NL7904766A - COMPOUND SF-1739 DERIVATIVES, METHOD FOR THE PREPARATION THEREOF, AND ANTIBACTERIAL AND ANTITUMOR PREPARATIONS CONTAINING THIS COMPOUND. - Google Patents

Description

49195 / Loi5 _ j ----- 'j Meiji Seika Kaisha Ltd., Chuo-ku, Tokyo, Japan.

| Compound SF-1739 derivatives, method for the preparation i thereof and antibacterial and anti-tumor preparations containing this compound.

t

The invention relates to a new group of derivatives * of compound SF-1739, processes for their preparation and antibacterial and anti-tumor preparations comprising at least one of these compounds; contain.

More particularly, the invention relates to new and useful derivatives of compound SF-1739, as further defined below, viz. compound SF-1739 HP, compound SF-1739 HP-G, compound SF-1739 HP-F, compound SF-1739 HP-3 and compound SF-1739 HP-5, methods for their preparation, as well as antibacterial and anti-tumor preparations, containing at least one of these compounds as an active ingredient. i |

From Jap.O.S, 125798/1976 it is disclosed that an antibiotic compound SF-1739 can be prepared by cultivating Streoto-! - | myces priseoplanus strain SF-1739, Also, according to the statement in the 15 annual report of Meiji Seika Laboratories, Vol. 16, p. 20, the compound SF-1739 is a yellow double acid base with an unclear chemical structure and physico-chemical and biological properties thereof are discussed in detail in said passage. Furthermore, it was known that the compound SF-1739 is particularly unstable in alkaline medium and even its free base is decomposed into various fractions, which do not show antibacterial activity after several days of standing. in the dry state, while being very stable in acidic environment.

The stability of compound SF-1739 under acidic conditions has been further investigated by us and it has been found that a new compound SF-1739 HP can be obtained by treating the compound 'SF-1739 with a strong acid and the thus obtained new ! compound shows strong antibacterial and anti-tumor action.

In addition, due to the fact that the new and useful compound SF-1739 HP exhibits significantly higher toxicity, we have further investigated derivatives of the compound SF-1739 HP

790 47 66 - 2 - v »in order to reduce its toxicity and it has also been found that a new group of derivatives of substance SF-1739 HP, η. 1. substance SF-1739 HP-C and substance SF-1739 HP-F, can be obtained by reacting compound SF-1739 HP with a cyanide or formamide and they can be used satisfactorily for the intended purpose.

On the other hand, we examined several other metabolites, which can be formed in a culture broth by culturing actinomycetes, such as Streptomyces griseoplanus SF-1739 (ap.O.S.

I | As a result, we have found that in a culture broth, yellow metabolites are formed which are distinctly different from compound SF-1739, although they also have Rf values, and that compound SF-1739 HP-3 and compound SF-1739 HP-5 as new antibiotic agents can be obtained from the yellow metabolites by] 3) treatment with a strong acid. The object of the invention is therefore to provide a new group of j: five antibiotic compounds; connection SF-1739 HP, connection SF-1739 ': HP-C, connection SF-1739 HP-F, connection SF-1739: HP-3 and connection SF-1739 HP-5.

Another object of the invention is to provide a method for the preparation of these antibiotic compounds.

| It is also an object of the invention to provide an antibacterial and anti-tumor preparation, which contains at least one of said derivatives of compound SF-1739 as active ingredient.

As noted above, the invention provides five different derivatives of the compound SF-1739. These derivatives and their respective preparation are described in detail below separately, I. Compound SF-1739 HP

I (l) Physico-chemical properties;

This material does not have a sharp melting point and melts under black over a wide range starting at about 150-18 ° C.

You have a UV absorption spectrum, as shown in Figure 1, in methano] (indicated by a solid line (——-} in Figure 1) with three absorption

λώ! maxima at 220 nm (E'a a 407}, 275 nm (132) and 535 nm (21), which are in .0.05 n HCl-95 $ methanol (indicated by the dotted line (....) in 35 Fig. 1) with absorbance maxima (two) at 265 nm 754), 410 (16) in 0.05 n NaOH-95P / aig methanol (indicated by a chain line 7904766 _ 3 _ *> ij (---) in Fig. 1) with absorption maxima at 221 nm = 440), 277 (124), j345 (shoulder) and 540 (24). It gives an infrared spectrum (in Nujol) i; as shown in Fig. 2 with characteristic absorption bands at! 3350, 1655, 1600, 1540, 1355, 1265, 1235, 1180, 1120, 1080, 1020, 1000, -1 5! 965, 945, 920, 910, 865, 830 , 790 and 750 cm and a kmr spectrum (in DO] as shown in Fig. 3. Its mass spectrum exhibits peaks at m / e 412,430, so that its molecular weight is estimated to be approximately that of compound SF-1739 Its analytical composition: is: C 62.19 $, Η 6.955 &, N 8.50 $, 0 22.36 $ (out of difference). It has a {ti 10 optical rotation dispersion curve as shown in Fig. 4, from which is calculated its specific rotation + 70 ° (in 0.05% methanol). It is a black-purple substance which is readily soluble in water and methanol, soluble in acetone and ethyl acetate and sparingly soluble in hexane. The Rf values on a silica gel thin layer chromatography plate are 0.45 when developing with chloroform: methanol (9: 1) and 0.23 when developing with π-butanol: methanol: 0.1 n HCl (4: 2: 1) ,, while the corresponding values for the substance SF-1739 are 0.76 and 0.39 respectively.The stability of compound SF-1739 HP is significantly better compared to that of the starting material material SF-20 1739 and stable in both acidic and alkaline environment. even after overnight in 5π HG1 at room temperature completely stable, while the starting material SF-1739 is almost completely converted into compound SF-1739 HP. Even after overnight in 0.1 n NaOH / methanol at room temperature, it does not show any marked reduction in antibacterial activity, while the starting material! SF-1739 is significantly deactivated. j t

(2) Preparation: I

This compound can be prepared from compound SF-1739 i! by treatment with an acid. As an acid to be used for this treatment, a mineral acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, or an organic acid, such as e.g. trifluoroacetic acid; acid, methanesulfonic acid or trifluoromethanesulfonic acid. The reaction parameters may vary depending on the nature and concentration of the acid used and the solvent to be used. In the case of a mineral acid, it is desirable that the treatment be carried out with cooling or at room temperature for_1 day to 1 week, when! £ 7904766? - 4-

"down a high concentration of 5-10 n is used or at room temperature or higher for 1 to several days when a lower concentration of up to 5 n is used. At an elevated temperature of more than B0 ° C the formation of by-products increased. The treatment proceeds rather quickly in an aqueous solution, while it proceeds more slowly in aqueous methanol. Conversion of the compound SF-1739 to compound SF-1739 HP can be effected at a pH

I down 3.

s

j After completion of treatment, compound SF-1739 HP

Easily recovered from the reaction mixture by a conventional method using the above physicochemical properties of compound SF-1739 HP. mixture can e.g. neutralized with a base, e.g. sodium wa- ! terrestrial carbonate, potassium carbonate or the like, until dry

5 I

15 and the residue is then extracted with methanol, after which the extract is purified directly by a preparative silica: gel thin layer chromatography. Instead, because less by-products are formed with this treatment, the reaction mixture can be concentrated, the residue in methanol is charged and the resulting solution is neutralized and then passed through a column of Sephadex LH-20 (trade name) which is then developed with methanol or a mixed solvent of ethyl acetate and methanol to purify the desired product.

II. Connection SF-1739 HP-C and SF-1739 HP-F.

25] Il-a. Connection SF-1739 HP-G.

! (1) Physico-chemical properties:

This compound does not have a sharp melting point and melts over a wide range, starting at about 120-150 ° C. He has a u, v. spectrum in methanol as shown in Fig. 5 · 30 (indicated by a solid line in Fig. 5) with three absorption maxima! Bijί at 222nm (EJ = 400), 273nm (146) and 540nm (30), taken in 0.1n HCl- * 1 cm 90} 4ig methanol (indicated by a dotted line in Fig. 5) with absorption

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maxima at 204 nm, 266 nm, 174) and 410 nm (22) and one in 0.1 n

Na0H-905 & methanol (indicated with a chain line in Fig. 5) with ab-1 ° ii 35 sorption maxima at 222nm (E ^ s 422), 275 nm (140) and 550 nm (32). It has an absorbance spectrum (in Nujol) as shown in Fig. 6 7904766-5 - f £ [typical characteristic absorption bands at 3350, 1660, 1535, 1355, 1265, »{1235, 1200, 1175, 1140, 1120, 1080, 1060, 1000, 940, 910, 880, 835 and -1,795 cm; optical rotation curve as shown in Fig.7 and k.m.r. spectrum (in D ^ O) as shown in Fig. 8. The analytical equation set is: C 59.5856, Η 6.1 <^ 6, N 12.63 $ and 0 21.65 $ ( from difference), It is a black-purple substance which is readily soluble in water and methanol, soluble in acetone and ethyl acetate, and sparingly soluble in hexane.

Its Rf values over silica gel thin, low plate are 0.40 when developed with chloroform: methanol (9: 1) and 0.70 when developed with ethyl acetate: methanol (3: 2), while the corresponding values for! compound SF-1739 is 0.26 and 0.31, respectively. It is stable in the dry state and in neutral, acidic and alkaline methanolic solution,: (Mb) Compound SF-1739 HP-F 15 (1) Physical -chemical properties:

This compound has no sharp melting point and melts under blackening over a wide range starting at about 110-140 ° C!

It has a UV absorption spectrum in methanol as indicated in j

Fig. 9 (indicated by a solid line in Fig. 9) with three absorbance 20 maxima at 220 nm, 275 nm (Ε1ί ° = 121) and 540 nm (24), which are in 0.1 ni cm HCl-90 $ ig methanol (indicated by a dotted line in Fig. 9) with absorbance maxima at 205 nm, 268 nm (E = ^ = 133) and 405 nm (19) and those in t cm 0.1 n NaOH-90% methanol ( indicated by a chain line in Fig. 9) at

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221 nm, 277 nm (£ * = 117) and 540 nm (29). It has an irabsorption t cm 25 spectrum (in Nujol) as shown in Fig. 10 with characteristic absorption bands at 3300, 1660, 1530, 1350 , 1310, 1265, 1235, 1205, 1175,] -is 1125, 1085, 1025, 1000, 940, 920, 830 and 795 cm. Its analytical composition is: C 57.26 $, H 6.33 $ , N $ 12.14 and 0 $ 24.27 (from difference). {

It is a black-purple substance that is easily soluble in water and methanol, is soluble in acetone and ethyl acetate, and is slightly soluble in hexane. Its Rf values over a silica gel thin layer plate are 0.28 when evolved in chloroform: methanol ( 9: 1) and 0.53 when developed with ethyl acetate: methanol (3: 2), while the corresponding i values for compound SF-1739 HP are 0.26 and 0.31, respectively.

35 It is stable in the dry state and in neutral and alkaline methano-; organic, but less stable in acidic methanolic solution. ; 7904766-6-I (H-c) preparation of bside compounds

Compound SF-1739 HP-C can be prepared from compound SF-1739 HP, which is obtained as mentioned under 1 (; 2), by reaction with a cyanide.

Among the cyanides which can be used, examples are mentioned an alkali metal, alkaline earth metal, metal or organic s amine (including ammonia) salt of hydrocyanic acid, such as sodium, potassium, lithium, magnesium or ammonium cyanide, or a compound capable of providing a cyanide ion (CN) secondary, such as bromine cyano. On the other hand, compound SF-1739 HP-F may be prepared from compound SF-173 ^ HP by reaction with formamide.tili In both cases, the reaction proceeds rapidly under cooling or at room temperature and is completed in 5-30 min. At an elevated temperature above room temperature, sometimes an increased formation of by-products occurs. of solvents for the reaction which may be used in the appropriate cases are mentioned: water, 1 an alcohol, dimethylformamide, a mixed solvent of a water-miscible organic solvent and water. In addition, formamide may be used to act as both a reagent and a solvent for the preparation of compound SF-1739 HP-F. After completion of the reaction, the desired product can be easily recovered and purified by a conventional method using the physicochemical properties of each compound. The reaction mixture may e.g. are concentrated to dryness and the residue is extracted with methanol and then the extract is directly purified by a preparative silica gel.

thin layer chromatography, j

Instead, the reaction mixture, because with each reaction

J

Less fewer by-products are formed, concentrated, the residue is dissolved in methanol and the resulting solution is then passed through a column of Sephadex LH-20 (trade name), which can then be developed with methanol or a mixed solvent of ethyl acetate and methanol to purify the desired product.

35 III. Compound SF-1739 HP-5 and Compound SF-1739 HP-3 __ _____ (m-a) Compound SF-1739 HP-5 7904766 * * -η - (l) Physico-chemical properties;

This substance is a black-pass powdery substance with no sharp melting point and melts under blackening over a wide range, starting at: about 150-180ij. It has, as shown in Fig. 11, a 5; uv absorption spectrum in methanol (indicated by a solid line in Fig. 11) with three absorbance maxima at 220 nm (E ^ = 375), 275 ran (156}, cm and 535 nm (28)), which are in 0.05 n HCl-95 $ ig methanol (indicated by a 10 / dotted line in Fig. 11) with two absorption maxima he 266 nm (E 'cm = 199) and 410 nm (22) and those in 0.05 n NaOH-95 $ methanol (indicated with a 10 chain line in Fig. 11) with absorption maxima at 276 nm (E ^ m = 148) and 550 nm (34). It has an absorbance spectrum (in Nujol) as shown in Fig. 12 with characteristic absorption bands at 3300, 1655, 1600.

1540, 1350, 1260, 1235, 1175, 1085, 1025, 1000, 905, 865, 835, 790 and '775 cm and also a b.m.r. spectrum (in D ^ O) as shown in Fig. 13.! Analysis of C-13 pm spectrum indicates that at least 19 carbon atoms are present in the molecule of compound SF-1739 HP-5. It is estimated to be about 550 by a vapor pressure method. Its analytical composition is: C 60.93 $, H 7.05 $, N 8.41 $ and 0 23.61 $ (from difference). It has good solubility in water and methanol, soluble in acetone and ethyl acetate and sparingly soluble in hexane

Rf values over a silica gel thin layer plate are 0.12 when developing with chloroform: methanol (9: 1) and 0.12 when developing with ethyl acetate: methanol (3: 2), while the corresponding values of compound SF -1739 HP are 0.26 and 0.31 respectively. It is stable in the dry state and in methanol, but slightly unstable in acidic methanol and less stable in alkaline methanol.

(Hi-b) Compound SF-1739 HP-3 (1) Physical chemical properties: j

This fabric is black-ocher and powdery, does not have a sharp melting point and melts under blackening over a wide range starting at about 130-150¾. It has, as shown in Fig. 14, an u.v. absorption spectrum in methanol (indicated by a solid line in 1 $!)

Fig. 14) with four absorbance maxima or bends at 219 nm (E ^ m = 890), 267 nm (314), 330 nm (shoulder) and 543 nm (54), recorded in 0.05 n HCl-95 $: 35 methanol (indicated by a dotted line in Fig. 14) with three maxima at 264 nm (E 3 .37g), 325 nm (62), 420 nm (40) and those in 0.05 n NaOH-; 7904766 - θ - 95P / cdg methanol ..... (indicated by a chain line in Fig. 14) with three maxima at 267 nm (E? ^ 0 = 276), 375 nm (44) and 543 nm (64) It also has an inch spectrum [in Nujol] as shown in Fig. 15, with characteristic absorption bands at 3355, 1680, 1655, 1600, 1545, 1350, 1310, 1265, 118D, 5 1155, 1085, 1070, 1055, 1020, 950, 955, 900, 835, and 790 cm "1 and a jk.mr spectrum (in D 2 O) as shown in Fig. 16. Its molecular weight is about 350 by a vapor pressure method. Its analytical composition *) *; theorem is: C 64.13%, H 5.01%, N 9.25%, 0 21.61% (from difference). It is very soluble in water and methanol, soluble in acetone and ethyl acetate, 10: and sparingly soluble in hexane. Its Rf values over silica gel j: thin layer plate are 0.22 when developing with chloroform: methanol (9: 1) | and 0.39 when developing with ethyl acetate: methanol (3: 2), while the corresponding values of compound SF-1739 HP are 0, respectively, 26 and 0.31. It is stable in neutral and acidic methanol, but less stable in alkaline methanol. J (II-c) Preparation of both compounds j

These compounds can be prepared from natural yellow metabolites by treatment with an acid; these metabolites are formed in a cultured broth by culturing actinomycetes, such as Streptomyces griseoplanus strain SF-1739, as described in the above-mentioned Jap.O.S.

As examples of acids which can be used for this treatment, mention is made of mineral acids such as hydrochloric acid, bromine water, barric acid and. sulfuric acid, and organic acids, such as trifluoroacetic acid, methanesulfonic acid and trifluoromethanesulfonic acid. The reaction parameters may vary depending on the nature and concentration of the acid used and the solvent to be used. In the case of a mineral acid in it is desirable to carry out the treatment under cooling or at room temperature for 1 day at 1 week if a high 30 'concentration of 5-10 n is used, or at room temperature or high temperature. | ger for 1 to several days, if a lower concentration of not more than 5 n is used. At an elevated temperature of more than 80 ° C, the formation of by-products is sometimes quite increased.

The treatment proceeds rather quickly in an aqueous solution, while it proceeds more slowly in aqueous methanol. Conversion of the yellow metal boites into compounds SF-1739 HP-3 and SF-1739 HP-5 takes place at 7904766-9. - *% no pH below 3.

After the completion of the treatment, the compounds SF-1739 HP-3 and SF-1739 HP-S can be easily recovered from the reaction mixture by a conventional method using the above physico-chemical properties of the compounds. SF-1739 HP-3 and SF-1739 HP-S. The reaction mixture may e.g. are neutralized with a base, e.g. sodium hydrogen carbonate or potassium carbonate, are concentrated to dryness and the residue is extracted; Methanol and then the extract is directly purified with a preparative silica gel thin layer chromatography. The reaction mixture can be substituted instead, because in this treatment less by-product; are formed, concentrated, the residue is dissolved in methanol and the resulting solution is neutralized and then passed through a column of Sephadex LH-20 (trade name), which can be developed with methanol or a mixed solvent of ethyl acetate -tate and methanol to purify the desired products.

(ill-d) For comparison, the SF-1739 strain, which can provide the starting yellow metabolites for this preparation, as well as the preparation of the yellow metabolites, are explained below.

20 Streptomyces griseoplanus strain SF-1739 is deposited another No. 3002 at the Technical Research Institute of Microbial Industry,

Agency of Industrial Science & Technology, Ministry of International Trade and Industry, Japan, and under No. 31451 to the American Type Culture Collection (ATCC), USA. Morphological features of the above-mentioned strain No. 3002 are as follows: (i Morphology:

Air mycelium grows abundantly on oatmeal agar, yeast! moutagar etc. with rich spore formation.Simple branches are observed but truss-like branches are not seen.At the top! 30: The air mycelium forms a loose open spiral. A specific il configuration, such as scleratia, is not observed. When observed under a microscope, the spore surface is warty but partially] like with a spine. The spores have an elliptical to short cylindrical shape and are 0.6-0.8 x 0.8-1.2 µm in size. Trace chains generally contain 10 or more traces per trace chain. ! ....... lil I .1.1. - _ _ U1L | ___ _____ „. ^ ^ * 7904766 ί <- 10- t (II) Growth on various media (observed after cultivation at 28 ° Cl.

Medium Growth and color Air Soluble mycelium pigment 5 Sucrose. good, pale gray no nitrate. agar yellow gray) Glucose. small, cream little, white no iasparagine.agar |

i I

; Glycerol. pale gray gray no 10 jasparagine agar i Starch.agar good, pale gray- no yellow gray, slightly olive gray olive gray jHavermeel.agar good, pale abundant, none j 15 l yellow gray gray; j

Yeast.mout.agar good, do not gray abundantly J

yellow-brown dark gray i \

Tyrosine.agar dark gray olive gray none!

Foodstuff. pale yellow-gray none 20 agar gray-yellow 1 (iU ·} Physiological properties:

Temperature range for growth: 20-40 ° C on yeast malt agar medium

Liquefaction of gelatin: slowly when grown at 20 ° C for no less than 21 days.

• o 25 Hydrolysis of starch: positive (strong at 28 C).

Skim milk skim: positive (strong at 28 ° C and 37 ° C).

Retonizing skim milk: positive (at 28 ° C and 37 ° C).

i

Melanin formation: negative, | ! (iV) Carbon source usage pattern (on Pridham-Gottlieb's agar 30 y medium at 2B0C). # ·· i D-glucose + I-inositol + i 0-fructose + L-arabinose +! D-xylose + Rhamnose + i D-mannitol + Sucrose + 35 Raffinose -

Summarizing the above properties, strain SF-1739 belongs to the genus Streptomyces, is spiral-shaped at the top of air mycelium and has a wartif spore surface. Growth on various media is gray to greyish yellow ruin and aerial mycelium is__ 7904766 * · »_-11 - _ j gray. Melanin formation is not observed, nor are soluble J pigments seen.

| The properties of the SF-1739 strain most strongly compare to those of Streptomyces gryseoplanus of the species of genus 5; Streptcmyces. More specifically, both are perfectly common in spiral formation, warty spore surface, gray air mycelium, no melanin j formation. Compared to strain SF-1739 with Streotomyces gryseoolanus as described in ISP (international Streptomyces Project) (see Jlnt.J. of Systemetic Bacteriology, J8, 124-126 (1968)), is described in ISP '10; reported strain differs from SF-1739 in poor growth on starch agar, consumption of raffinose and non-consumption of sucrose, L-inositol, D-mannitol and rhamnase, but the former is very similar to the latter in spore area that is warty, to slightly spine-backed. From the above it is likely that the strain SF-1739 belongs to the species Streptomyces griseoplanus because its morphological properties are completely similar and they also have other important properties in common. But the former differs from the strain mentioned in ISP in carbon source consumption throne and others.Therefore, the strain SF-1739 is called Streptomyces griseoplanus strain SF-1739.

Although the preparation is mainly set forth herein with reference to the strain SF-1739, it is known that different properties of all microorganisms belonging to the genus Streptomyces 25 are not fixed, but microorganisms of the genus Streotomyces can easily be varied naturally or artificially It should therefore be noted that all strains capable of producing the antibiotic yellow metabolites used as starting material and belong to the genus Streotomyces, including variants and mutants, according to the invention.

j; Culturing can be carried out satisfactorily in the same manner as is conventionally used for growing any strain of the genus Streptomyces. As components of the medium, one can! Use any known food material for the genus Streotomyces. As a carbon source, e.g. use glucose, sucrose, starch, glycerol, corn syrup, molasses, or soybean oil. As a nitrogen source: 7904766 9 _ ii -12 - soybean meal, wheat germ, meat extract, peptone, dry yeast, corn soak liquid, ammonium sulfate, sodium nitrate, etc. In addition, if necessary, inorganic salts such as calcium carbonate, sodium chloride, potassium chloride, phosphates, etc. can be added to a medium. Also a small amount of each substance which can promote the growth of the strain and accelerate the formation of the antibiotic yellow metabolites. : | The cultivation can be carried out according to the liquid culture, as is usually used for the preparation of known antibiotic substances, preferably in submerged culture. The cultivation temperature j is preferably in the range of 25-35 ° C, usually around 28 ° C. ] I ί

Maximum production can usually be obtained in 2-6 days. ; l 1

The metabolites thus collected in a culture broth are basic, semi-water-soluble substances, which are particularly unstable and have not been successfully isolated and identified. j i f

When using the above metabolites for the acid treatment to form compounds SF-1739 HP-3 and SF-1739 HP-5, a culture broth containing the metabolites can be treated with an acid as such, Instead and more easily, the metabolites can be concentrated and then subjected to the acid treatment! For this preferred concentration of the metabolites, any known technique commonly used for the recovery of a basic, semi-water-soluble natural product can be used. filtered, the filtrate basic, made, saturated with sodium chloride, ammonium sulfate, etc. and then extracted with a water immiscible organic solvent, e.g. n-butanol, ethyl acetate, butyl acetate, or ether. The filtrate can also be adsorbed on a cation exchange resin; 30 such as Amberlite IRC-50, CG-50, IR-120 or Dowex 50W and then elution can be done with an acid such as hydrochloric or sulfuric acid to obtain the metabolites in a concentrated state. j

In order to obtain the metabolites in the purer state, one can use any combination of the above extraction techniques and instead adsorption with a resin, e.g. | XAD-2, desorption, purification by column chromatography with Sephadex G-10j 790 4 7 66 * * -13- (trade name}, carboxymethylcellulose, etc. and / or deleted with a silicon dioxide gel thin layer plate, etc.

Finally, the thus concentrated and fractionated metabolites can preferably be used for the acid treatment to form compounds SF-1739 HP-3 and SF-1739 HP-5.

Biological activities of derivatives of compound SF-1739 of the invention are listed below. I

I. Antibacterial activity.

"I

Table A lists the minimum inhibitory concentration of the five derivatives of compound SF-1739 of the invention. j

Table A j

Antibacterial activity of derivatives of compound SF-1739 _MIC (iug / ml) _ j 15 Bacterium Compound SF-1739 _ HP HP-C HP-F HP-5 HP-3_

Bacillus subtilis ^ 0.09 0.78 1.56 12.5 3.1]

Staphylococcus aureus 209P <Q.09 3.125 1.25 50 3.1

Sarcina lutea <0.09 <0.19 0.39 6.25 0.78 20 Escherichia calx 3.125> 100> 100> 100> 100

Escherichia coli K-12R 3,125> 100: »00> 100> 100

Klebsiella pneumonia 3,125 50> 100 '. > 100> 100

Pseudomonasqaeruginosa 3.125> 100> 100> 100> 100

Proteus vulgaris 0.39 50 6.25> 100> IQQ

II. Anti-tumor activity a. In vitro cytooathogenic activity

Table B lists the minimum cytopathogenic concentration of the five derivatives of compound SF-1739 of the invention. j f b. In vivo carcinostatic activity in mice Male GDF 1 strain mice (approximately 5 weeks old, weight 19 ± 1 g, each group consisted of 3-5 animals) were intraperitanal; inoculated with P-388 leukemia cells at a concentration of 10 /; ; 0.02 ml / mouse Each substance to be tested was dissolved in water at the indicated dose and administered intraperitoneally with 2-0.2 ml / day / mouse? 35 for 3 consecutive days after 24 hours post-inoculation. Then an increase in rennet duration (11LSj was calculated. Results in Table C. j 7904766 9-14 - ~~ Table B ™

Test compound Minimum cytopathogenic concentration (jug / ml) * __________________ HeLa S3 Hep, nr. 2 Sarcoma 180 SF-1739 HP 0.9 0.4 0.4 5 SF-1739 HP-C 0.9 0.4 0.9 SF-1739 HP-F 0.9 0.4 0.9 SF-1739 HP-5 7.8 1.9 3.9 SF-1739 HP-3 3.9 a Determined after 48 hours of tissue culture.

10 Table C

: Test compound Dose (mg / kg) ILS (%) SF-1739 HP 2 75.0:; 1 43.3 ί 0.5 43.3! 15 _0.25_45.0 | SF-1739 HP-C 16 70.2 j

.8 53.8 I.

4 113.5 2 61.5 20 ___ 1_59.4 SF-1739 HP-F 16 47.1; _8_34.6 SF-1739 HP-5 40 56.7 20 51.9 25! 8 30.0-4.0 25.0 III. Acute Toxicity Table D reports the acute toxicity (LDgg) of the five derivatives of compound SF-1739 of the invention when administered intravenously to mice.

; Compound LD50 (mg / kg) SF-1739 HP "2 SF-1739 HP-C 20-25] SF-1739 HP-F> 25 35 I SF-1739 HP-5> 10 SF-1739 HP-3_> 10_ SF -1739 0.45

For the use of the derivatives of compound SF-1739 according to the invention for the treatment of different types of tumors, they can be administered orally or parenterally in the form of 7904766-15 preparation, usually mixed with a solid or liquid, pharmaceutically acceptable carrier or excipient.Hat solid preparation for ora The administration may consist of a capsule, a tablet, a granule, a lozenge or the like, and a topically applied composition 5: e.g. consist of a suppository or an ointment.The liquid preparation; can consist of e.g. a solution, a suspension, a syrup, and orally, (administered topically by injection. Such preoarates * 'can be easily formed from conventional materials by any suitable technique known to those skilled in the art. The amount of active ingredient in the relevant preparation or composition as well as the choice]

the form of preparation to be taken usually depends on S

»The nature and severity of the disease to be treated, the method of administration

ning, body weight and age of the patient, activity and toxicity of the derivatives of compound SF-1739 etc. I

In the case of an injectable preparation, it is desirable for adults to subcutaneously, intramuscularly or preferably in; to be administered intravenously or intraarterially in a daily dose of 1 - 100 mg over a consecutive number of days or in a dose of 2 - 20 mg every other day or every three days. It may sometimes be effective for the type of tumor to be used. to inject the preparation directly into the tumor.

For oral administration, it is desirable for adults to administer the preparation in a single daily dose of 1-500 mg every day or every other day.

When applied topically, the active ingredient may be applied directly to a diseased or diseased portion in the form of a mixture with a suitable base so that it contains 1-20% active ingredient. I

One or more active derivatives according to the invention can also be used. | use it alone, or in combination with other known anti-tumor agents and / or some immuno-accelerator.

In case the respective derivative of compound SF-1 i 1739 is to be used as an antimicrobial agent, in particular an antibacterial agent, it can also be administered orally or parenterally in the form of a solid or liquid preparation, such as ordinary It is used for other known antibacterial agents or antibiotics. As a preparation for oral administration, e.g. use a capsule 7904756 -16 - "1e, a tablet, a powder, a granule, a solution, a suspension or a syrup. For topical application, examples are given a suppository and an ointment. As a preparation for parenteral administration, use an injectable solution or suspension, and the preparation may be administered by subcutaneous, intramuscular or intravenous route. The amount of active derivative to be administered varies depending on the nature and severity of the disease, body weight

| I

the age of the patient, the activity and toxicity of the derivatives; ivates of compound SF-1739 and other factors, but the effective de-! 10 mg is for adults, usually used in a daily dose of 1-500 mg for oral administration in unit dosage form or various divided forms, or in a single dose of 11-100 mg for parenteral, e.g. Intramuscular or intravenous administration. A physician may choose and use a higher or lower dose, especially taking into account the severity of a disease, the patient's physical conditions and any adverse effects. \

The derivative of compound SF-1739 according to the invention may be used either as such or as a mixture with af in combination with some known antibacterial agent, such as various antibiotics,

The examples below serve to illustrate the invention.

Example I

; Preparation of compound SF-1739 HP

A solution of 6 mg SF-1739 hydrochloride in 3 ml 5N hydrochloric acid was allowed to stand at room temperature for 1 week, the solution was then neutralized with sodium hydrogen carbonate and then concentrated under reduced pressure to dryness. The residue was dissolved in a small amount of methanol, insolubles were filtered off and 30: the filtrate was concentrated. The residue was applied to a preparative silica gel thin layer chromatography plate (2 x: 100 x 100 mm), which was then developed with a mixed solvent of chloroform and methanol (9: 1). A purple band with Rf = 0.45 was cut from the plate and extracted with methanol.

The extract was concentrated to dryness. The residue was redissolved in a mixed solvent of methanol and acetone (2: 1) 790 4766 <17> and insolubles were filtered off. The filtrate was concentrated to dryness to give 3.3 rye compound SF-1739 HP were obtained,

I Example II

! Preparation of compound SF-1739 HP-C

To a solution of 71 rag compound SF-1739 HP in 5 ral water, 144 mg of sodium cyanide were added and the resulting mixture * was stored at room temperature for 30 rain, then concentrated to dryness below 35 ° C under reduced pressure with the addition of n Butanol. The residue was dissolved in a small amount of methanol, insolubles were filtered off and the filtrate was concentrated. {The residue was placed on a preparative silica gel gel thin layer chromatography plate (2 x 100 x 100 rara), which was then developed with a mixed solvent of ethyl acetate and methanol (3: 2). A: purple band with Rf of 0.70 was scraped off and extracted with methanol; The extract was concentrated to dryness and the residue was redissolved in a ranged solvent of methanol and acetone (2: 1), insolubles were filtered off and then the filtrate was concentrated to dryness giving 35 mg of compound SF-1739 HP-C were obtained.

Example IU

Preparation of compound SF-1739 HP-F

A solution of 35 mg of compound SF-1739 HP in 1.5 ml of pharmamide was stored at room temperature for 5 min. After that, the reaction mixture was concentrated to dryness under reduced pressure below 50 ° C. The residue was dissolved in a small amount methanol and the resulting! The solution was applied to a preparative silica gel thin layer chromatography plate (2 x 100 x 100 mm), which was then developed with a mixed solvent of ethyl acetate and methanol (3: 2). A purple band with Rf of 0 53 was scraped off and extracted with methanol. The extract was concentrated to dryness, the residue was.

30 again dissolved in a mixed solvent of methanol and acetone (2: 1), insolubles were filtered off and then the filtrate was concentrated to dryness to give 25 mg of compound SF-1739 HP-F.

Example IV

Preparation of compound SF-1739 HP-G

To a solution of 73 mg of compound SF-1739 HP in 2 ml _ 7904766 -18-

/ · V

methanol, 72 mg of potassium cyanide were added and the resulting mixture was stirred at room temperature for 5 min. The reaction mixture was applied to a preparative silica gel thin layer chromatography plate (2 x 100 x 100 mm), which was then developed with a mixed solvent of ethyl acetate and methanol (3: 2). A purple band with Rf of 0.70 was scraped off and extracted with methanol. The extract was concentrated to dryness, the residue was redissolved in a mixed solvent of methanol and acetone (2: 1), insolubilities were filtered and then the filtrate was concentrated to dryness to give 50 mg of compound SF-1739 HP-C. obtained.

Example V

Preparation of compounds SF-1739 HP-3, SF-1739 HP-5 and SFr-1739 HP "Spores of Streotomyces griseoplanus strain SF-1739 (registration 15002 at the Technical Research Institute of Microbial Industry)" were inoculated on 1.6 L of liquid medium containing 1.0% starch and 3.0% soybean meal (pH 7.0) and cultivated with shaking for 30 hours at 28 ° C using 16 Sakaguchi calves to obtain a seed culture.

The seed culture thus obtained was inoculated on 70 l of liquid medium containing corn syrup 3.0 $, soybean meal 2.0 $, beef extract M, 0 $, wheat germ 1.0 $ and sodium chloride 0.3 $ (pH 6.6). and the agitation shaking culture was carried out at 28 ° G for 90 hours using two fermentation vats each with a volume of 50 L.

. The broth broth was adjusted to pH 3-4 with 6N hydrochloric acid and filtered with filter acid, Hyflo Super Cel (trade name), s The filtrate (about 47 L) was adjusted to pH 6 with 3N sodium hydroxide and passed through a column of about 4 L of ion exchange resin, Am-; 30 berlite IRCi-50 (H +) (trade name) to adsorb antibiotic metabolites. The column was washed thoroughly with water and eluted with 0.2 N aqueous hydrochloric acid. The active fraction of about 4.5 L was saturated with sodium chloride, adjusted to pH 8.0 with sodium hydroxide and then extracted twice, each with 11 ethyl acetate under cooling. The ethyl acetate extract was back extracted with 200 ml of 0.05 N aqueous hydrochloric acid. The resulting aqueous solution (pH 2.0) was reduced under reduced pressure 7904766 -19 - concentrated to dryness to give 1.68 g of antibiotic metabolites as raw powder. The crude powder was dissolved in 20 ml of 5N hydrochloric acid, stored at room temperature for 1 week and then concentrated again under reduced pressure to dryness. residue was dissolved in 20 ml of methanol and the resulting yellow-red solution was neutralized with solid sodium hydrogen carbonate until it turned purple. Insolubilities were filtered off, the filtrate was concentrated and then the filtrate was applied to 7 preparative silica gel thin layer chromatography plates (2 x 100 x 100 mm), which were then unwound with a mixed solvent of ethyl acetate and methanol (3: 2). purple band with Hf of 0.12 was scraped from each plate and; Extracted with methanol. The combined extracts were concentrated to dryness to yield compound SF-1739 HP-5 as a crude powder. The crude powder was dissolved in a small amount of methanol and applied to three preparative silica gel thin layer chromatographs. fie plates were then developed with a mixed solvent of chloroform: methanol (9: 1). Purple bands with Rf of 0.12 were scraped, extracted with methanol, and the extract was concentrated to dryness. The residue was dissolved in a mixed solvent of methanol and acetone (3: 1), insolubles were filtered off and the filtrate was concentrated to dryness to give 153 mg of compound SF-1739 HP-5.

From the first silica gel thin layer chromatography plates, purple bands with 0.39 Rf were scraped off and extracted with methanol. The extract was concentrated to dryness, the residue was dissolved in a small amount of methanol and on a preparative silica gel thin layer. chromatography plate (2 x 100 x 100 mm), which was then developed with a mixed solvent of chloroform and methanol (9: 1). A purple band with Rf of 0.22 was scraped off and extracted with methanol. extract was dried

Concentrated, the residue was dissolved in a mixed solvent of methane nol and acetone (2: 1j, insolubles were filtered off, then the filtrate was concentrated to dryness to give 27 mg of compound SF-1739 HP-3.

35 Of the first silica gel thin layer chromatography.

Plates were scraped purple bands with Rf 0.31 and with metha7904766

Claims (9)

4. Compound SF-1739 HP-5 having the following physicochemical properties: (1) black-purple substance, 25 (2) U.v. absorption spectrum as indicated in Fig. 11, (3) I.r. absorption spectrum as indicated in fig. 12 characteristic absorption bands at 3300, 1655, 1600, 1540, 1350, 1260, 1235, 1175, 1085, 1025, 1000, 905, 865, 835, -790 and 775 cm 1,! (4) K .mr spectrum as shown in Fig. 13, 30 | (5) Elemental analysis: found C 60.93 $, H 7.05 $, N 8.41 $ j and 0 23.61 $ (from difference), j (s) Solubility: Easily insoluble in water and methanol, soluble in ethyl acetate and acetone and slightly soluble in hexane, (7) Chromatography: thin layer chromatography 00 silicon * dioxide gel Rf values = 0.12 (chloroform: methanol = 9: 1) and 0.12 (ethyl 7904766 4 *. ·· -22 - acetate: methanol = 3: 2), 5. Compound SF-1739 HP-3 with the following physicochemical properties: (1) black-purple substance, [2) UV, absorption spectrum as shown in Fig, 14, 5 (3) I.r. absorption spectrum as shown in Fig. 15 with typical absorption bands, at 3355, 1680, 1655, 1600, 1545, 1350, 131C, j1265, 1180, 1155, 1085, 1070, 1055, 1020, 950, 955, 900, 835 and 790 cnT? j (4) K.m.r. spectrum as shown in Fig. 16, | (5) Elemental analysis: found C 64.13%, H 5.01%, N 9.25%, 10 and 0 21.61% (from difference),! ί j (6) Solubility: Easily soluble in water and methanol], soluble in acetone and ethyl acetate, and slightly soluble in hexane, j (7) Chromatography: with a thin layer of silica chromatography Rf values = 0.22 (chloroform : methanol = 9: 1) and 0.39 (ethyl-15 acetate: methanol = 3: 2). f [ï 6. Process for the preparation of a compound SF-1739 HP with the following physicochemical properties: (1) black-purple substance, (2) U.v. absorption spectrum as shown in Fig. 1, 20 (3) I.r. absorption spectrum as shown in Fig. 2 with typical absorption bands at 3350, 1655, 1600, 1540, 1355, 1265, 1235,: 1180, 1120, 1080, 1020, 1000, 965, 945, 820, 910, 865, 830, 790 and 750! -1 cm, j W K.m.r. spectrum as indicated in Fig. 3 25> (5) Optical rotation dispersion curve as indicated in Fig. 4, (6) Elemental analysis: found C 62.19%, H 6.95%, N 8.50% i and 0 22 , 36% (from difference), ((7) Solubility: Easily soluble in water and methanol, oplos soluble in ethyl acetate and slightly soluble in hexane, 30 30 ((8) Chromatography: with thin layer chromatography on silica Rf values 0.45 (chloroform: methanol = 9: 1) and 0.23 (n-butancl: methanol: 0.1 n hydrochloric acid = 4: 2: 1), characterized in that a compound SF-1739 is subjected to an acid treatment, 7. Process for the preparation of a compound SF-1739 HP-C 35 with the following physicochemical properties: 790 4766 - 23 * *. * Γ ~ (1} black-purple substance, (2} UV absorption spectrum as indicated) in Fig. 5, (3} Ir absorption spectrum as indicated in Fig. 6 with typical absorption bands at 3350, 1660, 1600, 1535, 1355, 1265, 1235, 5; 1200, 1175, 1140, 1120, 1080, 1060, 1000, 940, 910, 880, 835 and 795 cnT? (4} Optical rotation dispersion curve as shown in Fig. 7 ', (5} Kmr spectrum as shown in Fig. 8; (6} Elemental analysis: found C 59 .58 $, H 6.14 $, N 12.63 $ 'and 0 21.65 (difference), 10 (7) Solubility: Easily soluble in water and methanol?, Soluble in acetone and ethyl acetate and slightly soluble in hexane, (8) Chromatography: thin layer chromatography on silica gel Rf values = 0.40 (chloroform: methanol = 9: 1) and 0.70 (ethyl acetate: methanol = 3: 2), characterized in that one is \ 15 a compound SF-1739 subject t to an acid treatment to form a compound SF-1739 HP and the latter compound reacts with a cyanide. i 8. Process for the preparation of a compound SF-1739 HP-F with the following physicochemical properties: 20 (1) black-purple substance, (2) U.v. absorption spectrum as shown in Fig. 9, (3) I.r. absorption spectrum as shown in Fig.10 with typical absorption bands at 3300, 1660, 1530, 1350, 1310, 1265, 1235, 1205, 1175, 1125, 1085, 1025, 1000, 940, 920, 830 and 795 cm ”1, (4) Elemental analysis: found C $ 57.26, H $ 6.33, N $ 12.14 and $ 24.27 (from difference), (5) Solubility: Easily soluble in water and methanol !, soluble in acetone and ethyl acetate and slightly soluble in hexane, (6) Chromatography: thin layer chromatography on silica gel Rf values = 0.28 (chloroform: methanol = 3: 2), characterized in that a compound SF-1739 is subjected to | A treatment with an acid to form a compound SF-1739 HP and the latter compound reacts with formamide. ; ( 9. Process for the preparation of a compound SF-1739 HP-5; 35 with the following physicochemical properties: {7904766 "24 - r (1) black-purple substance, (2) U.v. absorption spectrum as shown in Fig. 11, (3) I.r. absorption spectrum as shown in Fig. 12 with typical absorption bands at 3300, 1655,1600,1540, 1350, 1260, 1235, 5 1175, 1085, 1025, 1000, 905, 865, 835, 790 and 775 cm "1, i ] (4) Kmr spectrum as indicated in Fig.11, | (5) Elemental analysis: found C 60.93 $, H 7.05 $, N 8.41 $ i and 0 23.61 $ (from difference), (6) Solubility: Freely soluble in water and methanol, soluble in ethyl acetate and acetone and slightly soluble in hexane, (7) Chromatography: with thin layer chromatography on silica gel Rf values »0 12 (chloroform: methanol 9: 1 J and 0.12; (ethyl acetate: methanol 3:2), characterized in that an antibiotic metabolite is subjected to treatment with an acid, wherein the metabolite is obtained by cultivation of Streptomyces: griseoplanus strain SF-1739, followed by fractionation of a cultured broth. 10. Process for preparing a compound SF-1739 HP-3 having the following physicochemical properties: 20 (1) black-purple substance, (2) U.v. absorption spectrum as indicated in FIG. 14, j (3) I.r. absorption spectrum as shown in Fig. 15 with typical absorption bands at 3355, 1680, 1655, 1600, 1545, 1350, 1310, 1265, 1180, 1155, 1085, 1070, 1055, 1020, 955, 950, 900, 835 and 790 cm '] 25 y (4) Km spectrum as shown in Fig. 16,! (5) Elemental Analysis: Found C 64.13 $, H 5.01 $, N 9.25 $ | and 0 21.61 $ (out of difference)! | (6) Solubility: Freely soluble in water and methanol],: Soluble in acetone and ethyl acetate, and slightly soluble in hexane, 30 | (7) Chromatography: thin-layer chromatography on silica gel Rf values 0,2 0.22 (chloroform: methanol = 9: 1) and 0.39 (ethyl acetate: methanol = 3: 2), characterized in that an antibiotic metabolite is subjected to an acid treatment, the metabolite being obtained by cultivation of Streptomyces 35 griseoplanus strain SF-1739, followed by fractionation of a cultured 7904766 k-25- [antibacterial preparation, characterized in that It contains one or more of the following antibiotic agents as the active ingredient: Compound SF-1739 HP, Compound SF-1739 HP-C, Compound HP-F, Compound SF-1739 HP-5, and SF-1739 HP-3 , where the 5! compound SFr1739 HP has the following physicochemical properties !: | (1) black-purple fabric, j! (2} UV absorption spectrum as indicated in Fig. 1, (3) Ir absorption, spectrum as; indicated in-Tig.2 with characteristic absorption bands at 3350, 1655, 1600, 1540, 1355, 1265, 1235, : 10 11 180, 1120, 1080, 1020, 1000, 965, 945, 920, 910, 865, 830, 790 and 750 -1 cm,} | (4) Kmr, spectrum as shown in Fig. 3, (5) Optical rotational triispersion curve as shown in Fig. 4 ,; (δ) Elemental analysis: found C 62.19 $, H 6.95 $, N 8.50 $ f 15 and 0 22.36 $ (from difference), (7 ) Solubility: Easily soluble in water and methanol, i Soluble in ethyl acetate and slightly soluble in hexane,} (β) Chromatography: Thin layer chromatography on silica gel Rf values = 0.45 (chloroform: methanol = 9: 1) and 0.23 | 20 (π-butanol: methanol: 0.1 n hydrochloric acid = 4: 2: 1), the compound SF-1739 HP-C has the following physicochemical properties: (1) black-purple substance (2) UV absorption spectrum as shown in Fig. 5, (3) Ir absorption spectrum as shown in Fig. 6 with characteristic 25 absorption bands at 3350, 1660, 1600, 1535, 1355, 1265, 1235, 1200, 1175, 1140, 1120, 1080, 1060, 1000, 940, 910, 880, 835 and 795 cm "] ( 4) Optical rotation dispersion curve as shown in Fig. 7, ij (5) Kmr spectrum as indicated in Fig. 8, j (6) Elemental analysis: found C 59.58 $, H 6.14 $, N 12.63 $; 30. and 0 21.65 $ (from difference), j (7) Solubility: easily soluble in water and methanol, soluble in acetone and ethyl acetate and sparingly soluble in hexane, j (8) Chromatography: with thin layer chromatography 00 silicon dioxide Rf values = 0.40 (chloroform: methanol = 9: 1) and 0.70 (ethyl acetate: methanol »3: 2), the compound SF-1739 HP-F the following physico-chemical ei-j 7904766 · »—26 -" features: (1) black-purple fabric, (2) UV absorption spectrum as shown in Fig. 9, (3) Ir, absorption spectrum as shown in Fig. 10 with typical absorption bands at 3300, 1660, 1530, 1350, 1310, 1265, 1235, 5 1205, 1175, 1125, 1085, 1025, 1000, 940, 920, 830, and 795 cm-1, (4) Elemental Analysis: Found C 57.26 $ , H 6.33 $, N 12.14 $ and 0 24.27 $ (from difference), I | (5) Solubility: Easily soluble in water and methanol, soluble in acetone and ethyl acetate and slightly soluble in hexane, 10 (6) Chromatography: with thin layer chromatography on silica gel rf values = 0.28 (chloroform: methanol = 9: 1} and 0.83 (ethyl; acetate: methanol = 3: 2), the compound SF-1739 HP-5 shows the following physicochemical egg- Features: (l) black-purple fabric, j 15 (2 '} UV absorption spectrum as shown in Fig. 11, I' (3) Ir absorption spectrum as shown in Fig. 12 with features: labeling absorption bands at 3300 , 1655, 1600, 1540, 1350, 1260, 1235, 11175, 1085, 1025, 1000, 905, 865, 835, 790 and 775 cm "1 (4) Kmr spectrum as shown in Fig. 13, 20 (5 ) Elemental analysis: found C 60.93 $, H 7.05 $, N 8.41 $ j and 0 23.61 $ (from difference), j (6) Solubility: easily soluble in water and methanol, i; soluble , in ethyl acetate and acetone and slightly soluble in hexane,, (7) Chromatography: with thin layer chromatography on silicon Idioxyde gel Rf values 0.12 (chloroform: methanol = 9: 1) and 0.12 (ethyl acetate: methanol = 3: 2, and compound SF-1739 HP-3 the following physico-chemical egg; : The shelves have: (1) black-purple fabric, 790 4766 (2) UV, absorption spectrum as shown in Fig. 14, 30 (3) Ir absorption spectrum as shown in Fig. 15 with typical absorption bands at 3355, 1680, 1655, 1600, 1545, 1350, 1310, 1265, 1180, 1155, 1085, 1070, 1055, 1020, 955, 950, 900, 835 and 790 cm @ 4 Kmr spectrum as shown in Fig. 16,] ( 5) Elemental analysis: found C 64.13 $, H 5.01 $, N 9.25 $ 35 and 0 21.61 $ (from difference), (6) Solubility: Easily soluble in water and mathanol, j * - 27 - "— "... ... ---- '' - soluble in acetone and ethyl acetate and slightly soluble in hexane, (7) chromatography: with thin layer ohromatography on silica gel Rf values = 0.22 ( chloroform: methanol = 9: 1] and Q, 39 (ethyl acetate: methanol = 3: 2) 5, 12. Anti-tumor preparation with the character Recognize that the active ingredient j! contains one or more of the following: j SF-1739 HP compound, SF-1739 HP-C compound, SF-1739 compound: HP-F, SF-1739 HP-5 compound and SF-1739 HP-3, wherein the compound SF-1739 HP has the following physicochemical properties: (1) black-purple substance, (2) Li.v. absorption spectrum as shown in FIG. 1.1 (3} Ir absorption spectrum as shown in Fig. 2 with typical absorption bands at 3350, 1655, 1600, 1540, 1355, 1265, 1235, 1180, 1120, 1080, 1020, 1000, 965, 945 , 920, 910, 865, 830, 790 and 750 * -1; 15 cm, (4) Kmr spectrum as shown in Fig. 3, j (ö) Optical rotation dispersion curve as shown in Fig. 4, (6) Elemental analysis : found G 62.19 $, H 6.95 $, N 8.50 $, and 0 22.36 $ (from difference], 20 (7) Solubility: easily soluble in water and methanol, soluble in ethyl acetate and slightly soluble in hexane, (8) Chromatography: with thin layer chromatography on silica gel Rf values = 0.45 (chloroform: methanol = 9: 1) and 0.23 (π-butanol: methanol: 0.1 n hydrochloric acid = 4: 2: 1), the compound SF-1739 HP-G has the following physicochemical properties: (1) black-purple dust, (2) UV absorption spectrum as shown in Fig. 5, j (3) Ir absorption spectrum as indicated in Fig. 6 with characteristic absorption bands at 3350, 1660, 1600 , 1535, 1355, 1265, 1235, 30; 1200, 1175, 1140, 1120, 1080, 1060, 1000, 940, 910, 880, 835, and 795 cm "] * (4) Optical rotation dispersion curve as shown in FIG. 7, (5) K. Spectrum as indicated in Fig. 8, I (δ) Elemental analysis: found C 59.58 $, H 6.14 $, N 12.63 $ 'and 0 21.65 $ (from difference), * 35 ~ (7) Solubility: easily soluble in water and methanol, | 790 47 66 -28- "soluble in acetone and ethyl acetate and slightly soluble in hexane, (8) Chromatography: thin layer chromatography on silica gel Rf values = 0.4G (chloroform: methanol = 9: 1] and Q, 70 (ethyl] acetate: methanol ** 3: 2} f 5 the compound SF-1739 HP-F has the following physicochemical properties: (1) black-purple substance, (2) UV absorption spectrum as shown in FIG. 9,!; (3] Ir absorption spectrum as shown in Fig. 10 with characteristic absorption bands at 3300, 1660, 1530, 1350, 1310, 1265, 1235rj 10 1205, 1175, 1125, 1085, 1025, 1000 , 940, 920, 830, and 795 cnf1, yy (4) Elemental analysis: found C $ 57.26, H $ 6.33, N $ 12.14, and $ 24.27 (from difference),; (5) Solubility: Easily soluble in water and methanol, soluble in acetone and ethyl acetate, and slightly soluble in hexane, 15 (6) Chromatography: with thin layer chromatography on silica gel Rf values = 0.28 (chloroform: methanol sa 9: 1) and 0.53 (ethyl-a acetate: methanol = 3: 2), the compound SF-1739 HP-5 has the following physicochemical properties: (1) black-purple substance, 20 (2) U.v. absorption spectrum as indicated in Fig. 11, | (3) I.r, absorption spectrum as indicated in Fig. 12 with characteristic! marking absorption bands at 3300, 1655, 1600, 1540, 1350, 1260, 1235,! 1175, 1085, 1025, 1000, 905, 865, 835, 790 and 775 cm ”\ • (4) K.m.r. spectrum as shown in Fig. 13, 25 I (5) Elemental analysis: found C 60.93 $, H 7.05 $, N 8.41 $ I and 0 23.61 $ (from difference), i] (6) Solubility: Easily soluble in water and methanol, soluble in ethyl acetate and acetone and sparingly soluble in hexane, i (7) Chromatography: with thin layer chromatography on silica gel Rf values = 0.12 (chloroform: methanol = 9: 1) and 0.12 j ( ethyl acetate: methanol = 3: 2), and compound SF-1739 HP-3 has the following physicochemical properties: (1) black-purple substance, (2) UV absorption spectrum as shown in Fig. 14, 35 (3) I.r. absorption spectrum as shown in Fig. 15 with typical absorption bands, at 3355. ', 1680, 1655, 1600, 1545, 1350, 131C, 7904766 -29 - α 1265, ~ 1180, 1155, 1085, 1070, 1055, 1020 , 950, 955, 900, 835 and 790 cm "] (4) Kmr spectrum as shown in Fig.16, (5) Elemental analysis: found C 64.13 $, Η 5.01 $. * $ * 9, 25 $ and 0 21.61 $ (from difference), 5 (6) Solubility Very soluble in water and methanol, soluble in acetone and ethyl acetate and slightly soluble in hexane, (7) Chromatography: with thin layer chromatography on silica dioxide gel Rf values »0.22 (chloroform: methanol = 9: 1) and 0.39 (ethyl acetate: methanol = 3: 2), wherein the active ingredient is present in an amount sufficient is to eliminate or alleviate symptoms and signs of a cancer patient ii, s = =: = r =; sr = = ss ii • I.rile] ti 'isjiji! ij! 7904766