US3859286A - Bis-basic ketones of xanthene and xanthen-9-one - Google Patents

Bis-basic ketones of xanthene and xanthen-9-one Download PDF

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Publication number
US3859286A
US3859286A US097379A US9737970A US3859286A US 3859286 A US3859286 A US 3859286A US 097379 A US097379 A US 097379A US 9737970 A US9737970 A US 9737970A US 3859286 A US3859286 A US 3859286A
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Prior art keywords
xanthene
bis
carbon atoms
group
reaction
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US097379A
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Inventor
Robert W Fleming
Arthur D Sill
Francis William Sweet
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Richardson Vicks Inc
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Richardson Merrell Inc
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Priority to US097379A priority Critical patent/US3859286A/en
Priority to CA118,192A priority patent/CA948192A/en
Priority to NO3324/71A priority patent/NO135249C/no
Priority to GB4302671A priority patent/GB1313454A/en
Priority to IE1168/71A priority patent/IE35643B1/xx
Priority to IL37755A priority patent/IL37755A/xx
Priority to ZA716267A priority patent/ZA716267B/xx
Priority to AU33908/71A priority patent/AU453068B2/en
Priority to CH1501371A priority patent/CH562818A5/xx
Priority to DE19712151707 priority patent/DE2151707A1/de
Priority to JP8252971A priority patent/JPS5545549B1/ja
Priority to AT1010272A priority patent/AT317890B/de
Priority to AT956871A priority patent/AT319944B/de
Priority to NL7115559A priority patent/NL7115559A/xx
Priority to CS8104A priority patent/CS166791B2/cs
Priority to SE7115518A priority patent/SE382458B/xx
Priority to AR239429A priority patent/AR196404A1/es
Priority to HURI458A priority patent/HU163026B/hu
Priority to BE776535A priority patent/BE776535A/xx
Priority to FR7144506A priority patent/FR2118031B1/fr
Priority to ES397821A priority patent/ES397821A1/es
Priority to DK605771A priority patent/DK132275C/da
Priority to US05/333,768 priority patent/US3957989A/en
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Publication of US3859286A publication Critical patent/US3859286A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/78—Ring systems having three or more relevant rings
    • C07D311/80—Dibenzopyrans; Hydrogenated dibenzopyrans
    • C07D311/82—Xanthenes
    • C07D311/84—Xanthenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 9
    • C07D311/86—Oxygen atoms, e.g. xanthones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/78—Ring systems having three or more relevant rings
    • C07D311/80—Dibenzopyrans; Hydrogenated dibenzopyrans
    • C07D311/82—Xanthenes

Definitions

  • n is a whole integer from 4 to 6, and R is hydrogen, lower alkyl of from 1 to about 4 carbon atoms and can be linked to any one of the carbon atoms of the heterocyclic group; or
  • each A is a straight or branched alkylene chain of from 1 to about 6 carbon atoms; and each Y is A.
  • R and R are individually hydrogen, lower alkyl having from 1 to about 6 carbon atoms, cycloalkyl having from 3 to 6 carbon atoms, alkenyl of from 3 to 6 carbon atoms and having the vinyl unsaturation in order than the 1 position of the alkenyl group; or
  • R3 wherein n is a whole integer of 4 to 6, and R is hydrogen, lower alkyl of from I to about 4 carbon atoms and can be linked to any one of the carbon atoms of the heterocyclic group;
  • o -iLA-Y of Formula I can be linked to the tricyclic ring system of xanthene and xanthen-9-one by repalcement of any one of the four hydrogens of the benzenoid ring to which such group is attached.
  • one of the groups will be in any of the positions of I through 4 of the tricyclic ring system, and the other will be in anyof teh positions 5 through 8.
  • one of the basic ketone groups is in the 2-position and the other in the 7- position of the tricyclic ring system.
  • Each of the symbols A in the compounds of the above Formulas IV, V and VI is an alkylene group having from I to about 6 carbon atoms which can be a straight chain, that is, for example, CH -(CI-I wherein m is a whole integer from 0 to 5, or a branched chain.
  • Each of the alkylene groups as represented by A can be the same or different. Preferably these groups are the same.
  • alkylene groups as represented by A there can be mentioned, for example, methylene, 1,2-ethylene, 1,3-propylene, 1,4-butylene, 1,5-pentylene, 1,6hexylene, 2-methyl-l,4-butylene, 2- ethyll,4-butylene, 3-methyl-l ,S-pentylene and the like.
  • lower alkyl as used in reference to the compounds of Formula IV relates to straight or branched alkyl chains having from I to about 6 carbon atoms.
  • cycloalkyl groups as represented by each R and R in the compounds of Formula IV there can be mentioned, for example, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • R or R in the compounds of Formula IV represents an alkenyl group
  • the vinyl unsaturation is in a position other than the l-position of said alkenyl group.
  • alkenyl groups as can be represented by R or R there can be mentioned, for example, allyl, 3- butenyl, 4-hexenyl and the like.
  • heterocyclic groups in the compounds of Formula V can be 5-, 6- or 7-membered rings, that is, n is 4, 5 or 6.
  • the R group can be hydrogen or a straight or branched lower alkyl chain of from 1 to about 4 carbon atoms.
  • Illustrative of heterocyclic groups as represented by each there can be mentioned, for example, piperidino, pyrrolidino, 4-methylpiperidino, 3-methylpiperidino, 4- tert-butylpiperidino or the like.
  • X is oxygen or NR.
  • the R group can be hydrogen or a straight or branched lower alkyl chain of from I to about 4 carbon atoms.
  • heterocylic groups as represented by there can be mentioned, for example, morpholino, piperazino, N-(lower)alkylpiperazino, such as, for example, N-methylor N-ethylpiperazino and the like.
  • base compounds of this invention as represented by Formula I there can be mentioned 2,7- bis(dimethylaminoacetyl)xanthene, 2,7-bis(diethylaminoacetyl)xanthene, 2,7-bis[2-(N-methylcyclohexylamino)acetyl]xanthene, 2,7- bis(piperidinoacetyl)xanthene, 2,7-bis(morpholinoacetyl)xanthene, 2,7-bis(3-diethylaminopropionyl)xanthene, 2,6-bis(diethylaminoacetyl)xanthene, 2,7-bis(4-diethylaminobutyryl)xanthcne, 2,7- bis(4-piperidinobutyryl)xanthene, 2,7-bis(4- morpholinobutyryl) xanthene, 3,6-bis(3-piperidinopropionoyl)xanthene, 2,
  • Pharmaceutically acceptable acid additon salts of the base compounds of this invention are those of any suitable inorganic or organic acids.
  • Suitable inorganic acids are, for example, hydrochloric, hydrobromic, sulfuric or phosphoric acids and the like.
  • Suitable organic acids are, for example, carboxylic acids such as acetic, propinoic, glycolic, lactic, pyruvic, malonic, succinic, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic, salicylic, Z-phenoxybenzoic and the like, or sulfonic acids such as methane sulfonic, 2- hydroxyethane sulfonic acid and the like.
  • Monoor diacid salts may be formed, and the salts can be hydrated or substantially anhydrous.
  • the compounds of this invention are effective for inactivating or inhibiting a broad variety of viruses and can thus be employed as antiviral agents. These compounds are effective for preventing or inhibiting characteristic viral disease symptoms in a host by a wide variety of methods of application and composition. They can be administered for an antiviral effect by means which subject the host, or such host and a virus, to the active ingredients.
  • the host is subjected to the active ingredients by bringing together an active ingredient and host, for example, by applying or contacting the host with such active ingredient or simply administering the active ingredient to the host. This includes subjecting the host to such active ingredient prior to infection with a virus, that is, prophylactic use, as well as subjecting the host to such active ingredient after infection, that is, therapeutic use.
  • the replication of viruses is inhibited when the host is infected before or after being subjected to such ingredients.
  • administration by various routes of the active ingredients to an animal host prior to or after infection wtih the virus prevents or inhibits viral replication and the development of the various disease conditions characteristic of the particular virus.
  • infection we simply mean invasion of th host with a pathogenic virus.
  • host we mean viable biological material or intact animals which are capable of inducing the formation of interferon and which can support the replication of a virus.
  • the host is of animal and particularly warm blooded or mammallian orgin.
  • viable biological material such as can be used in the production of vaccines, for example, tissue cultures such as that of kidney, lung, amnion cells, embryos, for example, chick allantoic fluid; and various animals, for example, warm blooded animals such as birds or mammals, including mice, rats, guinea pigs, gerbils, ferrets and the like.
  • the mode of activity of the active ingredients is not rigorously defined.
  • the active ingredients induce the formation of interferon when a host is subjected to such ingredients.
  • Interferon is a known antiviral substance which is involved with the inhibition of the replication of virsuses in the presence of a host cell.
  • Some of the viruses suceptible to replication ihibition by interferon are set forth in Horsfall and Tamm, Viral and Rickettsial Infections of Man, 4th Edition (1965), J. B. Lippencott Company, pages 328-329.
  • the compounds of the present invention can be administered to animals such as warm blooded animals and particularly mammals to prevent or inhibit infections of picornavirus, for example, encephalomyocarditis; myxovirus, for example, Influenza A (lap/305); arbovirous, for example, Semliki forest; Herpes virus group, for example, herpes simplex; and poxviruses; for example, Vaccinia Il-ID.
  • picornavirus for example, encephalomyocarditis
  • myxovirus for example, Influenza A (lap/305)
  • arbovirous for example, Semliki forest
  • Herpes virus group for example, herpes simplex
  • poxviruses for example, Vaccinia Il-ID.
  • the administration When administered prior to infection, that is, prophylactically, it is preferred that the administration be within 0 to 96 hours prior to infection of the animal with pathogenic virus.
  • the administration When administered therapeutically to inhibit an infection, it is preferred that the administration be within
  • a daily dosage of the active ingredients will generally range from less than about 0.1 to over about 500 mg (milligram) per kg (kilogram) of body weight.
  • dosage levels of the administered active ingredient can be intravenous, 0.1 to about mg/kg; intraperitoneal, 0.1 to about 50 mg/kg; subcutaneous, 0.1 to about 250 mg/kg; oral, 0.1 to about 500 mg/kg and preferably about 1 to about 250 mg/kg; intranasal instillation, 0.1 to about 10 mg/kg; and aerosol, 0.1 to about 10 mg/kg of animal body weight.
  • novel compounds, together with conventional pharmaceutical carriers can be employed in unit dosage forms such as solids, for example, tablets or capsules or liquid solutions, suspensions or elixirs for oral administration and injections, or liquid solutions, suspensions, emulsions and the like for parenteral use.
  • the quantity of active ingredient in each dosage will generally differ depending on the type of unit dosage, the type of animal and its weight. Thus, each dosage can contain less than about 2.0 mg to over 3 grams of active ingredients in a significant quantity of a non-toxic pharmaceutical carrier of the type that can be taken orally, applied topically, bucally or parenterally.
  • the pharmaceutical carrier can, as previously indicated, be a sterile liquid such as water and oils, with or without the addition of a surfactant. Illudtrative of oils there can be mentioned those of petroleum, animal,
  • liquid carriers for example, peanut oil. soybean oil, mineral oil, sesame oil, and the like.
  • water, saline, aqueous dextrose, and related sugar solutions and glycols such as propylene glycol or polyethylene glycol are preferred liquid carriers, particularly for injectable solutions.
  • Sterile injectable solutions such as saline, for example, isotonic saline will ordinarily contain from about 0.5 to 25% and preferably from about 1 to 10% by weight of the active ingredient in the composition.
  • oral administration can be in a suitable suspension or syrup, in which the active ingredient ordinarily will constitute from about 0.5 to 10%, and preferably from about 1 to 5%, by weight.
  • the pharmaceutical carrier in such composition can be a watery vehicle such as an aromatic water, a syrup or a pharmaceutical mucilage; also, a suspending agent for viscosity control such as magnesium aluminum silicate, carboxymethylcellulose or the like as well as a buffer, preservative, etc.
  • the active ingredients can also be admixed in animal feed or incorporated into th animals drinking water.
  • an amount of active ingredient will be used to provide from about 0.0001 to 0.1% by weight of the active ingredient based on the total weight of feed intake. Preferably, from 0.001 to 0.02% by weight will be used.
  • the selection of the particular feed is within the knowledge of the art and willdepend, of course, on the animal, the economics, natural materials available, and the nature of the effect desired.
  • the active ingredients can be admixed in animal feed concentrates, suitable for preparation and sale to farmers or livestock growers for addition to the animals feedstuffs in appropriate proportion.
  • a finely divided solid preferably flours, such as wheat, corn, soya bean and cottonseed.
  • the solid adjuvant can be ground cereal, charcoal, fullers earth, oyster shell and the like. Finely divided attapulgite and bentonite can also be used.
  • the feed compositions can additonally contain other components of feed concentrates or animal feeds, as will be readily understood.
  • Other particularly important additives include proteins, carbohydrates, fats, vitamins, minerals, antibiotics, etc.
  • the active ingredients can be packaged in a pressurized aerosol container together with a gaseous or liquified propellant, for example, dicholorodifluoromethane, carbon dioxide, nitrogen, propane, etc. with the usual adjuvants such as cosolvents, and wetting agents, as may be necessary or desirable.
  • a gaseous or liquified propellant for example, dicholorodifluoromethane, carbon dioxide, nitrogen, propane, etc. with the usual adjuvants such as cosolvents, and wetting agents, as may be necessary or desirable.
  • Typical surface active agents (Kirk and Othmer, Encyclopedia of Chemical Terminology, 1954, Vol. 13, page 513), particularly emulsifiying and dispersing agents which can be used in the compositions of this invention are, for example, fatty alcohol sulfates such as sodium lauryl sulfate, aliphatic or aromatic sulfonates, such as sulfonated castor oil, and non-ionic types of emulsifying or dispersing agents such as the high molecular weight alkyl polyglycol ethers, such as dodecyl polyglycol ethers containing from about 25 to carbon atoms.
  • fatty alcohol sulfates such as sodium lauryl sulfate
  • aliphatic or aromatic sulfonates such as sulfonated castor oil
  • non-ionic types of emulsifying or dispersing agents such as the high molecular weight alkyl polyglycol ethers, such as dodecyl poly
  • a desirable mode of administration for the compounds (active ingredients) of this invention is parenterally, such as by normally liquid injectable compositions, for example, for intramuscular or subcutaneous administration.
  • the quantity of active ingredient can vary from about 0.05 to 20% by weight of the composition and preferably from about 0.1 to 10% by weight.
  • the parenteral compositions can contain a non-ionic surfactant such as those having an I-ILB (hydrophile-lipophile balance) of about 12 to 17.
  • Such formulations can be solutions, suspensions or emulsions in conventonal liquid pharmaceutical carriers, for example, sterile liquids such as water, saline, and aqueous dextrose (glucose) and related sugar solutions.
  • the quantity of surfactant in the for mulation can vary from about 5 to 15% by weight of the formulation.
  • the quantity of a compound of this invention, either in the base form or a pharmaceutically acceptable acid addition salt in such formulations, can vary over a broad range, such as that mentioned hereinbefore, that is, 0.05 to by weight of the formulation.
  • th active ingredient is in the base form.
  • the remaining component or components of such formulations can be a normally liquid pharmaceutical carrier, for example, isotonic aqueous saline, either alone or together with conventonal excipients for injectable compositions.
  • the surfactant can be a single surfactant having the above-indicated I-ILB or a mixture of two or more surfactants wherein such mixture has the indicated HLB.
  • the following surfactants are illustrative of those which can be used in such formulations.
  • A Polyoxyethylene derivatives of sorbitan fatty acid esters, such as the TWEEN series of surfactants, for example, TWEEN 80, and the like. The TWEENS are manufactured by Atlas Powder Company.
  • B High molecular weight adducts of ethylene oxide with a hydrophobic base formed by the condensation of propylene oxide with propylene glycol, for example, PLU- RONIC F-68 which is manufactured by Wyandotte Chemical Company.
  • the preferred surfactant is Polysorbate 80, U.S.P., a polyoxyethylene sorbitan monooleate.
  • acylation reaction may be carried out in a variety of solvents and under catalysis of a variety of Lewis acids.
  • the temperature and duration of the reaction may be varied to allow for optimum reaction conditions.
  • a preferred procedure is to combine one equivalent of xanthene with 2.5 equivalents of an acylating agent in methylene chloride followed by portionwise addition of aluminum chloride.
  • the temperature of the reaction is maintained below 0 with continuous stirring. After the additions are complete the temperature may be elevated to 25-40C. for 12 to 36 hours.
  • the reaction mixture is worked up in the usual manner by decomposing te complex with ice water/HCI.
  • the product obtained is recrystallized from methylene chloride, chloroform, or the like.
  • the procedure may be varied such that there is a reverse addition of acylating agent and Lewis acid, or a reverse addition of aromatic hydrocarbon and Lewis acid.
  • the more reactive halogen derivative that is, the biS(miodoalkanoyl)xanthene may be prepared from the corresponding bis-chloro derivative using a halogen exchange reaction under the conditions generally em ployed in the Conant-Finkelstein reaction.
  • ammonia or a compound which is a potential source of ammonia such as, for example, hexamethylenetetramine and the like; primary amines such as ethylamine, propylamine and the like; and secondary amines such as diethylamine, dibutylamine, piperidine, 4-methylpiperidine, morpholine, piperazine, N-ethylpiperazine, and the like.
  • the amination of bis(a -haloalkanoyl)xanthenes, 1, may be carried out under a variety of conditions.
  • compound 1 may be heated together with a large excess of the amine, 2, the excess amine serving as the reaction medium and the hydrohalide acceptor.
  • This method is particularly suitable for readily available amines, the excess of which can be easily removed from the reaction mixture by, for example, distillation at reduced pressure or by washing the product with water.
  • one equivalent of compound 1 and four equivalents of the amine, 2 may be heated together in one of a number of different types of solvents, for example, in aromatic solvents such as benzene, toluene, xylene, and the like; or ethers such as tetrahydrofuran, dioxane and the like; or ketones such as acetone, butanone and the like; or aprotic solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide and the like; or mixtures of these solvents with water.
  • aromatic solvents such as benzene, toluene, xylene, and the like
  • ethers such as tetrahydrofuran, dioxane and the like
  • ketones such as acetone, butanone and the like
  • aprotic solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide
  • reaction between compound 1 wherein the halogen is chlorine and the amine, 2 is frequently promoted by the addition of either sodium or potassium iodide, the iodide being used in either catalytic or stoichiometric amounts.
  • sodium or potassium iodide the iodide being used in either catalytic or stoichiometric amounts.
  • the reaction will proceed normally in 12 hours to 2 weeks at temperatures of -30 to C.
  • volatile amines are employed, the reaction is best carried out under pressure in a suitable pressure reactor or autoclave.
  • the amination reaction may be carried out on a derivative of compound 1 such as the xanthene or xanthen-9-one ketal derivatives, which may be prepared by allowing bis-w-haloalkanoyl-xanthene or zanthen-9-one derivative and an excess of ethyl orthoformate to react in the presence of an acid catalyst such as hydorchloric acid for several days in a polar solvent such as ethanol, tetrahydrofuran and the like.
  • the aminoketal derivative is hydrolyzed to the product of the invention by warming with dilute acid.
  • the compounds of Formula I wherein A is an alkylene chain of 3 to 6 carbon atoms and Z is H may also be prepared by the reaction of Grignard regent with a bis-ester or bisamide of xanthene as represented by the following reaction:
  • R and R are hydrogen or lower alkyl, or NR R taken together form a saturated monocyclic heterocyclic group such as piperidino or pyrrolidino;
  • R may be a straight or branched lower alkyl chain, or an aryl group such as phenyl, benzyl and the like;
  • X is bromine or chlorine,
  • p is an integer of from 3 to 6 and
  • Y may be any of the groups defined hereinbefore except those which contain a hydrogen attached to the nitrogen atom.
  • the Grignard reagent, 4 may be prepared by reacting magnesium and an aminoalkyl halide of the formula 'IAD 1490 110/11 nr inn thp rmnpmllv lrnnum nxidation of a corresponding diacetyl derivative with hypochlorite and the like.
  • Reaction 3 By combining one equivalent of compound 6 and two or more equivalents of compound 2 with three or more equivalents of formaldehyde, 7, the reaction will proceed in from 1 to 24 hours in solvents such as water, acetic acid, ethanol, butanol, dioxane, tetrahydrofuran and the like and at temperatures equivalent to the reflux temperature of the solvent.
  • solvents such as water, acetic acid, ethanol, butanol, dioxane, tetrahydrofuran and the like and at temperatures equivalent to the reflux temperature of the solvent.
  • solvents such as water, acetic acid, ethanol, butanol, dioxane, tetrahydrofuran and the like and at temperatures equivalent to the reflux temperature of the solvent.
  • solvents such as water, acetic acid, ethanol, butanol, dioxane, tetrahydrofuran and the like and at temperatures equivalent to the reflux temperature of the solvent.
  • formalin When formalin is used the reaction
  • the secondary amine, compound 2, employed in this reaction may be added to the reaction medium as the hydrochloride salt or as the base form with susequent in situ formation of the hydrochloride salt by the addition of hydrochloric acid.
  • typical secondary amines which may be utilized in the above reaction there can be mentioned, for example, dimethylamine, dibutylamine, piperidine, 4-methylpiperidine, morpholine, N-ethylpiperazine and the like.
  • the diacetyl xanthene compound, 6, may ber prepared by a Friedel-Crafts acylation reaction on xanthene or by a Grignard reaction of a xanthene bisamide, 3a, or a xanthene bis-ester, 3b, with methylmagnesium halide.
  • the xanthene bis-amides and bis-esters may be obtained by methods described hereinbefore.
  • the above oxidation reaction may be carried out using dichromate anion such as sodium dichromate or potassium dichromate as the oxidizing agent.
  • the reaction will proceed in from 15 minutes to 6 hours at a temperature of from 80 to 120C.
  • the amount of oxidizing agent is limited to the stoichiometric quantity required for oxidation of the 9-methylene group of the xanthene derivative.
  • Suitable solvents for this conversion are, for example, water, acetic acid, tert-butyl alcohol, and the like, or combinations of these solvents.
  • reaction R is a lower alkyl.
  • Hydrolysis and decarboxylation of the bis-phthalimido derivative, compound 10 can be carried out in solvents such as water, or lower alcohols such as ethanol, n-butanol and the like in the presence of acetic acid or mineral acids such as hydrochloric acid, sulfuric acid and the like, or mixtures of these acids.
  • solvents such as water, or lower alcohols such as ethanol, n-butanol and the like in the presence of acetic acid or mineral acids such as hydrochloric acid, sulfuric acid and the like, or mixtures of these acids.
  • the reaction will proceed in from 5 minutes to 48 hours at temperatures equivalent to the reflux temperature of the solvent.
  • the bis-phthalimido derivative, compound 10 may be prepared by an ester condensation [1. Shivers et al., J. Am. Chem. Soc. 69, 119 (1947)] ofa phthalimidoalkyl ester with a xanthene bis-lower alkyl ester, the preparation of which has been described hereinbefore.
  • EXAMPLE l1 EXAMPLE 12 2,7-BIS(PlPERlDlNOACETYL)XANTHENE HYDROCHLORIDE To a solution of 200 ml. of piperidine in 500 ml. of tetrahydrofuran were added 33.5 g (0.1 mole) of 2,7- bis(2-chloroaeetyl)xanthene and 2 g of potassium io- AiAn wit-1n ⁇ norm;r ⁇ n T!!! rnantinn mivturp um: allnu/Pri to stand for 7 days, filtered and the filtrate evaporated to dryness, leaving a residue which was treated with dilute acid and filtered.
  • the dihydrochloride salt was dissolved in water, filtered and the filtrate made alkaline with 20% NaOH solution. The resulting product was filtered, ehromatographed on alumina using hexane as the eluant, recrystallized from heptane and dried in vacuo to give the desired product. M.P. 63-65C.
  • R and R are individually selected from the group consisting of hydrogen, lower alkyl having from 1 to 6 carbon atoms, cycloalkyl having from 3 to 6 carbon atoms, alkenyl of from 3 to 6 carbon atoms and having the vinyl unsaturation in other than the l-position of the alkenyl group; or
  • n is a whole integer from 4 to 6
  • R is a member selected from the group consisting of hydrogen or lower alkyl of from 1 to 4 carbon atoms and can be linked to any one of the carbon atoms of the heterocyclic group;
  • X is a member selected from the group consisting of oxygen or NR, and R is hydrogen or lower alkyl of from 1 to 4 carbon atoms, or a pharmaceutically acceptable acid addition salt thereof.
  • each Y is the group group R3 8.
  • each Y is the group 10.
  • a compound of claim 13 wherein one of the groups is in the 2-position of the tricyclic rings and the other such group is in the 7-position.

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  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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US097379A 1970-12-11 1970-12-11 Bis-basic ketones of xanthene and xanthen-9-one Expired - Lifetime US3859286A (en)

Priority Applications (23)

Application Number Priority Date Filing Date Title
US097379A US3859286A (en) 1970-12-11 1970-12-11 Bis-basic ketones of xanthene and xanthen-9-one
CA118,192A CA948192A (en) 1970-12-11 1971-07-14 Bis-basic ketones of xanthene and xanthen-9-one and antiviral compositions thereof
NO3324/71A NO135249C (enrdf_load_stackoverflow) 1970-12-11 1971-09-07
GB4302671A GB1313454A (en) 1970-12-11 1971-09-15 Bis-basic ketones of xanthene and xanthen-9-one and antiviral compositions thereof
IE1168/71A IE35643B1 (en) 1970-12-11 1971-09-15 Bis-basic ketones of xanthene and xanthen-9-one and antiviral compositions thereof
IL37755A IL37755A (en) 1970-12-11 1971-09-17 Bis-basic ketones of xanthene and xanthen-9-one and antiviral compositions containing them
ZA716267A ZA716267B (en) 1970-12-11 1971-09-20 Bis-basic ketones of xanthene and xanthen-9-one and antiviral compositions thereof
AU33908/71A AU453068B2 (en) 1970-12-11 1971-09-27 Bis-basic ketones of xanthene and xanthen 9 one and antiviral compositions thereof
CH1501371A CH562818A5 (enrdf_load_stackoverflow) 1970-12-11 1971-10-14
DE19712151707 DE2151707A1 (de) 1970-12-11 1971-10-18 Basische bis-Ketone des Xanthens und Xanthen-9-ons mit antivirieller Wirkung
JP8252971A JPS5545549B1 (enrdf_load_stackoverflow) 1970-12-11 1971-10-20
AT956871A AT319944B (de) 1970-12-11 1971-11-05 Verfahren zur Herstellung neuer basischer Bis-ketone des Xanthens und Xanthen-9-ons bzw. von Salzen hievon
AT1010272A AT317890B (de) 1970-12-11 1971-11-05 Verfahren zur Herstellung neuer basischer Bis-ketone des Xanthen-9-ons bzw. von Salzen hievon
NL7115559A NL7115559A (enrdf_load_stackoverflow) 1970-12-11 1971-11-12
CS8104A CS166791B2 (enrdf_load_stackoverflow) 1970-12-11 1971-11-19
SE7115518A SE382458B (sv) 1970-12-11 1971-12-03 Forfarande for framstellning av bis-basiska ketoner av xanten och xanten-9-on med antivirusaktivitet.
AR239429A AR196404A1 (es) 1970-12-11 1971-12-06 Procedimiento para preparar bis-(cetonas basicas) de xanteno y de xanten-9-ona
HURI458A HU163026B (enrdf_load_stackoverflow) 1970-12-11 1971-12-08
BE776535A BE776535A (fr) 1970-12-11 1971-12-10 Cetones bis-basiques derivees du xanthene et de la xanthene-9-one, leurpreparation, et leurs utilisations therapeutiques
FR7144506A FR2118031B1 (enrdf_load_stackoverflow) 1970-12-11 1971-12-10
ES397821A ES397821A1 (es) 1970-12-11 1971-12-10 Procedimiento para la preparacion de cetonas bis-basicas dexanteno y de xanteno-9-ona teniendo actividad antiviral.
DK605771A DK132275C (da) 1970-12-11 1971-12-10 Analogifremgangsmade til fremstilling af antiviralt aktive 2,7-bis-(tert.aminoalkanoyl)-xanthener eller-xanthen-9-oner eller syreadditionssalte deraf
US05/333,768 US3957989A (en) 1970-12-11 1973-02-20 Antiviral compositions containing bis-basic ketones of xanthene and xanthen-9-one

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JP (1) JPS5545549B1 (enrdf_load_stackoverflow)
AR (1) AR196404A1 (enrdf_load_stackoverflow)
AT (2) AT317890B (enrdf_load_stackoverflow)
AU (1) AU453068B2 (enrdf_load_stackoverflow)
BE (1) BE776535A (enrdf_load_stackoverflow)
CA (1) CA948192A (enrdf_load_stackoverflow)
CH (1) CH562818A5 (enrdf_load_stackoverflow)
CS (1) CS166791B2 (enrdf_load_stackoverflow)
DE (1) DE2151707A1 (enrdf_load_stackoverflow)
DK (1) DK132275C (enrdf_load_stackoverflow)
ES (1) ES397821A1 (enrdf_load_stackoverflow)
FR (1) FR2118031B1 (enrdf_load_stackoverflow)
GB (1) GB1313454A (enrdf_load_stackoverflow)
HU (1) HU163026B (enrdf_load_stackoverflow)
IE (1) IE35643B1 (enrdf_load_stackoverflow)
IL (1) IL37755A (enrdf_load_stackoverflow)
NL (1) NL7115559A (enrdf_load_stackoverflow)
NO (1) NO135249C (enrdf_load_stackoverflow)
SE (1) SE382458B (enrdf_load_stackoverflow)
ZA (1) ZA716267B (enrdf_load_stackoverflow)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4061768A (en) * 1971-09-08 1977-12-06 Burroughs Wellcome Co. Certain cyclic carbonyl compounds used in the prophylaxis of allergic conditions
US4250097A (en) * 1978-03-08 1981-02-10 Syntex (U.S.A.) Inc. Compositions for and a method of preventing diabetic complications
US4496447A (en) * 1980-03-05 1985-01-29 Merck Patent Gesellschaft Mit Beschraenkter Haftung Aromatic-aliphatic ketones useful as photoinitiators
US6635786B2 (en) 2001-01-16 2003-10-21 Guilford Pharmaceuticals, Inc. Symmetrically disubstituted aromatic compounds and pharmaceutical compositions for inhibiting poly (ADP-ribose) glycohydrolase, and methods for their use
WO2016034963A1 (en) * 2014-09-04 2016-03-10 Basf Se Polycyclic photoinitiators
WO2021195400A1 (en) * 2020-03-26 2021-09-30 Provectus Pharmatech, Inc. Novel uses of halogenated xanthenes in oncology and virology

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4108896A (en) * 1972-12-21 1978-08-22 Richardson-Merrell Inc. Anthracene derivatives
US4008240A (en) * 1972-12-21 1977-02-15 Richardson-Merrell Inc. Xanthene and thioxanthene derivatives
US3817992A (en) * 1972-12-21 1974-06-18 Richardson Merrell Inc Xanthene and thioxanthene derivatives
JP7096817B2 (ja) * 2016-11-04 2022-07-06 オークランド ユニサービシーズ リミティド 三環式複素環式誘導体及びその使用

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3767674A (en) * 1971-10-01 1973-10-23 Ostra Lakemedel Ab Cyclohexeno thioxanthones

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ZA711333B (en) * 1970-03-27 1971-11-24 Richardson Merrell Inc Bis-basic ketones of fluorene and fluorenone

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3767674A (en) * 1971-10-01 1973-10-23 Ostra Lakemedel Ab Cyclohexeno thioxanthones

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4061768A (en) * 1971-09-08 1977-12-06 Burroughs Wellcome Co. Certain cyclic carbonyl compounds used in the prophylaxis of allergic conditions
US4250097A (en) * 1978-03-08 1981-02-10 Syntex (U.S.A.) Inc. Compositions for and a method of preventing diabetic complications
US4496447A (en) * 1980-03-05 1985-01-29 Merck Patent Gesellschaft Mit Beschraenkter Haftung Aromatic-aliphatic ketones useful as photoinitiators
US6635786B2 (en) 2001-01-16 2003-10-21 Guilford Pharmaceuticals, Inc. Symmetrically disubstituted aromatic compounds and pharmaceutical compositions for inhibiting poly (ADP-ribose) glycohydrolase, and methods for their use
US20040063785A1 (en) * 2001-01-16 2004-04-01 Guilford Pharmaceuticals, Inc. Symmetrically disubstituted aromatic compounds and pharmaceutical compositions for inhibiting poly (ADP-ribose) glycohydrolase, and methods for their use
WO2016034963A1 (en) * 2014-09-04 2016-03-10 Basf Se Polycyclic photoinitiators
US10113075B2 (en) 2014-09-04 2018-10-30 Igm Malta Limited Polycyclic photoinitiators
WO2021195400A1 (en) * 2020-03-26 2021-09-30 Provectus Pharmatech, Inc. Novel uses of halogenated xanthenes in oncology and virology
US11975106B2 (en) 2020-03-26 2024-05-07 Provectus Pharmatech, Inc. Uses of halogenated xanthenes in oncology and virology

Also Published As

Publication number Publication date
ES397821A1 (es) 1975-06-16
HU163026B (enrdf_load_stackoverflow) 1973-05-28
NL7115559A (enrdf_load_stackoverflow) 1972-06-13
AR196404A1 (es) 1973-12-27
DE2151707A1 (de) 1972-06-29
CH562818A5 (enrdf_load_stackoverflow) 1975-06-13
IE35643L (en) 1972-06-11
IE35643B1 (en) 1976-04-14
SE382458B (sv) 1976-02-02
NO135249C (enrdf_load_stackoverflow) 1977-03-09
JPS5545549B1 (enrdf_load_stackoverflow) 1980-11-18
AT317890B (de) 1974-09-25
DK132275B (da) 1975-11-17
CA948192A (en) 1974-05-28
FR2118031A1 (enrdf_load_stackoverflow) 1972-07-28
NO135249B (enrdf_load_stackoverflow) 1976-11-29
BE776535A (fr) 1972-04-04
CS166791B2 (enrdf_load_stackoverflow) 1976-03-29
IL37755A0 (en) 1971-11-29
FR2118031B1 (enrdf_load_stackoverflow) 1975-06-13
AT319944B (de) 1975-01-10
AU3390871A (en) 1973-04-05
IL37755A (en) 1974-07-31
AU453068B2 (en) 1974-09-19
ZA716267B (en) 1972-05-31
GB1313454A (en) 1973-04-11
DK132275C (da) 1976-04-12

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