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WO1980000791A1 - Produits pharmaceutiques presentant une activite (beta)-glucuronidase et/ou a dependance du ph et leurs methodes de preparation et leur utilisation dans le traitement selectifs des maladies - Google Patents

Produits pharmaceutiques presentant une activite (beta)-glucuronidase et/ou a dependance du ph et leurs methodes de preparation et leur utilisation dans le traitement selectifs des maladies Download PDF

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Publication number
WO1980000791A1
WO1980000791A1 PCT/US1979/000809 US7900809W WO8000791A1 WO 1980000791 A1 WO1980000791 A1 WO 1980000791A1 US 7900809 W US7900809 W US 7900809W WO 8000791 A1 WO8000791 A1 WO 8000791A1
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Prior art keywords
glucuronic acid
glucuronide
accordance
aglycone
compound
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PCT/US1979/000809
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English (en)
Inventor
D Rubin
Original Assignee
Schwimmer A
Schwartz I
D Rubin
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Priority claimed from US05/951,269 external-priority patent/US4584368A/en
Priority claimed from US05/951,270 external-priority patent/US4424348A/en
Priority claimed from US06/011,619 external-priority patent/US4327074A/en
Application filed by Schwimmer A, Schwartz I, D Rubin filed Critical Schwimmer A
Priority to DE792953223T priority Critical patent/DE2953223T1/de
Publication of WO1980000791A1 publication Critical patent/WO1980000791A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/0491—Sugars, nucleosides, nucleotides, oligonucleotides, nucleic acids, e.g. DNA, RNA, nucleic acid aptamers
    • 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
    • A61K31/7004—Monosaccharides having only carbon, hydrogen and oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/549—Sugars, nucleosides, nucleotides or nucleic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/18—Acyclic radicals, substituted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/20—Carbocyclic rings
    • C07H15/203—Monocyclic carbocyclic rings other than cyclohexane rings; Bicyclic carbocyclic ring systems
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/34—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving hydrolase
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5091—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing the pathological state of an organism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2123/00—Preparations for testing in vivo
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2334/00—O-linked chromogens for determinations of hydrolase enzymes, e.g. glycosidases, phosphatases, esterases
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/90—Enzymes; Proenzymes
    • G01N2333/914—Hydrolases (3)
    • G01N2333/924—Hydrolases (3) acting on glycosyl compounds (3.2)
    • 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

  • the present invention relates to the treatment of tumors exhibiting ⁇ -glucuronidase activity by means of glucuronides having toxic aglycones and, more particularly, to an improvement of such processes which eliminates damage to the kidneys.
  • the toxic aglycones may incorporate a nitrile group.
  • the invention further relates to the treatment of certain bacterial infections having ⁇ -glucuronidase activity.
  • the present invention further relates to a new class of glucuronides whose aglycone's activity or water solubility is pH dependent as well as the method of preparation of such glucuronides.
  • the present invention still further relates to a novel nitrile-containing glucuronide.
  • the present invention also relates to a diagnostic urinalysis test by which the presence of tumors having ⁇ -glucuronidase activity can be determined.
  • the Von Ardenne reference suggests broadly many types of aglycones which may be conjugated to glucuronic acid and will be active at the tumor site. These include, broadly, alkylating groups, antimetabolites, cytotoxins, membrane-active (lytic) groups, glycolysis stimulators, respiration inhibitors, inorganic and organic acids and cell cycle stoppers.
  • alkylating groups include, broadly, alkylating groups, antimetabolites, cytotoxins, membrane-active (lytic) groups, glycolysis stimulators, respiration inhibitors, inorganic and organic acids and cell cycle stoppers.
  • the East German patent also suggests many such combinations including 5-fluorouracil-glucuronide, methotrexate-glucuronide, 6-mercaptopurene-glucuronide, aniline mustard-glucuronide and many others.
  • the Offenle-gungsschrift also mentions a large number of glucuronides.
  • the Sweeney article relates to the anti-tumor activity of mycophenolic acid- ⁇ -D-glucuronides
  • Baba relates to the anti-tumor activity of 5-fluorouracil-O- ⁇ -D-glucuronide
  • Ball relates to the anti-tumor activity of p-hydroxy-aniline mustard glucuronide.
  • the Von Ardenne reference speaks of a method that yields a pH difference of at least 1 pH unit and may therefore by used as a basis for selectivity. It refers to reaching steady state conditions after hyperacidification in which the brain pH is 7.0 and the tumor tissue pH is approximately 5.5 to 6.0. Note also Von Ardenne, M. et al, Pharmazie, 32 (2): 74-75, 1977.
  • the Fenselau reference teaches a method for the biosynthesis of mandelonitrile ⁇ -D-glucuronic acid. While this method may be satisfactory for producing laboratory amounts of the compound, such a biosynthetic process would no doubt be very difficult and costly to commercialize.
  • the toxic aglycones will only be released at the tumor site itself due to deconjugation of the glucuronides by the action of ⁇ -glucuronidase. Without the alkalinization step, substantial amounts of toxic materials may be released, for example, in the kidneys, and the toxic aglycones so released may cause substantial damage to these organs. Thus, only through the use of the present invention can glucuronides of compounds toxic to tumor cells be used clinically with a great degree of safety. The greater the toxicity of the aglycones, the more important is the alkalinization step.
  • a further feature of the present invention is the use of certain novel glucuronide compounds which are parti cularly suitable for use in the present invention because of the significant pH differential between the tumor cells and surrounding healthy tissue. If the aglycone is more active at lower pH, or non-polar in acid condition and becoming polar only in alkaline condition, i.e., the aglycone is water-soluble at pH ranges above about 7 and lipid-soluble at pH ranges below 7, then the selectivity of the present invention is further increased. Using these new compounds, even if there is deconjugation elsewhere in the body, the aglycone will be water-soluble due to the alkaline pH and be washed out of the system quickly.
  • the aglycone will actually become attached to the tumor cells and will not become solubilized and washed away. Even if some amount of aglycone becomes removed from the locus of the tumor cells, they will immediately come into an alkaline environment and thus become water soluble and be quickly swept from the body.
  • novel glucuronides in this category are 2,4-dinitrophenol- ⁇ -D-glucuronic acid; 4-chloro-m-cresol- ⁇ -D-glucuronic acid; 4,6-dinitro-o-cresol- ⁇ -D-glucuronic acid; 4-chloro-3, 5-xylanol- ⁇ -D-glucuronic acid; chlorothymol- ⁇ -D-glucuronic acid; 2-phfenyl-6-chlorophenol- ⁇ -D-glucuronic acid; 5-chloro-7-iodo-8-quinolinol- ⁇ -D-glucuronic acid; and podophyllotoxin- ⁇ -D-glucuronic acid.
  • the chloro-m-cresol- ⁇ -D-glucuronic acid is of particular interest as it actually loses its toxic activity in an alkaline environment.
  • these novel compounds, and any other glucuronide compounds having cytotoxic aglycones also have an anti-bacterial activity, particularly against those types of bacteria having glucuronidase activity. It is known, for example, that streptococcus, staphylococcus and E. coli bacteria have ⁇ -glucuronidase activity. Therefore, if the glucuronides come into contact with these bacteria, they will become deconjugated and the cytotoxic aglycones will be toxic to the bacteria.
  • glucuronide compounds discussed hereinabove are preferred for use in the process of the present invention, it should be understood that the glucuronides of any anti-tumor drug, including those previously suggest in the prior art as being useful, may be used to greater advantage in the process of the present invention since the selectivity thereof will be increased by the alkalinization step.
  • Non-limiting examples of compounds, some of which may have been known, which may also be used in the present invention, even though they have no presently known differentiation of toxicity or solubility which is pH dependent, include 5-fluorouracil-O- ⁇ -D-glucuronic acid; p-hydroxy-aniline mustard- ⁇ -D-glucuronic acid; methotrexate- ⁇ -D-glucuronic acid; floxuridine- ⁇ -D-glucuronic acid; cytarabine- ⁇ -D-glucuronic acid; meIphalan- ⁇ -D-glucuronic acid; hydroxyurea- ⁇ -D-glucuronic acid; adriamycin- ⁇ -D-glucuronic acid; thiouracil- ⁇ -D-glucuronic acid; chlorophenol- ⁇ -D-glucuronic acid; methacrylonitrile- ⁇ -D-glucuronic acid; fluoroacetic acid- ⁇ -D-flucuronic acid; etc.
  • the anti-tumor toxicity of many conventional anti-cancer drugs requires that they penetrate to the nucleus or the mitochondria within the cell.
  • the drugs had to be designed to attack only cancer cells and not all of the other cells of the body with which they come into contact. This is why particular efforts have been made in the past to develop anti-neoplastic drugs which interfere with cell division. Many of these drugs must actually enter the nucleus of the cancer cell to be effective. For such drugs, therefore, one must always be concerned that they be transported without change through the membrane of the cancer cell before they can exert their toxic effects.
  • a particularly useful aglycone is one which exerts its cell toxicity by attacking the cell membrane itself. In this way one need not be concerned with the transfer mechanism of the drug through the membrane. Furthermore, by attacking the membrane the nature of the membrane is changed and the antigenic properties of the cells are changed. Therefore the immunilogical system of the host will aid the toxic agent in ridding the host of these cells. Accordingly a much lower dose need be used.
  • aglycones which exert this effect include phenol and cresol. Therefore particularly useful glucuronides for use in the process of the present invention include phenol- ⁇ -D-glucuronic acid and cresol- ⁇ -D-glucuronic acid.
  • Other steps for increasing ⁇ -glucuronidase activity at the tumor cells may also be undertaken.
  • One method of doing this is to elevate the temperature of the toxic cells at the time of treatment. This may be done by elevating the temperature of the entire body such as by use of a pyrogenic drug or by elevating the temperature soley in the area of the toxic cells, such as by microwave radiation or electrical current. Raising of the temperature increases ⁇ -glucuron idase activity thereby increasing the efficiency of the deconjugation of the glucuronides.
  • Local hypothermia in the region of suspected tumor cells is preferred to general hyperthermia because general hyperthermia will also increase the ⁇ -glucuronidase activity in healthy cells. However, because of the alkalinization step this is not a major problem. If the hyperthermia is local, then this provides an additional degree of certainty that the glucuronides will only become deconjugated at the tumor site.
  • the application of microwave treatment directed at the suspected tumor site is one way to achieve local hyperthermia. Due to the different electrical resistence of tumor cells, another method of achieving some degree of local hyperthermia is by administering a low electrical current through the body.
  • the methyl ester of the aglycone of the glucuronide may be converted to the barium salt, and the barium salt may be converted to the free acid by the use of sulfuric acid without deconjugation of the glucuronide.
  • removal of the acetyl protecting groups is accomplished in the same step, thus eliminating the need of a separate step to accomplish this function.
  • This novel step using barium hydroxide may also be used in the chemical synthesis of mandelonitrile ⁇ -D-glucuronic acid.
  • this process will fail when attempting to synthesize mandelonitrile ⁇ -D-glucuronic acid because when attempting to condense the methyl (tri-O-acetyl ⁇ -D-glucopyranosyl) halide-uronate with mandelonitrile, the mandelonitrile will tend to polymerize rather than to create the hemi-acetal bond with the glucuronic acid.
  • the method of synthesis of mandelonitrile ⁇ -D-glucuronic acid in accordance with the present invention comprises first converting mandelic acid to mandelic amide by reaction with gaseous ammonia.
  • the mandelic amide is then reacted with the methyl (tri-O-acetyl ⁇ -D-glucopyranosyl) bromideuronate to produce the methyl ester of the mandelic amide triacetyl glucuronic acid.
  • This compound may then be mixed with acetic anhydride to convert the mandelic amide to mandelonitrile. Treatment with barium hydroxide and sulfuric acid will produce the mandelonitrile ⁇ -D-glucuronic acid.
  • Another feature of the present invention resides in an additional safety feature by which the healthy tissues of the body are protected against possible release of hydrogen cyanide from nitrile-containing aglycones.
  • This feature is preferably in addition to the feature disclosed hereinabove with respect to pH adjustment. Even with such protection against deconjugation of the glucuronide at areas of the body other than tumors, concern has been expressed about possible cyanide poisoning when using nitrile containing glucuronides. For example, in Schmidt, E.S., et .al. J.A.M.A.
  • sodium thiosulfate is an antidote for cyanide poisoning.
  • Sodium thiosulfate in the presence of the enzyme rhodanase converts hydrogen cyanide to sodium thiocyanate.
  • glucuronide compounds In view of the relative lack of toxicity of glucuronide compounds, and in view of the mechanism of the present invention by which the toxic aglycone is released only at the tumor site, and further in view of the protection of the present invention against possible hydrogen cyanide release at other parts of the body, it is entirely possible to use glucuronides of other toxic nitrile-containing aglycones in the process of the present invention.
  • One such compound is methacrylonitrile ⁇ -D-glucuronic acid.
  • Another feature of the present invention is related to the extremely high tumor selectivity which is achievable in accordance with the present invention.
  • a radioactive isotope if one or more of the atoms of the aglycone is exchanged with a radioactive isotope, a local radioactivity can be exerted.
  • This method is not only important for diagnostic purposes to trace the tumor and its metastases, but if an isotope is chosen with ⁇ -radiation activity, then this method may also be used for local radiation treatment at the cancer site.
  • This use of radioactive isotopes is particularly important when using an aglycone which is known to be non-polar in acid condition and polar in alkaline condition.
  • the aglycone is accumulated at the cancer site not only because of the ⁇ -glucuronidase activity, but also because of its insolubility in water at the cancer site.
  • the compounds with the radioactive isotopes are washed away from the rest of the body.
  • the use of p-iodophenol ⁇ -D-glucuronic acid produces an aglycone, p-iodophenol, which fulfils these demands.
  • a radioactive isotope of iodine can be used as the iodine constituent of this compound. It is preferable to use 131 I for labelling and 133 I for treatment, as the former is richer in gamma radiation while the latter is richer in beta radiation. In order to prevent the iodine from migrating to the thyroid gland, premedication with non-radioactive Lugol's solution may be used for saturating the thyroid gland.
  • Another compound which can be easily radioactive labelled is the glucuronide of phenylsulfazole.
  • a radioactive sulfur atom can be used. This compound does not migrate to the thyroid gland, and the aglycone is not soluble in water.
  • the particular type of tumor involved has high ⁇ -glucuronidase activity. This may be done in a number of ways. One way is to assay tumor cells obtained in a biopsy for ⁇ -glucuronidase activity. If such a test is positive, then the pharmaceutical compositions of the present invention may be administered.
  • a second method is the administration of a glucuronide whose aglycone has been labelled with a radio-active isotope. If upon a full body scan it is found that the radioisotope is accumulated at any specific areas of the body, then this will indicate not only the location of the tumor but the fact that the tumor has sufficient ⁇ -glucuronidase activity to deconjugate. the glucuronide. After this has been determined, the appropriate amount of the glucuronide of choice may be administered.
  • Another method of diagnosing tumors which are treatable by means of the present invention is to test for the presence of free glucuronic acid in the urine. While the presence of glucuronides in the urine is common, the presence of free glucuronic acid in the urine, and particularly the presence of increasing amounts of glucuronic acid when tested over a period of several days, is a potent indication of the presence of tumors with ⁇ -glucuronidase activity.
  • glucuronic acid is a reaction product of such activity because the intercellular filaments and connective tissue are composed of polymers of which glucuronic acid is an element and which are known substrates for the enzyme ⁇ -glucuronidase.
  • a method of distinguishing free glucuronic acid from conjugated glucuronides in the urine is another feature of the present invention.
  • Both glucuronides and glucuronic acid give a chromogenic complex with tetraborate in concentrated sulfuric acid which reacts with m-hydroxydiphenyl to create a colored water-soluble complex.
  • lead acetate is added at an alkaline pH, the glucuronides precipitate and the addition of ditizone (dithiosemicarbizone makes a stable complex with the excess lead. Accordingly, an optical reading may be taken representative of the amounts of total glucuronides and free glucuronic acid after tetraborate and m-hydroxydiphenyl have been added.
  • a second reading may then be taken after the conjugated glucuronides and excess lead have been removed from the aqueous phase by the addition of basic lead acetate and after ditizone has been added.
  • the conjugated glucuronides can be removed by reaction with barium hydroxide. The addition of barium hydroxide to the urine sample will cause precipitation of the conjugated glucuron ides but not of the free glucuronic acid. After centrifugation and filtration the conjugated glucuronides are eliminated and what remains is only the free glucuronic acid. A reading representative of the amount of free glucuronic acid may then be taken. This alternative procedure bypasses the necessity of the use of ditizone. Best Mode for Carrying Out the Invention
  • glucuronide compounds having aglycones which are toxic to cancer cells have been described theoretically in the literature, very few have actually been produced. This is because they are very difficult to synthesize, particularly when the aglycone is a strong electron acceptor.
  • the improved method of the present invention avoids the problem and permits the production of conjugates of glucuronic acid of almost any type of aglycone.
  • the standard methods can be used to form the methyl ester of the triacetyl glucuronic acid conjugates but it is often quite difficult to go from the triacetyl methyl ester to the glucuronic acid conjugate. This problem has been solved by treatment in accordance with the process of the present invention.
  • glucuronides in accordance with the present invention and for use in the process of the present invention may be synthesized from methyl (tri-O-acetyl- ⁇ -D-gluco-pyranosyl bromide) uronate which is the active glucuronic acid and is formed in accordance with the teachings of Bollenback, G.N., et al, J. Am. Chem. Soc. 77,3310, (1955).
  • This compound is condensed with the aglycone in a solution of quinoline, phenol, methyl cyanide or methyl nitrite catalyzed by silver oxide or silver carbonate.
  • Another method of condensation is to use sodium or potassium hydroxide as the condensing agent in aqueous acetone solution.
  • the reaction scheme is illustrated as follows:
  • ROH is the desired aglycone
  • the protecting acetic acid groups may be removed by anhydrous sodium methoxide or anhydrous barium methoxide in accordance with the following reaction:
  • the acid may be produced by reacting the triacetyl methyl ester with barium hydroxide to produce the barium salt in accordance with the following reaction:
  • Example I shows the preparation of 2,4-dinitro phenol- ⁇ -D-glucuronic acid.
  • the free acid form of the compound was formed by treating the 2, 4-dinitrophenyl-methyl(tri-O-acetyl- ⁇ -D-glucopyranosyl bromide)-uronate with a one-half molar amount of barium hydroxide to produce the barium salt.
  • This hirium salt of the glucuronide precipitates as a white amorphous material.
  • An equimolar solution of H 2 SO 4 releases the free glucuronide. Distillation of the supernatant yielded bright yellow-brown crystals having a melting point of 179-180°C.
  • This compound was incubated with ⁇ -glucruronidase and produced 2, 4-dinitrophenol, thus confirming that the final product is indeed 2, 4-dinitrophenol- ⁇ -D-glucuronic acid.
  • the other glucuronides in accordance with the present invention e.g. chloro-m-cresol- ⁇ -D-glucuronic acid; 4, 6-dinitro-o-cresol- ⁇ -D-glucuronic acid; 4-chloro- 3, 5, -xylanol- ⁇ -D-glucuronic acid; chlorothymol-B-D-glucuro nic acid; 2-phenyl-6-chlorophenol- ⁇ -D-glucuronic acid; 5- chloro-7-iodo-8-quinolinol- ⁇ -D-glucuronic acid; and podo- phyllotoxin- ⁇ -D-glucuronic acid, as well as p-iodophenol- ⁇ - D-glucuronic acid and phenylsulfazole- ⁇ -D-glucuronic acid, may be made in a similar manner by reacting a stoichiometric excess of the aglycone with the methyl-(tri-O-acetyl- ⁇ -D-glu copyran
  • the solution is then diluted with 3 volumes chloroform and the chloroform-acetone layer washed with water and dried. After removal of the solvent, the crystals which are obtained are treated with a one half molar amount of barium hydroxide to produce the barium salt which is then treated with an equimolar solution of sulfuric acid to produce the free glucuronide.
  • glucuronide or a salt thereof which will ionize at the conditions of use, is the preferred form of the compounds to be used in accordance with the present invention.
  • pharmaceutically acceptable esters may also be used, although in most cases it would be expected that their activity would be somewhat lower due to their relatively lower affinity to ⁇ -glucuronidase. This is particularly true with respect to aglycones which are strong electron acceptors. Accordingly, whenever the term "glucuronide compound" is used in the present specification and claims it is understood to include not only the free glucuronic acid form of the conjugate but also pharmaceutically acceptable salts and esters thereof as discussed hereinabove, both in this and subsequent examples.
  • Mandelonitrile ⁇ -D-glucuronic acid may be synthesized, in accordance with the present invention, from methyl (tri-O-acetyl- ⁇ -D-glucopyranosyl bromide)-uronate, which is the active form of glucuronic acid, and may be produced in accordance with the teachings of Bollenback, G.N., et al, J. Am. Chem. Soc. 77, 3310, (1955). Since this compound cannot be directly conjugated with mandelonitrile, mandelic amide is first formed. This compound is formed by bubbling gaseous NH 3 into mandelic acid at 0°C as illustrated in reaction:
  • the mandelic amide is introduced to the methyl (tri- O-acetyl ⁇ -D-glucopyranosyl) bromide uronate in a solution of phenol catalyzed by a small catalytic amount of silver oxide.
  • phenol there may be used, as solvent, quinoline, methyl nitrile or methyl cyanide.
  • Silver car bonate may also be used as the catalyst.
  • Another method of condensation is to use sodium or potassium hydroxide as the condensing agent in aqueous acetone solution. A stoichiometric excess of mandelic amide is preferably used.
  • the reaction solution is maintained at room temperature for 24 hours or until the reaction is complete. The reaction is illustrated as follows:
  • the acid is produced by reaction of the triacetyl methyl ester obtained by reaction (III) with a 1/2 molar amount of 0.5 N barium hydroxide which is added slowly to this solution to form a white precipitate. Preferably an excess of barium hydroxide is added until there is no more precipitation.
  • the reaction can be illustrated as follows:
  • the mixture is then filtered and the supernatant is dried in vacuum and crystallized from ether.
  • Example III Synthesis of Methacrylonitrile ⁇ -D-Glucuronic Acid Methacrylonitrile ⁇ -D-glucuronic acid or other glucuronides of nitrile-containing cytotoxic compounds may be produced in accordance with the present invention in a manner similar to that disclosed in Example II though the step of converting the methacrylonitrile to methacrylamide prior to condensation with methyl (tri-0- acetyl- ⁇ -D-glucopyranosyl bromide)-uronate will not be necessary as there is not the same polymerization problem with methacrylonitrile as there is with mandelonitrile.
  • the preferred process when condensing the aglycone directly is to reach the stoichiometric excess of the aglycone (methacrylonitrile in the case of methacrylonitrile ⁇ -D-glucuronic acid) with the methyl (tri- 0-acetyl- ⁇ .-D-glucopyranosyl bromide)-uronate in 5 N potassium hydroxide and maintaining the reaction solution at room temperature for 24 hours. The solution is then diluted with 3 volumes chloroform and the chloroform-acetone layer washed with water and dried. After removal of the solven the crystals which are obtained are treated with a one half molar amount of barium hydroxide to produce the barium salt which is then treated with an equimolar solution of sulfuric acid to produce the free glucuronide.
  • NZW rabbits in the weight range of 2,000 to 3,200 g for females and 2,200 to 3,800 g for males were injected intravenously with mandelonitrile ⁇ -D-glucuronic acid solution.
  • Rabbits injected with saline alone served as the control.
  • the mandelonitrile ⁇ -D-glucuronic acid solution contained 10% mandelonitrile.
  • Table I gives the range finding screen.
  • LD 50 The acute median lethal intravenous dose (LD 50) and its 95% confidence limints calculated by the method of Weil, C. S., 1952, Biometrics, 8:249, to rabbits of mandelo-nitrile ⁇ -D-glucuronic acid 10% solution are calculated to be:
  • the maximum safe dose is on the order of 0.44 ml/kg body weight, and it is believed that this limit should not be exceeded in human therapy.
  • the presence of tumor having high ⁇ -glucuronidase activity Prior to therapeutic treatment with compounds of the present invention, the presence of tumor having high ⁇ -glucuronidase activity must be diagnosed. The most positive way to definitively ascertain whether a tumor is present having high ⁇ -glucuronidase activity is to conduct a biopsy and to assay the tumor cells obtained for ⁇ -glucuronidase activity. This, of course, is not feasible for most kinds of tumor. Another way to diagnose for the presence of tumors having ⁇ -glucuronidase activity, is to conduct a urine test in order to determine the presence of free glucuronic acid.
  • Example V Test for Glucuronic Acid in Urine
  • glucuronides and glucuronic acid give a chromogenic complex with tetraborate and concentrated sulfuric acid which reacts with m-hydroxydiphenyl to create a colored water-soluble complex. Furthermore, glucuronides precipi tate with basic lead acetate when pH is 8, while the free glucuronic acid is not affected by the lead acetate. Complexing the excess lead with dithiocarbizone forms a stable complex with lead which can be removed, thus leaving free glucuronic acid.
  • test tube is then heated for 5 minutes in boiling water and immediately cooled in ice until it becomes cold. Twenty microliters of 0.15% m-hydroxydiphenyl in 0.5% NaOH is then added. After waiting 5 minutes, the optical density is read at a wave-length of 5200 ⁇ . The reading obtained represents the amount of free glucuronic acid present in the urine.
  • the total amount of free and conjugated glucuronic acid is simply determined by directly treating the sample with tetraborate and hydroxydiphenyl, without first removing the free glucuronides. Reading at a wavelength of 5200 ⁇ will give the indication of the total amount of conjugated glucuronides and free glucuronic acid which is present.
  • the optical density is read at a wavelength of 5200 ⁇ .
  • the reading obtained represents the amount of free glucuronic acid present in the urine.
  • the relative amount of the total of conjugated glucuronides and free glucuronic acid which is present may be read in the same manner as set forth hereinabove in Example V.
  • the first step of the treatment is to give him a dose of glucose as, for example, 100 g of honey, glucose or other sugar. Approximately 1 hour later, an intravenous drip is begun of a solution in distilled water containing approximately 10% glucose and 60 milli-equivalents sodium bicarbonate. Approximately 1 liter is administered, assuming no contraindications, and the pH of the urine is checked to determine that it has reached a pH of approximately 7.4. This will establish that the system has become alkalinized and it is now safe to administer the glucuronide. Another liter of the same glucose-bicarbonate solution, but also including the desired amount of glucuronide, is then administered.
  • a glucuronide of a nitrile-containing cytotoxic aglycone is being used, immediately before, during or after administration of the glucuronide, 50 cc of a 25%. solution of sodium thiosulfate is administered, preferably intravenously by slow drip.
  • the sodium thiosulfate is, preferably included in the glucose-bicarbonate-glucuronide solution which is being dripped intravenously. However, it may also be continued afterward for a greater margin of safety. If there are contraindications for the administration of bicarbonate, then antacid may be orally administered
  • the important criterion is that the pH of the urine become approximately 7.4 and remain so during treatment.
  • the hyperacidification of the tumor cells is caused by a hyperglycemic condition in the patient. Therefore any hyperglycemic agent may be used as the hyperacidification agent, as for example, fructose, galactose, lactose or glucagon. Furthermore, it should be understood that this hyperglycemic condition may be effected in any known manner. For example, if the patient is diabetic then the condition can be brought about by decreasing the insulin administration.
  • any agent which will raise the pH of the urine to approximately 7.4 can be used as the alkalinizing agent, including sodium or potassium bicarbonate or citrate, or other basic salts or antacids. While it is preferred that these be administered intravenously, they may be administered orally.
  • approximately 7.4 is used in the present specification and claims, with respect to the pH level to be maintained in the rest of the body, it should be understood that a pH level slightly above or below 7.4 may be used, although not preferred. As the pH decreases from 7.4 the ⁇ -glucuronidase activity increases (until the optimal pH is reached). Furthermore, below ph 7.0 the rest of the body will not be alkaline but will be acid.
  • a pH level of 7.4 is preferred as this is physiological pH and cannot be harmful to the body, and it is known that the ⁇ -glucuronidase activity in healthy organs is substantially nil at this pH level.
  • the dosage of the glucuronides should be monitored to avoid any side effects due to the massive release of toxins caused by the dying cancer cells. It may be preferable to to treat with glucuronides in short courses of several days, leaving several days in between, to allow any toxins released by the dying cancer cells to leave the body before the further treatment continues.
  • the glucuronides may be administered by any means of parenteral administration. However, the glucuronides should not be administered orally as it is known that ⁇ -glucuronidase is present in the digestive tract. The sodium thiosulfate, however, can be administered orally if a proper enteric coating is provided to avoid release in the stomach.
  • glucuronide to be administered to any given patient must be determined empirically and will differ depending on the condition of the patient. Relatively small amounts of glucuronide can be administered at first with steadily increasing daily dosages if no adverse effects are noted. Of course, the maximum safe toxicity dosage as determined in routine animal toxicity tests should never be exceeded. It is clear that any tumor cells having ⁇ -glucuronidase activity may be treatable in accordance with the present invention with the remaining organs of the body being protected by the alkalinization step. Tumors which are known to have ⁇ -glucuronidase activity include solid breast tumors and their metastases, bronchogenic carcinoma and its metastases and lymphomas.
  • neoplasms that do not have high ⁇ -glucuronidase activity include leukemia. It must be understood, however, that this list is not meant to be complete, and that the prior art is aware of many other tumors that have ⁇ -glucuronidase activity. However, whether or not the art is presently aware that any given tumor has ⁇ -glucuronidase activity, this can be determined by any of the various methods of diagnosis discussed in the present speci- and if it is determined that the tumor does have ⁇ -glucuronidase activity, the therapeutic treatment of the present invention can be effectively used.
  • a method should be selected by which the temperature is raised as much as possible without risking, damage to healthy portions of the body, such as the eyes.
  • An increase of about 2°C for whole body hyperthermia and as much as 4.5°C for local hyperthermia is preferred.
  • the hyperthermia should be timed to last about an hour at the time of greatest glucuramide concentration at the tumor site. For example, when local microwave treatment is selected, it should begin about one half hour after commencement of the intravenous glucuronimide drip and be continued for about an hour.
  • the proper dosage of known pyrogens to achieve the desired degree of hyperthermia would be known to those skilled in the art or could be easily empirically determined. A dosage of about 30 mg/day for dinitraphenol, for example, would be apt.
  • an aglycone labelled with a radioactive isotope is to be administered, the labelling may be accomplished by any method known per se. For diagnostic purposes only, relatively small amounts of these labelled glucuronides may be administered. They are otherwise administered in the same manner as set forth in Example VI for non-labelled glucuronides. Scanning of the body to determine whether any of the radio-labelled aglycone is retained by the body will indicate whether a tumor is present having ⁇ -gluduroni-dase activity and will also indicate where the tumor or any metastases thereof may be found. As noted above, gamma ray emitting isotopes, such as. 131 I, are particularly suitable for this purpose.
  • the radio-labelled glucuronides may also be used for in situ radiation therapy, particularly if an isotope is used having high beta-radiation activity, such as 1331. This will give the dual effect of attacking the cancer cells not only with the toxic aglycones but also with the beta-radiation. Again, the method of administration will be the same as set forth in Example VI.
  • Another utility for the present invention is the use of the boron-containing aglycone. It is already known that if boron atoms are bombarded with neutrons, they will break into lithium with the consequent release of positrons. If the boron atoms are attached to tumor tissue at the time, the positrons will be abruptly absorb by the tumor tissue which will be lethal thereto. This process will have outstanding utility when the boron atoms are concentrated exclusively at the tumor cells in accordance with the process of the present invention.
  • an acid-alkaline pH differential will be created between the tumor cells and healthy cells.
  • compounds whose activity or solubility is pH-dependent may be administered directly, without first conjugating a glucuronide. Such compounds will selectively attack the acidified tumor cells without harming the remainder of the body which has an alkaline pH.
  • the patient is first given an oral dose of hyperglycaemic agent, such as 100 g of honey, glucose or other sugar. Approximately 1 hour later, an intravenous drip is begun of a solution in distilled water containing approximately 10% glucose and 60 milliequivalents sodium bicarbonate. Approximately 1 liter is administered, assuming no contraindications, and the pH of the urine is checked to determine that it has reached a pH of approximately 7.4. This will establish that the system has become alkalinized and it is now safe to administer the acid-active compound. Another liter of the same glucose-bicarbonate solution, but also including the desired amount of acid-active compound, is then administered. This is repeated daily as needed.
  • hyperglycaemic agent such as 100 g of honey, glucose or other sugar.
  • Glucuronide administration may be used in the treatment of bacterial infections if the bacteria involved are known to have ⁇ -glucuronidase activity. Examples of such bacteria are streptococci, staphylococci, and E. coli. The method of treatment of such bacterial infections will be similar to the method set forth in Example VI except that no hyperacidification will be necessary. This is so because bacterial ⁇ -glucuronidase is active at higher pH levels than ⁇ -glucuronidase of normal healthy internal organs. Furthermore, such a hyperacidification step would not affect the pH of the bacteria as its mechanism is specific to tumor cells.
  • the first step in antibacterial administration is an intravenous drip of distilled water and 60 milliequivalents sodium bicarbonate. Approximately one liter is administered and the pH of the urine is checked to determine that it has reached a pH of approximately 7.4. Another liter of the same bicarbonate solution, but also including the desired amount of glucuronide, is then administered in the same manner. This treatment may be repeated daily if necessary.
  • the alkalinizing agent may also be orally administered and any agent may be used that will alkalinize the body to an extent such that the pH of the urine becomes approximately 7.4.
  • the glucuronide should not be administered orally but it may be administered by any means pf parenteral administration.
  • Certain known anti-bacterial drugs having adverse side-effects may also be administered as glucuronides in accordance with the method of the present invention in order to reduce or eliminate these adverse effects.
  • chloroamphenicol is known to have a bone marrow depression effect which will not take place if the glucuronide is used.
  • Neomycin is a known antibacterial which cannot be administered internally because of its toxicity. However, it can be orally administered for the treatment of infections of bacteria having high ⁇ -glucuronidase activity if first conjugated to glucuronic acid.
  • the radioisotope-labelled aglycone diagnostic procedure discussed hereinabove with respect to tumor diagnosis may also be used to determine the existance and location of bacterial infections.
  • a patient complaining of pain in the area of the appendix can receive the radio-labelled glucuronides. If no accumulation of isotope is found in the area then inflammation caused by bacteria with ⁇ -glucuronidase activity as a cause of the pain can be ruled out. In most instances inflammation in appendicitis is due to infection by bacteria with ⁇ -glucuronidase activity. Other use of such a diagnostic procedure would be obvious to those skilled in this art.
  • any known conjugatable antibiotic may be conjugated with glucuronic acid for use against ⁇ -glucuronidase containing infections.
  • This has the advantage of greatly diminishing the amount of free antibiotic circulating in the blood stream. The only antibiotic which is released will be released at the site of the infection. Therefore much smaller dosages may be given.
  • the glucuronides of the present invention can serve as an internally administered local antibiotic. Because of the known ⁇ -glucur ⁇ riidase activity in the digestion tract, no glucuronide should be administered orally, although any mode of parenteral administration is permissible. If the antibiotic aglycone is known not to have any effect on the kidneys, then the alkalinization step can be eliminated.
  • Example X Biosynthesis of Mandelonitrile ⁇ -D-Glucuronic Acid
  • a 22 cc solution of 5% mandelonitrile (benzaldehyde cyanohydrin) in propylene-glycol is prepared and an intra- muscular injection of this solution is given to a donkey or a goat.
  • the 24 hr. urine is collected and acidified with acetic acid until the pH becomes 4.
  • the urine is then filtered through a fiberglass filter and the filtrate is treated in any one of the following three different ways :
  • a saturated solution of lead acetate is added to the filtrate.
  • the white precipitate that appears is separated by centrifuge and filtered.
  • the filtrate is alkalined with NH 3 to pH 8 and then a saturated solution of basic lead acetate is added.
  • the precipitate is washed with colder water and gaseous H 2 S is bubbled into it, the black precipitate of lead sulfide being separated.-
  • the filtrate is put into a vacuum until the volume is reduced to one third.
  • a brown paste is achieved which is dissolved in absolute alcohol and kep overnight.
  • the solution is filtered and the filtrate is vacuumized and ether added.
  • the mandelonitrile ⁇ -D-glucuronic acid is crystallized from the ether solution.
  • the urine is acidified with hydrochloric acid to pH 4 and filtered through a fiberglass filter. Afterwards, the solution is dried in a vacuum state and the residue is dissolved in ether and recrystallized from the ether solution.
  • mandelic amide (2-hydroxybenzamide) 20 g is mixed with goat or donkey food and the urine is collected for 24 hours.
  • the mandelic amide glucuronide is separated by any of the methods described hereinabove.
  • Acetic anhydride is then added and the glucuronide (2,3,4-triacetate glucopyranose mandelonitrile) is precipitated with barium hydroxide.
  • the barium is removed with sulfuric acid and the glucuronide is recovered in vacuum as described hereinabove.

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Abstract

Des tumeurs hyperacidifiees ayant une haute activite (Beta)-glucuronidase peuvent etre traitees par des glucuronides dont l'aglycone est toxique pour les cellules tumorales avec une grande surete envers le reste du corps en administrant en premier lieu un agent d'alcalinisation en une quantite suffisante pour maintenir le niveau du pH des tissus non-tumoraux a environ 7,4 pendant le traitement aux glucuronides. Ceci entraine l'inactivation de l'activite de la (Beta)-glucuronidase dans le reste du corps. Lorsque des aglycones contenant un reste nitrile sont utilisees du thiosulfate de sodium est egalement administre pour eviter l'empoisonnement par le cyanure. Des glucuronides nouveaux sont decrits dont les aglycones exercent un effet toxique plus important dans un environnement acide ou qui ne sont solubles dans l'eau que dans un environnement alcalin. De tels composes ont une utilite particuliere dans le procede ci-dessus. En substituant des radio-isotopes dans l'aglycone, le diagnostic et la therapeutique par irradiation in situ peuvent etre effectues. Des cellules bacteriennes ayant une activite (Beta)-glucuronidase peuvent etre egalement decelees et traitees en accord avec la presente invention. Un test de l'urine est decrit pour determiner la quantite d'acide de glucuronique libre dans l'urine ce qui est une indication de la presence d'une tumeur dans un organisme ayant une forte activite (Beta)-glucuronidase. Des procedes nouveaux pour synthetiser les glucuronides utilises dans la presente invention sont egalement decrits.
PCT/US1979/000809 1978-10-13 1979-10-02 Produits pharmaceutiques presentant une activite (beta)-glucuronidase et/ou a dependance du ph et leurs methodes de preparation et leur utilisation dans le traitement selectifs des maladies WO1980000791A1 (fr)

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US4490523A (en) * 1981-11-10 1984-12-25 Ely J. Rubin Mandelonitrile triacetyl glucuronate and process for preparing same
WO1996030003A1 (fr) * 1995-03-30 1996-10-03 Werner Kreutz Medicaments pour le traitement selectif des tissus affectes par des tumeurs
WO2014138723A2 (fr) * 2013-03-08 2014-09-12 Cognate3 Llc Boisson d'optimisation physique

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AU594855B2 (en) * 1988-01-15 1990-03-15 Baker Norton Pharmaceuticals, Inc. Glucuronic acid derivatives of opioid antagonists

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US3880995A (en) * 1973-05-14 1975-04-29 Lilly Co Eli Treatment of arthritis with mycophenolic acid and derivatives
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USRE29465E (en) * 1972-08-14 1977-11-01 Eli Lilly And Company Psoriasis treatment with mycophenolic acid
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Cited By (5)

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Publication number Priority date Publication date Assignee Title
US4490523A (en) * 1981-11-10 1984-12-25 Ely J. Rubin Mandelonitrile triacetyl glucuronate and process for preparing same
WO1996030003A1 (fr) * 1995-03-30 1996-10-03 Werner Kreutz Medicaments pour le traitement selectif des tissus affectes par des tumeurs
US5985927A (en) * 1995-03-30 1999-11-16 Kreutz; Werner Medicaments for the selective treatment of tumor tissues
WO2014138723A2 (fr) * 2013-03-08 2014-09-12 Cognate3 Llc Boisson d'optimisation physique
WO2014138723A3 (fr) * 2013-03-08 2014-11-06 Cognate3 Llc Boisson d'optimisation physique

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