Clarithromycin and new derivatives of erythromycin

  • Takashi Adachi
  • Shigeo Morimoto
Part of the Milestones in Drug Therapy MDT book series (MDT)


Since erythromycin’ s the discovery in 1952 [1], it has been one of the most useful macrolide antibiotics, having the highest antibacterial activity and low toxicity. In order to achieve high antibacterial activities against a wide variety of pathogens and favorable pharmacokinetic properties, tremendous efforts have been made related to chemical modification [2, 3]. In the 1970s and 1980s, dirithromycin, flurithromycin, and davercin were synthesized and evaluated. Erythromycin itself is quite unstable under acidic conditions, so esters, salts, and various formulations also have been developed.


Antibacterial Activity Antimicrob Agent Macrolide Antibiotic Mycobacterium Avium Complex High Antibacterial Activity 
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  1. 1.
    McGuire JM, Bunch PL, Anderson RC, Boaz HE, Flynn EH, Powell EH, Smith JW (1952) Ilotycin, a new antibiotic. Antibiot Chemother 2: 281–283Google Scholar
  2. 2.
    Omura S (ed) (1984) Macrolide antibiotics — chemistry,biology and practice. Academic Press, Orlando, FLGoogle Scholar
  3. 3.
    Bryskier AJ, Butsler J-P, Neu HC, Tulkens PM (eds) (1993) Macrolides — chemistry,pharmacology and clinical uses. Arnette Blackwell, ParisGoogle Scholar
  4. 4.
    Morimoto S, Takahashi Y, Watanabe Y, Omura S (1984) Chemical modification of erythromycins I. Synthesis and antibacterial activity of 6-O-methylerythromycins A. J Antibiot 37: 187–189PubMedCrossRefGoogle Scholar
  5. 5.
    Morimoto S, Misawa Y, Adachi T, Nagate T, Watanabe Y, Omura S (1990) Chemical modification of erythromycins II. Synthesis and antibacterial activity of 0-alkyl derivatives of erythromycin A. J Antibiot 43: 286–294PubMedCrossRefGoogle Scholar
  6. 6.
    Morimoto S, Adachi T, Misawa Y, Nagate T, Watanabe Y, Omura S (1990) Chemical modification of erythromycins IV. Synthesis and biological properties of 6–0-methylerythromycM B. J Antibiot 43: 544–549PubMedCrossRefGoogle Scholar
  7. 7.
    Iwasaki H, Sugawara Y, Adachi T, Morimoto S, Watanabe Y (1993) Structure of 6–0-methylerythromycin A (clarithromycin). Acta Cryst C49:1227–1230Google Scholar
  8. 8.
    Omura S, Morimoto S, Nagate T, Adachi T, Kohno Y (1992) Research and development of clarithromycin. Yakugaku zasshi 112: 593–614PubMedGoogle Scholar
  9. 9.
    Flynn EH, Murphy HW, McMahon RE (1955) Erythromycin. II. Des-N-methylerythromycin and N-methyl-C14-erythromycin. J Am Chem Soc 77: 3104–3106CrossRefGoogle Scholar
  10. 10.
    Kurath P, Jones PH, Egan RS, Perun TJ (1971) Acid-degradation of erythromycin A and erythromycin B. Experientia 21: 362CrossRefGoogle Scholar
  11. 11.
    Suwa T, Kohno Y, Yoshida H, Morimoto S, Suga T (1989) Uptake of O-alkylerythromycin derivatives in the lung tissue and cell of rats. J Pharm Sci 79: 783–784CrossRefGoogle Scholar
  12. 12.
    Watanabe Y, Morimoto S, Adachi T, Kashimura M, Asaka T (1993) Chemical modification of erythromycins IX. Selective methylation at the C-6 hydroxyl group of erythromycin A oxime derivatives and preparation of clarithromycin. J Antibiot 46: 647–660PubMedCrossRefGoogle Scholar
  13. 13.
    Watanabe Y, Adachi T, Asaka T, Kashimura M, Matsunaga T, Morimoto S (1993) Chemical modification of erythromycins XII. A facile synthesis of clarithromycin (6–0-methylerythromycM A) via Z-silylethers of erythromycin A derivatives. J Antibiot 46: 6–0PubMedCrossRefGoogle Scholar
  14. 14.
    Morimoto S, Adachi T, Matsunaga T, Kashimura M, Asaka T, Watanabe Y, Sota K, Sekiuchi K (1991) Erythromycin A derivatives. US Patent 4990602 [Chem Abstr (1990)113: 1326941]Google Scholar
  15. 15.
    Kawashima Y, Morimoto S, Matsunaga T, Kashimura M, Adachi T, Watanabe Y, Hatayama K, Hirono S, Moriguchi I (1990) Studies on selectivity of 0-methylation of erythromycin derivatives based on molecular mechanics and molecular orbital methods. Chem Pharm Bull 38: 1485–1489CrossRefGoogle Scholar
  16. 16.
    GOO H, Kawashima Y, Kashimura M, Morimoto S, Osawa E (1993) Origin of regioselectivity in the 0-methylation of erythromycin as elucidated with the aid of computational conformational space search. J Chem Soc Perkin Trans 2: 1647–1654Google Scholar
  17. 17.
    Morimoto S, Nagate T, Sugita K, Ono T, Numata K, Miyachi J, Misawa Y, Yamada K, Omura S (1990) Chemical modification of erythromycins III. In vitro and in vivo antibacterial activities of new semisynthetic 6–0-methylerythromycins A, TE-031 (clarithromycin) and TE-032. J Antibiot 43: 295–305PubMedCrossRefGoogle Scholar
  18. 18.
    Ono T, Numata K, Inoue M, Mitsuhashi S (1988) Bacteriological evaluation of TE-031 (A56268), a new macrolide antibiotic: in vitro and in vivo antibacterial activity. Chemother 36 (Suppl. 3): 1–34Google Scholar
  19. 19.
    Nagate T, Sugita K, Numata K, Ono T, Miyachi J, Morikawa E, Omura S (1988) Antibacterial activities of TE-031 (A-56268), a new macrolide antibiotic. Chemother 36 (Suppl. 3): 129–155Google Scholar
  20. 20.
    Fernandes PB, Bailer R, Swanson R, Hanson CW, McDonald E, Ramer N, Hardy D, Shipkowitz N, Bower RR, Gade E (1986) In vitro and in vivo evaluation of A-56268 (TE-031), a new macrolide. Antimicrob Agents Chemother 30: 865–873PubMedCrossRefGoogle Scholar
  21. 21.
    Hardy DJ, Hensey DM, Beyer JM, Vojtko C, McDonald EJ, Fernandes PB (1988) Comparative in vitro activities of new 14-, 15- and 16 membered macrolides. Antimicrob Agents Chemother 32: 1710–1719PubMedCrossRefGoogle Scholar
  22. 22.
    Suwa T, Yoshida H, Fukushima K, Nagate T (1989) Comparative pharmacokinetics of TE-031 and erythromycin stearate in rats and mice. Chemother 36 (Suppl. 3): 198–204Google Scholar
  23. 23.
    Kohno Y, Yoshida H, Suwa T, Suga T (1989) Comparative pharmacokinetics of clarithromycin (TE-031), a new macrolide antibiotic, and erythromycin in rats. Antimicrob Agents Chemother 33: 751–756PubMedCrossRefGoogle Scholar
  24. 24.
    Kohno Y, Yoshida H, Yoshitomi S, Suwa T (1989) Metabolic fate of TE-031 (A-56268)(VII) uptake into the lung. Chemother 36 (Suppl. 3): 257–263Google Scholar
  25. 25.
    Kohno Y, Yoshida H, Suwa T, Suga T (1990) Uptake of clarithromycin by rat lung cells. J Antimicrob Chemother 26: 503–513PubMedCrossRefGoogle Scholar
  26. 26.
    Kohno Y, Ohta K, Suwa T, Suga T (1990) Autobacteriographic studies of clarithromycin and erythromycin in mice. Antimicrob Agents Chemother 34: 562–567PubMedCrossRefGoogle Scholar
  27. 27.
    Saito A, Ishikawa K, Shinohara M, Fukuhara I, Nakayama I, Tomizawa M, Sato K (1988) Preclinical and clinical studies on TE-031 (A-56268). Chemother 36 (Suppl. 3): 521–537Google Scholar
  28. 28.
    Adachi T, Morimoto S, Watanabe Y, Sota K (1988) Isolation and identification of metabolites of TE-031 (A-56268) in human. Chemother 36 (Suppl. 3): 264–273Google Scholar
  29. 29.
    Adachi T, Morimoto S, Kondoh H, Nagate T, Watanabe Y, Sota K (1988) 14-Hydroxy-6–0- methylerythromycins A, active metabolites of 6–0-methylerythromycin A in human. J Antibiot 41: 966–975PubMedCrossRefGoogle Scholar
  30. 30.
    Adachi T, Morimoto S, Watanabe Y, Kamiya N, Iwasaki H (1989) Crystal and molecular structure of (14R)-14-hydroxy-6–0-methylerythromycin A. J Antibiot 42: 1012–1014PubMedCrossRefGoogle Scholar
  31. 31.
    Adachi T (1989) 15-Membered macrolides via translactonization in 14-hydroxy-6-O-methylerythromycin A. J Org Chem 54: 3507–3510CrossRefGoogle Scholar
  32. 32.
    Suwa T, Yoshida H, Kohno Y, Yoshitomi S, Kamei K (1988) Metabolic fate of TE-031 (A-56268) (IV) Metabolism of14C-TE-031 in rats and dogs. Chemother 36 (Suppl. 3): 227–237Google Scholar
  33. 33.
    Inouye S, Shomura T, Tsuruoka T, Omoto S, Niida T, Umemura K (1972) Isolation and structure of two metabolites of macrolide antibiotic, SF-837 substance. Chem Pharm Bull 20: 2366–2371PubMedCrossRefGoogle Scholar
  34. 34.
    Shomura T, Someya S, Murata S, Umemura K, Nishio M (1981) Metabolism of 9,3“-diacetylinidecamycin. II. The structures of several metabolites of 9,3”-diacetylmidecamycin. Chem Pharm Bull 29: 2413–2419PubMedCrossRefGoogle Scholar
  35. 35.
    Morishita M, Ohno M, Serizawa K, Fujiwara T, Sakakibara H (1984) Isolation and identification of metabolites of TMS-19-Q. Chemother 32 (Suppl. 6): 85–92Google Scholar
  36. 36.
    Nagate T, Ono T, Sugita K, Akashi T, Morikawa E, Miyazaki M, Takeichi C, Omura S (1988) Antibacterial activities of M-5, the most active metabolite of TE-031 (A-56268) in man. Chemother 36 (Suppl. 3): 156–169Google Scholar
  37. 37.
    Suwa T, Ohtake T, Urano H, Kodama T, Nakamura M, Iwatate C, Watanabe T (1988) Metabolic fate of TE-031 (A-56268) (IX), Absorption and excretion in humans (HPLC method). Chemother 36: 933–940Google Scholar
  38. 38.
    Hardy DJ, Swanson RN, Rode RA, Marsh K, Shipkowitz NL, Clement JJ (1990) Enhancement of the in vitro and in vivo activities of clarithromycin against Haemophilus influenzae by 14- hydroxy-clarithromycin, its major metabolite in humans. Antimicrob Agents Chemother 34: 1407–1413PubMedCrossRefGoogle Scholar
  39. 39.
    Powel M, Chen HY, Weinhardt B, Williams JD (1991) In-vitro cidal activity of clarithromycin and its 14-hydroxy metabolite (A-62671) against Haemophilus influenzae. J Antimicrob Chemother 27: 694–696CrossRefGoogle Scholar
  40. 40.
    Olsson-Liljequist B, Hoffman BM (1991) In-vitro activity of clarithromycin combined with its 14-hydroxy metabolite A-62671 against Haemophilus influenzae. J Antimicrob Chemother 27(Suppl. A): 11–17PubMedCrossRefGoogle Scholar
  41. 41.
    Sasaki J, Mizoue K, Morimoto S, Adachi T (1988) Microbial transformation of 6-O-methylerythromycin derivatives. J Antibiot 41: 908–915PubMedCrossRefGoogle Scholar
  42. 42.
    Adachi T, Sasaki J, Omura S (1989) Hydroxylation and N-demethylation of clarithromycin (6–0- methylerythromycin A) by Mucor circinelloides. J. Antibiot 42: 6–0CrossRefGoogle Scholar
  43. 43.
    Finch RG (1997) Overview of the clinical use of macrolides and streptogramins. Infect Dis Ther 1997: 3–26Google Scholar
  44. 44.
    Langtry HD, Brogden RN (1997) Clarithromycin. A review of its efficacy in the treatment of respiratory tract infections in immunocompetent patients. Drugs 53: 973–1004PubMedCrossRefGoogle Scholar
  45. 45.
    Tartaglione TA (1996) Therapeutic options for the management and prevention of Mycobacterium avium complex infection in patients with the acquired immunodeficiency syndrome. Pharmacother 16: 171–182Google Scholar
  46. 46.
    Mertl SL (1996) The role of clarithromycin in the prophylaxis of disseminated Mycobacterium avium-intracellulare infection in patients with AIDS. Pharmacother 16: 393–400Google Scholar
  47. 47.
    Wright J (1998) Current strategies for the prevention and treatment of disseminated Mycobacterium avium complex infection in patients with AIDS. Pharmacother 18: 738–747Google Scholar
  48. 48.
    Markham A, McTavish D (1996) Clarithromycin and omeprazole as Helicobacter pylori eradication therapy in patients with H. pylon-associated gastric disorders. Drugs 51: 161–178PubMedCrossRefGoogle Scholar
  49. 49.
    NIH consensus development panel on Helicobacter pylori in peptic ulcer disease (1994) Helicobacter pylori in peptic ulcer disease. JAMA 272: 65–69CrossRefGoogle Scholar
  50. 50.
    Soll AH (1996) Medical treatment of peptic ulcer disease: Practical guidelines. JAMA 275: 622–629PubMedCrossRefGoogle Scholar
  51. 51.
    The European Helicobacter pylori study group (1997) Current European concepts in the management of Helicobacter pylori infection. The Maastricht Consensus Report. Gut 41: 8–13CrossRefGoogle Scholar
  52. 52.
    Kudoh S, Uetake T, Hagiwara K, Hirayama M, Hus L, Kimura H, Sugiyama Y (1987) Clinical effect of low-dose long-term erythromycin chemotherapy on diffuse panbronchiolitis. Jpn J Thorac Dis 25: 632–642Google Scholar
  53. 53.
    Sawaki M, Mikasa K, Konishi M, Maeda K, Narita N (1998) Clinical study of long-term treatment using erythromycin in chronic lower respiratory tract infection Jpn J Chemother 46: 239–247Google Scholar
  54. 54.
    Goswami SK, Kivity S, Marom Z (1990) Erythromycin inhibits respiratory glycoconjugate secretion from human airways in vitro. Am Rev Respir Dis 141: 72–78Google Scholar
  55. 55.
    Tamaoki J, Isono K, Sakai N, Kanemura T, Konno K (1992) Erythromycin inhibits Cl secretion across canine tracheal epithelial cells. Eur Respir J 5: 234–238PubMedGoogle Scholar
  56. 56.
    Ichikawa Y, Ninomiya H, Koga H, Tanaka M, Kinoshita M, Tokunaga N, Yano T, Oizumi K (1992) Erythromycin reduces neutrophils and neutrophil-derived elastolytic-like activity in the lower respiratory tract of bronchiolitis patients. Am Rev Respir Dis 146: 196–203PubMedGoogle Scholar
  57. 57.
    Kadota J, Sakito O, Kohno S, Sawa H, Mukae H, Oda H, Kawakami K, Fukushima K, Hiratani K, Hara K (1993) A mechanism of erythromycin treatment in patients with diffuse panbronchiolitis. Am Rev Respir Dis 147: 153–159PubMedCrossRefGoogle Scholar
  58. 58.
    Keicho N, Kudoh S, Yotsumoto H, Akagawa KS (1993) Antilymphocytic activity of erythromycin distinct from that of FK506 or cyclosporin. J Antibiot 46: 1406–1413PubMedCrossRefGoogle Scholar
  59. 59.
    Keicho N, Kudoh S, Yotsumoto H, Akagawa KS (1993) Erythromycin promotes monocyte to macrophage differentiation. J Antibiot 47: 80–89CrossRefGoogle Scholar
  60. 60.
    Takeda H, Ohotami H, Ohgaki N (1994) Basic action of macrolide to diffuse panbronchiolitis Antibiot Chemother 10: 1305–1312Google Scholar
  61. 61.
    Kashimura M, Asaka T, Misawa Y, Matsumoto K, Morimoto S (2001) Synthesis and antibacterial activity of the tricyclic ketolides TE-802 and its analogs. J Antibiot 54:664–678PubMedCrossRefGoogle Scholar
  62. 62.
    Asaka T, Kashimura M, Ishii T, Matsuura A, Suzuki K, Ohyauchi R, Matsumoto K, Numata K, T, Akashi T, Adachi T, Morimoto S (1997) New macrolide antibiotics, acylides (3–0-acy3–0–0- desosaminylerythronolides); Synthesis and biological properties. 37th ICAAC Toronto, Canada, Abstract F-262Google Scholar
  63. 63.
    Asaka T, Kashimura M, Manaka A, Tanikawa T, Ishii T, Sugimoto T, Suzuki K, Sugiyama H, Akashi T, Saito H, Adachi T, Morimoto S (1999) Structure activity studies leading potent acylides: 3–0-acy3–0–0-desosaminylerythronolide 11,12—carbamates. 39th ICAAC San Francisco, California, Abstract F-2159Google Scholar
  64. 64.
    Or Y, Clak RF, Wang S, Chu DTW, Nilius AM, Flamm RK, Mitten M, Ewing P, Alder J, Ma Z (2000) Design, synthesis and antimicrobial activity of 6–0-substituted ketolides active against resistant respiratory tract pathogens. J Med Chem 43: 6–0PubMedCrossRefGoogle Scholar
  65. 65.
    Denis A, Agourideas C, Auger JM, Benedetti Y, Bonnefoy A, Bretin F, Chantot JF, Dussarat A, Fromentin C, D’Ambrieres SG et al (1999) Synthesis and antibacterial activity of HMR3647. A new ketolide highly potent against erythromycin-resistant and susceptible pathogens. Bioorg Med Chem Lett 9: 3075–3080PubMedCrossRefGoogle Scholar

Copyright information

© Springer Basel AG 2002

Authors and Affiliations

  • Takashi Adachi
    • 1
  • Shigeo Morimoto
    • 1
  1. 1.Medicinal Research LaboratoriesTaisho Pharmaceutical Co., Ltd.Saitama-shi, SaitamaJapan

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