylmethyl, diphenylmethyl, triphenylmethyl, α-naphthyldiphenylmethyl, 9-anthrylmethyl; 4-methylbenzyl 2,4,6-trimethylbenzyl, 3,4,5-trimethylbenzyl, 4-methoxybenzyl, 4-methoxyphenyldiphenylmethyl, 2-nitrobenzyl, 4
-Nitrobenzyl, 4-chlorobenzyl, 4-bromobenzyl, 4-cyanobenzyl, 4-cyanobenzyldiphenylmethyl, bis (2-nitrophenyl) methyl, lower alkyl such as piperonyl, lower alkoxy, nitro, halogen, cyano An “aralkyl group” such as a lower alkyl group substituted with 1 to 3 aryl groups in which the aryl ring is substituted with: methoxymethyl, 1,1-dimethyl-1-methoxymethyl, ethoxymethyl, Lower alkoxymethyl groups such as propoxymethyl, isopropoxymethyl, butoxymethyl, t-butoxymethyl; lower alkoxylated lower alkoxymethyl groups such as 2-methoxyethoxymethyl; 2,2,2-trichloroethoxymethyl, bis ( Two
-Alkoxymethyl group "such as halogenated lower alkoxymethyl group such as -chloroethoxy) methyl; lower alkoxylation such as 1-ethoxyethyl, 1-methyl-1-methoxyethyl, 1- (isopropoxy) ethyl "Substituted ethyl group" such as ethyl group; halogenated ethyl group such as 2,2,2-trichloroethyl; aryl-selenylated ethyl group such as 2- (phenylzelenyl) ethyl; acetoxymethyl, dimethylaminoacetoxymethyl , An acyloxyalkyl group such as propionyloxymethyl, butyryloxymethyl, pivaloyloxymethyl, 1-acetoxyethyl; methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl, propoxycarbonyloxymethyl, isopropoxycarbonyloxymethyl, bromo. Alkoxycarbonyloxy methyl,
Isobutoxycarbonyloxymethyl, cyclohexyloxycarbonyloxymethyl, cyclohexyloxycarbonyloxy (cyclohexyl) methyl, 1- (methoxycarbonyloxy) ethyl, 1- (ethoxycarbonyloxy) ethyl, 1- (propoxycarbonyloxy) ethyl, 1- (Isopropoxycarbonyloxy) ethyl, 1- (butoxycarbonyloxy) ethyl, 1- (isobutoxycarbonyloxy) ethyl, 1
-(T-Butoxycarbonyloxy) ethyl, 1- (cyclohexyloxycarbonyloxy) ethyl, 1-
Alkoxycarbonyloxyalkyl groups such as (ethoxycarbonyloxy) propyl; oxodioxolenyl such as 4-methyl-oxodioxolenylmethyl, 4-phenyloxodioxolenylmethyl, oxodioxolenylmethyl Examples thereof include "carbonyloxyalkyl groups" such as alkyl groups; "phthalidyl groups" such as phthalidyl, dimethylphthalidyl, and dimethoxyphthalidyl: "aryl groups" such as phenyl and indanyl.

Further, the F-12436s of the present invention have various stereoisomers. In the present invention, equal and unequal mixtures of these isomers are all represented by a single formula. Therefore, in the present invention, all of these isomers and a mixture of these isomers are also included.

Further, in the present invention, when F-12436s form a solvate (for example, a hydrate), these are also included.

For example, the F-12436s of the present invention are
When left in the atmosphere or recrystallized, water may be absorbed, adsorbed water may adhere, or a hydrate may be formed. The present invention includes such a solvate.

Further, the present invention includes all compounds which are metabolized in the living body and converted into F-12436, so-called prodrugs.

The above-mentioned SANK 26995 strain producing the novel compound F-12436 of the present invention was isolated from the fruiting bodies of disc fungi that had grown on decayed trees collected in the Hananuki Valley of Ibaraki Prefecture.

The mycological properties of the SANK 26995 strain are as follows.

Ascos are superficial and interspersed on the matrix. It has a clear handle, and when dried, it is a club-shaped to funnel-shaped, with the edges rolled inside. The diameter and height are about 0.6 mm. The grain layer and outer surface are orange. Hairs are straight, multicellular, colorless, rough, but 1-several cells at the tip are smooth. The width is 3 to 5 μm, which is a constant thickness, but the tip portion is enormous in a club shape. The maximum length is 100 μm. The asci are cylindrical club-shaped and their size is 37-45 x
3.5-4.5 μm, a hook-shaped structure is recognized at the base, and the tip is subconical. Ascospores are elliptical to spindle-shaped, and their size is 5-7.5 x 2-2.5 μm.
It is a single cell and colorless. The side thread is spear-shaped and extends about 10 μm longer than the ascus. The outer skin layer is light to light brown and presents a rectangular fungal tissue. The pulp layer exhibits entangled fungal tissue.

The culture properties of this strain are as follows. When this strain is cultured on PDA at 20 ° C. for 2 weeks, the diameter of the colony reaches 15 mm. The hyphae are densely assembled, partly buried and partly superficial. Aerial mycelia develop in a bundle, colonies have a fluffy surface, and rise slightly toward the center. The edge of the colony has an irregular sawtooth shape. Both front and back are pale yellow.

As a result of searching for strains corresponding to this strain from the above-mentioned mycological properties, Raitvir, A. et al. Written "The
Genus Dasycyphella, EEST
INSV Teaduste Akadeemia T
oimised ", 26, 29-35 (197).
7 years) described in Dasycyphella
It was in good agreement with the description of nivea (Dasifera nivea). Therefore, this strain was designated as Dasycypher
a nivea (Kunze: Fr.) Raitv.
It was identified as the SANK 26995 strain. This strain is hereinafter referred to as "Dasciella nivea SANK 26995 strain".

The SANK 26995 strain is Dasy.
scyphella neverea (Kunze: F
r. ) Raitv. As SANK 26995 strain, 1
Deposited on December 01, 995 at the Institute of Biotechnology, Institute of Biotechnology, Ministry of International Trade and Industry, with deposit number FERM BP
-5323 is attached.

As is well known, discophytes can be used naturally or artificially (for example, ultraviolet irradiation, irradiation,
Mutation is liable to occur due to chemical treatment, etc.), and the same applies to the SANK 26995 strain of the present invention. The SANK 26995 strain referred to in the present invention includes all mutants thereof. Further, these mutants also include those obtained by genetic methods such as recombination, transduction, transformation and the like. That is, the SANK 26995 strain producing F-12436, mutants thereof and strains not clearly distinguished from them are all SANK.
26995 strain.

[0053]

DETAILED DESCRIPTION OF THE INVENTION To obtain the F-12436s of the present invention, the culturing of these microorganisms is carried out in a medium such as those used to produce other fermentation products. Such a medium contains a carbon source, a nitrogen source and an inorganic salt that can be assimilated by the microorganism.

Generally, carbon sources include glucose, fructose, maltose, sucrose, mannitol, glycerol, dextrin, oats, rye,
Corn starch, potato, corn flour,
Examples include soybean oil, cottonseed oil, molasses, citric acid, tartaric acid, and the like. These carbon sources may be used alone in the medium, or some carbon sources may be used in combination in the medium.

The exact amount of carbon source used in the medium depends on the other components in the medium, but it usually varies from 1 to 10% by weight of the amount of medium.

As the nitrogen source, a substance containing a protein is generally used in the fermentation process. Suitable nitrogen sources include soybean flour, bran, peanut flour, cottonseed flour, casein hydrolyzate,
Examples include pharmamin, fish meal, corn steep liquor, peptone, meat extract, yeast, yeast extract, malt extract, sodium nitrate, ammonium nitrate, ammonium sulfate and the like. Various nitrogen sources are 0.2-6% by weight
Can be used alone or in combination.

The carbon source and nitrogen source are generally used in combination, but need not be in pure form. Less pure ones containing trace amounts of growth factors, vitamins and mineral nutrition may be used. In addition, usual salts capable of obtaining ions such as sodium, potassium, magnesium, ammonium, calcium, phosphate, sulfate, chloride, and carbonate may be added to the medium. In addition, when a sulfur compound that can be assimilated by bacteria is added to the medium, the production amount of the target substance may increase. For example, zinc sulfate, copper sulfate, ferrous sulfate, sulfates such as ammonium sulfate, thiosulfates such as ammonium thiosulfate,
Inorganic sulfur compounds such as sulfites such as ammonium sulfite; Sulfur-containing amino acids such as cystine, cystine, L-thiazolidine-4-carboxylic acid, organic sulfur compounds such as sulfur-containing peptides such as hypotaurine and glutathione Ferrous sulfate If necessary, heavy metals such as copper sulfate, vitamins such as vitamin B ₁ and biotin, and cell growth promoting substances such as thiamine may be added. It also contains manganese, iron, molybdenum, zinc and other trace metals. If necessary, an antifoaming agent such as silicone oil, polyalkylene glycol ether, vegetable oil, animal oil, or a surfactant may be added to the medium, particularly if the nutrient medium is considerably foamed (especially during liquid culture). Is preferred). Dasifera Nivea SANK 269
P of the medium for culturing 95 strains to produce F-12436
H can be changed to 5.0-7.0.

The growth temperature of the bacterium is 15 ° C. to 37 ° C., but the growth range of 22 ° C. to 35 ° C. is good, and 22 ° C. to 26 ° C. is suitable for the production of F-12436. .

The culturing method is not particularly limited and may be a culturing method generally used for microorganisms, such as a stirring culturing method,
A shaking culture method, an aeration culture method and the like can be used. Suitably, the stirring culture method which is an aerobic liquid culture method,
The shaking culture method or the aeration culture method is more preferable, and the shaking culture method is more preferable. The aeration and agitation culture method is industrially preferable.

For small-scale culture, it is preferable to carry out shaking culture at 23 ° C. for several days. Cultivation begins in a Erlenmeyer flask with 1-2 stages of seed development. The developing medium of the seed can use a combination of carbon and nitrogen sources. Seed flask in a constant temperature incubator 23
Shake at 7 ° C. for 7 days or until fully grown. The grown seed is used to inoculate a second seed or production medium. If an intermediate development step is used, it is grown in essentially the same way and partially used to inoculate the production medium. The inoculated flask is shaken at constant temperature for several days, and after the incubation is completed, the contents of the flask are centrifuged or filtered.

In the case of large-scale culture, it is preferable to culture in a suitable tank equipped with a stirrer and an aeration device. According to this method, the nutrient medium can be prepared in the tank. The nutrient medium is sterilized by heating to 121 ° C., after cooling, the sterile medium is inoculated with the pre-grown seeds. Culture is 23
It is carried out by aeration stirring at ℃. This method is suitable for obtaining large amounts of compounds.

F-12 produced over the course of culture
The change with time of the amount of 436s can be measured using high performance liquid chromatography. Usually, the maximum production of F-12436s is reached after 120 to 200 hours of culture.

After the completion of the culture, the F-12436s existing in the liquid portion and the microbial cells in the culture solution are separated from the microbial cells and other solid portions by a filtration operation using diatomaceous earth as a filter aid or by centrifugation to separate the cells. It can be obtained by extracting and purifying F-12436s present in the filtrate or supernatant and in the bacterial cells by utilizing their physicochemical properties. For example,
The F-12436s present in the filtrate or the supernatant are extracted with an organic solvent immiscible with water under acidic pH conditions, for example, ethyl acetate, chloroform, ethylene chloride, methylene chloride-butanol alone or in combination thereof. It can be purified. Alternatively, as an adsorbent, for example, activated carbon or Amberlite XA which is an adsorbent resin
D-2, XAD-4 (manufactured by Rohm and Haas Company), etc., Diaion HP-10, HP-20, CHP-2
0, HP-50 (manufactured by Mitsubishi Kasei Co., Ltd.) and the like are used. A liquid containing F-12436 is passed through a layer of the adsorbent as described above to adsorb and remove impurities, or after adsorbing F-12436, methanol water,
It can be obtained by eluting with acetone water, butanol water or the like. In addition, F-124 existing in the bacterial cells
The 36-class compounds are obtained by extracting with 50-90% hydrous acetone or hydrous methanol to remove the organic solvent, and then performing the same extraction and purification operation as for the filtrate.

F-12436 thus obtained
Examples of the class are adsorption column chromatography using a carrier such as silica gel and magnesium-silica gel florisil, partition column chromatography using Sephadex LH-20 (manufactured by Pharmacia), Cosmo Seal 140C ₁₈ -OPN ( It can be purified by column chromatography using a reverse phase carrier such as a trade name, manufactured by Nacalai Tesque Co., Ltd., and high performance liquid chromatography using a normal phase or reverse phase column.

F-12436s can be separated and purified by repeatedly using the above separation and purification means alone or in appropriate combination.

The F-12436s have a carboxyl group. The reaction for protecting the carboxyl group is performed by the following method.

1) When the protecting group for the carboxyl group is a "lower alkyl group", a "halogeno lower alkyl group" or an "aralkyl group", 1-1) the reaction is carried out in a solvent containing the carboxyl group and the corresponding alcohol. (Preferably, the alcohol itself corresponding to the ester residue portion is used as a solvent.), And it is achieved by reacting with an acid catalyst and performing solvolysis.
The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but preferably, aliphatic hydrocarbons such as hexane and heptane;
Aromatic hydrocarbons such as benzene, toluene, xylene; methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, halogenated hydrocarbons such as dichlorobenzene; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane ,
Ethers such as dimethoxyethane and diethylene glycol dimethyl ether; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone and cyclohexanone; nitriles such as acetonitrile and isobutyronitrile; formamide, N, N-
Examples thereof include amides such as dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone and hexamethylphosphorotriamide. As the acid catalyst used,
It is not particularly limited as long as it is used as an acid catalyst in a usual reaction, but preferably, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid and phosphoric acid, acetic acid, formic acid, oxalic acid and methane. Bronsted acids such as organic acids such as sulfonic acid, paratoluenesulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid; Lewis acids such as boron trichloride, boron trifluoride, boron tribromide; or acidic ion exchange resins The organic acid is preferable, and the strong organic acid is more preferable. The reaction temperature is 0 ° C. to the boiling point of the solvent used, and preferably 50 ° C. to the boiling point of the solvent used. The reaction time varies depending mainly on the reaction temperature, the starting compound, the reaction reagent or the type of solvent used, but is usually 10 minutes to 6 days, and preferably 30 minutes to 3
Days.

1-2) Alternatively, the reaction is carried out by reacting a carboxyl group with (i) a halogenating agent (for example, phosphorus pentachloride, thionyl chloride, oxalyl chloride, etc.) at room temperature for 30 minutes to 5 minutes.
Treatment with a corresponding acid halide or (ii) a chloroformate such as methyl chloroformate and ethyl chloroformate in the presence of an organic base such as (ii) triethylamine to convert to a corresponding acid anhydride. After that, in an inert solvent (not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, preferably benzene,
Aromatic hydrocarbons such as toluene and xylene; halogenated hydrocarbons such as methylene chloride and chloroform; esters such as ethyl acetate and propyl acetate; ethers such as ether, tetrahydrofuran, dioxane and dimethoxyethane. -Ters or nitriles such as acetonitrile), bases (eg triethylamine etc.)
In the presence of a corresponding alcohol (potassium t-butoxide is preferable when producing t-butyl ester) and −10 ° C. to 150 ° C., preferably around room temperature,
10 minutes to 15 hours, preferably 30 minutes to 10 hours,
It can also be achieved by a reaction method.

1-3) Alternatively, the reaction is carried out by reacting the carboxyl group with a diazoalkane such as diazomethane or diazoethane (usually an ether solution of diazoalkane) at around room temperature (under heating if necessary depending on the type of reaction system). It may be carried out.), Also achieved by the method of contacting.

After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, when an acidic ion exchange resin is used as the acid catalyst, it is obtained by filtering and distilling the solvent from the filtrate, and when using another acid catalyst, the reaction mixture is appropriately neutralized. Then
If insolubles are present, they are removed by filtration, water and an immiscible organic solvent such as ethyl acetate are added, and after washing with water, the organic layer containing the target compound is separated and dried over anhydrous magnesium sulfate or the like. , Obtained by distilling off the solvent. If necessary, the obtained target compound can be obtained by a conventional method,
For example, recrystallization, reprecipitation, or a method commonly used for separation and purification of organic compounds, such as Sephadex L.
H-20 (Pharmacia), Amberlite XAD
-11 (manufactured by Rohm and Haas), Diaion HP-20 (manufactured by Mitsubishi Kasei Co., Ltd.), a method using a synthetic adsorbent such as partition column chromatography, or silica gel or It can be separated and purified by appropriately combining normal-phase / reverse-phase column chromatography methods (preferably high-performance liquid chromatography) using alkylated silica gel and eluting with a suitable eluent.

2) When the protective group for the carboxy group is "alkoxymethyl group", "substituted ethyl group", "carbonyloxyalkyl group", "phthalidyl group", "aryl group", 2-1) the reaction is carboxyl This is achieved by reacting ^a group in which the hydrogen atom of the group or the carboxyl group is substituted with a metal such as sodium or potassium with a compound having the general formula ^Ra- Xa.

In the above formula, ^Ra represents the above-mentioned "alkoxymethyl group", "substituted ethyl group", "carbonyloxyalkyl group", "phthalidyl group" or "aryl group".

X ^a is, for example, a halogen atom such as chlorine, bromine or iodine; a lower alkanesulfonyloxy group such as methanesulfonyloxy or ethanesulfonyloxy; a halogeno such as trifluoromethanesulfonyloxy or pentafluoroethanesulfonyloxy. Lower alkanesulfonyloxy group; benzenesulfonyloxy,
p-toluenesulfonyloxy, arylsulfonyloxy groups such as p-nitrobenzenesulfonyloxy, etc.,
A group that leaves as a nucleophilic residue is shown.

Examples of the compound having R ^a -X ^a include acetoxymethyl chloride, pivaloyloxymethyl bromide, acyloxyalkyl halides such as pivaloyloxymethyl chloride, ethoxycarbonyloxymethyl chloride, iso Alkoxycarbonyloxyalkyl halides such as propoxycarbonyloxymethyl chloride, 1- (ethoxycarbonyloxy) ethyl chloride, 1- (ethoxycarbonyloxy) ethyl iodide, phthalidyl halides or (5-methyl-2-oxo- 5-Methyl-1,3-dioxolen-4-yl) methyl halides can be mentioned.

The reaction is carried out in a solvent in the presence of a base. The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, and is preferably an aliphatic hydrocarbon such as hexane or heptane;
Aromatic hydrocarbons such as benzene, toluene, xylene; methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, halogenated hydrocarbons such as dichlorobenzene; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane ,
Ethers such as dimethoxyethane and diethylene glycol dimethyl ether; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone and cyclohexanone; nitriles such as acetonitrile and isobutyronitrile; formamide, N, N-
Examples thereof include amides such as dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone and hexamethylphosphorotriamide.

The base used is not particularly limited as long as it is used as a base in a usual reaction, and preferably alkali metal carbonates such as sodium carbonate, potassium carbonate and lithium carbonate; carbonic acid. Alkali metal hydrogen carbonates such as sodium hydrogen, potassium hydrogen carbonate, lithium hydrogen carbonate; alkali metal hydrides such as lithium hydride, sodium hydride, potassium hydride; sodium hydroxide, potassium hydroxide, barium hydroxide , Alkali metal hydroxides such as lithium hydroxide;
Inorganic bases such as alkali metal fluorides such as sodium fluoride and potassium fluoride; alkali metal such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium t-butoxide, lithium methoxide Alkoxides; mercaptan alkali metals such as sodium methyl mercaptan and sodium ethyl mercaptan; N-methylmorpholine, triethylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline, 4 -(N, N-dimethylamino) pyridine,
2,6-di (t-butyl) -4-methylpyridine, quinoline, N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] nona
5-ene, 1,4-diazabicyclo [2.2.2] octane (DABCO), 1,8-diazabicyclo [5.
4.0] organic bases such as undec-7-ene (DBU) or organic metal bases such as butyllithium, lithium diisopropylamide, lithium bis (trimethylsilyl) amide. Generally, the reaction is at -20 ° C to 120 ° C, preferably 0-80 ° C.
It is achieved by reacting for 0.5 to 10 hours.

2-2) Alternatively, in the reaction, a carboxyl group or a group in which a hydrogen atom of the carboxyl group is substituted with a metal such as sodium or potassium is prepared by the general formula ^Ra- OH.
It is achieved by reacting a compound having the formula (I) with a condensing agent and a catalytic amount of a base.

(In the above formula, R ^a has the same meaning as described above.) The reaction is preferably carried out in the presence of a solvent. The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, and is preferably aliphatic hydrocarbons such as hexane and heptane; benzene, toluene and xylene. Aromatic hydrocarbons; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, dichlorobenzene; esters such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate, diethyl carbonate Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; nitriles such as acetonitrile and isobutyronitrile; formamide, N, N-dimethylformamide, N, N-dimethyl Acetamide, N- methyl-2-pyrrolidone, N-
Amides such as methylpyrrolidinone and hexamethylphosphorotriamide can be mentioned. Examples of the condensing agent used include N-hydroxysuccinimide,
1-hydroxybenzotriazole, N-hydroxy-
N-hydroxy derivatives such as 5-norbornene-2,3-dicarboximide; disulfide compounds such as 2,2′-dipyridyldisulfide; N, N′-
Succinic acid compounds such as disuccinimidyl carbonate; phosphinic chloride compounds such as N, N'-bis (2-oxo-3-oxazolidinyl) phosphinic chloride; N, N'- Disuccinimidyl oxalate (DSO), N, N'-diphthalimido oxalate (DPO), N, N'-bis (norbornenyl succinimidyl) oxalate (BNO), 1,
1'-bis (benzotriazolyl) oxalate (BB
TO), 1,1'-bis (6-chlorobenzotriazolyl) oxalate (BCTO), 1,1'-bis (6-
Oxalate derivatives such as trifluoromethylbenzotriazolyl) oxalate (BTBO); triarylphosphines such as triphenylphosphine, diethyl lower azodicarboxylates such as diethyl azodicarboxylate-triphenylphosphine -Triarylphosphines such as triarylphosphines; N-ethyl-
N-lower alkyl-5-arylisoxazolium-3'-sulphonates such as 5-phenylisoxazolium-3'-sulphonate; N ', N'-dicyclohexylcarbodiimide (DCC) Like N ', N'
-Dicycloalkylcarbodiimides, 1-ethyl-3
-(3-dimethylaminopropyl) carbodiimide (E
Carbodiimide derivatives such as DAPC); diheteroaryl diselenides such as di-2-pyridyl diselenide;
Arylsulfonyltriazolides such as p-nitrobenzenesulfonyltriazolide; 2-halo-1-lower alkylpyridinium halides such as 2-chloro-1-methylpyridinium iodide; such as diphenylphosphoryl azide (DPPA) Diarylphosphoryl azides; 1,1′-oxalyldiimidazole,
Imidazole derivatives such as N, N'-carbonyldiimidazole; 1-hydroxybenzotriazole (HO
Benzotriazole derivatives such as BT); dicarboximide derivatives such as N-hydroxy-5-norbornene-2,3-dicarboximide (HONB); preferably diarylphosphoryl azides. Is. The base used is not particularly limited as long as it is used as a base in a usual reaction, but preferably N-methylmorpholine, triethylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methyl are used. Piperidine, pyridine, 4-pyrrolidinopyridine, picoline, 4-
Examples of organic bases such as (N, N-dimethylamino) pyridine, 2,6-di (t-butyl) -4-methylpyridine, quinoline, N, N-dimethylaniline, N, N-diethylaniline. You can In addition, 4- (N, N-dimethylamino) pyridine and 4-pyrrolidinopyridine are
Catalytic amounts can also be used in combination with other bases,
In addition, in order to effectively carry out the reaction, quaternary ammonium salts such as benzyltriethylammonium chloride and tetrabutylammonium chloride, dibenzo-
Crown ethers such as 18-crown-6 can also be added. Reaction temperature is -20 ° C to 80 ° C
The temperature is preferably 0 ° C. to room temperature. The reaction time varies depending mainly on the reaction temperature, the starting compound, the reaction reagent or the type of solvent used, but is usually 10 minutes to 3 days, and preferably 30 minutes to 1 day.

2-3) Alternatively, in the reaction, a carboxyl group or a group in which a hydrogen atom of the carboxyl group is substituted with a metal such as sodium or potassium is prepared by the general formula ^Ra- OH.
It is achieved by reacting a compound having ## STR6 ## with a halogenated phosphoric acid diester such as diethyl chlorophosphate and a base in a solvent.

(In the above formula, R ^a has the same meaning as described above.) The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, and is suitable. Include aliphatic hydrocarbons such as hexane and heptane; aromatic hydrocarbons such as benzene, toluene and xylene;
Halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, dichlorobenzene; esters such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate, diethyl carbonate; diethyl ether, diisopropyl ether Ethers such as ter, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; nitriles such as acetonitrile and isobutyronitrile; formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N- Methyl-2-
Mention may be made of amides such as pyrrolidone, N-methylpyrrolidinone and hexamethylphosphorotriamide. As the base to be used, the same base as described in 2-1) above can be used. The reaction temperature is 0 ° C to the reflux temperature of the solvent used, and preferably room temperature to 50 ° C. The reaction time is
The reaction time is usually 10 minutes to 3 days, preferably 30 minutes to 1 day, varying mainly depending on the reaction temperature, the raw material compound, the reaction reagent or the type of solvent used.

The lower alkylation can also be carried out by reacting with a dialkyl sulfuric acid such as dimethyl sulfuric acid or diethyl sulfuric acid according to a conventional method.

After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration, water and an immiscible organic solvent such as ethyl acetate are added, and after washing with water, the organic layer containing the target compound is separated. It is obtained by distilling off the solvent after drying over anhydrous magnesium sulfate and the like. If necessary, the obtained target compound is subjected to a conventional method such as recrystallization, reprecipitation, or a method commonly used for separation and purification of organic compounds, such as silica gel, alumina, magnesium-silica gel florisil, etc. Adsorption column chromatography using a carrier; Sephadex LH-20 (Pharmacia), Amberlite XAD-11 (Rohm and
Haas Co., Ltd.), Diaion HP-20 (manufactured by Mitsubishi Kasei Co., Ltd.), a method using a synthetic adsorbent such as partition column chromatography, or normal phase / reverse using silica gel or alkylated silica gel. It can be separated and purified by appropriately combining a phase column chromatography method (preferably high performance liquid chromatography) and eluting with a suitable eluent.

The F-12436s of the present invention have an antibacterial action and are useful as a preventive or therapeutic drug for bacterial infections.

When the F-12436s of the present invention are used as prophylactic or therapeutic agents for bacterial infections, they are administered in various forms. The administration form is not particularly limited and is determined according to various formulation forms, patient age, sex and other conditions, degree of disease and the like. For example, tablets, pills, powders, granules, syrups, solutions, suspensions, emulsions, granules and capsules are orally administered. In the case of an injection, it may be administered alone or mixed with an ordinary replenisher such as glucose or amino acid, and then intravenously administered. Further, if necessary, it may be administered intramuscularly, intracutaneously, subcutaneously or intraperitoneally. In the case of suppositories, they are administered rectally.

In these various preparations, the main ingredient is an excipient, a binder, a disintegrant, a lubricant, a solubilizer, a flavoring agent,
It can be formulated using known auxiliaries usually used in the field of known pharmaceutical preparations such as coating agents.

In the case of molding into tablets, those conventionally known in this field can be widely used as carriers, for example, lactose, sucrose, sodium chloride, glucose, urea, starch,
Binding of excipients such as calcium carbonate, kaolin, crystalline cellulose, silicic acid, water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone sugar Agent, dry starch, sodium alginate, agar powder, laminaran powder, sodium hydrogen carbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, disintegrants such as lactose, white sugar, stearin, cacao Decay inhibitors such as butter and hydrogenated oil, quaternary ammonium bases, absorption promoters such as sodium lauryl sulfate, humectants such as glycerin and starch, adsorbents such as starch, lactose, kaolin, bentonite and colloidal silicic acid. , Ltd. talc, stearates,
Lubricants such as boric acid powder and polyethylene glycol can be exemplified. Furthermore, tablets are tablets that have been given a normal coating as necessary,
For example, a sugar-coated tablet, a gelatin-coated tablet, an enteric-coated tablet, a film-coated tablet, a double tablet, or a multi-layer tablet can be used.

In the case of molding in the form of pills, those conventionally known in this field can be widely used as carriers, for example, excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin and talc, and Arabic. Examples thereof include rubber powder, tragacanth powder, a binder such as gelatin and ethanol, a disintegrating agent such as laminaranthantene, and the like. In the case of molding in the form of suppositories, various carriers conventionally known in this field can be widely used, and examples thereof include polyethylene glycol, cocoa butter, higher alcohols, esters of higher alcohols, gelatin, and semisynthetic glycerides. it can.

When prepared as an injection, the solution and suspension are preferably sterilized and isotonic with blood, and when formed into a solution, emulsion and suspension, they are diluted. All the agents conventionally used in this field can be used as the agent, for example, water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol,
Examples thereof include polyoxyethylene sorbitan fatty acid esters. In this case, a sufficient amount of salt, glucose, or glycerin to prepare an isotonic solution may be contained in the pharmaceutical preparation, and a usual solubilizing agent, buffer, soothing agent, etc. may be added. You may add.

If necessary, coloring agents, preservatives, fragrances,
Flavors, sweeteners, etc. and other pharmaceuticals may be included.

The amount of the active ingredient compound contained in the above-mentioned pharmaceutical preparation is not particularly limited and can be appropriately selected within a wide range, but it is usually 1-70% by weight, preferably 1-30% by weight in the total composition. Is appropriate.

The dose varies depending on symptoms, age, weight, administration method, dosage form, etc., but is usually 1 for adults.
2,000 mg per day (upper limit is preferably 200 m)
g, more preferably 20 mg), and the lower limit is 0.
001 mg (preferably 0.01 mg, more preferably 0.1 mg) can be administered.

[0092]

EXAMPLES Next, the present invention will be described in more detail by way of examples, but the present invention is not limited thereto.

Example 1 F-12436s (1) Cultured D. fermenta nivea SANK 26995 strain was aseptically sterilized (121 ° C., 20 minutes). One platinum loop was placed in a 500 ml Erlenmeyer flask containing 80 ml of a medium having the following composition. The cells were brought into contact with each other and cultured at 23 ° C. for 7 days in a rotary shaker at 210 rpm (7 cm radius of rotation).
Using the thus obtained culture solution as a seed culture solution, 10% of the seed culture solution was inoculated into 36 500 ml Erlenmeyer flasks containing 80 ml of the same composition medium, and the seed culture solution was inoculated at 23 ° C.
The culture was carried out for 7 days on a rotary shaker at 210 rpm (7 cm radius of rotation).

[0094]

[Table 1] Medium composition ───────────────────────────── Glycerol 30 g Glucose 30 g Soybean flour (NISSIN SOYA FLOWER )) 10 g yeast extract (manufactured by Difco) 2.5 g soluble starch (Kanto Chemical Co., Inc.) 20 g gelatin (Kanto Chemical Co., Ltd.) ^* 2.5 g ammonium nitrate 2.5 g antifoam ^** 0.5 ml tap water 1000 ml ─────────────────────────────── pH 6.5 (before sterilization).

^* Use after dissolving in hot water.

^** Nissan Disform CB-44
10% acetone solution of 2 (manufactured by NOF CORPORATION).

(2) Isolation and Purification 2880 ml of the obtained culture solution was added to 3000 rpm, 1
By centrifuging for 0 minutes, the mixture was separated into a supernatant and a precipitate (cell portion). 1.5 liter of the obtained supernatant was adjusted to pH with hydrochloric acid.
After adjusting to 4, the mixture was extracted by adding an equal amount of ethyl acetate.
In addition, 1 liter of acetone was added to the precipitate (cell portion) and the mixture was stirred. After 1 hour of stirring, the solution was filtered and the filtrate was collected. After acetone was distilled off from the filtrate, hydrochloric acid was added to the aqueous layer to adjust the pH.
Adjusted to 3.0. Then, 2 liters of ethyl acetate was added to the aqueous layer for extraction. The ethyl acetate extracted in addition to the supernatant and the ethyl acetate extracted in addition to the aqueous layer were combined, then washed with water and dried over anhydrous sodium sulfate. The extract was concentrated to dryness under reduced pressure to obtain 7.47 g of an oily substance. The obtained oily substance was dissolved in 50 ml of 60% methanol,
It was adsorbed on a Cosmo Seal column (size, 3.5 × 25 cm). Then, the mixture was developed with the same solvent and then eluted with 50% acetonitrile. Fraction containing F-12436A
1.4 g and 1.3 g of a fraction containing F-12436B and F-12436C were collected. Fractions containing F-12436A were loaded onto a Sephadex LH-20 column (size,
6.5 × 48 cm) and eluted with a mixed solvent of methylene chloride-ethyl acetate-methanol (2: 2: 1). When the mixed solvent is concentrated to dryness, F-12436A 66
0 mg was obtained. Next, F-12436B and F-
The fraction containing 12436C was also applied to a column (size, 6.5 × 48 cm) of Sephadex LH-20 in the same manner as the fraction containing F-12436A, and methylene chloride-ethyl acetate-methanol (2: 2: 1). Elution with a mixed solvent of No. 1 and concentration of the mixed solvent to dryness yielded 1.02 g of powders of F-12436B and F-12436C. The obtained powder was dissolved in 10 ml of methanol, and subjected to high performance liquid chromatography and fractionated (preparative conditions, column: Senshupack ODSH-5251 (2.5 ×
250 cm), eluent: acetonitrile-0.2% trifluoroacetic acid water = 7: 3, flow rate: 10 ml / min). F-1
Collecting fractions containing 2436B and F-12436C,
Each was concentrated. Then, when subjected to lyophilization, F-1
2436B 630 mg and F-12436C 28
0 mg was obtained.

[0098]

[Test Example] Test Example 1 F-12436A and F-12436C
Antibacterial activity of F-12436 against general Gram positive and negative bacteria
Minimum inhibitory concentration (MIC) of A and F-12436C
Was measured by an agar medium dilution method using a normal agar medium (manufactured by Eiken Chemical Co., Ltd.).

Table 2 shows the results.

[0100]

[Table 2] ─────────────────────────────────── Minimum inhibitory concentration (MIC) (μg) / Ml) F-12436A F-12436C ─────────────────────────────────── Staphylococcus aureus 209P 3.1 25 Staphylococcus aureus 56R 6.2 25 Staphylococcus aureus 535 (MRSA) 6.2 25 Enterococcus faecalis 681 12.5 50 Escherichia coli NHIJ>200> 200 Salmonella Enteritidis>200> 200 Klebshera new monnier 806>200> 200 ───── ────────────────────────────── As shown in Table 2, F-12436A and F-1
2436C was effective against general Gram-positive bacteria.

[0101]

[Formulation Example] Next, a formulation example will be given. Formulation Example 1 Oral capsule

[0102]

Table 3 Formulation F-12436A 30 mg Lactose 170 mg Corn starch 150 mg Magnesium stearate 2 mg ──────────────────────────── 352 mg The powders of the above formulation were mixed and passed through a 30 mesh sieve, then 352 mg of this powder was placed in a gelatin capsule,
Use as a capsule.

[0103]

INDUSTRIAL APPLICABILITY The novel compound F-12436 of the present invention exhibits antibacterial action and is useful as a preventive or therapeutic drug for various bacterial infections.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Office reference number FI technical display area // (C12P 7/42 C12R 1: 645)

Claims (10)

[Claims] 1. A compound of the formula (I) F-12436A, a salt thereof or a compound having a protected carboxyl group. 2. Formula (II): F-12436B, a salt thereof, or a compound having a protected carboxyl group. 3. Formula (III): F-12436C, a salt thereof, or a compound having a protected carboxyl group. 4. F-1243 having the following physicochemical properties.
6A: (1) Property of substance: acidic fat-soluble powder. (2) Molecular formula: C ₂₈ H ₄₀ O ₈ (3) Molecular weight: 504 (measured by high resolution FAB-MS method) (4) Elemental analysis value: (%) Measured value as C ₂₈ H ₄₀ O ₈ · H ₂ O : C 64.62, H 7.88 Calculated value: C 64.35, H 8.10 (5) Specific rotation: [α] _D ²⁵ -67.7 ° (C 1.
06, methanol) (6) Ultraviolet absorption spectrum (λ _max nm (ε)): The ultraviolet absorption spectrum measured in methanol is as shown below. 237 (6400) (7) Infrared absorption spectrum: ν _max cm ^-1 Potassium bromide (KBr) The infrared absorption spectrum measured by the tablet method is as shown below. 3466, 2948, 1736, 1674, 1631, 1458, 1442, 1
391, 1205, 1185, 1095, 1001, 974, 904. (8) ¹ H-nuclear magnetic resonance spectrum: (δ, ppm) Nuclear magnetic resonance spectrum (360 MHz) measured by using tetramethylsilane as an internal standard in deuterated methanol is
It is as follows. 6.90 (1H, s), 4.96 (2H, s), 3.08 (1H, d), 2.79 (2H, q),
2.65 (2H, q), 2.38 (1H, q), 2.17 (1H, m), 1.84 (1H, m),
1.0-1.7 (11H, m), 1.39 (3H, s), 0.96 (3H, s), 0.94 (3
H, s), 0.82 (3H, s), 0.77 (3H, s). (9) ¹³ C-nuclear magnetic resonance spectrum: (δ, ppm) A nuclear magnetic resonance spectrum (90 MHz) measured by using tetramethylsilane as an internal standard in deuterated methanol is as shown below. 201.5 (s), 198.9 (s), 174.7 (s), 171.7 (s), 148.8
(s), 139.2 (d), 88.3 (s), 70.7 (s), 62.6 (d), 6
0.9 (d), 60.7 (t), 51.2 (s), 50.4 (d), 45.9 (t),
45.9 (t), 44.2 (t), 43.5 (t), 37.9 (s), 34.5 (s),
33.2 (q), 30.7 (q), 27.8 (q), 25.8 (t), 25.
3 (t), 21.7 (q), 19.7 (t), 19.3 (t), 16.5 (q). (10) High-performance liquid chromatography: Separation column: Senshupack ODS H-2151 (column φ6 × 150 mm, manufactured by Senshu Kagaku Co., Ltd.) Mobile layer: Acetonitrile-0.2% trifluoroacetic acid water = 7: 3 Flow velocity: 1 0.5 ml / min Retention time: 6.8 min The salt or its carboxyl group protected compound. 5. F-1243 having the following physicochemical properties.
6B: (1) Properties of substance: acidic fat-soluble powder. (2) Molecular formula: C ₂₈ H ₄₂ O ₈ (3) Molecular weight: 506 (measured by high resolution FAB-MS method) (4) Specific rotation: [α] _D ²⁵ −0.5 ° (C 1.3
(5) Methanol) (5) Ultraviolet absorption spectrum (λ _max nm (ε)): The ultraviolet absorption spectrum measured in methanol is end absorption only. (6) ¹ H-nuclear magnetic resonance spectrum: (δ, ppm) The nuclear magnetic resonance spectrum (360 MHz) measured by using tetramethylsilane as an internal standard in deuterated methanol is
It is as follows. 5.71 (1H, d), 4.81 (2H, m), 4.79 (1H, q), 4.75 (1H, s),
4.55 (1H, s), 4.15 (1H, d), 3.26 (1H, d), 2.75 (2H, q),
2.65 (2H, q), 2.40 (1H, d), 2.20 (1H, q), 2.04 (1H, d)
t), 1.95 (1H, d), 1.0-1.8 (10H, m), 1.45 (3H, s), 0.90
(3H, s), 0.83 (3H, s), 0.72 (3H, s). (7) ¹³ C-nuclear magnetic resonance spectrum: (δ, ppm) A nuclear magnetic resonance spectrum (90 MHz) measured by using tetramethylsilane as an internal standard in deuterated methanol is as shown below. 174.8 (s), 172.3 (s), 151.1 (s), 133.9 (s), 126.7
(d), 107.3 (t), 70.7 (s), 67.2 (d), 66.1 (d), 6
5.3 (t), 62.9 (s), 61.5 (d), 56.9 (d), 52.6 (d),
46.2 (t), 45.9 (t), 43.3 (t), 40.5 (s), 40.2 (t),
39.1 (t), 34.6 (s), 34.2 (q), 27.8 (q), 25.
5 (t), 24.9 (t), 22.2 (q), 20.4 (t), 15.2 (q). (8) High-performance liquid chromatography: Separation column: Senshupack ODS H-2151 (column φ6 × 150 mm, manufactured by Senshu Kagaku Co., Ltd.) Mobile layer: Acetonitrile-0.2% trifluoroacetic acid water = 7: 3 Flow velocity: 1 .5 ml / min Retention time: 4.0 min The salt or its carboxyl group protected compound. 6. F-1243 having the following physicochemical properties:
6C: (1) Properties of substance: acidic fat-soluble powder. (2) Molecular formula: C ₂₈ H ₄₂ O ₈ (3) Molecular weight: 506 (measured by high resolution FAB-MS method) (4) Ultraviolet absorption spectrum (λ _max nm (ε)): Ultraviolet absorption spectrum measured in methanol Is as shown below. 228 (5000) (5) ¹ H-nuclear magnetic resonance spectrum: (δ, ppm) Nuclear magnetic resonance spectrum (360 MHz) measured using tetramethylsilane as an internal standard in deuterated methanol is
It is as follows. 6.79 (1H, d), 4.76 (2H, s), 4.64 (1H, d), 2.80 (1H, q),
2.71 (2H, s), 2.64 (2H, s), 2.09 (1H, m), 1.94 (1H, m),
1.78 (1H, m), 1.70 (1H, m), 1.2-1.7 (10H, m), 1.37 (3
H, s), 1.04 (3H, s), 0.92 (3H, s), 0.90 (3H, s), 0.86 (3
H, s). (6) ¹³ C-nuclear magnetic resonance spectrum: (δ, ppm) The nuclear magnetic resonance spectrum (90 MHz) measured by using tetramethylsilane as an internal standard in deuterated methanol is as shown below. 201.9 (s), 174.7 (s), 172.1 (s), 149.7 (d), 134.8
(s), 85.7 (s), 70.6 (s), 65.7 (d), 63.4 (d), 61.
6 (t), 52.1 (d), 51.5 (d), 50.9 (s), 46.1 (t), 4
5.8 (t), 44.3 (t), 43.5 (t), 38.1 (s), 34.1 (s),
33.9 (q), 32.3 (t), 30.8 (q), 28.3 (t), 27.7
(q), 22.3 (q), 20.9 (t), 19.9 (t), 17.0 (q). (7) High-performance liquid chromatography: Separation column: Senshupack ODS H-2151 (column φ6 × 150 mm, manufactured by Senshu Kagaku Co., Ltd.) Mobile layer: Acetonitrile-0.2% trifluoroacetic acid water = 7: 3 Flow velocity: 1 .5 ml / min Retention time: 4.8 min The salt or its carboxyl group protected compound. 7. A dasifera.
F-1 characterized by culturing F-12436A, F-12436B and / or F-12436C-producing bacteria belonging to the genus and collecting F-12436A, F-12436B and / or F-12436C from the culture
2436A, F-12436B and / or F-12
436C manufacturing method. 8. F-12436A belonging to the genus Dasifera,
The F-12436B and / or F-12436C producing strains are cultivated by dasciella nivea.
nivea) SANK 26995 strain (FERM B
The method according to claim 7, which is P-5323). 9. A medicine comprising F-12436A, F-12436B and / or F-12436C, a salt thereof or a compound having a protected carboxyl group thereof. 10. A preventive or therapeutic agent for a bacterial infection, which comprises F-12436A, F-12436B and / or F-12436C, a salt thereof or a compound having a protected carboxyl group thereof as an active ingredient.