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WO1987004708A1 - Nouvelles compositions a base de dioxolane et procedes d'utilisation - Google Patents

Nouvelles compositions a base de dioxolane et procedes d'utilisation Download PDF

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Publication number
WO1987004708A1
WO1987004708A1 PCT/US1987/000134 US8700134W WO8704708A1 WO 1987004708 A1 WO1987004708 A1 WO 1987004708A1 US 8700134 W US8700134 W US 8700134W WO 8704708 A1 WO8704708 A1 WO 8704708A1
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WIPO (PCT)
Prior art keywords
compositions
contacting
amount
effective
inhibiting
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/US1987/000134
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English (en)
Inventor
Ashok D. Patil
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Harbor Branch Oceanographic Institute Foundation Inc
Original Assignee
Harbor Branch Oceanographic Institution Inc
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Filing date
Publication date
Application filed by Harbor Branch Oceanographic Institution Inc filed Critical Harbor Branch Oceanographic Institution Inc
Publication of WO1987004708A1 publication Critical patent/WO1987004708A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/02—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 2
    • C07D317/04—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 2 not condensed with other rings

Definitions

  • This invention relates to new dioxolane organic compounds which have useful antibacterial, antifungal and antitumor activity.
  • this invention relates to new dioxolane compositions derived from marine organisms, i.e., marine sponge, of the family Halichondriidae.
  • Tumors are common in a variety of mammals and the prevention, control of the growth and regression of tumors in mammals is important to man.
  • the term tumor refers to abnormal masses of new tissue growth which is discordant with the economy of the tissue of origin or of the host's body as a whole.
  • Tumors inflict mammals and man with a variety of disorders and conditions including various forms of cancer and resultant cancerous cachexia.
  • Cancerous cachexia refers to the symptomatic discomfort that accompanies the infliction of a mammal with a tumor. These symptoms include weakened condition of the inflicted mammal as evidenced by, for example, weight loss.
  • Cancer is second only to heart and vascular diseases as a cause of death in man.
  • Considerable research and resources have been devoted to oncology and antitumor measures including chemotherapy. While certain methods and chemical compositions have been developed which aid in inhibiting, remitting, cr controlling the growth of tumors new methods and antitumor chemical compositions are needed.
  • Bacteria are of practical importance to man. While some bacteria are useful in industry and for soil fertilization, others are harmful. Bacteria are responsible for diseases in man, other animals and plants including, for example in man botulism, diphtheria, tetanus and tuberculosis. Bacteria also cause large economic damage due to spoiling of various foods (e.g., milk products). While many methods and chemical compositions have been utilized in controlling bacteria caused disease and other maladies, new antibacterial methods and chemical compositions are needed.
  • fungi may cause various diseases and infections in man including mycotic disease (e.g., pulmonary candidiasis and pulmonary blastomycosis.)
  • mycotic disease e.g., pulmonary candidiasis and pulmonary blastomycosis.
  • Certain yeastlike organisms e.g. cryptococcus neoformans
  • Cryptococcus neoformans may cause serious infections of the central nervous system.
  • More commonly known fungal infections in humans and mammals include ringworm (fungus infections of hair and nail areas), as well as, resistant infections of the skin.
  • Many other fungal infections inflict humans and mammals in the areas of skin, mucous membranes, intestinal tract, vaginal area and lungs.
  • Plants are also attacked by various fungi.
  • fungus infections amounts to billions of dollars annually.
  • Various inorganic and organic fungistats and fungicides have been tried with limited success. It is of course important for the fungistat or fungicide to kill the fungi but not the plant and to leave no toxic residue on the edible part of the plant.
  • Various methods have been utilized to combat fungus infection in agriculture including the foliage fungicide method by which plants are coated with a preventive weather-resistant fungicide. Seed treatment and soil treatment methods require fungicides that are safe for seeds and resist degradation by soil and soil microorganisms.
  • Chemotherapeutants are fungicides which permeate the plant to protect new growth or eliminate infections which have already occurred within the plant.
  • Agricultural fungistats and fungicides and their application must also meet very stringent requirements and regulations, which have been promulgated, for example, in the United States.
  • Considerable research and resources have been devoted to combatting fungal infections in both mammals and plants. While some antifungal agents and methods have been developed that inhibit the spread of fungus and fungus-caused diseases in both mammals and plants and treat infected mammals and plants new methods and antifungal chemical compositions are needed.
  • R is an alkyl group of up to 20 carbon atoms.
  • the composition is substantially pure and R is an alkyl group of from 13 to 17 carbon atoms.
  • the invention comprises compositions of the formulae (1-5): wherein R is
  • the invention also comprises antitumor, antibacterial, and antifungal compositions comprising, as active ingredient, an effective antitumor, antibacterial and antifungal amount, respectively, of one or more compositions according to formulae I and 1-5 and a non-toxic pharmaceutically acceptable carrier or diluent.
  • the invention also comprises a process to produce the compounds of formulae I and 1-5. The process comprises the steps of collecting marine sponge, of the family Halichondriidae; contacting the sponge with a suitable organic solvent; obtaining an extract thereof; and isolating a compound according to formula I from the extract.
  • the suitable organic solvent is selected from the group consisting of methanol, hexane, methylene chloride, acetone, methyl ethyl ketone, ethyl acetate, ethanol, and methyl isobutyl ketone.
  • the invention further comprises a method for inhibiting tumors in a host and a therapeutic method for treating cancerous cachexia comprising contacting a tumor with an effective antitumor amount of one or more compositions of formulae I and 1-5.
  • the invention further comprises a method for inhibiting the growth of bacteria comprising contacting bacteria with an effective antibacterial amount of one or more compositions of formulae I and 1-5.
  • the invention further comprises a method for inhibiting the growth of fungus comprising contacting fungus with an effective antifungal amount of one or more compositions of formulae I and 1-5.
  • R is an alkyl group of from 1 to 20 carbon atoms.
  • the composition is substantially pure and R is an alkyl group of 13 to 17 carbon atoms.
  • the invention comprises compositions of the formulae (1-5):
  • an antitumor composition comprising as active ingredient an effective antitumor amount of one or more of the compositions described above and identified by formulae I and 1-5 in a non-toxic pharmaceutically acceptable carrier or diluent. While effective amounts may vary, as conditions in which the antitumor compositions are used vary, a minimal dosage required for activity is generally between 0.01 and 100 micrograms against 10 5 tumor cells.
  • non-toxic pharmaceutically acceptable carriers or diluents include, but are not limited to, the following: ethanol, dimethyl sulfoxide and glycerol.
  • a method for inhibiting tumors in a host comprising contacting a tumor with an antitumor amount of one or more compositions according to formulae I and 1-5.
  • the effectiveness of the compositions of the invention for inhibiting tumors indicates their usefulness for controlling tumors in hosts including mammals and for treating cancerous cachexia.
  • an antibacterial composition is provided comprising as active ingredient an effective antibacterial amount of one or more of the compositions described above and identified by formulae I and 1-5 in non-toxic pharmaceutically acceptable carrier or diluent.
  • a minimal dosage required for activity is generally between 5 and 25 micrograms or less against Bacillus subtilis bacteria showing a zone of inhibition of at least 8mm.
  • Useful examples of non-toxic pharmaceutically acceptable carriers or diluents include, but are not limited to, the following: ethanol, dimethyl sulfoxide and glycerol.
  • a method for inhibiting bacteria in a host comprising contacting bacteria with an antibacterial amount of one or more compositions according to formulae I and 1-5.
  • the effectiveness of the compositions of the invention for inhibiting bacteria indicates their usefulness for controlling bacteria and bacterial related diseases in hosts including mammals. Further, such compositions may be utilized to prevent or retard spoilage of food due to the presence and growth of bacteria.
  • an antifungal composition comprising as active ingredient an effective antifungal amount of one or more of-the compositions described above and identified by formulae I and 1-5 in a non-toxic pharmaceutically acceptable carrier or diluent. While effective amounts may vary, as conditions in which the antifungal compositions are used vary, a minimal dosage required for activity is generally 1.0 or less micrograms against Saccharomyces, cerevisiae fungi showing a zone of inhibition of growth of at least 8mm.
  • non-toxic pharmaceutically acceptable carriers or diluents include, but are not limited to, the following: ethanol, dimethyl sulfoxide and glycerol.
  • a method for inhibiting fungus in a host comprising contacting fungus with an antifungal amount of one or more compositions according to formulae I and 1-5.
  • the effectiveness of the compositions of the invention for inhibiting fungus indicates their usefulness for controlling fungus and fungus related diseases in hosts including mammals. Further, such compositions may be useful as agricultural fungicides.
  • a process to produce a compound according to formulae I and 1-5 comprises the step of: collecting marine sponge of the family Halichondriidae; contacting the collected sponge with a suitable organic solvent; obtaining an extract of the solvent and sponge mixture; and isolating a compound according to formula I.
  • a detailed description and explanation of a preferred embodiment of the process of the invention to produce the compound according to formulae I and 1-5 is as follows: marine sponge of the family Halichondriidae, is collected from rock surfaces in the Bahamas off Chubb Cay at a depth of 2,500 feet. The sponge is contacted with methanol (a first solvent) in a mortar or blender. The methanol extract is concentrated and triturated with hexane (a second solvent) and methylene chloride (a third solvent) to give an organic residue. The residue is grossly separated into fractions which yield various compositions. Treatment with ethereal diazomethane yields a fraction containing two methyl esters. The ester fraction then is hydrolyzed with 5% aqueous alcoholic potassium hydroxide. Compositions according to the invention are isolated by various chromatographic techniques from the fractions obtained.
  • a suitable first solvent should be capable of extracting a compound according to any one of formulae I and 1-5 from other components of the sponge.
  • suitable first solvents which may be substituted for methanol include, but are not limited to, the following organic solvents: methyl ethyl ketone; ethyl acetate; ethanol; acetone; and methyl isobutyl ketone.
  • Suitable second and third solvents should be capable of triturating and separating into various fractions the various compounds of formulae I and 1-5 from other components that may be present in the first solvent extract.
  • Suitable second and third solvents which may be substituted for either hexane or methylene chloride or both, include, but are not limited to, either hexane or methylene chloride alone or the following organic solvents: chloroform; trichloroethylene; and lower substituted benzenes.
  • Suitable fractionation and isolation techniques include various chromatographic techniques such as high-performance liquid chromatography (HPLC) with a suitable column as would be known to those skilled in the art [e.g., a Whatman partisil column (M9 50/9.4] eluted with a suitable solvent [e.g., methanol: 0.01N Sodium acetate, 85:15].
  • HPLC high-performance liquid chromatography
  • a suitable solvent e.g., methanol: 0.01N Sodium acetate, 85:15.
  • HPLC Hydrolysis of the active ester with 5% aqueous alcoholic potassium hydroxide followed by HPLC (ODS-3 Whatman, 85:15, MeOH:0.01 N NaOAc) provided the five epidioxy saturated long chain acids (1-5) as colorless liquids.
  • compositions of Formula I were utilized to illustrate the antitumor effectiveness of the compositions of Formula I, and particularly compositions 3 and 4 of the examples.
  • a sample of the composition to be assayed is added to each well or tube in an amount of from 200 ug/ml and 100 ug/ml for screening.
  • DDC of known active compounds use log concentrations from 100 ug/ml to .01 ug/ml for range-finding assay; when range has been determined, use five concentrations between highest and lowest active concentrations.
  • Tube assays Mix tube well on vortex and remove 0.5 ml aliquot and add to
  • Tubes are loosely covered with parafilm.
  • Chloroform and butanol cannot be used in the plastic 24-well plates - use glass tubes.
  • Extracts were screened against bacterium Bacillus subtilis and fungus Saccharomyces Cerevisiae using pre-seeded 85-mm petri dishes. Bioassay discs (6-mm) were loaded with 40 microliters of test sample, air dried and applied to the plates. These were incubated at 35°C for 18 h and the diameters of the inhibition zones were recorded.
  • Acids 1-5 show 20-mm zone of inhibition at a concentration of 25 ug/disc vs. Bacillus subtilis and a 32mm zone of inhibition at 10 ug/disc vs. Saccharomyces cerevisiae. These zones of inhibition at the reported concentration of acids 1-5 show that these acids are effective for inhibiting the growth of bacteria and fungi.
  • compositions of examples 1-5 such as an ester or fluorinated derivative may possess antitumor activity analogous to these preferred embodiments described above.
  • compositions described herein may have other useful applications such as, for example, analgesic applications.
  • Application of the compositions of the present invention can be accomplished by any suitable therapeutic method and technique as is presently or prospectively known to those skilled in the art.
  • the present invention cover the modifications and variations of this invention provided that they come within the scope of the appended claims and their e ⁇ uivalents.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Nouvelles compositions à base de dioxolane utiles en tant que compositions antitumorales, antibactériennes et antifongiques, procédé de production de ces compositions et procédé d'inhibition de tumeurs, bactéries et champignons par l'utilisation des ces compositions. Plus particulièrement, les nouvelles compositions à base de dioxolane sont des composés organiques dérivés d'éponges marines, de la famille Halichondriidae.
PCT/US1987/000134 1986-02-04 1987-01-21 Nouvelles compositions a base de dioxolane et procedes d'utilisation Ceased WO1987004708A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US82592086A 1986-02-04 1986-02-04
US825,920 1986-02-04

Publications (1)

Publication Number Publication Date
WO1987004708A1 true WO1987004708A1 (fr) 1987-08-13

Family

ID=25245242

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1987/000134 Ceased WO1987004708A1 (fr) 1986-02-04 1987-01-21 Nouvelles compositions a base de dioxolane et procedes d'utilisation

Country Status (3)

Country Link
EP (1) EP0255829A1 (fr)
JP (1) JPS63502279A (fr)
WO (1) WO1987004708A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009026348A3 (fr) * 2007-08-20 2009-04-16 Harvard College Agents antifongiques synthétisés par un streptomycète

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Journal of the American Chemical Society, Volume 105, No. 26, 1983, American Chemical Society, (Washington, US), D.W. PHILLIPSON et al.: "Antifungal Peroxide-Containing Acids from Two Caribbean Sponges", see pages 7735-7736 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009026348A3 (fr) * 2007-08-20 2009-04-16 Harvard College Agents antifongiques synthétisés par un streptomycète

Also Published As

Publication number Publication date
JPS63502279A (ja) 1988-09-01
EP0255829A1 (fr) 1988-02-17

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