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Thienamycin Related Antibiotics PS-6 and PS-7, Process for Their

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Thienamycin Related Antibiotics PS-6 and PS-7, Process for Their Europâisches Patentamt O 001 567 European Patent Office (1Î) Publication number: Office européen des brevets Bl @ EUROPEAN PATENT SPECIFICATION @ Date of publication of patent spécification: 02.12.81 © Int. ci.3: C 07 D 487/04, C 12 P 17/18, A 61 K 31/40 number: 78100993.1 @ Application //C12R1/465, (C07D487/04, @ Date of filing: 26.09.78 209/00, 205/00) (54) Thienamycin related antibiotics PS-6 and PS-7, process fortheir production and compositions containing them. (§) Priority: 13.10.77 JP 121857/77 © Proprietor: SANRAKU-OCEAN CO., LTD. 29.12.77 JP 160424/77 1 5-1 , Kyobashi 1 -chome Chuo-ku Tokyo (JP) @ Date of publication of application: 02.05.79 Bulletin 79/9 @ Inventor: Okamura, Kazuhiko Kamiwada Danchii 1-1307 2412 Kamiwada Yamato-shi Kanagawa-ken (JP) (45) Publication of the grant of the European patent: Inventor: Hirata, Shoji 02.12.81 Bulletin 81/48 51-8, Aza Tateminami Watari-cho Watari-gun Miyagi-ken (JP) Inventor: Okumura, Yasushi (§) Designated Contracting States: 534-1, Ueki BE CH DE FR GB LU NL SE Kamakura-shi Kanagawa-ken (JP) Inventor: Fukagawa, Yasuo 1194-146 Imaizumi @ References cited: Kamakura-shi Kanagawa-ken (JP) None Inventor: Shimauchi, Yasutaka 1-101-13. Yurigaoka Ninomiya-machi Kanagawa-ken (JP) Inventor: Ishikura, Tomoyuki 640, Kowada Chigasaki-shi Kanagawa-ken (JP) Inventor: Kouno, Kageaki 7-1 6-3, Ikegami Ohta-ku Tokyo (JP) Inventor: Lein, Joseph 4, Thornwood LN Fayetteville New York (US) (74) Representative: Kraus, Walter, Dr. et al, Patentanwalte Dres. Kraus & Weisert Irmgardstrasse 1 5 D-8000 Miinchen 71 (DE) Note: Within nine monthsfrom the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1 ) European patent convention). Courier Press, Leamington Spa, England. BACKGROUND OF THE INVENTION The present invention relates to new antibiotics, their preparation and to uses as antimicrobial agents. Some antibiotics having β-lactamase inhibitory activity or β-lactamase inhibitory agents have so far been known. For example, the following have been reported: MC696-SY2-A and B isolated from the culture broth of a MC696-SY2-producing strain belonging to the genus Streptomyces (U.S. Patent 3,981,788: Derwent CPI 19171X), MM4550 or MM13902 isolated from a cultivation product of an MM4550 or MM 13902 producing strain which belongs to the genus Streptomyces (German Appin. DOS 2513855: Derwent CPI 67721W; German Appln. DOS 2,513,854: Derwent CPI 67720W), clavulanic acid isolated from a cultivation product of Streptomyces clavuligerus (German Appln. DOS 2,517,316: Derwent CPI 72840W), and the like. The antibiotic thienamycin having a penicillin-like chemical skeleton and the derivatives thereof have also been reported (U.S. Patent 3,950,357: Derwent CPI 31696X; German Appln. DOS 2,652,677: Derwent CPI 40282Y; Belgian Patent 848,346: Derwent CPI 34505Y; Belgian Patent 848,349: Derwent CPI 34507: German Appln. DOS 2652680: Derwent CPI 40283Y; German Appln. DOS 2,652,675: Derwent CPI 40280Y: German Appln. DOS 2,652,674: Derwent CPI 40279Y; German Appln. DOS 2,652,676: Derwent CPI 40281 Y). The content of the European patent application number 79 300 712.1 filed on April 26, 1979 and published on November 14, 1979 (publication No. 0 005 349) is partially comprised in the state of the art as far as it is supported into the two British basic patent applications 18101/78 filed on May 6, 1978 and 24358/78 filed on May 30, 1978 from which priorities are claimed. Compounds of the following formula (A): wherein R'3 is a lower alkyl or tripenylmethyl group are disclosed in British patent applications 18,101/78 and 24,358/78 and not described either in Japanese patent applications 121,857/77 or 160,424/77 on which the present application is based. Such compounds correspond to compounds of the following formula (1): in which R, is hydrogen, R3 is lower alkyl or triphenylmethyl and R2 is -CH=CH-. The present inventors discovered a novel antibiotic, β-lactam antibiotic "PS-5", of the following formula which is not described in the aforesaid prior literature references, and already disclosed it in Japanese Patent Applications Nos. 35375/77 and 94651/77. SUMMARY OF THE INVENTION This invention relates to new antibiotics and the derivatives thereof. More particularly, it is concerned with novel antibiotics defined as PS-6 and PS-7 and the derivatives thereof, which have strong antibiotic activity, β-lactamase inhibitory activity and ability to synergistically enhance the antibiotic activity of penicillins, cephalosporins or the like against β-lactamase producers. It also pertains to a method for producing these novel antibiotic substances, and to antibiotic compositions containing these substances. The first object of the present invention is to provide new antibiotic substances PS-6 and PS-7 having both strong antibiotic activity and A-lactamase inhibitory activity. The second object of the present invention is to provide ester derivatives, particularly the trityl derivative, of the antibiotic PS-6 which also show strong antibiotic activity and β-lactamase inhibitory activity. Another object of this invention is to show that the new antibiotic PS-6 and PS-7 and the trityl derivative thereof, also have the ability to synergistically enhance the antibiotic activity of penicillins, cephalosporins or the like against β-lactamase-producing resistant bacteria. Still another object of this invention is to provide methods for producing the antibiotics PS-6 and PS-7 by a fermentation process. Yet another object of this invention is to provide methods for producing the derivatives of the antibiotics PS-6 and PS-7, and more particularly, the ester derivatives, above all, the trityl derivative. A further object of this invention is to provide compositions of the antibiotic PS-6 or its trityl derivative and the antibiotic PS-7 for use in infectious diseases caused by Gram-positive and Gram- negative bacteria, including synergistic combinations with penicillins, cephalosporins and other β- lactamase sensitive antibiotics. Other objectives of this invention will become apparent from the following description. The present invention provides a compound of the formula wherein R, is CH3 and R2 is -CH2-CH2-, or R, is H and R2 is -CH=CH-; and R3 represents hydrogen, lower alkyl or triphenylmethyl, provided that R3 is hydrogen when R, is H and R2 is -CH=CH-, and salts of the compound of formula (I) in which R3 is hydrogen. A compound of formula (I) in which R, is CH3 and R2 is -CH2-CH-2, i.e. is called "antibiotic PS-6" in the present specification and the appended claims. A compound of formula (I) in which R1 is H, and R2 is -CH=CH-, i.e. is called "antibiotic PS-7" in the present specification and the appended claims. DETAILED DESCRIPTION OF THE INVENTION These antibiotics PS-6 and PS-7 and their derivatives are described below in detail. [I] Antibiotic PS-6 The antibiotic PS-6 is characterized by the following physico-chemical properties and biological properties: Physico-chemical properties of antibiotic PS-6 (1) Paper chromatography The antibiotic PS-6 (sodium salt) indicates the following Rf values when descending paper chromatography is conducted with the use of Toyo Filter Paper No. 50 (Toyo Roshi Kaisha Ltd.) and the following solvents: Acetonitrile/Tris/EDTA (Note 1): Rf=0.41 Ethanol/water (7/3): Rf=0.65 [Note 1: Mixed solvent composed of 120 ml of acetonitrile, 30 ml of 1/10 M tris-(hydroxymethyl)- aminomethane-hydrochloric acid buffer (pH 7.5) and 1 ml of 1/10 M sodium ethylenediamine tetraacetate aqueous solution (pH 4.5).] Solvent ratios in this specification are expressed as volume to volume unless otherwise mentioned. (2) Thin layer chromatography (TLC) The following Rf values of antibiotic PS-6 (sodium salt) are obtained when thin layer. chromatography is conducted with the use of Chromatogram Sheet 13254 Cellulose (No. 6065) (Trademark of Eastman Kodak Co., Ltd.) and the following developing solvents. n-Butanol/ethanol/water (4/1/5) (Upper layer): Rf=0.67 n-Propanol/water (8/2): Rf=0.69 n-Butanol/i-Propanol/water (7/7/6): Rf=0.70 Acetonitrile/water (8/2): Rf=0.63 (3) High voltage paper electrophoresis The following behavior is observed in a buffer solution having the following composition and pH when the antibiotic PS-6 (sodium salt) is subjected to electrophoresis on Toyo Filter Paper No. 50 (Toyo Roshi Kaisha Ltd.) by using a high voltage paper electrophoresis apparatus (Savant Instrument Inc., High Voltage Power Supply HV 3000 A, Flat Place Electrophoresis Chamber FP 18A). The antibiotic is seen to migrate through a distance of at least 5 mm, usually 10-40 mm toward the anode when passing a current for 30 minutes on a potential gradient of 42 V/cm in a buffer (pH 8.6) composed of 3000 ml water, 3.3 g barbital and 25.5 g sodium barbital. (4) Behavior against A-lactamase The activity is inactivated by β-lactamase of Bacillus cereus. (5) Distinction among acid, neutral and base Antibiotic PS-6 is a mono-basic acid having one carboxyl group in the molecule. (6) UV absorption spectrum Characteristic UV absorption maximum of antibiotic PS-6 (sodium salt) is as follows: (7) IR absorption spectrum Characteristic IR absorption maxima of the antibiotic PS-6 (sodium salt) measured by KBr tablet method are as follows: approximately 1760 cm-1 (-CO-in β-lactam
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