US3476738A - Pentakis(n-(sulfomethyl))circulin and salts thereof - Google Patents

Pentakis(n-(sulfomethyl))circulin and salts thereof Download PDF

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US3476738A
US3476738A US687488A US3476738DA US3476738A US 3476738 A US3476738 A US 3476738A US 687488 A US687488 A US 687488A US 3476738D A US3476738D A US 3476738DA US 3476738 A US3476738 A US 3476738A
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circulin
pentakis
sulfomethyl
methanesulfonate
salts
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Alexander D Argoudelis
Joseph E Grady
Gordon C Sayer
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Pharmacia and Upjohn Co
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Upjohn Co
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/50—Cyclic peptides containing at least one abnormal peptide link
    • C07K7/54—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring
    • C07K7/60—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring the cyclisation occurring through the 4-amino group of 2,4-diamino-butanoic acid
    • C07K7/62—Polymyxins; Related peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • Circulin is a polypeptide antibiotic containing free amino groups and amide (peptide) linked nitrogen.
  • Circulin A and circulin B are the major components of circulin. The structural formulas of circulin A and B have been elucidated and published. Both circulin A and B have five free amino groups and it is these groups which first react with formaldehyde to yield the water insoluble pentakis [N-(hydroxymethyl)]circulin. This compound is then treated with an alkali metal bisulfite or ammonium bisulfite to yield an alkali metal or ammonium salt, respectively, of pentakis[N-(sulfomethyl) ]circulin.
  • pentakis [N-(sulfomethyl)]circulin and its pharmoologically acceptable salts show less toxicity in mammals than does circulin per se, without a change in antibacterial spectrum.
  • pentakis[N-sulfomethyl)]circulin and its pharmacologically acceptable salts have a better therapeutic index than circulin.
  • the compound of this invention also is more active than polymyxin methanesulfonate (colistin methanesulfonate) against Escherichia coli and Pseudomo nas aeruginosa infections in mice.
  • polymyxin methanesulfonate colistin methanesulfonate
  • This difference in activity between the methanesulfonates of polymyxin and circulin is unexpected because polymyxin per se and circulin per se have about the same activity against these bacteria in mice.
  • There is nothing in the antibiotic art which teaches or even suggests that the antibacterial activities would become different when the methanesulfonate derivatives of circulin and polymyxin are produced.
  • the prior art discloses methanesulfonates of polypeptide antibiotics other than circulin. These methanesulfonates are disclosed as being made to reduce toxicity prob lems associated with use of the parent antibiotic.
  • Wilkinson U.S. Patent 3,044,934 discloses that the methanesulfonate of polymyxin reduces undesirable local effects of polymyxin.
  • Lewis et al. US. Patent 3,205,137 discolses that the methanesulfonate of bacitracin overcomes the toxicity of bacitracin to the kidneys.
  • Pentakis[N-(sulfomethyl)]circulin is produced by first reacting circulin with formaldehyde to yield the water insoluble pentakis[N-(hydroxymethyl)]circulin. This compound is then treated with an alkali metal bisulfite or ammonium bisulfite to yield an alkali metal or ammonium salt, respectively, of pentakis[N-(sulfomethyl)]circulin.
  • pharmacologically acceptable salts of pentakis- [N-(sulfomethyl)]circulin can be made by cationic metathesis in either aqueous or alcoholic solutions using procedures known to the art.
  • Suitable cations are those of the non-toxic alkaline earth elements as well as those of organic amines, such as lower alkyl amines (e.g. triethylamine), N-ethylpyridine, procaine, and the like.
  • mice Groups of 10 CF-l male albino mice weighing 18-20 gms. were infected intraperitoneally with approximately lethal doses of a standardized frozen suspension of either Escherichia coli or Pseudomonas aeruginosa. Four groups of ten infected mice each were treated immediately and once per day for the next three days (total of four doses) via the subcutaneous route with 2X increment dilutions of circulin sulfate, circulin methanesulonate, colistin sulfate, or colistin methanesulfonate. All antibiotic preparations were dissolved in 0.05 M, phosphate buffer, pH 7.0.
  • the novel compound of the invention is active against Pseudomo'nas aeruginosa, Salmonella, Shigella, Escherichia coli, Klebsiella, pneumoniae, and Aerobacter aerogenes.
  • the novel compound of this invention can be used to inhibit the growth of E. coli in paper mill systems where this organism has been found to be an odor producer.
  • this novel compound can be used in fish meal to prevent contamination by Salmonella.
  • Pentakis[N-(sulfomethyl)]circulin, and its pharmacologically acceptable salts,- is partiularly useful to treat animals, for example, laboratory mice infected by Gram-negative bacteria, for example, E. coli or Pseudomonas aeruginosa.
  • PentakisIN-(sulfomezllyl)]circulin sodium salt Pentakis[N-(hydroxymethyl)]circulin (2.5 g.), prepared as in Example 1, was finely divided by trituration and added portionwise to a hand-stirred solution of sodium bisulfite (1.0 g.) in deionized water (15 ml.). Virtually complete dissolution was achieved by mechanical stirring while maintaining the mixture at 4050 C. for one hour. The turbid solution was then clarified by filtration and freeze-dried to yield pentakis[N-(sulfomethyl)] circulin sodium salt as an oil-white solid (3.4-1 g.) having the following characteristics:
  • Pentakis[N-(sulfomethyl)]circulin potassium, lithium and ammonium salts can be prepared as above by substituting potassium bisulfite, lithium bisulfite and ammonium bisulfite, respectively, for the sodium bisulfite.
  • Pentakis[N-(sulfomethyl) ]circulin alkali metal and ammonium salts can be converted to the free acid form by neutralizing with an acid or by contacting with a cationic resin at an acidic pH.
  • Hayashi et a1 Bull. Inst. Chem. Res. (Kyoto) 43, 273- 274 (1965).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Description

United States Patent Office US. Cl. 260112.5 2 Claims ABSTRACT OF THE DISCLOSURE Pentakis[N-(sulfomethyl)]circulin and its pharmacologically acceptable metal, ammonium and amine salts. These compounds can be used to inhibit the growth of Gram-negative bacteria.
CROSS-REFERENCE TO RELATED APPLICATION This application is a continuation-in-part of copending application Ser. No. 427,957, filed Jan. 25, 1965, now abandoned.
BRIEF SUMMARY OF THE INVENTION This invention is directed to novel compounds derived from the antibiotic circulin. Circulin is a polypeptide antibiotic containing free amino groups and amide (peptide) linked nitrogen. Circulin A and circulin B are the major components of circulin. The structural formulas of circulin A and B have been elucidated and published. Both circulin A and B have five free amino groups and it is these groups which first react with formaldehyde to yield the water insoluble pentakis [N-(hydroxymethyl)]circulin. This compound is then treated with an alkali metal bisulfite or ammonium bisulfite to yield an alkali metal or ammonium salt, respectively, of pentakis[N-(sulfomethyl) ]circulin.
The novel compound of the invention, pentakis [N-(sulfomethyl)]circulin and its pharmoologically acceptable salts, show less toxicity in mammals than does circulin per se, without a change in antibacterial spectrum. Thus, pentakis[N-sulfomethyl)]circulin and its pharmacologically acceptable salts have a better therapeutic index than circulin. (The relationship between the desired and undesired effects of a drug is termed its therapeutic index-see The Pharmacological Basis of Therapeutics, third edition, by L. S. Goodman and A. Gillman, on page 22.) Unexpectedly, the compound of this invention also is more active than polymyxin methanesulfonate (colistin methanesulfonate) against Escherichia coli and Pseudomo nas aeruginosa infections in mice. This difference in activity between the methanesulfonates of polymyxin and circulin is unexpected because polymyxin per se and circulin per se have about the same activity against these bacteria in mice. There is nothing in the antibiotic art which teaches or even suggests that the antibacterial activities would become different when the methanesulfonate derivatives of circulin and polymyxin are produced.
The prior art discloses methanesulfonates of polypeptide antibiotics other than circulin. These methanesulfonates are disclosed as being made to reduce toxicity prob lems associated with use of the parent antibiotic. For example, Wilkinson U.S. Patent 3,044,934 discloses that the methanesulfonate of polymyxin reduces undesirable local effects of polymyxin. Lewis et al. US. Patent 3,205,137 discolses that the methanesulfonate of bacitracin overcomes the toxicity of bacitracin to the kidneys.
3,476,738 Patented Nov. 4, 1969 DETAILED DESCRIPTION OF THE INVENTION Pentakis[N-(sulfomethyl)]circulin is produced by first reacting circulin with formaldehyde to yield the water insoluble pentakis[N-(hydroxymethyl)]circulin. This compound is then treated with an alkali metal bisulfite or ammonium bisulfite to yield an alkali metal or ammonium salt, respectively, of pentakis[N-(sulfomethyl)]circulin.
Other pharmacologically acceptable salts of pentakis- [N-(sulfomethyl)]circulin can be made by cationic metathesis in either aqueous or alcoholic solutions using procedures known to the art. Suitable cations are those of the non-toxic alkaline earth elements as well as those of organic amines, such as lower alkyl amines (e.g. triethylamine), N-ethylpyridine, procaine, and the like.
The antibacterial properties of polymyxin sulfate, polymyxin methanesulfonate, circulin sulfate and circulin methanesulfonate were determined against the Gramnegative microorganisms Escherichia coli and Pseudomonas aeruginosa: in mice infected with these bacteria. The conditions of the tests and results are as follows:
Groups of 10 CF-l male albino mice weighing 18-20 gms. were infected intraperitoneally with approximately lethal doses of a standardized frozen suspension of either Escherichia coli or Pseudomonas aeruginosa. Four groups of ten infected mice each were treated immediately and once per day for the next three days (total of four doses) via the subcutaneous route with 2X increment dilutions of circulin sulfate, circulin methanesulonate, colistin sulfate, or colistin methanesulfonate. All antibiotic preparations were dissolved in 0.05 M, phosphate buffer, pH 7.0. Deaths of the treated and non-treated control animals were recorded for seven days and the median protective dose of each compound was calculated by the Spearman-Karber (Statistical Methods in Biological Assays, 2nd ed. Hafner Publishing Co., New York, N.Y., 1964, at pp. 524-530) method programmed for an IBM 360 digital computer. The results are summarized in the following table:
MEDIAN PROTECTIVE DOSE 1 Calculated on a weight basis.
Note:
(a) The results for the compounds circulin methanesulfonate and colistin methanesulfonate against E. coli infections, differ from each other by a statistically significant amount (p.:0.05).
(b) The results for the compounds circulin methanesulfonate and colistin methanesulfonate against P. aeraginosa infections, differ from each other by a statistically significant amount (p.=0.05).
The novel compound of the invention is active against Pseudomo'nas aeruginosa, Salmonella, Shigella, Escherichia coli, Klebsiella, pneumoniae, and Aerobacter aerogenes. Thus, the novel compound of this invention can be used to inhibit the growth of E. coli in paper mill systems where this organism has been found to be an odor producer. Also, this novel compound can be used in fish meal to prevent contamination by Salmonella. Pentakis[N-(sulfomethyl)]circulin, and its pharmacologically acceptable salts,- is partiularly useful to treat animals, for example, laboratory mice infected by Gram-negative bacteria, for example, E. coli or Pseudomonas aeruginosa.
The following examples are illustrative of the process and products of the present invention, but are not to be construed as limiting.
3 EXAMPLE 1 Pentakis [N-(hydr xymethyl) ]circulin Circulin sulfate (5.0 g.) was dissolved in deionized water (35 ml.) by portionwise addition with mechanical stirring, to give a clear, pale yellow solution (ph 6.3). Aqueous formaldehydre (15 ml., 37% w./v.) was added and the resultant solution (ph 3.1) was poured slowly into 0.1 N aqueous sodium hydroxide solution (125 ml.). Pentakis[N-(hydroxymethyl)]circulin precipitated as a yellowish-white particulate solid which was removed by filtration in vacuo. The residue was slurried and refiltered three times with 50 ml. portions of deionized water. Pentakis[N-(hydroxymethyl)]circulin was obtained as an offwhite solid (3.38 g.) having the following characteristics:
Elemental analysis.Calcd for C H N O C, 52.79; H, 8.40; N, 16.98. Found: C, 53.36; H, 8.86; N, 16.75. Calculated molecular weight: 1319.64.
EXAMPLE 2 PentakisIN-(sulfomezllyl)]circulin sodium salt Pentakis[N-(hydroxymethyl)]circulin (2.5 g.), prepared as in Example 1, was finely divided by trituration and added portionwise to a hand-stirred solution of sodium bisulfite (1.0 g.) in deionized water (15 ml.). Virtually complete dissolution was achieved by mechanical stirring while maintaining the mixture at 4050 C. for one hour. The turbid solution was then clarified by filtration and freeze-dried to yield pentakis[N-(sulfomethyl)] circulin sodium salt as an oil-white solid (3.4-1 g.) having the following characteristics:
Elemental analysis.Calcd for C H N O S Na C, 39.81; H, 6.05; N, 12.81; S, 9.16. Found: C, 35.52; H, 6.90; N, 10.98; S, 9.27. Calculated molecular weight: 1749.89.
Pentakis[N-(sulfomethyl)]circulin potassium, lithium and ammonium salts can be prepared as above by substituting potassium bisulfite, lithium bisulfite and ammonium bisulfite, respectively, for the sodium bisulfite.
Pentakis[N-(sulfomethyl) ]circulin alkali metal and ammonium salts can be converted to the free acid form by neutralizing with an acid or by contacting with a cationic resin at an acidic pH.
EXAMPLE 3 By substituting the circulin sulfate in Example 1 by circulin A sulfate, there is obtained pentakis[N-(hydroxymethyl) ]circulin A.
4 EXAMPLE 4 By substituting the circulin sulfate in Example 1 by circulin B sulfate, there is obtained pentakis[N-(hydroxymethy1)]circulin B.
EXAMPLE 5 By substituting pentakis[N-(hydroxymethyl)]circulin in Example 2 by pentakis[N-(hydroxymethyl) ]circulin A, as obtained in Example 3, there is obtained pentakis[N- (sulfomethyl) ]circulin A sodium salt.
EXAMPLE 6 References Cited UNITED STATES PATENTS 2,779,705 1/1957 Peterson et al. l67-65 3,044,934 7/1962 Wilkinson l67-65 3,061,515 10/1962 Fardig 167-65 3,205,137 9/1965 Lewis et al. 16765 3,317,506 5/1967 Wilkinson 260112.5
OTHER REFERENCES Grady et al.: Fed. Proc. 17, 23 (1958).
Hayashi et a1: Bull. Inst. Chem. Res. (Kyoto) 43, 273- 274 (1965).
Logemann et al.: Arzneimmittelforschung 5, 213-220 (1955).
Suzuki et al.: J. Biochem. 54, 412418 (1963).
LEWIS GOTTS, Primary Examiner M. KASSENOFF, Assistant Examiner US. Cl. X.R. 997, 150, 158; l62l61;424-177
US687488A 1967-12-04 1967-12-04 Pentakis(n-(sulfomethyl))circulin and salts thereof Expired - Lifetime US3476738A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3926921A (en) * 1973-03-27 1975-12-16 Crinos Industria Farmaco Pharmaceutical compositions comprising mixed salts of sulfoglycopeptides with metal and organic bases

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2779705A (en) * 1949-05-06 1957-01-29 Upjohn Co Circulin derivatives and circulin recovery
US3044934A (en) * 1960-05-19 1962-07-17 Burroughs Wellcome Co Parenteral administration of methanesulphonate of polymyxin a, b or e
US3061515A (en) * 1960-05-09 1962-10-30 Bristol Myers Co Methane sulfonates of telomycins
US3205137A (en) * 1963-03-19 1965-09-07 Warner Lambert Pharmaceutical Bacitracin derivatives
US3317506A (en) * 1962-12-13 1967-05-02 Burroughs Wellcome Co Preparation of sodium or potassium salts of polymyxin b and e or colistin formaldehyde-bisulfite reaction products

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2779705A (en) * 1949-05-06 1957-01-29 Upjohn Co Circulin derivatives and circulin recovery
US3061515A (en) * 1960-05-09 1962-10-30 Bristol Myers Co Methane sulfonates of telomycins
US3044934A (en) * 1960-05-19 1962-07-17 Burroughs Wellcome Co Parenteral administration of methanesulphonate of polymyxin a, b or e
US3317506A (en) * 1962-12-13 1967-05-02 Burroughs Wellcome Co Preparation of sodium or potassium salts of polymyxin b and e or colistin formaldehyde-bisulfite reaction products
US3205137A (en) * 1963-03-19 1965-09-07 Warner Lambert Pharmaceutical Bacitracin derivatives

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3926921A (en) * 1973-03-27 1975-12-16 Crinos Industria Farmaco Pharmaceutical compositions comprising mixed salts of sulfoglycopeptides with metal and organic bases

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