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WO1987004159A1 - Compositions anti-tumorales a base de cyclohexanone et de ses derives - Google Patents

Compositions anti-tumorales a base de cyclohexanone et de ses derives Download PDF

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Publication number
WO1987004159A1
WO1987004159A1 PCT/US1987/000020 US8700020W WO8704159A1 WO 1987004159 A1 WO1987004159 A1 WO 1987004159A1 US 8700020 W US8700020 W US 8700020W WO 8704159 A1 WO8704159 A1 WO 8704159A1
Authority
WO
WIPO (PCT)
Prior art keywords
composition according
compositions
tumor
composition
contacting
Prior art date
Application number
PCT/US1987/000020
Other languages
English (en)
Inventor
Tatsuo Higa
Paul J. Scheuer
Original Assignee
Harbor Branch Oceanographic Institution, Inc.
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 Harbor Branch Oceanographic Institution, Inc. filed Critical Harbor Branch Oceanographic Institution, Inc.
Publication of WO1987004159A1 publication Critical patent/WO1987004159A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
    • C07C49/703—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups
    • C07C49/713—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups a keto group being part of a six-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
    • C07C49/753—Unsaturated compounds containing a keto groups being part of a ring containing ether groups, groups, groups, or groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
    • C07D303/02—Compounds containing oxirane rings
    • C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
    • C07D303/32—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by aldehydo- or ketonic radicals

Definitions

  • Antitumor cyclohexanone compositions and derivatives thereof a process of producing the compositions an method for inhibiting tumors utilizing the compositions. More particularly, the compositions are cyclohexanone and rivatives thereof which are derived from marine organisms, i.e., the acorn worm, Ptychodera sp.
  • This invention relates to new cyclic organic compounds which have useful antitumor activity. More particularly, this invention relates to new cyclohexanone and cyclohexanone derivative antitumor compositions derived from marine organisms, i.e., the acorn worm, Ptychodera sp.
  • 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.
  • Oncology and antitumor measures including chemotherapy.
  • certain methods and chemical compositions have been developed which aid in inhibiting, remitting or controlling the growth of tumors new methods and antitumor chemical compositions are needed.
  • the invention comprises compositions
  • X 1 and X 2 are the same or different and are a halogen, hydroxy, or hydrogen; R, 1 and R 2 are selected from the group consisting of hydroxy, lower acyloxy and lower alkoxy.
  • the composition is substantially pure and X 1 or X 2 is bromine, R 1 is a lower acyloxy or alkoxy which has from 1 to 4 carbon atoms.
  • the invention comprises compositions of the formulae (V-IX):
  • the invention also comprises an antitumor composition
  • an antitumor composition comprising, as active ingredient, an effective antitumor amount of one or more compositions according to formulae I-IX and a non-toxic pharmaceutically acceptable carrier or diluent.
  • the invention also comprises a process to produce the compounds of formulae I-IX.
  • the process comprises the steps of collecting acorn worm, Ptychodera, sp., contacting the acorn worm with a suitable organic solvent; homogenizing the acorn worm and solvent mixture to obtain an extract thereof; and isolating a compound according to formulae l-IX from the extract.
  • the suitable organic solvent is selected from the group consisting of acetone, methyl ethyl ketone, ethyl acetate, methanol, 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-IX.
  • compositions of the general formulae (I-IV) are provided to achieve the objects in accordance with the purposes of the invention, as embodied and fully described herein, the invention comprises compositions of the general formulae (I-IV)
  • X 1 and X 2 are the same or different and are a halogen, hydroxy, or hydrogen; R, 1 and R 2 are selected from the group consisting of hydroxy, lower acyloxy and lower alkoxy.
  • the composition is substantially pure and X or
  • X 2 is bromine
  • R 1 is a lower acyloxy or alkoxy having from 1 to 4 carbon atoms.
  • the invention comprises
  • compositions of the formulae (V-IX) are compositions of the formulae (V-IX)
  • 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-IX 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 tumor cells.
  • non-toxic pharmaceutically acceptable carriers or diluents include, but are not limited to, the following: ethanol, dimethyl sulf oxide 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-IX.
  • 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.
  • a process to produce a compound according to formulae I-IX comprises the step of: collecting acorn worm Ptychodera sp.; contacting the collected acorn worm with a suitable organic solvent; homogenizing the solvent and acorn worm mixture to obtain an extract of the solvent; and isolating a compound according to formulae I-IX.
  • a detailed description and explanation of a preferred embodiment of the process of the invention to produce the compound according to formulas l-ix is as follows: acorn worm Ptychodera sp., is collected from submarine caves in the vicinity of Maui, Hawaii. The acorn worm is homogenized with acetone (a first solvent) in a mortar or blender.
  • the acetone extract is concentrated and partitioned between water (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.
  • Compositions according to the invention are isolated by various chromatographic techniques from the fractions obtained. While acetone, water and methylene chloride are the presently preferred choices for the first, second and third solvents, respectively, other suitable solvents may be substituted.
  • a suitable first solvent should be capable of extracting a compound according to any one of formulae I-IX from other components of the acorn worm.
  • Suitable first solvents which may be substituted for acetone include, but are not limited to, the following organic solvents: methyl ethyl ketone; ethyl acetate; methanol; ethanol; and methyl isobutyl ketone.
  • Suitable second and third solvents should be capable of extracting and separating into various fractions the various compounds of formulae I-IX from other components that may be present in the first solvent extract.
  • Suitable second and third solvents which may be substituted for either water or methylene chloride or both include, but are not limited to either water or methylene chloride alone or, the following organic solvents: chloroform; trichloroethylene; hexane, and lower alkanes. Different ratios of first, second and third solvents and any combination may be used in the invention as would be known to those skilled in the art.
  • Suitable fractionation and isolation techniques include various chromotography techniques such as, high pressure liquid chromato ⁇ raphy (HPLC) with a suitable column as would be known to those skilled in the art (e.g., a Whatman partisil column (M9 50/10) eluted with a suitable solvent such as, for example, 4:1 to 2:1, hexanes: ethyl acetate.
  • HPLC high pressure liquid chromato ⁇ raphy
  • Acorn worm, Ptychodera sp., 294 gms (wet weight with a minor amount of silt) was collected from submarine caves of Maui, Hawaii and was homogenized with acetone in a mortar.
  • the acetone extract (800 ml) was concentrated and partitioned between water and CH 2 Cl 2 , (3x200 ml)to give 740 mg of organic residue.
  • the residue was grossly separated on a silica gel (25 g) column (2:1 hexanes-EtOAc) into 15 fractions. Elution volume and yield of each fraction are shown in Table 1.
  • the compound (5) was most abundant and obtained from fractions 4-12 in total 67.6 mg. A part of the sample was repurified by HPLC to give a glass which solidified during storage in a freezer. An attempt to recrystallize the solid from cyclohexane-benzene was unsuccessful, presumably because of partial epimerization of the compound to compound 2 (above). Optical rotation of the pure sample was recorded as [a] D 23 + 130° (c 0.1,
  • compositions of Formulae I, II, and IV corresponding to compositions 1, 2 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.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Epoxy Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

Compositions anti-tumorales à base de cyclohexanone et de ses dérivés, procédé de préparation de ces compositions et procédé d'inhibition de tumeurs à l'aide de ces compositions. Ces compositions sont en particulier du cyclohexanone et ses dérivés extraits d'organismes marins, c'est-à-dire du balane, espèce Ptychodera.
PCT/US1987/000020 1986-01-08 1987-01-06 Compositions anti-tumorales a base de cyclohexanone et de ses derives WO1987004159A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US81713686A 1986-01-08 1986-01-08
US817,136 1986-01-08

Publications (1)

Publication Number Publication Date
WO1987004159A1 true WO1987004159A1 (fr) 1987-07-16

Family

ID=25222407

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1987/000020 WO1987004159A1 (fr) 1986-01-08 1987-01-06 Compositions anti-tumorales a base de cyclohexanone et de ses derives

Country Status (3)

Country Link
EP (1) EP0252144A1 (fr)
JP (1) JPS63502277A (fr)
WO (1) WO1987004159A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0338796A3 (en) * 1988-04-19 1990-05-16 Teijin Limited 2-substituted-2-cyclopentenones
US5216183A (en) * 1988-04-19 1993-06-01 Teijin Limited Cyclopentanone/cyclopentenone derivative

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, Vol. 64, 1966, (Columbus, Ohio, USA), T. BERMAN et al., "The Pathway of Myo-Inositol Degradation in Aerobacter Aerogenes. Dehydrogenation and Dehydration", see column 8543f,g, & J. Biol. Chem. 241(4), 800-6 (1966) *
J.A.C.S., Vol. 107, 1985 (American Chemical Society, USA), R.A. ALEKSEJCZYK et al., "Benzene Diol Epoxides", pages 2554-2555, see page 2554, compounds 5,6,7 *
J.A.C.S., Vol. 95, No. 23, 1973 (American Chemical Society, USA), C.D. SNYDER et al., "Stereochemistry of Quinate-Shiki-Mate Conversions. Synthesis of (-)-4-Epishikimic Acid", pages 7821-7828, see page 7822, compound 3 *
Tetrahedron Letters, No. 48, 1974 (Pergamon Press, GB), A. ICHIHARA et al., "Facile Synthesis of Quinone Epoxides and Epoxy-Cyclohexenones via Retro Diels-Alder Reaction", pages 4231-4234, see page 4233, compounds 14,15; page 4234, line 12 *
Tetrahedron, Vol. 35, 1979 (Pergamon Press Ltd, GB), A. ICHIHARA et al., "Facile Synthesis of Quinone Epoxides and 5,6-Epoxy-4-Hydroxy-2-Cyclohexenones via the Retro-Diels-Alder Reaction", pages 2861-2866, see page 2862, compounds 10,11; page 2865, column 1, lines 2,3; page 2865, column 2 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0338796A3 (en) * 1988-04-19 1990-05-16 Teijin Limited 2-substituted-2-cyclopentenones
US5216183A (en) * 1988-04-19 1993-06-01 Teijin Limited Cyclopentanone/cyclopentenone derivative

Also Published As

Publication number Publication date
JPS63502277A (ja) 1988-09-01
EP0252144A1 (fr) 1988-01-13

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