WO1998011903A1 - Derives du chitosane destines au traitement de tumeurs malignes - Google Patents

Derives du chitosane destines au traitement de tumeurs malignes Download PDF

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Publication number
WO1998011903A1
WO1998011903A1 PCT/EP1997/004577 EP9704577W WO9811903A1 WO 1998011903 A1 WO1998011903 A1 WO 1998011903A1 EP 9704577 W EP9704577 W EP 9704577W WO 9811903 A1 WO9811903 A1 WO 9811903A1
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WO
WIPO (PCT)
Prior art keywords
chitosan
group
structural elements
derivative
pharmaceutical composition
Prior art date
Application number
PCT/EP1997/004577
Other languages
English (en)
Inventor
Claus Timmermans
Original Assignee
Chicura Coöperatie U.A.
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Chicura Coöperatie U.A. filed Critical Chicura Coöperatie U.A.
Priority to AU43811/97A priority Critical patent/AU4381197A/en
Publication of WO1998011903A1 publication Critical patent/WO1998011903A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/06—Tripeptides
    • A61K38/063—Glutathione
    • 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
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/716—Glucans
    • A61K31/722—Chitin, chitosan
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K9/00—Peptides having up to 20 amino acids, containing saccharide radicals and having a fully defined sequence; Derivatives thereof
    • C07K9/001—Peptides having up to 20 amino acids, containing saccharide radicals and having a fully defined sequence; Derivatives thereof the peptide sequence having less than 12 amino acids and not being part of a ring structure
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
    • C08B37/0024—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid beta-D-Glucans; (beta-1,3)-D-Glucans, e.g. paramylon, coriolan, sclerotan, pachyman, callose, scleroglucan, schizophyllan, laminaran, lentinan or curdlan; (beta-1,6)-D-Glucans, e.g. pustulan; (beta-1,4)-D-Glucans; (beta-1,3)(beta-1,4)-D-Glucans, e.g. lichenan; Derivatives thereof
    • C08B37/0027—2-Acetamido-2-deoxy-beta-glucans; Derivatives thereof
    • C08B37/003—Chitin, i.e. 2-acetamido-2-deoxy-(beta-1,4)-D-glucan or N-acetyl-beta-1,4-D-glucosamine; Chitosan, i.e. deacetylated product of chitin or (beta-1,4)-D-glucosamine; Derivatives thereof

Definitions

  • the invention relates to the use of chitosan derivatives for treating malignant tumours, to a pharmaceutical composition to be used therefor, as well as to new chitosan derivatives and their method of preparation.
  • cytostatica The tumoricidally active pharmaceuticals, generally called cytostatica, at present available and in use in hospitals and clinics for the chemotherapeutic treatment of cancer and related diseases, are generally not sufficiently effective in the dosages which are acceptable with regard to their often serious side-effects.
  • Tumoricidal properties are ascribed to chitosan and its oligomers.
  • Suzuki and coworkers A.
  • a pharmaceutical composition comprising in a therapeuti- cally effective amount a chitosan derivative.
  • This chitosan derivative comprises at least approx . 20% of structural elements having the general formula I
  • R is a hydrogen atom, or a (C -C, ) alkylcarbonyl group wherein the alkyl group may be substituted with ca ' rboxy, hydroxy or (Ci-C,,) alkoxy; or wherein OR is a sulfated or phosphated hydroxy group; p and q are each independently 0 or 1; R, is a straight or branched, saturated or unsaturated aliphatic (C, -C l6 ) hydrocarbylene group, optionally substituted with 1-3 hydroxy groups; and R represents 1-8 moieties, selected from amino acids and peptideous compounds; as well as functional derivatives thereof.
  • chitosan derivatives have strong tumour-growth inhibiting properties, as opposed to chitosan or its oligomers. Therefore, even at low dosages these chitosan derivatives can be used to reach an effective therapy.
  • chitosan derivatives to be used according to the invention such as N-carboxybutyl chitosan and the lacta e of chitosan - levulinic acid - condensate (containing 2 - methylpyrrolidon-1-yl-deoxyglycose residues) , can inhibit tumour-growth with over 50% when used in acceptable dosages .
  • chitosan derivatives are to be understood to comprise, in addition to derivatives of chitosan itself, derivatives of chitosan oligomers from six derivatized glucosamine residues up.
  • the above-defined chitosan derivative preferably consists of at least 40% of the above structural elements of formula I, most preferably of at least 60% thereof; the remainder may consist of unconverted or acetylated glucosamine residues without adversely influencing its properties.
  • Functional derivatives of the above chitosan derivatives comprise esters with lower alkanols, cyclic condensation products such as lactones and lactames, amides with lower alkylamides, and salts, in particular salts with basic substances such as alkali metal hydroxides or ammonia.
  • peptideous compound or peptide-like compound is to be understood to mean a compound having at least one peptide bond in its molecule, such as glutathione and its thiol-derivatives .
  • examples of such derivatives are S- alkylated glutathione, e.g. the S-methyl and S-ethyl ethers of glutathione, S-acylated glutathione, e.g. S- acetylglutathione, and S-sulfated and S-phosphated glutathione .
  • Preferred chitosan derivatives to be used according to the method of the invention are derived from a chitosan oligomer having 8-30 glucosamine residues, which derivative comprises the structural elements of formula I above, wherein : R is a hydrogen atom or an acetyl group; p and q are each independently 0 or 1; R. is a straight or branched ( C l - C ) alkylene group, and R represents 1-4 moieties, derived from glutathione, alanme, lysme or leucme; as well as salts or cyclic condensation products thereof.
  • chitosan derivatives to be used according to the present invention are known per se Muzzarelli has investigated the wound-healing properties of N-carboxybutyl chitosan (Carbohydrate Polymers 1993, 20. 7-16).
  • N-carboxybutyl chitosan Carbohydrate Polymers 1993, 20. 7-16
  • various N-subst - tuted chitosan derivatives are described, e.g as wetting (moistening) agents for the skin and mucous membrane.
  • the present invention also relates to a pharmaceutical composition to be used m the above-defined method of combating tumours, comprising m addition to a pharmaceutically acceptable carrier and optional auxilia- ries, as the active ingredient a new chitosan derivative comprising at least approx. 20% of structural elements having the general formula II
  • the above new chitosan derivatives of the invention can be prepared in a manner known per se for related compounds, e.g. in that an N-carboxyalkylchitosan or an N- carboxyalkylcarbonylchitosan is reacted with an amino acid, a peptide or a peptideous compound, after which the deriva- tive obtained is functionalised, if desired, by a conversion into its salt or in its cyclic condensation product.
  • the formation of the starting N- carboxyalkyl (carbonyl) chitosan can be performed, e.g. in a corresponding manner as described in U.S.
  • Chitosan flakes (10 g, MW approx. 300,000, deacetylation 80%) is suspended in a solution of 5 g levulinic acid and 1 g glutathione in 1 1 water. The suspension is stirred for 6 hours to give a viscous solution. Under vigorous stirring a solution of 500 mg of NaN0 2 in 50 ml water is added to achieve partial depolymerization of the chitosan; the viscosity of the solution decreases gradually. After stirring for 30 min. the chitosan has a MW of beneath 30,000. By adding a solution of 1 g NaBH, in 50 ml water further depolymerization is stopped. The desired reactions take place under the reducing conditions of the added borohydrate.
  • the stirring is continued until the develop- ment of gas has stopped.
  • the sodium salt of the title product is precipitated by the addition of 10% aqueous NaOH (to pH 8.0).
  • the product is obtained as a microcrystalline material by filtration, e.g. by using a glass filter, and is washed with water (lx) and 70% aquous ethanol (lx) .
  • an aqueous solution of the free acid can be obtained by acidification with 10% aqueous HC1 to pH 5-6, producing a clear, slightly viscous solution.
  • chitosan sebacoylalanine is prepared from chitosan, sebacic acid and alanine .
  • the proliferation of malignant epithelial cells is investigated in vitro. Two cell- densities are used: 6,000 cells/well and 12,000 cells/well.
  • the following chitosan derivatives are investigated: chitosan sebacoylalanine, obtained according to Example I, and carboxybutylchitosan, known per se, the former substance in a 1% aqueous solution, the latter in a 2% aqueous solution.
  • the test concentration is 4 mg of solution per ml.
  • a photometric test method is used to determine the inhibition of the proliferation of the cells, applying MTT as the vital colouring agent.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Organic Chemistry (AREA)
  • Biochemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Biophysics (AREA)
  • Immunology (AREA)
  • Genetics & Genomics (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Materials Engineering (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Polymers & Plastics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Polysaccharides And Polysaccharide Derivatives (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne l'utilisation d'un dérivé du chitosane comprenant au moins approximativement 20 % d'éléments structurels de la formule générale (I), ainsi que des dérivés fonctionnels dudit chitosane servant à la préparation d'une composition pharmaceutique destinée au traitement de tumeurs malignes chez un être vivant à sang chaud. Dans ladite formule (I), R est un atome d'hydrogène ou un groupe alkylcarbonyle (C1-C4), le groupe alkyle pouvant être subtitué par carboxy, hydroxy ou alcoxy (C1-C4); ou OR est un groupe hydroxy sulfaté ou phosphaté; p et q sont chacun, indépendamment, 0 ou 1; R1 est un groupe hydrocarbyle (C1-C16) saturé ou insaturé, droit ou ramifié, éventuellement substitué par 1 à 3 groupes hydroxy; et R2 représente 1 à 8 fractions choisies dans des acides aminés ou des composés peptidiques. L'invention concerne en outre une composition pharmaceutique, de nouveaux dérivés du chitosane et leur procédé de préparation.
PCT/EP1997/004577 1996-09-18 1997-08-15 Derives du chitosane destines au traitement de tumeurs malignes WO1998011903A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU43811/97A AU4381197A (en) 1996-09-18 1997-08-15 Chitosan derivatives for treating malignant tumours

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP96202598 1996-09-18
EP96202598.7 1996-09-18

Publications (1)

Publication Number Publication Date
WO1998011903A1 true WO1998011903A1 (fr) 1998-03-26

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ID=8224390

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1997/004577 WO1998011903A1 (fr) 1996-09-18 1997-08-15 Derives du chitosane destines au traitement de tumeurs malignes

Country Status (2)

Country Link
AU (1) AU4381197A (fr)
WO (1) WO1998011903A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2454221A (en) * 2007-11-01 2009-05-06 Mohamed Abdelhafez El-Far Chemically modified chitosan as an anticancer agent
US8119780B2 (en) 2006-06-02 2012-02-21 Synedgen, Inc. Chitosan-derivative compounds and methods of controlling microbial populations

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0544000A1 (fr) * 1990-08-17 1993-06-02 Drug Delivery System Institute, Ltd. Derive de n-acetylcarboxymethylchitosan et procede de production
JPH05271094A (ja) * 1992-03-26 1993-10-19 Fuji Photo Film Co Ltd カルボキシメチル化キチン誘導体を用いる癌転移抑制剤
JPH072679A (ja) * 1993-05-18 1995-01-06 Tamatsukuri Kk 腫瘍免疫治療剤
WO1996026965A1 (fr) * 1995-03-02 1996-09-06 Akzo Nobel N.V. Preparation a haut rendement d'oligomeres de chitine, des dimeres aux decameres

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0544000A1 (fr) * 1990-08-17 1993-06-02 Drug Delivery System Institute, Ltd. Derive de n-acetylcarboxymethylchitosan et procede de production
JPH05271094A (ja) * 1992-03-26 1993-10-19 Fuji Photo Film Co Ltd カルボキシメチル化キチン誘導体を用いる癌転移抑制剤
JPH072679A (ja) * 1993-05-18 1995-01-06 Tamatsukuri Kk 腫瘍免疫治療剤
WO1996026965A1 (fr) * 1995-03-02 1996-09-06 Akzo Nobel N.V. Preparation a haut rendement d'oligomeres de chitine, des dimeres aux decameres

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
DATABASE WPI Section Ch Week 9346, Derwent World Patents Index; Class B04, AN 93-365160, XP002027600 *
DATABASE WPI Section Ch Week 9511, Derwent World Patents Index; Class A96, AN 95-077961, XP002027601 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8119780B2 (en) 2006-06-02 2012-02-21 Synedgen, Inc. Chitosan-derivative compounds and methods of controlling microbial populations
US8658775B2 (en) 2006-06-02 2014-02-25 Shenda Baker Chitosan-derivative compounds and methods of controlling microbial populations
US9029351B2 (en) 2006-06-02 2015-05-12 Synedgen, Inc. Chitosan-derivative compounds and methods of controlling microbial populations
US9732164B2 (en) 2006-06-02 2017-08-15 Synedgen, Inc. Chitosan-derivative compounds and methods of controlling microbial populations
US10494451B2 (en) 2006-06-02 2019-12-03 Synedgen, Inc. Chitosan-derivative compounds and methods of controlling microbial populations
GB2454221A (en) * 2007-11-01 2009-05-06 Mohamed Abdelhafez El-Far Chemically modified chitosan as an anticancer agent

Also Published As

Publication number Publication date
AU4381197A (en) 1998-04-14

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