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United States Patent (19) 11 Patent Number: 4,952,690 Gosteli Et Al

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United States Patent (19) 11 Patent Number: 4,952,690 Gosteli Et Al United States Patent (19) 11 Patent Number: 4,952,690 Gosteli et al. 45) Date of Patent: Aug. 28, 1990 (54) 6-SUBSTITUTED THIA-AZA COMPOUNDS 4,447,360 5/1984 Gosteli et al. .................. 260/239 A 4,500,457 2/1985 Gosteli et al. ... 260/245.2 R 75 Inventors: Jacques Gosteli, Basel; Ivan Ernest, 4,515,717 5/1985 Gosteli et al. ..... as a s 260/239 A Birsfelden, both of Switzerland; 4,518,533 5/1985 Gosteli et al...... ... 260/245.4 Marc Lang, Mulhouse, France; 4,524,028 6/1985 Gosteli et al. ..... ... 260/239 A Robert B. Woodward, Cambridge, 4,543,257 9/1985 Cama et al. ... ... 540/310 ... 540/359 Mass. 4,614,614 9/1986 Ernest et al. 4,616,007 10/1986 Lang ................................... 514/192 73) Assignee: Ciba-Geigy Corporation, Ardsley, 4,656,165 4/1987 Lang ................................... 514/192 N.Y. 4,826,832 5/1989 Lang ................................... 540/310 21 Appl. No.: 396,783 Primary Examiner-Mark L. Berch (22 Filed: Aug. 21, 1989 Attorney, Agent, or Firm-JoAnn Villamizar 57) ABSTRACT Related U.S. Application Data The invention relates to azetidin-2-ones of the formula 60 Continuation of Ser. No. 152,526, Feb. 5, 1988, aban doned, which is a division of Ser. No. 57,082, Jun. 3, 1987, abandoned, which is a division of Ser. No. 208,105, Nov. 18, 1980, Pat. No. 4,692,442, which is a continuation of Ser. No. 7,453, Jan. 29, 1979, aban doned. (30) Foreign Application Priority Data Feb. 2, 1978 CH) Switzerland...................... 1140/78-3 51) Int. C.’.................. C07D 205/09; CO7D 205/08; CO7D 499/00; A61K 31/425 wherein Ra represents hydroxy-lower alkyl, R1 repre 52 U.S. C. .................................................... 540/357 sents hydrogen, an organic radical bonded by a carbon 58) Field of Search ......................................... 540/357 atom to the ring carbon atom or an etherified mercapto group, R2 together with the carbonyl group to which (56) References Cited it is attached is a protected carboxyl group and Z' is U.S. PATENT DOCUMENTS oxygen, sulfhur or an optionally substituted methyli 4,123,539 10/1978 DiNinno ............................. 424/270 dene group, functional groups in the radicals Ra, R1 and 4,168,314 9/1979 Christensen et al. .... ... 424/270 Z' optionally being in protected form. The azetidinones 4,260,618 4/1981 Christensen .......... ... 424/263 are useful intermediates for the preparation of penem 4,272,437 6/1981 Menard ............ ... 540/30 antibiotics. 4,331,676 5/1982 Gosteli et al. .... ... 424/270 4,364,865 12/1982 Ernest et al. ..... ... 260/239 A 4,431,588 2/1984 Pfaender ............................. 540/310 12 Claims, No Drawings 4,952,690 1. 6SUBSTITUTED THAAZA COMPOUNDS CROSS REFERENCE TO RELATED APPLICATION This application is a continuation application of appli 7 1 cation Ser. No. 152,526 filed Feb. 5, 1988, now aban doned; which is a divisional application of application and may systematically be called 7-oxo-4-thia-l- Ser. No. 057,082, filed June 3, 1987, now abandoned, 10 azabicyclo3,2,0hept-2-ene. For the sake of simplicity it which is a divisional application of application Ser. No. is referred to hereinafter as "2-penem', wherein the 208,105 filed Nov. 18, 1980 now U.S. Pat. No 4,692,442, following numbering derived from penam and custom which is a continuation application of application Ser. ary in penicillin chemistry shall be used: No. 007,453 filed Jan. 29, 1979, now abandoned. 15 The present invention relates to new bicyclic thia-aza 6 s S compounds containing a £8-lactam ring substituted in 2 the 3-position and having antibiotic properties. Since the discovery of penicillin, numerous bicyclic 7 4. thia-aza compounds having a B-lactam structure have of 3 become known. A survey of earlier works is made by E. H. Flynn, "Cephalosporins and Penicillins', Academic The present invention relates to 2-penem-3-carboxy Press, New York and London, 1972. More recent devel lic acid compounds of the formula opments are described by J. Cs. Jászberényi et al., Progr.Med. Chem, Vol. 12, 1975, 395-477, and a P. G. 25 Ra s (I) Sammes, Chem. Rev. 1976, Vol. 76, No. 1, 113-155 and V by various authors at an international symposium of the C-R Chemical Society held in Cambridge, England in June, O N / 1976, (subsequent publication: J. Elks, "Recent Ad vances in the Chemistry of S-lactam Antibiotics', The 30 Chemical Society, Burlington House, London, 1977). in which Apart from the usual penam and cephen compounds Ra represents an organic radical bonded by a carbon carrying an acylamino group in the 6- or 7-position, atom to the ring carbon atom, a free, etherified or such compounds that are unsubstituted in these posi 35 esterified hydroxy or mercapto group or a halogen tions have also become known, for example 3-carboxy aton, 2,2-dimethylpenam (J. P. Clayton, J. Chem. Soc., 1969, R represents hydrogen, an organic radical bonded by a 2123) and 3-methyl-4-carboxy-3-cephem (K. Kiihlein, carbon atom to the ring carbon atom, or an etherified Liebigs Ann., 1974, page 369 and D. Bormann, ibid., mercapto group, and page 1391). 3-carboxy-2,2-dimethylpenam compounds, R2 represents a hydroxy group or an radical that to gether with the carbonyl grouping-CO=O)-forms that instead of the customary 6,8-acylamino group have a protected carboxyl group, a 6a-chloro or 6a-bromo group, have been described by and to salts of such compounds with salt-forming I. McMillan and R.J. Stoodley, Tetrahedron Lett. 1205 groups, processes for the manufacture of such com (1966), and J. Chem. Soc. C 2533 (1968), whilst corre 45 pounds, pharmaceutical preparations containing com sponding 6a-hydroxy-, 6a-acetoxy- and 6a-phenox pounds of the formula I with pharmacological proper yacetoxy-2,2-dimethylpenam-3-carboxylic acids have ties, and the use of the new compounds either as phar been described by D. Hauser and H. P. Sigg, Helv. macologically active substances, preferably in the form Chimica Acta 50, 1327 (1967). None of these com of pharmaceutical preparations, or as intermediates. pounds, however, has any, or any substantial, antibiotic 50 An organic radical Rabonded by a carbon atom to activity. the ring carbon atom is especially a saturated or unsatu 6-acylamino-2-penem-3-carboxylic acid compounds rated, optionally substituted, aliphatic, cycloaliphatic, having an antibiotic activity that contain the novel 2 cycloaliphatic-aliphatic, aromatic or aliphatic hydro penem ring system are described in DOS No. 2655298. carbon radical having up to 18, preferably up to 10, 2-penem compounds carrying in the 6-position sub 55 carbon atoms, or an optionally substituted heterocyclor stituents other than acylamino are not so far known. heterocyclyl-lower alkyl radical having up to 10 carbon atoms and up to 4 ring hetero atoms selected from the The problem underlying the present invention is to group nitrogen, oxygen and/or sulphur, especially op produce bicyclic thia-aza compounds containing a B tionally substituted lower alkyl or lower alkenyl, op lactam ring that possess the 2-penem ring system substi tionally functionally modified carboxyl, or optionally tuted in the 6-position and that are active against both substituted cycloalkyl, cycloalkenyl, cycloalkyl-lower penicillin-sensitive and penicillin-resistant bacteria. alkyl, cycloalkyl-lower alkenyl, cycloalkenyl-lower The manufacture according to the invention of the alkyl, phenyl, phenyl-lower alkyl or phenyl-lower alke novel compounds and the new intermediates required nyl. Examples of substituents of such radicals are op therefor open up new fields in which research into other 65 tionally functionally modified, such as optionally etheri commercially valuable compounds can be carried out. fied or esterified hydroxy or mercapto groups, for ex The ring system of the compounds of the present ample hydroxy, lower alkoxy, for example methoxy or invention has the formula ethoxy, lower alkanoyloxy, for example acetoxy or 4,952,690 3 4. propionoxy, hydroxysulphonyloxy present in said form, cyclopentyl or cyclohexyl, whereas a cyloalkyl-lower halogen atoms, for example chlorine or bromine, or alkyl radical Ra contains, for example, 4 to 7 carbon lower alkylthio groups, for example methylthio; option atoms and is, for example, cyclopropylmethyl, cy ally functionally modified carboxyl groups, such as clobutylmethyl, cyclopentylmethyl or cyclohexyl carboxyl, lower alkoxycarbonyl, for example:methoxy methyl. carbonyl or ethoxycarbonyl groups, carbamoyl or cy A cycloalkenyl radical Rais a corresponding cycloal ano; also nitro; sulpho present in salt form, or optionally kyl radical having one or optionally two C-C double substituted amino, such as amino mono-substituted or bonds, such as cyclohexenyl, for example cyclohexenyl, di-substituted by lower alkyl, for example methyl or or cyclohexadienyl, for example cyclohexa-1,4-dienyl ethyl or by acyl, such as lower alkanoyl, for example 10 A cycloalkyl-lower alkenyl radical or cycloalkenyl acetyl, or amino di-substituted by lower alkylene, for lower alkyl radical Rais, for example, cyclohexylvinyl, example 1,4-butylene or 1,5-pentylene. cyclohexylally, or cyclohexenylmethyl or cyclohexa A lower alkyl radical Ra contains up to 7, especially 1,4-dienylmethyl. up to 4, carbon atoms, and is, for example, methyl, A phenyl or a phenyl-lower alkyl radical, for example ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl or 15 a benzyl or 1- or 2-phenylethyl radical Ramay be substi pentyl. Substituted lower alkyl R is especially substi tuted, preferably in the aromatic radical, for example by tuted methyl,
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