ANTHRACYCLINE COMPOUNDS, A PROCESS FOR THEIR PREPARATION AND THEIR USE AS MEDICAMENTS

Abstract: The present invention relates to novel anthracycline deriv­ atives of formula: where R is any one of the following groups and a process for their preparation, which comprises aerobi­ cally cultivating a microorganism strain of the genus Actino­ madura being capable of producing said compound. The com­ pounds exhibit anti-tumor and anti-microbial properties and can, therefore, be used as medicaments.

Description: MICROBIAL CHEMISTRY RESEARCH FOUNDATION Anthracycline compounds, a process for their preparation and their use as medicaments The present invention relates to novel anthracycline compouns. Anthracycline compounds such as adriamycin, daunomycin and acranomycin are important caneer-control antibiotics which are extensively used in cancer chemotherapy. Concerted efforts are being made by many researchers to develop various analogs and derivatives of these anthracycline compounds. The physiological actiyities of,most compounds are largely depedent on their chemical structures. Anthracycline compounds are not an exception and there exists an ever increasing demand for developing derivatives that differ from the existing compounds with respect to the type of the aglycon and sugar portions, and to the substituents on such portions. The present invention relates therefore to anthrÅa- cycline compounds (barminomycins), having the following formula (I): EMI1.1 where R is any one of the following groups (a) to (d): EMI2.1 or acid addition salts thereof. The anthracycline compounds of the present invention have the chemical structure represented by the formula (Z), The substituent R can be (a), (b), (c) or (d), and each of them exists in two stereoisomeric forms with respect to the asymetric carbon at 51 position. A compound having (a), (b) or (c) as the substituent R is readily interconvertible in a stereospecific manner and usually exists in the form of a mixture of two of such groups in equilibrium, as shown below: EMI3.1 (aldehyde + primary amine type) (carbinolamine type) (imine type) The equilibrium shown above has a tendency to shift toward (c) in organic solvents and toward (a) in the presence of water and acids. Since two stereoisomers exist for the substituent R, the tautomer can also exist in one of the two forms, which will hereunder be referred to as barminomycin I and barminomycin II, respectively. The compound of the present invention having (d) as substituent R may be obtained by reducing barminomycin I or II (as will be described later in this specification); the compound obtained by reducing barminomycin I with NaBH3CN and the one obtained by reducing barminomycin II with NaBE3CN are hereunder referred to as barminomycin Ir and barminomycin IIr,.respectively. Both barminomycin I and II are currently obtained only by means of cultivating microorganisms and their chemical structures have been determined as follows by the sequence of analysis shown in Fig. 1. Both barminomycin I and II present a main ion peak at m/z = 639 in FD-MS,¯and the two compounds are in close agreement in terms of absorption in the ultraviolet and visible ranges, absorption in the infrared range and the 1H-NMR spectrum. However, in view of the differences that exist with respect to the Rf values on TLC and specific rotations, it has been suggested that the compounds are two different stereoisomers. Both compounds yielded a red aglycon by heating at 85eC for 30 minutes in 0.1 N Ect, and as a result of 1B-NMR spectrum, mass spectrum and other analyses, this aglycon was identified as carminomycin (Formula 2) (see Journal of Antibiotics, 29, 469 - 471, 1976). The aglycon from each compound also yielded a red glycoside by partial hydrolysis at 30 C in 1% sulfuric acid. Each of the resulting glycosides was in close agreement with an authentic sample of carminomycin I (Formula 3) in terms of the Rf values on silica gel TLC, specific rotation and 1B-NMR spectra (see Journal of Antibiotics, 27, 254 - 259, 1974). When barminomycin I was dissolved in a mixture of methanol and 1 N aqueous acetic acid (2:1) and the solution reduced with NaBH3CN, two red glycosides formed. On the basis of data on specific rotation 27 + 178 (c 0.02, basis CHCt3); documented as +170.40 (c 0.053, CHCL3)), FD-MS (m/z = 660 M + H) +) and 1B-NMR spectrum (see Table 1), one of the two glycosides was identified as carminomycin III (Formula 4) (identical with 4-hydroxy baumycin A1 or rubeomycin A1; see Antibiotiki, 488 - 492, 1980; Journal of Antibiotics, 34, 774 - 776, 1981; and Journal of Antibiotics, 34, 938 - 950, 1981). The other reduced form (barminomycin Ir) was fairly close to the first glycoside except that it gave a main ion peak at m/z = 642 (M + H) + in FD-MS, that 33 carbon atoms were identified in 13C-NMR spectrum (Fig. 8) and that chemical shifts of carbon at 3' position (51.6 ppm) and 6" position (52.8 ppm) in the 13C-NMR spectrum changed appreciably as compared with the shifts for carminomycin III. Analysis of the 1E¯NMR spectrum of barminomycin Ir (Fig. 5) revealed that it had the structure represented by Formual 5. When barminomycin II was likewise reduced with NaBH3CN carminomycin II (Formula 4) (identical with 4hydroxy baumycin A2 or rubeomycin A; see the references listed for carminomycin III) ([&alpha;]D27 + 124 (c 0.015, CHCl3); documented as 120.6 (c 0.199, CHCl3); m/z = 660 (M + H)+ in FD-MS; and 1E¯NMR spectrum (Table 1)) and barminomycin IIr were obtained. The latter compound was found to have the structure represented by formula 5 in view of its FD-MS (m/z a 642 (M + H) +) and ÚH-NMR spectra data (Fig. 7). It should, however, be mentioned that barminomycin Ir and IIr would be two stereoisomers at 5 position in consideration of the differences that exist typically with respect to Rf values on silica gel TLC and specific rotation. These facts and the physicochemical properties of the two compounds (to be described hereinafter) indicate that each of barminomycin I and barminomycin II is one of the compounds represented by Formula 1 or a tautomer thereof and that the two compounds are stereoisomers at 5" position. These structures of barminomycin I and II are also supported by the fact that they are interconvertible when they are stored in the form of solutions, etc. Table 1 1H-NMR Spectral Data for Carminomycin III and II (400 MHz in d-CHCl3) EMI7.1 <tb> <SEP> Carminomycin <SEP> III <SEP> Carminomycin <SEP> II <tb> Assignment <SEP> # <SEP> (ppm) <SEP> <SEP> signal <SEP> pattern <SEP> # <SEP> (ppm) <SEP> <SEP> signal <SEP> pattern <tb> <SEP> 7"-CH3 <SEP> 1.06 <SEP> d <SEP> 1.17 <SEP> d <tb> <SEP> 4"-CH3 <SEP> 1.23 <SEP> d <SEP> 1.20 <SEP> d <tb> <SEP> 6'-CH3 <SEP> 1.32 <SEP> d <SEP> 1.30 <SEP> d <tb> <SEP> 2' <SEP> -CH2 <SEP> #1. <SEP> <SEP> 80 <SEP> m <SEP> 1. <SEP> 90 <SEP> m <tb> <SEP> 2" <SEP> -CH2 <SEP> 1. <SEP> 85 <SEP> m <SEP> 1. <SEP> 86 <SEP> m <tb> <SEP> 8-Hax <SEP> 2. <SEP> 08 <SEP> dd <SEP> 2. <SEP> 09 <SEP> dd <tb> <SEP> 8-Heq <SEP> 2. <SEP> 29 <SEP> ddd <SEP> 2.31 <SEP> ddd <tb> <SEP> COCH3 <SEP> 2. <SEP> 42 <SEP> s <SEP> 2. <SEP> 41 <SEP> s <tb> <SEP> 10-Hax <SEP> 2. <SEP> 98 <SEP> d <SEP> 2.94 <SEP> d <tb> <SEP> 3' <SEP> -H <SEP> 3. <SEP> 09 <SEP> m <SEP> 3. <SEP> 29 <SEP> , <SEP> m <tb> <SEP> 10-Heq <SEP> 3. <SEP> 23 <SEP> dd <SEP> 20 <SEP> <tb> <SEP> 6"-HB <SEP> 3.41 <SEP> br <SEP> d <SEP> }3.54 <SEP> m <tb> <SEP> 6"-HA <SEP> 3.51 <SEP> dd <tb> <SEP> 5" <SEP> -H <SEP> 3. <SEP> 80 <SEP> m <SEP> 3. <SEP> 84 <SEP> m <tb> <SEP> 4' <SEP> -H <SEP> s <SEP> <SEP> 3. <SEP> 93 <SEP> br <SEP> s <SEP> 3. <SEP> 80 <SEP> m <tb> <SEP> 5'-H <SEP> 4.14 <SEP> dq <SEP> 4.14 <SEP> dq <tb> <SEP> 3'-H <SEP> 4.17 <SEP> m <SEP> 4.23 <SEP> m <tb> <SEP> 1' <SEP> -H <SEP> 4. <SEP> 74 <SEP> t <SEP> 4. <SEP> 85 <tb> <SEP> 7-H <SEP> S <SEP> 5. <SEP> 20 <SEP> br <SEP> s <SEP> 5. <SEP> 18 <SEP> br <SEP> s <tb> <SEP> 1'-H <SEP> 5.44 <SEP> dd <SEP> 5.48 <SEP> dd <tb> <SEP> 3-H <SEP> 7. <SEP> 31 <SEP> dd <SEP> 7. <SEP> 26 <SEP> dd <tb> <SEP> 2-H <SEP> 7. <SEP> 71 <SEP> dd <SEP> 7. <SEP> 67 <tb> <SEP> 1-H <SEP> 7.87 <SEP> dd <SEP> 7.77 <tb> Physicochemical Properties of Barminomycin Barminomycin I and II in accordance with the present invention and their respective reduced forms, barminomycin Ir and lir, have the physicochemical data shown in Table 2. The samples of barminomycin I and II used in the measurements were the tautomers prepared in Example 2 to be described hereinafter. Table 2 Physicochemical Data of Barminomycia Compounds EMI8.1 <SEP> I <SEP> II <SEP> Ir <SEP> IIr <tb> 1. <SEP> Color <SEP> red <SEP> orange <SEP> red <SEP> orange <SEP> red <SEP> orange <SEP> red <SEP> orange <tb> 2. <SEP> FD-MS, <SEP> m/s <SEP> 639 <SEP> (M)+ <SEP> 639 <SEP> (M)+ <SEP> 642 <SEP> (M <SEP> # <SEP> N)+ <SEP> 642 <SEP> (M <SEP> + <SEP> N)+ <tb> 3. <SEP> Melting <SEP> point <SEP> - <SEP> - <SEP> 129 <SEP> # <SEP> 134 C <SEP> 124 <SEP> # <SEP> 132 C <tb> 4. <SEP> Specific <SEP> rotation <SEP> +235 <SEP> +184 <SEP> +294 <SEP> +187 <tb> <SEP> (c <SEP> 0.017, <SEP> CHCl3) <SEP> (c <SEP> 0.025, <SEP> CHCl3) <SEP> (c. <SEP> 0.043, <SEP> CHCl3) <SEP> (c <SEP> 0.023, <SEP> CHCl3) <tb> 5. <SEP> Absorption <SEP> spectrum <SEP> 233 <SEP> (712) <SEP> 233 <SEP> (702) <SEP> 233 <SEP> (666) <SEP> 233 <SEP> (663) <tb> <SEP> for <SEP> UV <SEP> and <SEP> visible <SEP> 253 <SEP> (505) <SEP> 253 <SEP> (499) <SEP> 253 <SEP> (489) <SEP> 253 <SEP> (486) <tb> <SEP> bands <SEP> 291 <SEP> (150) <SEP> 291 <SEP> (145) <SEP> 290 <SEP> (145) <SEP> 290 <SEP> (148) <tb> <SEP> #max, <SEP> nm <SEP> (D11% <SEP> cm) <SEP> 491 <SEP> (275) <SEP> 491 <SEP> (270) <SEP> 491 <SEP> (272) <SEP> 490 <SEP> (270) <tb> <SEP> in <SEP> 0.1 <SEP> M <SEP> HCl <SEP> - <SEP> 90% <SEP> MeOH <SEP> 525 <SEP> (180) <SEP> 525 <SEP> (176) <SEP> 525 <SEP> (179) <SEP> 525 <SEP> (177) <tb> 6. <SEP> IR <SEP> absorption <SEP> Fig. <SEP> 2 <SEP> Fig. <SEP> 3 <SEP> Fig. <SEP> 4 <SEP> Fig. <SEP> 5 <tb> <SEP> spectrum <SEP> (in <SEP> d-CHCl3) <SEP> (in <SEP> d-CHCl3) <SEP> (as <SEP> KBr <SEP> tablet) <SEP> (as <SEP> KBr <SEP> tablet) <tb> 7. <SEP> ÚH-NMR <SEP> spectrum <SEP> Table <SEP> 3 <SEP> Table <SEP> 3 <SEP> Fig. <SEP> 5 <SEP> Fig. <SEP> 7 <tb> 8. <SEP> Rf <SEP> values <SEP> on <SEP> 0.42 <SEP> 0.35 <SEP> 0.34 <SEP> 0.29 <tb> <SEP> silica <SEP> gal <SEP> TLC*1 <tb> 9. <SEP> tR*2 <SEP> in <SEP> HPLC <SEP> 7.0 <SEP> min <SEP> 8.5 <SEP> min <SEP> 7.6 <SEP> min <SEP> 7.2 <SEP> min <tb> Table 2 (continued) EMI9.1 10. <SEP> Stability <SEP> Decomposed <SEP> on <SEP> Decomposed <SEP> on <SEP> Instable <SEP> to <SEP> Instable <SEP> to <tb> <SEP> silica <SEP> gel <SEP> silica <SEP> gel <SEP> acids <SEP> and <SEP> light <SEP> acids <SEP> and <SEP> light <tb> <SEP> and <SEP> during <SEP> and <SEP> during <tb> <SEP> concentration <SEP> concentration <tb> <SEP> procedures <SEP> procedures <tb> <SEP> Instable <SEP> to <SEP> Instable <SEP> to <tb> <SEP> acids <SEP> and <SEP> light <SEP> acids <SEP> and <SEP> light <tb> 10. <SEP> Solubility <tb> (1) <SEP> Soluble <SEP> chloroform, <SEP> chloroform, <SEP> chloroform, <SEP> chloroform <tb> <SEP> ethyl <SEP> acetate, <SEP> ethyl <SEP> acetate, <SEP> ethyl <SEP> acetate, <SEP> ethyl <SEP> acetate, <tb> <SEP> ethanol, <SEP> ethanol, <SEP> ethanol, <SEP> ethanol, <tb> <SEP> methanol, <SEP> methanol, <SEP> methanol, <SEP> methanol, <tb> <SEP> acetonitrile, <SEP> acetonitrile, <SEP> acetonitrile, <SEP> acetonitrile, <tb> <SEP> dimethyl <SEP> sulfoxide <SEP> dimethyl <SEP> sulfoxide <SEP> dimethyl <SEP> sulfoxide <SEP> dimethyl <SEP> sulfoxide <tb> (2) <SEP> Sparingly <SEP> soluble <SEP> water, <SEP> water, <SEP> water, <SEP> water, <tb> <SEP> hexane, <SEP> hexane, <SEP> hexane, <SEP> hexane, <tb> <SEP> petroleum <SEP> ether <SEP> petroleum <SEP> ether <SEP> petroleum <SEP> ether <SEP> petroleum <SEP> ether <tb> (Notes) *1 Developing solvent: : chloroform - methanol - acetic acid - water (60:10:1:1) *2 Column : Nucleosil 5C18 (4.6 x 250 mm) (product of N-Nagel) Eluent : acetonitrile - 0.2% aqueous phosphoric acid (40:60) Flow rate : 1.5 ml/min Table 3 ÚH-NMR Spectral Data for Barminomycin I and II (400 MHz, in 2:1 d-CHCl3/d-MeOH EMI10.1 <tb> <SEP> Barminomycin <SEP> I <SEP> # <SEP> Barminomycin <SEP> II <tb> <SEP> Integra- <SEP> Signal <SEP> Integra- <SEP> Signal <tb> 6 <SEP> (ppm) <SEP> tion <SEP> pattern <SEP> 6 <SEP> (ppm) <SEP> tion <SEP> pattern <tb> <SEP> 1.21 <SEP> 3H <SEP> d <tb> <SEP> 1.23 <SEP> 3H <SEP> d <SEP> 1.18 <SEP> X <SEP> 1.33 <SEP> 9H <SEP> dx3 <tb> <SEP> 1.27 <SEP> 3H <SEP> d <tb> <SEP> 1.72 <SEP> 2H <SEP> m <SEP> 1.75 <SEP> # <SEP> 1.98 <SEP> 4H <SEP> m <tb> <SEP> 1.89 <SEP> 2H <SEP> m <tb> <SEP> 2.15 <SEP> 1H <SEP> dd <SEP> 2.13 <SEP> 1H <SEP> dd <tb> <SEP> 2.37 <SEP> 1H <SEP> ddd <SEP> 2.38 <SEP> 1H <SEP> ddd <tb> <SEP> 2.43 <SEP> 3H <SEP> s <SEP> 2.43 <SEP> 3H <SEP> s <tb> <SEP> 3.07 <SEP> 113 <SEP> d <SEP> 3.05 <SEP> 1H <SEP> d <tb> <SEP> 3.18 <SEP> 1H <SEP> m <SEP> #3.15 <SEP> <SEP> 1H <SEP> m <tb> <SEP> 3.23 <SEP> 1H <SEP> dd <SEP> 3.21 <SEP> 1H <SEP> dd <tb> #3.53 <SEP> <SEP> 1H <SEP> m <SEP> 3.47 <SEP> 1H <SEP> m <tb> <SEP> 3.60 <SEP> 1H <SEP> br <SEP> s <SEP> 3.57 <SEP> 113 <SEP> br <SEP> s <tb> <SEP> 4.03 <SEP> 1H <SEP> m <SEP> 3.96 <SEP> 1H <SEP> m <tb> <SEP> 4.17 <SEP> 1H <SEP> <SEP> dq <SEP> 4.20 <SEP> 1H <SEP> dq <tb> <SEP> 5.24 <SEP> 1H <SEP> dd <SEP> 5.23 <SEP> 1H <SEP> dd <tb> <SEP> 5.47 <SEP> 1H <SEP> dd <SEP> 5.47 <SEP> 113 <SEP> dd <tb> <SEP> 7.35 <SEP> 1H <SEP> dd <SEP> 7.33 <SEP> 1H <SEP> dd <tb> <SEP> 7.76 <SEP> 1H <SEP> dd <SEP> 7.75 <SEP> 1H <SEP> dd <tb> <SEP> 7.91 <SEP> 1 <SEP> dd <SEP> 7.90 <SEP> 1H <SEP> dd <tb> Preparation of Barminomycin As already mentioned, the anthracycline compounds, barminomycin I and Ii, are currently produced only by means of cultivating microorganisms. They may, however, be produced by chemical synthetic or microbiological modification of anlogous comounds, or by fully chemical synthetic procedures. In producing the end compound of the present invention by cultivation of a microorganism, one that belongs to the genus Actinomadura and which has the ability to produce the anthracycline compound, barminomycin I or II. The present inventors have established that the strain MG463-yF4 which they have isolated has the ability to produce barminomycin I and II, but it should be noted that other suitable strains may be isolated from nature by conventional techniques for isolating antibiotic-producing microorganisms. It is also possible to enhance the barminomycin I- or II-producing ability of the strain MG463-yF4 and other barminomycin I- or II- producing microorganisms by treating them with radiation or by subjecting them to other suitable treatments. Microorganisms having the ability to produce barminomycin I or II may be induced by genetic engineering techniques wherein the gene DNA harboring genetic information that is related to barminomycin production is introduced by transformation, cell fusion or other suitable methods. Barminomycin Ir and lir are prepared by reducing barminomycin I and II, respectively, using chemical synthetic procedures. The strain MG463-yF4 that has been identified by the present inventors as a microorganism having the ability to produce the anthracycline compound, barminomycin, is specifically described below. (A) Origin and Accession Number The strain MG463-yF4 is an actinomycete isolated by the Institute of Nicrobial Chemistry in October 1982 from soil sampled in Nangoku-shi, Soch, Japan. This strain was deposited with the Fermentation Research Institute, the Agency of Industrial Science and Technology on November 24, 1983 and was given the accession number, FERM-P No. 7352. (B) Mycological Properties (= BERE-BP 1044) (1) Morphology Strain MG463-yF4 as observed under a microscope has a fairly long mycelium extending from a branched aerial hypha. The aerial mycelium bears a hooked chain of spores and a pseudo-sporangium (2 - 4 pm in diameter) at the tip, with a chain of 10 or more spores forming a tight spiral coil. The spores have a moóth surface. (2) State of Growth on Media In the following description, color standards are bracketed and are in accordance with the Color Harmony Manual of Container Corporation of America. (a) Sucrose-nitrate agar medium (incubated at 270C) Adhering white to light pink [5ba, Shell Pink] aerial mycelia form on an orange [Sgc, Peach Tan] to light red 16-1/2 ic, Coral Rose] growth. Slightly purplish soluble pigment forms. (b) Glucose-asparagine agar medium (incubated at 27 C) The growth ranges from light yellow [2ea, Lt Wheat 2gc, Bamboo] to dull yellow orange [31c, Amber] in color. No adhering aerial mycelia form. No soluble pigment observed. (c) Glycerin-asparagine agar medium (ISP-medium 5, incubated at 270C) The growth is dull orange [3ic, Pastel Orange] in color. No adhering aerial mycelia form. No soluble pigment observed. (d) Starch-inorganic salt agar medium (ISP-medium 4, incubated at 27 C) Adhering white to light pink aerial mycelia form on a light reddish orange t5ic, Lt Persimmon] to light red [6ie, Coral Rose] growth. No soluble pigment observed. (e) Tyrosine agar medium (ISP-medium 7, incubated at 270 C) The growth ranges from light orange to light yellow brown [3ic, Lt Amber] in color. No adhering aerial mycelia form. No soluble pigment observed. (f) Nutrient agar medium (incubated at 270C) The growth ranges from dull red purple to red purple [6-1/2 ni, Rose Brown] in color. No adhering aerial mycelia form. No soluble pigment observed. (g) Yeast-malt agar medium (ISP-meidum 2, incubated at 270C) The growth is dull red [6-1/2 ne, Brick Red]. No adhering aerial mycelia form. No soluble pigment observed. (h) Oatmeal agar medium (ISP-medium 3, incubated at 270C) Adhering white to light pink aerial mycelia form on a light red purple t7iC Colonial Rose] to dull red purple [Sle, Rose Wine] growth. The soluble-pigmentis tinged with red purple. Upon dropwise addition of 0.5% aqueous NaOH, the growth and soluble pigment turn blue purple, while they turn to the orange color upon addition of 0.5 N aqueous HCt. (i) Glycerin-nitrate agar medium (incubated at 270C) The growth is light reddish orange ±4it, Pastel Orange - Sic, Lt Persimmon], No adhering aerial mycelia form. No soluble pigment observed. (j) Starch agar medium (incubated at 270C) Thin film of white aerial mycelia forms on a colorless to light pink growth. No soluble pigment observed. (k) Calcium malate agar medium (incubated at 27eC) The growth is colorliss to yellow brown [3gc, Lt Tan]. No adhering aerial mycelia form. No soluble pigment observed. (±) Cellulose (synthetic solution containing filter paper chips, incubated at 27 C) A thin film of white aerial mycelia forms on a light pink [7ec,.Rose Mist] growth. (m) Gelatin stab culture In incubation on a simple gelatin medium at 200 C, a light orange to dull red 16ic, Coral Rose - 71e, Antique Rose] occurs. No adhering aerial mycelia form, and no soluble pigment observed. In incubation on a glucose-peptone gelatin medium at 270C, a colorless to light orange growth occurs. No adhering aerial mycelia form and no soluble pigment observed. (n) Skimmed cow's milk (incubated at 370C) The growth is light reddish brown t5ic, Lt Persimmon]. No adhering aerial mycelia form, and no soluble pigment observed. (3) Physiological Properties (a) Growth temperature range Growth test was conducted on starch-inorganic salt agar (ISP-medium 4) at varying temperatures of 20 C, 240C, 270C, 300C, 370C and 500C. Except at 500C, the microorganism grew at each of the temperatures tested, but an optimal temperature would be' in the range of 27 - 370C. (b) Liquefaction of gelatin (on 15% simple gelatin at 200 C, and on glucose-peptone gelatin at 270C) No liquefaction was observed in 28-day cultivation on simple gelatin or glucose-peptone gelatin. (c) Hydrolysis of starch (incubated either on starchinorganic salt agar medium or on starch agar medium at 270C) No hydrolysis was observed in 21-day cultivation on the starch-inorganic salt agar medium or on the starch agar medium. (d) Coagulation and peptonization of skimmed cow's milk (incubated on skimmed cow's milk at 370C) Neither coagulation nor peptonization was observed in 28-day incubation. (e) Formation of melanine pigment (incubated at 270C on (i) each or tryptone-yeast broth, ISP-medium 1, (ii) peptone-yeast-iron agar, ISP-medium 6, and (iii) tyrosine agar, ISP-medium 7) Negative on each medium. (f) Utilization of carbon sources (on Pridham-Gottlieb agar medium, ISP-medium 9, incubated at 270C) The microorganism grew utilizing L-arabinose, D-xylose, D-glucose and D-rhamnose, but it would not utilize D-fructose, sucrose, inositol, raffinose or D-mannitol. (g) Dissolution of calcium malate (on calcium malate agar at 27it) No dissolution of calcium malate was observed. (h) Reduction of nitrate (in aqueous solution of peptone containing 0.1% KNO3, ISP-medium 8, at 27it) Positive. The above observations can be summarized as follows: morphologically, the strain MG463-yF4 has spiral formation on a well extending aerial mycelium and bears a characteristic pseudo-sporangium. The spore has a smooth surface. It grows on a variety of media, providing light orange to light red growths or a dull red purple growth, with adhering white to light pink aerial mycelia. A red purple soluble pigment is observed on an oatmeal agar medium and the color of the pigment changes with pH. No melanine-like pigment forms, with negative proteolysis and starch hydrolysis. The strain MG463-yF4 belongs to Type IIIB proposed by Lechevalier et al. (International Journal of Systematic Bacteriology, 20, 435, 1970) for classification of the predominant components of cell walls, in that the whole cell did contain meso-2,6-diaminopimelic acid and such sugar components as glucose,-mannose, ribose and madurose. In consideration of these facts, the strain MG463-yF4 is assumed to be an Actinomycete of the genus Actinomadura. The following two species which are listed in a reference table for the microorganisms of Actinomadura (The Biology of the Actinomycetes and Related Organisms, 12, 30, 1977) seem homologous to the strain MG463-yF4: they are Actinomadura roseoviolacea (Nonomura et al., Hakko Xogaku Zasshi, 49, 904, 1971) and Actinomadura carminata (Gorse et al., Antibiotiki, 8, 675, 1973). These two species are believed to be very closely related to each other except for the color of the aerial hypha. According to the reference table mentioned above, carminata forms pale lilac to reddish lilac or reddish purple aerial hyphae on oatmeal agar while roseoviolacea provides pink red aerial hyphae. It is therefore desirable to conduct experiments for comparing each of these species with the strain MG463-yF4 but the present inventors were unable to obtain a sample of Actinomadura carminata. The following table shows the results of experimental comparison between the strain MG463-yF4 and Actinomadura roseoviolacea IMC A-0013 (KCC A-0145). The reported data for Actinomadura carminata are reproduced in the right hand column of the table. Table EMI19.1 <SEP> MG463-yF4 <SEP> Actinomadura <SEP> roseoviolacea <SEP> Actinomedura <SEP> carminata <tb> <SEP> IMC <SEP> A-0013 <SEP> (EXX <SEP> A-0145) <tb> Morphology <SEP> of <SEP> serial <SEP> Hooked <SEP> to <SEP> tight <SEP> spiral <SEP> coil, <SEP> Hooked <SEP> to <SEP> tight <SEP> spiral <SEP> coil, <SEP> Straight <SEP> to <SEP> tight <SEP> spiral <tb> mycelium <SEP> with <SEP> pseudo-sporangium <SEP> with <SEP> pseudo-sporangium <SEP> with <SEP> pseudo-sporangium <tb> Spore <SEP> surface <SEP> smooth <SEP> smooth <SEP> smooth <tb> Colour <SEP> of <SEP> serial <SEP> mycelium <SEP> white <SEP> - <SEP> pale <SEP> pink <SEP> white <SEP> - <SEP> pale <SEP> pink <SEP> white <SEP> - <SEP> pink <tb> Color <SEP> of <SEP> growth <SEP> dull <SEP> orange <SEP> - <SEP> light <SEP> red <SEP> - <SEP> light <SEP> orange <SEP> - <SEP> light <SEP> red <SEP> - <SEP> light <SEP> red <SEP> - <SEP> red <SEP> purple <SEP> <SEP> dull <SEP> red <SEP> purple <SEP> dull <SEP> red <SEP> purple <SEP> blackish <SEP> purple <tb> Soluble <SEP> pigment <SEP> - <SEP> to <SEP> red <SEP> purple <SEP> - <SEP> to <SEP> red <SEP> purple <SEP> - <SEP> to <SEP> purple <tb> pH <SEP> dependency <SEP> of <SEP> the <SEP> color <SEP> + <SEP> NaOH, <SEP> blue <SEP> purple <SEP> + <SEP> NaOH, <SEP> blue <SEP> purple <tb> of <SEP> soluble <SEP> pigment <SEP> + <SEP> HCl, <SEP> orange <SEP> + <SEP> HCl, <SEP> orange <tb> Formation <SEP> of <tb> melanine-like <SEP> pigment <SEP> - <SEP> - <SEP> (ISP-mediums <SEP> 1, <SEP> 6 <SEP> and <SEP> 7) <tb> Hydrolysis <SEP> of <SEP> starch <SEP> - <SEP> Coagulation <SEP> of <SEP> cow's <SEP> milk <SEP> - <SEP> Peptonization <SEP> of <SEP> cow's <SEP> milk <SEP> - <SEP> (reported <SEP> as <SEP> +, <SEP> weak) <tb> Table (continued) EMI20.1 Liquefaction <SEP> of <SEP> gelatin <SEP> (reported <SEP> as <SEP> +) <tb> <SEP> simple <SEP> gelatin <SEP> - <SEP> <SEP> glucose-peptone <SEP> gelatin <SEP> - <SEP> Utilization <SEP> of <tb> carbon <SEP> sources <tb> <SEP> D-glucose <SEP> + <SEP> + <tb> <SEP> L-arabinose <SEP> + <SEP> + <tb> <SEP> D-xylose <SEP> (+) <SEP> # <tb> <SEP> D-lactose <SEP> # <SEP> # <tb> <SEP> Sucrose <SEP> # <SEP> # <tb> <SEP> Inositol <SEP> # <SEP> # <tb> <SEP> L-rhamnose <SEP> + <SEP> + <tb> <SEP> Raffinose <SEP> # <SEP> # <tb> <SEP> D-mannitol <SEP> # <SEP> # <tb> Optimal <SEP> temperature <SEP> range <SEP> 27 <SEP> # <SEP> 37 C <SEP> 27 <SEP> # <SEP> 37 C <SEP> 28 <SEP> # <SEP> 30 C <tb> <SEP> (reported <SEP> as <SEP> 30 <SEP> # <SEP> 40 C) <tb> Antibiotics <SEP> produced <SEP> carminomycin, <SEP> rubeomycin, <SEP> none <SEP> reported <SEP> carminomycin <tb> <SEP> etc. <tb> # : Probably negative As the above table shows, the strain MG463-yF4 has close resemblance to the Actinomadura roseoviolacea strain IMC A-0013 except for the slight difference with respect to the utilization of D-xylose. According to the literature, Actinomadura roseoviolacea is weakly positive in terms of gelatin liquefaction and cow's milk peptonization, but in the actual test conducted, negative results were obtained. The literature lacks data for most of the physiological and biochemical properties of Actinomadura carminata, a known carminomycin producing microorganism; this species differs from the strain MG463-yF4 with respect to the optimal temperature range, but it is not known whether the properties of the two species differ in other respects. In aspects of morphology and cultivation, no great difference seems to exist between MG463-yF4 and Actinomadura carminata. The differences between Actinomadura carminata and Actinomadura roseoviolacea are also unclear. Therefore, although it is definitely concluded that the strain MG463-yF4 is very closely associated with Actinomadura roseoviolacea, the possibility that Actinomadura carminata producing a similar antibiotic is also a related species cannot be excluded. It is essential to obtain a sample of Actinomadura carminata by some means and to conduct tests for comparing it with the strain MG463-yF4. With all the observations taken together, the present inventors identified strain MG463-yF4 as being closely related to both Actinomadura roseoviolacea and Actinomadura carminata. Production of Barminomycin I and II by Cultivation The anthracycline compounds, Barminomycin I and II, of the present invention can be produced by aerobically cultivating a barminomycin I- or II- producing microorganism of the genus Actinomadura on a suitable medium and recovering the end product from the culture. The medium may contain any of the nutrient sources that can be utilized by the selected barminomycin I- or Il-producing microorganism. Usable carbon sources include glycerin, glucose, sucrose, maltose, dextrin, starch, and fats and oils. Usable nitrogen sources include organics such as soybean meal, cottonseed oil cake, meat extract, peptone, dried yeast, yeast extract and corn steep liquor, and inorganics such as ammonium salts and nitrates, such as, for example, ammonium sulfate, sodium nitrate and ammonium chloride. If necessary, inorganic salts such as sodium chloride, potassium chloride, phosphates and heavy metal salts may be added to the medium. In order to prevent foaming during fermentation, suitable - anti-foaming agents such as silicone and soybean oil may be added in suitable amounts as effected in the usual practice. Aerobic liquid submerged culture is the most appropriate method as is commonly employed in the production of antibiotics. A suitable temperature for cultivation ranges from 20 to 350C, with the 25 - 30 C range being preferred. The amount of barminomycin I or II produced by this method, whether it is a shake culture or culture under aeration and agitation, reaches a peak in 3 - 5 days. The above procedures will yield a culture in which barminomycin I or II has been accumulated. Part of barminomycin I or II is present in the cells of the cultured microorganism but most of the antibiotic is present in the filtrate of the culture. Any suitable method may be used to recover barminomycin I or II from the culture. One method depends on the principles of extraction. More specifically, barminomycin I or II in the filtrate Of the culture may be extracted with water-immiscible solvents for barminomycin I or II, such as, for example, ethyl acetate, butyl acetate, chloroform and butanol (high extraction efficiency is attained if the filtrate of the culture has a neutral or slightly basic pH). If the antibiotic is present in the cells of the cultured microorganism, the cells are collected by filtration, centrifugation or other suitable techniques and the antibiotic may be recovered by treatment with ethyl acetate, chloroform, methanol, ethanol, butanol, acetone, methyl ethyl ketone, HCt solution or acetic acid solution. The culture may be immediately subjected to the above procedures of extraction without isolating the cells. The cells may be disrupted prior to extraction. The counter current distribution method may be included within the category of extraction techniques. Another method that can be used to recover barminomycin I or II from the culture depends on the principles of adsorption, wherein an already liquid material containing the desired antibiotic, such as the filtrate of the culture or an extract that has been obtained by the first method, is subjeted to column chromatography, liquid chromatography or other analyses using a suitable adsorbent, say, Dia-Ion HP20 (Mitsubishi Chemical Industries, Limited), alumina, silica gel, or "Sephadex LH20" (Pharmacia Fine Chemicals), and the adsorbed antibiotic is eluted with a suitable solvent. The eluate is subsequently concentrated to dryness under vacuum to obtain a crude product of barminomycin I or II as a red powder. The crude product of barminomycin I or II may be purified by performing the required number of cycles of the extraction and adsorption processes described above, which may be combined as required and optionally followed by recrystallization. Suitable purification techniques that may be used in combination include column chromatography using adsorbents and gel filtration aids such as silica gel, wSephadex LH20", a weakly acidic ion-exchange resin and wDia-lon EP20", liquid chromatography using suitable solvent, counter current distribution, and thin-layer chromatography. A specific purification process may proceed as follows: the crude powder of barminomycin I or II is dissolved in a small amount of chloroform; the solution is loaded onto a silica gel column and fractions are eluted with a suitable solvent; those fractions containing the desired substance are combined and concentrated under vacuum; the concentrate is subjected to thin-layer chromatography and the desired components are recovered to obtain a substantially homogeneous product. This product may be further purified by high-pressure liquid chromatography. Synthetic Chemical Modification of Barminomycin I and II and Production Thereof Barminomycin Ir or lIr of the present invention can be produced by reducing the corresponding barminomycin I or II through synthetic chemical means. The reduction reaction may be carried out by any appropriate methods commonly used in organic synthetic chemical fields. For example, barminomycin I or II may be dissolved in methanol and reacted with NaBH3CN. The resulting barminomycin Ir or IIr may be isolated and purified by any suitable method such as chromatography on silica gel that is routinely employed for anthracycline glycosides. The so obtained barminomycin compounds (I, Ir, II and IIr) may be converted to the corresponding acid addition salts by known methods such as, for example, treatment with an inorganic acid such as hydrochloric acid, sulfuric acid or phosphoric acid, or an organic acid such as acetic acid, propionic acid, maleic acid, oleic acid, palmitic acid, citric acid, succinic acid, tartaric acid, fumaric acid, pantothenic acid, lauric acid, or sulfonic acid. Uses of Barminomycin The barminomycin compounds of the present invention have a cancer-control activity and strong anti-microbial activities and are useful as medicines. Some of the biological activities of the barminomycin compounds are described below. (1) Cytotoxicity (on tissue culture) The barminomycin compounds of the present invention were capable of inhibiting the growth of cultured P388 leukemia cells in very low concentrations. In addition, these compounds exhibited cytotoxicity levels ranging from 1 to over 100 times the values for adriamycin and other anthracycline compounds of the carminomycin series. For further detail, see the following table. EMI26.1 <tb> <SEP> Compound <SEP> IC50 <SEP> ( g/ml) <tb> <SEP> Compound <SEP> Barminomycin <SEP> I <SEP> # <SEP> <SEP> 0.00001 <tb> of <SEP> Barminomycin <SEP> II <SEP> # <SEP> 0.00002 <tb> <SEP> the <SEP> Barminomycin <SEP> Ir <SEP> 0.0015 <tb> <SEP> invention <SEP> Barminomycin <SEP> IIr <SEP> 0.002 <tb> <SEP> Carminomycin <SEP> I <SEP> 0.002 <tb> <SEP> Control <SEP> Carminomycin <SEP> II <SEP> 0.010 <tb> <SEP> compound <SEP> Carminomycin <SEP> III <SEP> 0.006 <tb> <SEP> Adriamycin <SEP> 0.013 <tb> (2) Anti-tumor activity L1210 leukemia cells (1 x 105 per animal) were transplanted intraperitoneally into CDF1 mice. Immediately after the transplantation, 0.25 mt of a selected test compound in solution was administered intraperitoneally in accordance with the schedule shown below. The anti-tumor activities of the test compounds in terms of percentage life prolongation (T/C%) are listed in the same table, with the number of days of survival of control mice to which physiological saline had been administered being taken as 100 (day 0 means the day of L1210 transplantation). EMI27.1 <tb> Dose <SEP> Barminomycin <SEP> I <SEP> Barminomycin <SEP> II <tb> (g/mouse/day) <SEP> <tb> <SEP> 0.25 <SEP> Intoxicated <SEP> to <SEP> death <SEP> Intoxicated <SEP> to <SEP> death <tb> <SEP> at <SEP> 4 <SEP> days, <SEP> 120% <SEP> at <SEP> 4 <SEP> days, <SEP> and <tb> <SEP> 5 <SEP> days <tb> <SEP> 0.125 <SEP> tendency <SEP> of <SEP> tendency <SEP> of <tb> <SEP> intoxication, <SEP> 147% <SEP> intoxication, <SEP> 173% <SEP> <tb> <SEP> 0.0625 <SEP> 213%, <SEP> 147% <SEP> tendency <SEP> of <tb> <SEP> intoxication <SEP> > <SEP> 500%, <tb> <SEP> 173% <tb> <SEP> 0.313 <SEP> > 500%, <SEP> 147% <SEP> 140% <tb> <SEP> 0.0157 <SEP> 187%, <SEP> 120% <SEP> 120% <tb> <SEP> 0.0078 <SEP> 160% <SEP> > 500%, <SEP> > 500% <tb> Administration schedule: 0 - 10 days (daily) EMI28.1 <tb> Dose <SEP> Barminomycin <SEP> Ir <SEP> Barminomycin <SEP> IIr <tb> (;ig/mouse/day) <SEP> <tb> <SEP> 40 <SEP> # <SEP> Intoxication, <SEP> 25% <SEP> Intoxication, <SEP> 37% <tb> <SEP> 20 <SEP> Intoxication, <SEP> 37% <SEP> Intoxication, <SEP> 43% <tb> <SEP> 10 <SEP> Tendency <SEP> of <tb> <SEP> intoxication, <SEP> 49% <SEP> 86% <tb> <SEP> 5 <SEP> 141% <SEP> 123% <tb> <SEP> 2.5 <SEP> 129% <SEP> 129% <tb> <SEP> - <SEP> 1.25 <SEP> 97%, <SEP> 123 <SEP> <tb> Administration schedule: 0 - 9 days (daily) (3) Antimicrobial activity The antimicrobial activities of barminomycin I and Ir of the present invention, and that of carminomycin III were determined by the agar dilution method. The minimum inhibitory concentration (MIC) data for each antibiotic are listed in the following table. MIC ( g/ml) EMI29.1 <SEP> Barminomycin <SEP> I <SEP> Barminomycin <SEP> Ir <SEP> Carminomycin <SEP> III <tb> Staphylococcus <SEP> aureus <SEP> FAD <SEP> 209P <SEP> 0.2 <SEP> 0.78 <SEP> 3.12 <tb> S. <SEP> aureus <SEP> Smith <SEP> 0.2 <SEP> 0.78 <SEP> 3.12 <tb> S. <SEP> aureus <SEP> MS8710 <SEP> 0.2 <SEP> 1.58 <SEP> 1.56 <tb> S. <SEP> aureus <SEP> MS9610 <SEP> 0.2 <SEP> 1.58 <SEP> 1.56 <tb> Micrococcus <SEP> Lysodelkticus <SEP> IFO <SEP> 3333 <SEP> 0.2 <SEP> 0.78 <SEP> 1.56 <tb> Bacillus <SEP> subtilis <SEP> PCI <SEP> 219 <SEP> < 0.1 <SEP> 0.39 <SEP> 1.56 <tb> E. <SEP> coli <SEP> NIHJ <SEP> 3.12 <SEP> 50 <SEP> > 50 <tb> E. <SEP> coli <SEP> K-12 <SEP> 0.78 <SEP> 6.25 <SEP> > 50 <tb> E. <SEP> coli <SEP> BE1121 <SEP> < 0.1 <SEP> 0.2 <SEP> 1.56 <tb> EMI30.1 (E. <SEP> coli) <SEP> BE1186 <SEP> < 0.1 <SEP> 0.2 <SEP> 1.45 <tb> (Klebsiella <SEP> pneumoniae) <SEP> PCI <SEP> 602 <SEP> 0.39 <SEP> 6.25 <SEP> 50 <tb> (Serratia <SEP> marcescens) <SEP> 0.78 <SEP> 3.12 <SEP> 25 <tb> (Proteus <SEP> vulgaris) <SEP> 0X19 <SEP> 3.12 <SEP> > 50 <SEP> > 50 <tb> (Pseoudomonas <SEP> aeruginosa) <SEP> A3 <SEP> 1.56 <SEP> 12.5 <SEP> > 50 <tb> (Mycobacterium <SEP> smegmatis) <SEP> 607 <SEP> 0.78 <SEP> 6.25 <SEP> 6.25 <tb> Experiments Example 1 (1) Preparation of seed culture A medium having the following composition was used. Glucose 1% Glycerol 1% Sucrose 1% Oatmeal 0.5% Adipron (trademark) 2% Press-yeast (trademark) 1% Casamino acids 0.5% Calcium carbonate 0.2% (pH 7.0 before sterilization) A portion (100 m±) of this medium was poured into a 500-mt Erlenmeyer flask and sterilized. The medium was then inoculated with a loopful of a slant culture of MG463-yF4. The medium was shake-cultured in a rotary shaker at 300C for 5 days to prepare a seed culture. (2) Fermentation A medium having the following composition was used. Glycerol v 3% Fish meal 2% Calcium carbonate 0.2% A 30-t jar fermenter was charged with 15 liters of the above specified medium, which was inoculated with 500 mt of the previously prepared seed culture. Cultivation was conducted at 270C for 48 hours under agitation at 150 rpm and aeration at a rate of 15 l/min. (3) Recovery of barminomycin I and II The resulting liquid culture was subjected to filtration and, the filtrate, after pE adjustment to 5.0, was adsorbed on a column (4.0 x 40 cm) of ZDia-Ion EP-20 . The column was washed with 6 liters each of water and 50% methanol and eluted with 5 liters of 1008 methanol. The eluates were concentrated to obtain 3.0 g of a red crude powder containing both barminomycin I and II. The powder was dissolved in a small amount of chloroform and the solution was passed through a column packed with 50 g of silica gel (Kieselgel 60 of Merck). The column was eluted by density gradient of a mixture of chloroform and methanol. The fractions containing barminomycin 1 and II were concentrated to obtain 40 mg of a red crude powder containing both barminomycin I and II. Example 2 The red crude powder (40 g) obtained in Example 1 was dissolved in a small amount of chloroform and the solution was spread on 10 thin layers of silica gel (Kieselgel# 60F253 of Merck, 20 x 20 cm) which were developed with a 70:10:1:1 mixture of chloroform, methanol, acetic acid and water. The separating barminomycin I and II fractions were collected and eluted from the silica gel plates with a 2:1 mixture of chloroform and methanol. The so obtained fractions were further purified by highs pressure liquid chromatography on Nucleosil 5C181 using a 40:60 mixture of acetonitrile/0.2% aqueous phosphoric acid as an eluant. The pure red powders of barminomycin I and II were obtained in respective amounts of 3.06 mg and 3.07 mg. Example 3 A sample (4.5 mg) of the barminomycin I prepared in Example 2 was dissolved in 5 mt of methanol and reacted with 2 mg of NaBH3CN for 15 minutes. After extraction with 20 m± each of water and chloroform, the chloroform layer was concentrated under vacuum. The concentrate was adsorbed on thin silica gel layers and developed with a 10:1 mixture of chloroform and methanol. The separating barminomycin Ir fractions were collected and eluted from the silica gel plates with a 1:1 mixture of chloroform and methanol. The so obtained fractions were concentrated and loaded on a column (1.0 x 20 cm) of "Sephadex L8209 equilibrated with a 1:1 mixture of chloroform and methanol. The column was eluted with a solution of the same composition. The eluates were evaporated to dryness under vacuum, producing 2.5 mg of barminomycin Ir. The same procedures were repeated to obtain barminomycin lir from barminomycin II. 4. Brief Description of the Drawings Fig. 1 is a flow sheet showing the sequence for analyzing the structures of'the antibiotic compounds of the present invention; Fig. 2 is a sketch of an infrared absorption spectrum chart of barminomycin I (in chloroform) of the present invention; Fig. 3 is a sketch of an infrared absorption spectrum chart of barminomycin II (in chloroform) of the present invention; Fig. 4 is a sketch of an infrared absorption spectrum chart of barminomycin Ir (as KBr tab.) of the present invention; Fig. 5 is a sketch of 1H-NMR spectrum chart of barminomycin Ir of the present invention; Fig. 6 is a sketch of an infrared absorption spectrum chart of barminomycin IIr (as RBr tab.) of the present invention; ; Fig. 7 is a sketch of 1E-NMR spectrum chart of barminomycin IIr of the present invention; Fig. 8 is a sketch of 13C-NMR spectrum chart of barminomycin Ir of the present invention.

Claims: Claims: 1. A compound of the formula I EMI35.1 where R is any one of the following groups (a) to (d) EMI35.2 EMI36.1 or acid addition salts thereof. 2. A process for the preparation of compounds of the formula I as defined in claim 1 wherein R is one of the radicals (a), (b) or (c), which comprises aerobically cultivating a microorganism strain of the genus Actinomadura being capable of producing said compound in a nutrient medium containing carbon sources, nitrogen sources and optionally inorganic salts and/or anti foaming agentstrecovering the compounds produced from the culture by extraction with organic solvents and subjecting the extracts to chromatography. 3. The process as defined in claim 2 wherein the strain is cultivated at a temperature of from 20 to 350C and the cultivation time is 3 to 5 days. 4. The process as defined in claims 2 and 3 wherein the extracts of the cells and/or the culture filtrate are subjected to column chromatography, liquid chromatography or other methods using a suitable adsorbent. 5. The process as defined in claims 2 to 4 wherein the strain MG 463-yF4 (FERM P No. 7352) of the genus Actinomadura is used. 6. A process for the preparation of compounds of the formula I as defined in claim 1, wherein R is the radical EMI37.1 which comprises reducing a compound of the formula I wherein R is the radical EMI37.2 with NaBH3CN. 7. A pharmaceutical composition which comprises as active ingredient a compound as defined in claim 1 in association with a pharmaceutically acceptable carrier. 8. Use of a compound as defined in claim 1 for the pre paration of a medicament having anti-tumor and anti microbial activities. Patent Claims for Austria: 1. A process for the preparation of compounds of the formula I EMI38.1 where R is any one of the following groups (a) to (c) EMI38.2 which comprises aerobically cultivating a micro organism strain of the genus Actinomadura being capable of producing said compound in a nutrient medium containing carbon sources, nitrogen sources and optionally inorganic salts thereof and/or anti-foaming agents, recovering the compounds produced from the culture by extraction with organic solvents and subjecting the extracts to chromatography. 2. The process as defined in claim 1 wherein the strain is cultivated at a temperature of from 20 to 350C and the cultivation time is 3 to 5 days. 3. The process as defined in claims 1 and 2 wherein the extracts of the cells and/or the culture filtrate are subjected to column chromatography, liquid chromato graphy or other methods using a suitable absorbent. 4. The process as defined in claims 1 to 3 wherein the strain MG 463-yF4 (FERM P-No. 7352) is used. 5. A process for the preparation of compounds of the formula I as defined in claim 1, wherein R is the radical EMI39.1 which comprises reducing a compound of the formula I wherein R is the radical EMI40.1 with NaBH3CN.

Inventors: HAMADA, MASA, IMOTO, MASAYA, NAGANAWA, HIROSHI, ODAGAWA, ATSUO, SAWA, TSUTOMU, TAKAHASHI, YOSHIKAZU, TAKEUCHI, TOMIO, UCHIDA, TAKESHI, UMEZAWA, HAMAO, PROF.
Applicants: MICROBIAL CHEMISTRY RESEARCH FOUNDATION
Application year: 1986
Main classification: C07H15
IPC codes: A61K31, A61P35, C12R1, C12P19, C07H15