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WO1997035590A1 - 10-aza-9-deoxo-11-deoxy-erythromycine a et derives combines a du sulfisoxazole - Google Patents

10-aza-9-deoxo-11-deoxy-erythromycine a et derives combines a du sulfisoxazole Download PDF

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Publication number
WO1997035590A1
WO1997035590A1 PCT/US1997/004743 US9704743W WO9735590A1 WO 1997035590 A1 WO1997035590 A1 WO 1997035590A1 US 9704743 W US9704743 W US 9704743W WO 9735590 A1 WO9735590 A1 WO 9735590A1
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WO
WIPO (PCT)
Prior art keywords
hydrogen
amino
alkyl
erythromycin
erythromycin derivative
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US1997/004743
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English (en)
Inventor
Chris E. Platt
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Individual
Original Assignee
Individual
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Filing date
Publication date
Application filed by Individual filed Critical Individual
Publication of WO1997035590A1 publication Critical patent/WO1997035590A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof

Definitions

  • TITLE 10-Aza-9-Dcoxo-11-Deoxy-Erythromycin A and Derivatives Combined with
  • the present invention relates to a novel group of chemical compounds providing antibacterial activity, and which are useful in the therapy of bacterial infections in mammals. More specifically, the invention relates to compositions including the derivatives of the welUknown antibiotic, erythromycin A.
  • the erythromycin derivatives act by binding to the 50S ribosomal subunit of susceptible microorganisms and, thus, interfere with microbial protein synthesis. Nucleic acid synthesis is not affected.
  • the suifisoxazole inhibits bacterial synthesis of dihydrofolic acid by preventing the condensation of the ptcndine with para-aminobenzoic acid through competitive inhibition of the enzyme dihydopteroate synthetase.
  • the erythromycin derivative After absorption the erythromycin derivative is largely bound to plasma proteins and readily diffuses into most body fluids. Rapid distribution of erythromycin derivative into tissues and high concentration within cells results in higher concentrations in tissues than in serum or plasma. Erythromycin derivative seems to concentrate in fibroblasts and phagocytes as demonstrated by in vivo incubation techniques.
  • Such derivatives are modifications of the well-known antibiotic, erythromycin A, having the following structure:
  • the erythromycin derivatives of the present invention relate to the compounds of the following structure and derivatives thereof, which form a novel class of 14-mcmbcred azalides
  • the inventive step in the present invention is that these compounds are combined with suifisoxazole for enhanced antibacterial activity.
  • the present invention provides for novel pharmaceutical compositions and methods for their use as antibacterial agents.
  • the present invention stems from the discovery that certain erythromycin derivatives are easily tolerated by patients without causing gastrointestinal disturbances. Additionally when combined with suifisoxazole, resistance to Entcrococcus Faecalis, methacillin-resistant stapylococci, and erythromycin resistant gram-positive strains is achieved.
  • the inventive combination provides protection from a greater antibacterial spectrum then either erythromycin or suifisoxazole alone.
  • this new invention not only saves lives by providing a combination that overcomes medication resistance but is more easily tolerated without stomach upset and vomiting; side effects experienced by many people taking erythromycin alone.
  • the basis for the present invention is the pharmaceutical composition of an erythromycin derivative combined with acetylsulfisoxazole according to the structural formulas shown in Claim 1 below, where R is hydrogen; C1-C10 alkylcarbonyl, or substituted C1-C10 alkyl wherein said substituent is amino or cyano; and R1 and R2 are independently hydrogen, hydroxyl or amino; and including the pharmaceutical salts and esters thereof.
  • Chemically acetylsulfisoxazole is N-(3,4,-Dimetly-5-isoxazole)-N-sulfanylactamide.
  • Suifisoxazole, where the acetyl group is replaced by H is an alternative substitution in the invention.
  • erythromycin derivative include, but are not limited to, the structural formulas as shown in either Claim 3 where R is methyl, R' is H and R 2 , in Claim 5 where R is ammino alkyl carbonyi, R 1 is H and R 2 is OH, and in Claim 6 where R is cyano, R 1 is an ammino group, and R 1 is H.
  • composition of the present invention may be formulated wherein the erythromycin derivative has the general structural formula as shown below in Claim 2, including the pharmaceutically acceptable salts, esters and metal complexes thereof, wherein R 1 is hydrogen, C1-C10 alkyl carbonyi or unsubstituted or substituted C1-C10 alkyl wherein the substituent is amino or cyano; R 2 and R 3 are hydrogen; R 1 and R 1 together are oxo; R 4 is hydrogen or C1-C10 alkylcarbonyl; R 5 and R' arc independently hydrogen, hydroxy or amino; R 5 and R 6 together are oxo or oximino; R 7 and R 8 are independently hydrogen, C1-C10 alkyl or phenylsulfonyl; R 9 Is hydrogen, or C1-C10 alkylc ⁇ rbony, and R 10 is hydrogen.
  • operable substitutions for the nine variables include the following:
  • the mixture ratio by weight, of erythromycin to suifisoxazole may range from 100:1 to as much as 1 :1, and even trace amounts of suifisoxazole may be operative.
  • the preferred ratio is 100:38.
  • the erythromycin and suifisoxazole are prepared following standard laboratory procedures and processes that all competent workers in the field of the present invention will know.
  • the various alternative formulations of the present invention may take the form of a compressed pill, a powder in an easy to swatlow caplet, or even as a fluid dissolved in a liquid such as water. In all cases, the formulation is to be taken orally.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Molecular Biology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des compositions pharmaceutiques d'un dérivé d'érythromycine combiné à du sulfisoxazole. Ces compositions pharmaceutiques sont représentées par les formules développées (I) et (II), dans lesquelles R est hydrogène, alkylcarbonyle en C1-C10 ou alkyle substitué en C1-C10, le substituant étant un amino ou un cyano; R<1> et R<2> désignent chacun indépendamment hydrogène, hydroxyle ou amino. L'invention concerne également les sels et les esters pharmaceutiques des dites compositions.
PCT/US1997/004743 1996-03-25 1997-03-24 10-aza-9-deoxo-11-deoxy-erythromycine a et derives combines a du sulfisoxazole Ceased WO1997035590A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US62226096 1996-03-25
US08/622,260 1996-03-25

Publications (1)

Publication Number Publication Date
WO1997035590A1 true WO1997035590A1 (fr) 1997-10-02

Family

ID=24493534

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1997/004743 Ceased WO1997035590A1 (fr) 1996-03-25 1997-03-24 10-aza-9-deoxo-11-deoxy-erythromycine a et derives combines a du sulfisoxazole

Country Status (1)

Country Link
WO (1) WO1997035590A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004052904A3 (fr) * 2002-12-12 2004-09-02 Pliva Istrazivacki Inst D O O Derives 9a-n-(n'-carbamoyl-$g(g)-aminopropyle), 9a-n-(n'- -thiocarbamoyl-$g(g)-aminopropyle), 9a-n-[n'-(($g(b)-cyanoethyl)-n'-carbamoyl-$g(g)-aminopropyle] et 9a-n-[n'-($g(b)-cyanoethyl)-n'-thiocarbamoyl-$g(g)-aminopropyle] n'-substitues de 9-deoxo-9-dihydro-9a-aza-9a-homoerythromycine a et 5-o-desosaminyl-9-deoxo-9- dihydr
US7365056B2 (en) 2002-11-11 2008-04-29 Glaxosmithkline Istrazivacki Centar Zagreb D.O Substituted 9a-N-(N′-(sulfonyl)phenylcarbamoyl)derivatives of 9-deoxo-9-dihydro-9a-aza-9a-homoerithomycin A and 5-0-desosaminyl-9-deoxo-9-dihydro-9-a-aza-9a-homoerithronolide A
JP4796300B2 (ja) * 2002-08-29 2011-10-19 ファイザー インコーポレイテッド モチライド化合物

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Volume 22, Number 1, issued July 1982, TARPAY et al., "In Vitro Activity of Antibiotics Commonly Used in the Treatment of Otitis Media Against Streptococcus Pneumoniae Isolates With Different Susceptibilites to Penicillin", pages 145-147. *
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Volume 32, Number 2, issued February 1988, DOERN et al., "National Collaborative Study of the Prevalence of Antimicrobial Resistance Among Clinical Isolates of Haemophilus Influenzae", pages 180-185. *
M. WINDHOLZ et al., "The Merck Index, an Encyclopedia of Chemicals, Drugs and Biologicals, Tenth Edition", Published 1983, by MERCK & CO., INC. (N.J.), page 16, Number 104. *
THE JOURNAL OF INFECTIOUS DISEASES, Volume 170, Number 1, issued 1994, HUGHES et al., "Relative Potency of 10 Drugs With Anti-Pneumocyctis Carinii Activity in an Animal Model", pages 906-911. *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP4796300B2 (ja) * 2002-08-29 2011-10-19 ファイザー インコーポレイテッド モチライド化合物
US7365056B2 (en) 2002-11-11 2008-04-29 Glaxosmithkline Istrazivacki Centar Zagreb D.O Substituted 9a-N-(N′-(sulfonyl)phenylcarbamoyl)derivatives of 9-deoxo-9-dihydro-9a-aza-9a-homoerithomycin A and 5-0-desosaminyl-9-deoxo-9-dihydro-9-a-aza-9a-homoerithronolide A
WO2004052904A3 (fr) * 2002-12-12 2004-09-02 Pliva Istrazivacki Inst D O O Derives 9a-n-(n'-carbamoyl-$g(g)-aminopropyle), 9a-n-(n'- -thiocarbamoyl-$g(g)-aminopropyle), 9a-n-[n'-(($g(b)-cyanoethyl)-n'-carbamoyl-$g(g)-aminopropyle] et 9a-n-[n'-($g(b)-cyanoethyl)-n'-thiocarbamoyl-$g(g)-aminopropyle] n'-substitues de 9-deoxo-9-dihydro-9a-aza-9a-homoerythromycine a et 5-o-desosaminyl-9-deoxo-9- dihydr
CN100335489C (zh) * 2002-12-12 2007-09-05 普利瓦研究院有限公司 半合成的氮杂环内酯系列的大环内酯类抗生素
US7342000B2 (en) 2002-12-12 2008-03-11 Glaxosmithkline Istrazivacki Center Zagreb Semisynthetic macrolide antibiotics of the azalide series

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