WO1986003738A1 - Compositions anti-tumorales et anti-virales de cyclohexadienone - Google Patents

Compositions anti-tumorales et anti-virales de cyclohexadienone Download PDF

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WO1986003738A1
WO1986003738A1 PCT/US1985/002469 US8502469W WO8603738A1 WO 1986003738 A1 WO1986003738 A1 WO 1986003738A1 US 8502469 W US8502469 W US 8502469W WO 8603738 A1 WO8603738 A1 WO 8603738A1
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compositions
composition
formula
contacting
compound
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PCT/US1985/002469
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Kenneth M. Snader
Tatsuo Higa
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Snader Kenneth M
Tatsuo Higa
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Priority claimed from US06/744,620 external-priority patent/US4921873A/en
Priority claimed from US06/772,330 external-priority patent/US4708962A/en
Application filed by Snader Kenneth M, Tatsuo Higa filed Critical Snader Kenneth M
Publication of WO1986003738A1 publication Critical patent/WO1986003738A1/fr

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    • 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
    • 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
    • A61K31/12—Ketones
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/51—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition
    • C07C45/511—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition involving transformation of singly bound oxygen functional groups to >C = O groups
    • C07C45/515—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition involving transformation of singly bound oxygen functional groups to >C = O groups the singly bound functional group being an acetalised, ketalised hemi-acetalised, or hemi-ketalised hydroxyl group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/65—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by splitting-off hydrogen atoms or functional groups; by hydrogenolysis of functional groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C07C45/70—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form
    • C07C45/71—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form being hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/78—Separation; Purification; Stabilisation; Use of additives
    • 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
    • C07C49/603—Unsaturated compounds containing a keto groups being part of a ring 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
    • C07C49/647—Unsaturated compounds containing a keto groups being part of a ring having unsaturation outside the 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
    • C07C49/687—Unsaturated compounds containing a keto groups being part of a ring containing halogen
    • 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
    • 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
    • C07C49/757—Unsaturated compounds containing a keto groups being part of a ring containing —CHO groups

Definitions

  • This invention relates to new cyclohexadienone derivatives which have useful antiviral and antitumor activity. More particularly, this invention relates to cyclohexadienone derivatives with antiviral and antitumor activities which are derived from marine organisms, i.e. red alga.
  • Viral diseases contribute to inflictions in humans including common colds, herpes and cancer and the importance of their control is obvious. Also important is control of viral diseases in animals for economic reasons as well as the ability of such animals to become virus reservoirs or carriers which facilitate the spreading of viral diseases to humans. Viral plant diseases have been known to have a disruptive effect on the cultivation of fruit trees, tobacco, and various vegetables. Insect viral diseases are also of interest because of the insects' ability to transfer viral diseases to humans.
  • Schizymenia epiphytica Turnerella pennyi and mixtures thereof as effective to inhibit the growth of herpes simplex virus, type 1 and type 2, and herpes zoster, and to relieve the pain caused by infection attributable to such viruses.
  • U.S. Patent 4,162,309 describes the use of water soluble extracts from marine red algae selected from a group consisting of Neodilsea americana and
  • the entire disclosures of U.S. Patent Nos. 4,162,308 and 4,162,309 are hereby incorporated herein by reference.
  • Crews et al disclose halogenated monoterpenes which are extracted from red algae Chondrococcus hornemanni with methylene chloride.
  • halogenated monoterpenes were shown to be bioactive in various applications and biotoxic against insects.
  • a furthur co-pending application of the present inventors filed concurrently herewith relates to compounds prepared from red algae and extracts of sea hares, which diet on red algae, comprising certain halogenated chamigrenes which show antitumor activity.
  • tumor refers to abnormal masses of new tissue growth which is discordant with the economy of the tissue of origin or the host's body as a whole. 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.
  • 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.
  • the seriousness of cancer is well known, e.g., cancer is second only to heart and vascular diseases as a cause of death in man.
  • Oncology and antitumor measures including chemotherapy. While 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 a composition of the general formula (I) :
  • R 1 groups are the same or different and are hydrogen or a lower alkyl group
  • X is a lower alkyl, hydroxy, lower acyloxy, lower alkoxy, fluoro, chloro, bromo or iodo group
  • R 2 is hydroxy, a lower acyloxy group, a halogenated lower acyloxy group or halogen.
  • R 1 is a methyl group
  • R 2 is an acetyloxy group
  • X is methyl, chloro, or bromo.
  • the invention comprises a composition of the formula:
  • the invention also comprises an antiviral or antitumor composition
  • an antiviral or antitumor composition comprising, as active ingredient, an effective antiviral or antitumor amount of one or more of the compositions according to Formula I or preferably Formula II and a non-toxic pharmaceutically acceptable carrier or diluent.
  • the invention also comprises a process to produce the compounds of Formula I comprising the steps of: collecting red alga; contacting the alga with a suitable organic solvent to obtain an extract; and isolating a compound of Formula I.
  • the process comprises the steps of: collecting red alga, particularly Desmia hornemanni; contacting the alga with a suitable organic first solvent to obtain extract; removing the solvent containing a derivative of the first compound of Formula I, preferably an alcohol derivative of Formula II; isolating the derivative of Formula II by conventional means, preferably chromatography; and acetylating the alcohol derivative to yield the compound of Formula II.
  • the invention further comprises a method for inhibiting viruses or tumors comprising contacting a virus or tumor with an effective antiviral or antitumor amount of one or more compositions of Formula I or preferably Formula II.
  • the invention further comprises a composition of the general formula (III) :
  • R is:
  • X 1 is an oxygen
  • X 2 is hydrogen halogen, lower alkyl group or alkylsulfenyl group, sulfur or an imine group
  • Y is oxygen or sulfur
  • Z is oxygen, sulfur or an imine group
  • both R 1 groups are the same and are hydrogen or a lower alkyl group
  • R 2 is H or a lower alkyl group
  • n is from 1 to 5.
  • R 1 and R 2 are methyl groups, and X 1 and Y are oxygen.
  • the invention comprises compositions of the Formulae:
  • the invention also comprises an antitumor composition
  • an antitumor composition comprising, as active ingredient, an effective antitumor amount of one or more of the compositions according to Formula I or III or preferably one of Formula IV, V, VI or VII and a non-toxic pharmaceutically acceptable carrier or diluent.
  • the invention also comprises a process to produce the compounds of Formula III comprising the steps of: collecting red alga; contacting the alga with a suitable organic solvent to obtain an extract; and synthesizing and isolating a compound of Formula III.
  • the invention further comprises a method for inhibiting tumors comprising contacting a tumor with an effective antitumor amount of one or more compositions of Formula I or III or preferably one of Formula IV, V, VI or VII.
  • the invention also comprises a method for treating cancerous cachexia comprising inhibiting, remitting or controlling the growth of tumors or tumor cells which symptomatically cause the conditions of cancerous cachexia.
  • R 1 groups are the same or different and are hydrogen or a lower alkyl group
  • X is a lower alkyl, hydroxy, lower acyloxy, lower alkoxy, fluoro, chloro, bromo or iodo group
  • R 2 is hydroxy, a lower acyloxy group, a halogenated lower acyloxy group or a halogen.
  • the lower alkyl and acyloxy groups have from one to five carbon atoms, more preferably from one to three carbon atoms, and most preferably, the lower alkyl group is methyl and the lower acyloxy group is acetyloxy.
  • X is a methyl, chloro or bromo group, more preferably, X is a chloro group.
  • a preferred embodiment of the invention comprises a composition of the structure II as indicated below:
  • an antiviral composition comprising as active ingredient an effective antiviral amount of one or more of the compositions described above and identified by Formulas I and II and a non-toxic pharmaceutically acceptable carrier or diluent. While effective amounts may vary, as conditions in which the antiviral compositions are used vary, a minimal dosage required for activity is generally between 50 and 200 micrograms against 25-80 plaque-forming units of virus.
  • non-toxic pharmaceutically acceptable carriers or diluents include, but are not limited to, the following: ethanol; dimethyl sulfoxide; and glycerol.
  • a process to produce a compound according to Formula I comprises the steps of: collecting red alga, particularly Desmia hornemanni (also known as Chondrococcus hornemanni); contacting the alga with a suitable organic solvent to obtain an extract of the solvent; and isolating a compound according to Formula I.
  • acetone and methylene chloride are the presently preferred choices for first and second solvents, other suitable solvents may be substituted for acetone and/or methylene chloride.
  • a suitable first solvent should be capable of extracting a compound according to Formula I from other components of the red alga.
  • 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.
  • a suitable second solvent should be capable of extracting and separating the compound of Formula I from other components that may be present in the first solvent extract.
  • Suitable second solvents which may be substituted for methylene chloride include, but are not limited to, the following organic solvents: chloroform; trichloroethylene; hexane; and lower alkanes.
  • the methylene chloride extract is removed and concentrated by evaporation of the methylene chloride solvent by either gentle heating or reduced pressure.
  • An alcohol derivative of the compound of Formula II is isolated from the methylene chloride extract by chromatography.
  • Any suitable chromatography technique may be used, but it has been found that first subjecting the methylene chloride extract to chromatography on a silica gel column, by eluting with hexane-acetone in an approximate ml. ratio of 7:3 hexane to acetone to obtain a major fraction of the alcohol derivative of Formula II and then further separating the major fraction on a thin layer chromatography grade silica gel column by flash chromatography yields the pure alcohol derivative of the compound according to Formula II.
  • Other eluents and columns may be substituted as would be known to those skilled in the art.
  • the alcohol derivative of the compound of Formula II was found to decompose at room temperature in two hours so it is important to carry out the next step as soon as possible.
  • the alcohol derivative of the compound of Formula II is acetylated with acetic anhydride and pyridine mixture in a ml. ratio of approximately 1:1 of acetic anhydride to pyridine for about ten minutes. While a mixture of acetic anhydride and pyridine is the present preferred choice of acetylation agents other suitable agents may be substituted such as, for example: isopropenyl acetate and acetyl chloride substituted for acetic anhydride; and N-methyl morpholine and N-methyl pyrrolidine substituted for pyridine. The excess acetic anhydride and pyridine is removed by evaporation to yield pure compound according to Formula II.
  • virus cells are inhibited in growth or killed by a method comprising contacting a virus with an effective antiviral amount of one or more compositions according to Formulas I and/or II.
  • the minimal effective amount as stated above is generally from 50 to 100 micrograms for 25 to 80 plaque forming units of virus cells.
  • the compound of Formulas I and II are active for inhibiting or killing a diverse range of viruses including, but not limited to, the RNA viruses, vesicular stomatitis (herein "VSV), arenaviruses, coronaviruses, influenza viruses and the DNA viruses, herpes simplex-I (herein "HSV-I”), other herpes viruses, adenoviruses and papovaviruses.
  • VSV vesicular stomatitis
  • HSV-I herpes simplex-I
  • other herpes viruses adenoviruses and papovaviruses.
  • compositions of the invention for inhibiting virus cells indicates that the compositions of Formulae I and II should also be useful in controlling viral infections in host animals and plants which are caused by a virus which is thus inhibited or destroyed.
  • Viral infections which may be controlled by utilizing compositions of the present invention include, but are not limited to, those caused by RNA viruses such as arenaviruses, coronaviruses, reoviruses, influenza viruses, and viral infections caused by the DNA viruses such as herpes viruses, adenoviruses and papova viruses.
  • the invention may also be useful in controlling common viral infections of plants.
  • R is:
  • X 1 is an oxygen, sulfur or an imine group
  • X 2 is hydroen, halogen, lower alkyl group, or an alkyl sulfenyl group
  • Y is oxygen or sulfur
  • Z is oxygen, sulfur or an imine group
  • R 1 groups are the same or different and are hydrogen or a lower alkyl group
  • R 2 is H or a lower alkyl group
  • n is from 1 to 5.
  • the lower alkyl groups have from one to five carbon atoms, more preferably from one to three carbon atoms, and most preferably, the lower alkyl group is methyl.
  • X 1 and Y are oxygen.
  • a preferred embodiment of the invention comprises a composition of the structure IV, V, VI or VII as indicated below:
  • an antitumor composition comprising as active ingredient an effective antitumor amount of one or more of the compositions described above and identified by Formulas I - VII and 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 1 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 process to produce a compound according to Formula III comprises the step of: collecting red alga, particularly Desmia hornemanni (also known as
  • Chondrococcus hornemanni contacting the alga with a suitable organic solvent to obtain an extract of the solvent; and synthesizing and isolating a compound according to Formula III.
  • a detailed description and explanation of a preferred embodiment of the process of the invention for producing a compound according to Formula III is as follows. Red alga, Desmia hornemanni is collected at Cape Zampa, Okinawa. The alga is then contacted with acetone (a first solvent) to obtain an acetone extract from the red alga. The acetone extract is then concentrated by evaporation through either heat or reduced pressure and the acetone residue contacted with methylene chloride to obtain a methylene chloride extract.
  • acetone and methylene chloride are the presently preferred choices for first and second solvents, other suitable solvents may be substituted for acetone and/or methylene chloride.
  • a suitable first solvent should be capable of extracting a compound according to Formula I from other components of the red alga.
  • Suitable first solvents which may be substituted for acetone include, but are not limited to, the following polar organic solvents: methyl ethyl ketone; ethyl acetate; methanol; ethanol; and methyl isobutyl ketone.
  • a suitable second solvent should be capable of extracting and separating the compound of Formula I from other components that may be present in the first solvent extract.
  • Suitable second solvents which may be substituted for methylene chloride include, but are not limited to, the following organic solvents: chloroform; trichloroethylene; hexane; and lower alkanes. Different ratios of first to second solvents may be used in the invention as would be known to those skilled in the art.
  • the methylene chloride extract is removed and concentrated by evaporation of the methylene chloride solvent by either gentle heating or reduced pressure.
  • An alcohol derivative (VIII) of a compound according Formula I is isolated from the methylene chloride extract by chromatography.
  • the alcohol derivative has the following Formula:
  • Any suitable chromatography technique may be used, but it has been found that first subjecting the methylene chloride extract to chromatography on a silica gel column, by eluting with hexane-acetone in an approximate ml. ratio of 7:3 hexane to acetone to obtain a major fraction containing a compound of
  • X 3 is Cl or Br.
  • a compound of Formula IX is obtained by isolating a volatile oil fraction from the methylene chloride extract subjected to chromatography as described above for obtaining the alcohol derivative of Formula I (Formula VIII), and obtaining from said volatile oil fraction a halogen derivative of the compound of Formula I having the Formula IX.
  • the halogen derivative IX is treated with a base such as potassium hydroxide in methanol (e.g. 10% KOH-methanol) to yield (after isolation, e.g., separation by thin layer chromatography) a major amount of a ketal of formula V and a minor amount of a vinyl ether of Formula IV.
  • a base such as potassium hydroxide in methanol (e.g. 10% KOH-methanol) to yield (after isolation, e.g., separation by thin layer chromatography) a major amount of a ketal of formula V and a minor amount of a vinyl ether of Formula IV.
  • a compound according to Formula VI is obtained by hydrolysis of the ketal of Formula V with, for example, methanol and hydrochloric acid (e.g. 1:1 by volume of MeOH: 5N HCl) .
  • a compound according to Formula VII is synthesized by treating a compound of Formula VIII, obtained as described above, with a base such as potassium hydroxide and dioxane (e.g. 1:1 by volume of 1% KOH in H 2 O: dioxane).
  • a base such as potassium hydroxide and dioxane (e.g. 1:1 by volume of 1% KOH in H 2 O: dioxane).
  • tumors and tumor cells are inhibited by a method comprising contacting a tumor with an effective antitumor amount of one or more compositions according to Formulae I - VII.
  • the minimal effective amount as stated above is generally from 1 to 100 micrograms for 10 5 tumor cells.
  • Formulae I - VII are active for inhibiting a diverse range of tumors including, but not limited to human lung, colon and mammary tumors such as lung carcinoma A549, ileocecal adenocarcinoma HCT-8, and human breast carcinoma MCF-7.
  • compositions of the invention for inhibiting tumors indicates that the compositions of Formulae I - VII should also be useful in controlling tumors in host animals.
  • compositions of the invention are effective for inhibiting or destroying viruses and tumors and therefore controlling diseases, disorders and symptomatic discomfort caused by or related to such viruses and tumors in fulfillment of the objects of the invention.
  • the slurry was filtered to provide an acetone extract.
  • the acetone extract was concentrated under vacuum at room temperature and admixed with 100 mis. of methylene chloride in a separatory funnel.
  • the methylene chloride fraction was removed and concentrated to give 13.2 gms of crude oil.
  • the slurry was filtered to provide an acetone extract.
  • the acetone extract was concentrated under vacuum at room temperature and admixed with 100 mis. of methylene chloride in a separatory funnel.
  • the methylene chloride fraction was removed and concentrated to yield 13.2 gms. of crude oil.
  • Vinyl ether (2) had the following characteristics: oil, ⁇ max (EtOH) 235 (E 6000), 218 nm (614000); IR (film) 2960, 1665, 1625, 1580, 1400,
  • ketal (3) can be produced by treating a sample (9.3 mg) of Compound (Y) in 5 N methanolic KOH (1 ml) allowing it to stand at room temperature for 20 hours. After adding 5.0 ml. water the mixture was extracted with CH 2 Cl 2 . The CH 2 Cl 2 solution was dried over sodium sulfate and concentrated to give ketal (3) (6.4 mg, 87-97%).
  • the methylene chloride extract was subjected to chromatography on a silica gel column, by eluting with 7:3 hexane-acetone. A volatile oil fraction was obtained which contains a composition (6).
  • Composition (7) was a light yellow oil; IR (Film) 3260, 3060, 2975, 2940, 2875, 2110, 1665, 1630, 1475, 1400, 1380, 1360, 1305, 1255, 1180, 1135, 1085, 985, 950, 930, 910 and 840 cm -1 .
  • Composition (8) was a light yellow oil; IR (film) 3050, 2970, 2940, 2870, 1670, 1640, 1480, 1400, 1380, 1360, 1250, 1200, 1170, 1130, 1020, 960, 910, 840 cm -1 .
  • Read wells e.g. compound of Formula II 16 (++) where 16 indicates zone of cytotoxicity as the diameter in mm (6 mm to 16 mm) and (++) indicates the inhibition of plaque formation: complete inhibition (+++), a few plaques around the outside of well (++), definite inhibition (+), questionable inhibition (+/-), no inhibition (-), and no conclusion due to complete cytotoxicity.
  • composition (1) shows def ini te ant iviral activi ty 16 ( ++ ) fo r the compound.
  • Compound (1) shows antiviral activity in minimal effective amounts of from 50 to 100 micrograms for 25 to 80 plaque forming units of virus cells.
  • 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 ana lowest active concentrations.
  • Chloroform and butanol cannot be used in the plastic 24-well plates - use glass tubes.
  • results of the above assay show compounds of formulae II, V, VI and VII are cytotoxic in vitro against P-388 murine leukemia cells showing estimated ID 50 's (dose which kills 50% of the cells) of 37, 70, 70 and 5 micrograms per milliliter respectively.
  • Compounds IV, V, VI and VII are cytotoxic in vitro against L-1210 murine leukemia cells showing 15%, 17%, 41% and 25% survival at 200 micrograms per milliliter respectively.
  • Compound VII shows an estimated ID 50 of 0.7 micrograms per milliliter against L-1210 murine leukemia cells. The following table summarizes these results.

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Abstract

Compositions anti-tumorales et anti-virales, un procédé de production de ces compositions et un procédé inhibiteur de virus et de tumeurs qui utilise ces compositions. En particulier, ces compositions sont des dérivés de cyclohexadienone tirés d'algues rouges Desmia hornemanni.
PCT/US1985/002469 1984-12-17 1985-12-13 Compositions anti-tumorales et anti-virales de cyclohexadienone WO1986003738A1 (fr)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
US772,330 1977-02-25
US68227884A 1984-12-17 1984-12-17
US682,278 1984-12-17
US06/744,620 US4921873A (en) 1984-12-17 1985-06-14 Antiviral and antitumor cyclohexadienone compositions
US744,620 1985-06-14
US06/772,330 US4708962A (en) 1984-12-17 1985-09-04 Antiviral and antitumor cyclohexadienone compositions

Publications (1)

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WO1986003738A1 true WO1986003738A1 (fr) 1986-07-03

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EP (1) EP0205576A1 (fr)
CA (1) CA1257281A (fr)
WO (1) WO1986003738A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1942093A1 (fr) * 2007-01-08 2008-07-09 Golden Biotechnology Corp. Nouveaux composés de cyclohéxénone à partir de camphorata antrodia et application associée

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4162309A (en) * 1978-04-10 1979-07-24 Calvin Natasha I Water soluble extracts of certain marine red algae and processes for use thereof

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4162309A (en) * 1978-04-10 1979-07-24 Calvin Natasha I Water soluble extracts of certain marine red algae and processes for use thereof

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Experientia, Volume 27, No. 1, 1972, H.V. SECOR et al.: "Synthesis and Photolysis of 2-Formyl-4,4-Dimethyl-2,5-Cyclohexadienone", see page 19 *
Tetrahedron Letters, Volume 26, No. 19, 1985, T. HIGA: "2- (1-chloro-2 Hydroxyethyl) -4,4-Dimethyl Cyclohexa- 2,5-Dienone: A Precursor of 4,5-Dimethylbenzo (b) Furan from the Red Alga Desmia Hornemanni" pages 2355 - 2356, see page 2235-6 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1942093A1 (fr) * 2007-01-08 2008-07-09 Golden Biotechnology Corp. Nouveaux composés de cyclohéxénone à partir de camphorata antrodia et application associée

Also Published As

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EP0205576A1 (fr) 1986-12-30
CA1257281A (fr) 1989-07-11

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