JPS62120388A - Halogenated derivative of substance sf-2370 and production thereof - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I (X is Cl, Br or I; Y is H, Cl or Br). USE:An antimicrobial agent, antifungal agent, hypotensive agent and diuretic agent. PREPARATION:An antibiotic substance SF-2370 expressed by formula II is reacted with a halogenating agent, preferably N-halogenosuccinimide, preferably in an inert solvent, e.g. THF, etc., at 20-25 deg.C to carry out halogenation reaction. The reaction proceeds under condition of ordinary temperature, e.g. at 20-25 deg.C, but the temperature may be increased to 60-80 deg.C for accelerating the reaction.

Description

[Detailed Description of the Invention] (Field of Industrial Application) Does the present invention have antibacterial, antifungal, antihypertensive, and diuretic effects?
The present invention relates to a novel halogenated derivative of 5F-2370 material having a temperature of π, and to a method for producing this novel conductor.

(Conventional technology and problems to be solved) The antibiotic 5F-2370 substance is a
5F, an actinomycete belonging to the genus
This is a new antibiotic isolated from the culture solution of the -2370 strain (Feikoken Senpo No. 77 Otsu θ), and it has antibacterial and antifungal effects.
(Tokuton Sho Tata-2IO!- related to the applicant's application)
24 No. Specification Cap 1゜5F-2370 JJ! For example, does T have a strong control effect on rice and leaf blight as an agricultural fungicide? (Japanese Patent Application No. 737/1983), but for use in other fields, for example as a medical therapeutic agent, F3
The p4.370 substance has insufficient antibacterial activity. Therefore, 5F-2370 substance? In order to use it more effectively, it is desirable to enhance its activity through formulation technology, chemical conversion, etc.

The present inventors investigated the entire chemical structure of the 5F-2370 substance and found that it has the chemical structure shown in the linear formula (n) 0()OCH3 (T.

Antibiotics magazine volume 3r% 74137~/l
t3 Rip shell (/rigg Yunen) λ. Next, from the chemical structural formula of the formula (ID), the complete inference of the fhi chemical reactivity of the 8F-2370 substance [7
Therefore, various studies7 were carried out with the aim of enhancing anti-inflammatory activity.
5F-2370 The aromatic ring hydrogen of the substance can be replaced with a halogen atom. The following formula (1) [wherein, X represents chlorine, bromine or iodine atom gold t2, Y
8F- represented by hydrogen, 3 chlorine or 7 bromine atoms]
We succeeded in attaching 2370 substances to completely new halogen derivatives. When we investigated the antibacterial, antifungal activity and other physiological activities of this new SF-CoJ70 substance halogen F-Tsubaba conductor of formula (I), we found that it not only enhanced its antibacterial and antifungal effects; It has now been discovered that it also exhibits various physiological activities such as surface pressure lowering and diuretic effects. In other words, we discovered a new active substance, 5F-2370 derivative, and expanded the use of the 8F-2j7θ substance to the pharmaceutical field by converting it into a halogen rust conductor.

The present invention has now been completed.

(Means for solving problems) Therefore, the gist of the first invention is as follows.

The following formula ([I [Wherein, X represents a chlorine, bromine or iodine atom.

Y represents hydrogen or a bromine atom]
-2370 substance is a derivative of Sogen.

In the halogenated derivative of formula (I), when X is chlorine and Y is a hydrogen atom, when X and Y are both chlorine atoms, when X is bromine and Y is a hydrogen atom, There are two types, one in which Y is both a bromine atom, one in which X is an iodine, and one in which Y is a hydrogen atom, and may be a monohalogenated form or a dihalogenated form.

Furthermore, the gist of the second invention is that the above formula (■)
5F-jJ7i7 A process for producing a derivative of the 8F-2370 substance of the formula (r), which comprises converting all of the halogen substances.

Compound #-j of the present invention (1) Raw material SF-co37θ substance (produced by reacting 1. halogenating agent to (1), preferably in an inert solvent, to perform a halogenation reaction) The desired halogenated derivative of formula (I) can be obtained by purification and isolation in a conventional manner. Examples of the halogenating agent to be used include those known in the art. chlorine, bromine, iodine, sulfuryl)lides, and N
- Examples include halogenocono, phosphoric acid imide, etc. Among these, pure products are easily available and easy to handle.
Rogenconophosphoric acid imide is preferred. Examples of inert solvents that can be used include alcohols such as tetrahydrofuran, dioxane, lower alkanols, and non-halogen hyalkanes. Starting material 5F-237
Tetrahydrofuran and dioxane, which dissolve 0 substances well, are preferred. The halogenation reaction is carried out at room temperature 1 e.g. -〇, 2
The reaction proceeds under conditions of 1°C, but for the purpose of accelerating the reaction, it can be heated, for example, to-go'c. The progress of the reaction can be easily observed by analytical methods such as silica gel thin h chromatography. Isolation of the new rust conductor (I) from the reaction solution is as follows:
8F-J370710 is novel as a crystalline material, carried out by commonly used purification methods such as solvent extraction, washing, or recrystallization or column chromatography.
Genf derivative (1) is obtained.

The novel 5F-2370 derivative (1) &l of the present invention was found to have hypotensive and diuretic effects.

Below, all experimental examples are given to fully illustrate the antihypertensive and diuretic effects of the product of the present invention.

Experimental Example 1 Antihypertensive effect of DOOA/5aline in hypertensive rats.

D00A/saIine hypertensive rats were prepared by the method described below, and the hypotensive effect of the 5p-2370 substance halogenated derivative (1) of the present invention was investigated using a non-invasive method.

That is, one Wk of an SD rat weighing between iro and 20Q2 was excised and removed under ether anesthesia, and then the rat was raised with 1 saline as its drinking water. During the pre-R period,
D OOA (deoxycorticosterone)
A 4t4 gum arabic suspension of e acetate J was subcutaneously administered to /θ Misaki/ky. Of these slowly bred rats, all rats whose blood pressure was consistently at /70 or higher after more than a week had passed after the operation were selected and used as test animals.

5F-2370 substance derivative (I) as a test drug! It was suspended in aqueous gum arabic solution and administered orally. Blood pressure was measured at a certain time after administration using the following method.

That is, the test rat gold was kept warm at 37°C for about 5 minutes.
．． One tail artery? Inflate well and use a non-invasive blood pressure measurement device (
It was measured by the tail cuff method using UM'0')k manufactured by Shishi Seisakusho. The results are shown in Table 1.

Table 1 D00A/5aline blood pressure lowering effect in hypertensive rats Dose (yrq/kg, P,
O, J f & major blood pressure lowering value (-H2
J OJ 4**Hydroflumeth
iazide J O/! *(Comparison) *P (0,0!, **Pku0,0/ Comparison with pre-administration value.

Experiment example Antihypertensive effect on spontaneous hypertension (SHRJVc).

Of the 8HH purchased by Charles River Japan = 9,
Animals with blood pressure of /7 (7 waHt or higher) were adopted as test animals.Others were kept at 8F in the same manner as Experiment 1 and rry+.
-2370 Substance Derivative (1) T-administration, all blood pressure drop values were measured. The results are shown in the table below.

Table 8. Blood pressure lowering effect in H'EL.
j 0 2 j *Don't spoil the invention!
3Q 2ri8* p < o, o
r Compared with the pre-administration value.

Experimental example 3 Effects on urine volume and electrolyte excretion.

- The test compound was suspended in a gum arabic solution and orally administered to SD rats (/details!) that had been fasted overnight. 30 minutes after administration of the test substance, physiological saline solution, j rat/
/ 00? The animals were orally loaded at a rate of 1,000,000 yen, and the urine excreted within a certain period of time was collected into one individual metabolic cage. The collected urine was measured for urine volume and urinary N*il'z. Urinary N1
The amount is ion analyzer Mo-del 4AO7A
(ORION Res, ) Measured from VC. NaUrine test strips (Multi-Istics) for general properties of urine
It was examined qualitatively from llC. The full results are shown in Table J.

Table 3 Urine volume and urinary Na + excretion amount
/l! 30237**lμ3* Inventive accessory /Q //ko
Evening? 30 109 iAO* Invention fhi object 4c 30 zr
l /34 (Inventive addition! 30
2AA** ttlHydrofltrne
thiazide '0'koJ/!
7** (comparison) J O/ j t # / r'; r** control (c
ontro+) - 100 100
Experimental example≠ Acute toxicity of the additive of the present invention? The test was conducted by oral administration using a collar. The results are shown in Omotehiro.

Table ≠ Invention / / 000 /
/ tko000 4t/Yumoto invention monster ko 1000 0/! 2
000 //! In addition, the above-mentioned Experimental Example 7 - Inventive additive 11 Inventive compound 1 Inventive sweet 3, Inventive compound q1 Inventive compound 2 in French refer to Example 1 described later. -Acquired in Buddha
dibrominated 8F-2370 substance, monobrominated SF-
Co370 substance, monoiodized 5F-JJ70 substance,
Dichlor ratio 5F-2370 substance, monochlorination 5F-J
J70 refers to g7 quality.

From the above animal experiment examples, it is clear that the halogenated derivative (I) of the 5F-2370 substance of the present invention has a blood pressure lowering effect and a diuretic effect, and its effect is similar to that of the known drug Hydrofume th. i ax ide
It was higher than rifI etc. Since the acute toxicity value in mice is still low, it is highly anticipated that it will be used as a drug for dogs.

A production example of the compound (1) of the present invention will be shown below as an example.

Example 1 Production of dibrominated 5F-2370 substance (invention compound 1).

5F-1370 Substance 1.02 Total Tet 2 Hydro 7 Run JO
d, added 100'q of N-bromosuccinimide, and heated at 20-2J°C for 7. ! Allowed time to react.

The reaction solution was concentrated under reduced pressure, and methanol was added to the solid residue, heated, stirred, and then cooled. 7. The crystalline substance was filtered to obtain dibrominated 8F-2370'Jt.

Collection @ /, 079. Yield: 7f41 Decomposition point: R, f value (Merck's silica gel TLO: solvent system,
ethyl acetate): 0. ip hiro.

'H-NMR spectrum C0DOt3, ppm)
: 1.60 s, 7. Prs.

7, r j d, 7j / d d, 7. Koj
d, 7. /3d, bu, 77dd.

! j J brs, J', λA s, 14. A
Od, g, J7s, <4. ／／s
, 3Jridd,! , 04Ad, 2. /! s.

i sous vector (FD): 623. t2r, Bucore (
M'') Example comonobrominated 5F-237 (7 substances (inventive compound 2)
Manufacturing of.

5F-2370 substance/, Of gold tetrahydro 72in 3Q
- dissolved in N-bromosuccinimide El, OaV
2. Add all at 20-20℃ for 2 nights. was allowed to react for a period of time.

The reaction solution was concentrated under reduced pressure, and the residue was washed with 20 methanol and filtered to obtain a crude mass (crude straw rs).
s). Silica gel 70? Column chromatography using gold (solvent system, toluene-ethyl acetate <t
: i, o2i)) / 7” o A IIZ
8 F -2J 70 substances 0) 4c, r I q
t- got it.

Yield gJ4. Decomposition point: 27r℃.

, Rf value (measurement conditions are the same as Example 1): o, zt
t'H-NMR spectrum C0DOt3, ppm)
-III Rim.

11.0! d, 7. POd, 7J7m, 7jC4m
, 7,23m, 7,0rid d, A, 7td d,
ip, 04tbrs, 41.7/brs, μ,
jOd, 4t, 37m, u, 10s, J, 7rdd
, J, -2? dd, 2. /6s.

Mass spectrum (FDJ: Ori, 1417 (Mj
) Example 3 Production of monoiodinated 5F-2370 substance (additional material 3 of the present invention).

5F-JJ70 substance/,09tl-1-,,N-iodosuccinimide diO dissolved in tetrahydrofuran JO1d
0 x was added and allowed to react at 20.21°C for 2 days. Reaction liquid?
The mixture was extracted with ethyl acetate IθOd and water 10° and separated into 1-acetic acid and ethyl R', washed with water, and dried over anhydrous sodium sulfate. The solid residue obtained in step 7 of [Concentrating the ethyl acetate solution] was purified by column blotting using 100f of silica gel (solvent system: toluene-dioxane (1:1)).

Fractionate the eluate into 7 fractions and examine each fraction by thin layer chromatography. Ffk open system: Ethyl acetate J Rf value fO
All the tough fractions were collected and condensed under reduced pressure to yield a crystalline material. After washing with hot methanol and drying, the monoiodized 5F-237(1) substance 24LO
We obtained η.

Yield 11, 2 decomposition points 7 to 7! 2℃'H-NM
R spectrum (01) O20, ppm): I, t
Od.

r, o u d, otsuri/d, 7. jjm, 7. $
jt, 7. aJdd, 7.09d, G, 7Jr
dd, βObrs, IAJJ d, ≠, 4L2
d, It, 10s.

J, r4Ldd, L2jdd, 2. /As. Nao,
f) The NMrL x vector curve diagram is shown in I of the attached drawing.
! / Shown in the figure.

Mass spectrum (8JM8): Polygonum 4c (M-Example 1 Dichlorf-8F-2370 substance (invention compound da λ and monochlorinated 8F-2370 substance (invention compound j))
Manufacturing of.

5F-Jj7Q substance I 7ay all te all cyto 2hydrone/1 dissolved, N-chlorosuccinimide l tade l IF
was added, and the reaction was carried out at 20-2J°C. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified with silica gel 70? It was subjected to column chromatography using gold (solvent system: toluene-ethyl acetate (/:/)). The eluate f4cd was fractionated, and each fraction was examined by thin layer chromatography in the same manner as in Example 3. Rf value Q,! 2. All fractions of the substances shown were collected, and after being ampered under reduced pressure, methanol was added to 7-all, the precipitated crystals were passed through, and dichlorinated 8F-2370 substance 14 was obtained.
7 wqt-obtained. Yield: 31 yen, decomposition point: r~300°C
.

Mass spectrum (FDJ:jJ7(M”J.

Rf value O, substance indicating octopus eluted n iFi? After collecting and concentrating under reduced pressure, methanol was added to precipitate crystals of monochlorinated 5F-2370 substance, which were collected in a furnace. Yield/4ig cape (yield 3μ width) 9 decomposition point Kota 3~ko94L°C Mass spectrum (FD) ”, jO/ (M”J.

In addition, SF used as a raw material additive in the method of the present invention
Since the '-2370 substance is itself a new substance, an example of its production is shown below as a reference example.

Reference Example/(SF-Jj7 (Production of 7 Substances) Culture medium containing Fuglucose Co., 04. Wheat Germ/, 0%, Bare 1 O0! Wound, Yeast Extract O, t%, Calcium Carbonate 0./Excellent) (pH 7.0) was dispensed into a total 100 d Erlenmeyer flask and sterilized at 120°C for 3 minutes.
7 (7 (Feikoken Bacteria No. 77tO)) and incubated at 2r℃.
Culture was carried out at 220 revolutions per minute for 7 days. This culture-
〇df glucose/, J-4. Wheat germ/, 04. Cones deep puri force -/, Q%.

A production medium consisting of 7 armamedia o, res, calcium carbonate 0.3 mL (pH 7,0) was inoculated into a jerk amentor, and cultured with aeration (aeration volume) for 5 days at ℃. A 00 rrl per minute, revolutions per minute !00 revolutions) l-. After the culture was completed, the cultured cells were obtained by filtration using diatomaceous earth as an auxiliary agent. This body VC70
Add % acetone water r00ptlf and extract all the effective fraction,
All bacterial cells were isolated from each house. The extracted liquid was then concentrated under reduced pressure to remove acetone, and ethyl acetate/gold was added to the resulting condensed liquid and shaken.

The active ingredients were extracted. Repeat this extraction operation twice,
Obtained ethyl acetate extract j00df anhydrous sulfuric acid) I
After drying with Jum, it was concentrated under reduced pressure to obtain an oily substance. This oily substance [0-hexane? In addition, the resulting precipitate was collected to obtain 214 ml of crude material. This crude material was dissolved in chloroform.
Ethyl acetate<io:i) was dissolved in a mixture of silica gel Q-
200 (manufactured by Wako Tsumugi Kogyo Co., Ltd.) 60-0 column and developed with a chloroform-ethyl acetate (to:i) mixed solution MengOO-. The developing solution is silica gel thin layer chromatography (
Merck & Co., Kieselgel% tOF Kotaμ, 77/4t
:Developing solvent: ethyl acetate), ultraviolet M (co! μnm)
J t-Spots that can be identified by irradiation and 1. te l'Lf
Value θ, tt′f? and Sarcina lutea (8
arcinalutes'? All fractions showing antibacterial activity in a paper-disc bioassay using pI11# were collected. This active fraction was concentrated to dryness under reduced pressure to give 2r6wq.
A pale yellow powder of gold was obtained. This crude powder was dissolved in ethyl acetate and subjected to preparative silica gel thin layer chromatography (Merck Kieselgel 60F Co!μ, R7UG, developing solvent:
Ethyl acetate) Purple conduction, active part CRf value o, r r)
-2 or 6 and 9. Extracted with ethyl acetate. After completely concentrating the extract under reduced pressure, methanol was added and left overnight to obtain 8F-23.
72 pale yellow crystals of 70 substances were obtained.

Reference Example 2 (Production of SF-2370 Substance) A seed culture of Actinomadura sp. 5F-2370 obtained in the same manner as described in Reference Example 1/1 was added to the production medium 3! T? include! O2 jar 77, )' 7
The aerated stirring culture was carried out at 21rC for t days (aeration rate: 3 seconds per minute, 1 rotation speed: 200 revolutions per minute). The operation of adding 70 winter acetone water Konat to the body and extracting all the active ingredients was performed twice, and the whole bacterial cells were separated to obtain an extract rOtk.This extract was condensed under full vacuum to remove all the acetone.
To the obtained condensate, 30 tf of ethyl acetate was added, and all the effective fraction was extracted by pressing with Ir for a minute. After drying the ethyl acetate extract over anhydrous sodium sulfate, the extract was crushed under reduced pressure to obtain pale yellow crude crystals 332. This coarse crystal? Recrystallization from a chloroform-methanol solution was repeated twice to obtain pale yellow crystals of substance 8F-2370.

Further, for more detailed physical properties and manufacturing method of the 5p-jJ70 substance, please refer to the patent application No. 27Oj filed by the present applicant.
Reference is made to the description in the specification of No. 24.

[Brief explanation of drawings]

Figure 1 shows monoiodized 5F obtained in Example 3 of the present invention.
-2370 substance ζ) (-NMR spectrometer 1 (in deuterated chloroform, Hiro θOM Hz measurement).

Claims (1)

[Claims] 1. The following formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, X represents a chlorine, bromine or iodine atom, and Y represents a hydrogen, chlorine or bromine atom. SF-2 represented by
370 Substance A compound that is a halogenated derivative. 2. The compound according to claim 1, wherein in formula (I), X is a chlorine atom and Y is a hydrogen atom. 3. The compound according to claim 1, wherein in formula (I), X and Y are chlorine atoms. 4. The compound according to claim 1, wherein in formula (I), X is a bromine atom and Y is a hydrogen atom. 5. The compound according to claim 1, wherein in formula (I), X and Y are bromine atoms. 6. The compound according to claim 1, wherein in formula (I), X is an iodine atom and Y is a hydrogen atom. 7. The following formula (II) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (II) The following formula (I) ▲ Mathematical formula, chemical formula, which is characterized by halogenating the antibiotic SF-2370 substance , tables, etc. ▼ (I) SF-2 represented by [In the formula, X represents a chlorine, bromine or iodine atom, and Y represents a hydrogen, chlorine or bromine atom]
370 Substance A method for producing a compound that is a halogenated derivative.