US3817992A - Xanthene and thioxanthene derivatives - Google Patents

Xanthene and thioxanthene derivatives Download PDF

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Publication number
US3817992A
US3817992A US00317128A US31712872A US3817992A US 3817992 A US3817992 A US 3817992A US 00317128 A US00317128 A US 00317128A US 31712872 A US31712872 A US 31712872A US 3817992 A US3817992 A US 3817992A
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bis
xanthene
thioxanthene
virus
compounds
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US00317128A
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A Sill
F Sweet
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Richardson Vicks Inc
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Richardson Merrell Inc
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Priority to US00317128A priority Critical patent/US3817992A/en
Priority to ZA738215*A priority patent/ZA738215B/xx
Priority to AU61884/73A priority patent/AU476380B2/en
Priority to CA184,442A priority patent/CA1018973A/en
Priority to IL43665A priority patent/IL43665A/en
Priority to DE2362695A priority patent/DE2362695A1/de
Priority to GB5825873A priority patent/GB1416749A/en
Priority to FR7345509A priority patent/FR2211233B1/fr
Priority to JP48141917A priority patent/JPS4988874A/ja
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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

Definitions

  • virus infections is primarily achieved by means of immunization vaccines.
  • immunization vaccines For example, poliomyelitis, smallpox, measles and influenza are well recognized diseases in which viral vaccines have proven effective.
  • viral vaccines have had only a moderate success in animal prophylaxis.
  • Each vaccine acts primarily against a specific virus and is not heterophilic in the protection it offers.
  • vaccines do not provide a practical solution against the wide array of infectious viruses, even where limited as for example, solely to respiratory viruses.
  • This invention relates to new derivatives of xanthene and thioxanthene, to their preparation and to their use as pharmaceutical agents. More particularly, the compounds of the present invention are 2,7-bis basic vinylene derivatives of xanthene and thioxanthene whichare useful as antiviral agents. Still more particularly, the compounds of the present invention maybe represented by the following general formula:
  • Y is oxygen or sulfur;
  • A is a straight or branched alkylene chain having from 1 to 4 carbon atoms; and R and R are each 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 having from 3 to 6 carbon atoms in which the unsaturation is in a position other than in the 1-position of the alkenyl group, and when R and R, are 3 taken together with the nitrogen atom to which they are attached represent the pyrrolidinyl, morpholino or piperidino radical; and their pharmaceutically accept- In the above reaction, the symbols A, R, R and Y have the values previously assigned to them.
  • compositions are administered either prior to infection, as with a prophylactic use or treatment, or they may be therapeutically administered subsequent to infection, as with a curative use or treatment.
  • the compounds of this invention may also be applied externally or topically directly at the situs of infection or they may be administered internally or systemically, irrespective of whether the treatment is prophylactic or curative in nature. In either event, replication of the virus is inhibited or prevented with the concomitant result that the various disease symptoms characteristic of the pathogenic virus infection are no longer present.
  • each side chain can be viewed as consisting essentially of a basic amino function located at the terminal end of the side chain, an a, B-unsaturated or vinylene function located at the proximal end of the side chain, which also serves as a bridging function connecting the side chain to the aromatic nucleus, and an alkylene chain of determinate length which separates the vinylene function from the terminal basic amino function.
  • the alkylene chain which separates the vinylene group from the basic amino group consists of from i to 4 carbon atoms and represents either a straight or branched alkylene chain. Additionally, each of the alkylene groups may be the same or different; preferably, however, both alkylene groups are the same. Illustrative of the various alkylene groups which can be represented by the symbol A are methylene, ethylene, trimethylene, l-methylethylene, tetramethylene, and 2- methyltrimethylene.
  • the basic amino function represented by the symbol Rs N R can be a primary, secondary or a tertiary amino group.
  • each amino group is a tertiary amine.
  • the symbols R and R represent either hydrogen or a lower alkyl group.
  • the term lower alkyl as used herein with regard to the basic amino function relates to groups having from I to 6 carbon atoms. Illustrative of such groups can be.mentionedboth straight or branched chain alkyl radicals such as: methyl, ethyl, n-propyl, isopropyl n-butyl, sec-butyl, isoamyl, n-pentyl and nhexyl.
  • R and R each represent lower alkyl, a preferred subgenus is-formed.
  • Each R and R can also represent a'cycloalltyl group having from 3 to 6 carbon atoms.
  • Illustrative of such groups are the cyclopropyl, cyclobutyhcyclopentyl and j cyclohexyl radicals.
  • R and R also represent an alkenyl group having from 3 to 6 carbon atoms. In addition to the unsaturation which must be present, this unsaturation must be in a position other than the l-position of the alkenyl group in order to prevent hydrolysis from occurring.
  • Illustrative of such groups are the allyl, 3- tsn n lh -bezrsn i a s- R and R may also be joined with the nitrogen atom to which they are attached to represent various saturated monocyclic, heterocyclic radicals. Typical of such heterocyclic groups are the l-pyrrolidinyl, piperidino ormorpholino radicals. Compounds containing these groups are readily prepared and typify saturated monocyclic, heterocyclic radicals which are generally useful in lieu of the dilower alkylamino groups present in the compounds of this invention.
  • the vinylene portion of the molecule serves as a bridging function which anchors the basic alkylene side chain to the aromatic nucleus.
  • the compounds of the present invention are characterized by the fact that they are unsaturated and further, that this unsaturation lies in an a, B-position with respect to the aromatic nucleus.
  • the aromatic nucleus consists of either xanthene or thioxanthene, depending upon whether the symbol Y is oxygen or sulfur.
  • compositions represented by formula (1) are intended to apply to any non-toxic organic or inorganic acid addition salts of the base compounds represented by formula (1).
  • inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulphuric, and phosphoric acids and acid metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate.
  • organic acids which form suitable salts include the mono, di and tricarboxylic acids.
  • Illustrative of such acids are, for example, acetic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic, phydroxybenzoic, phenylacetic, cinnamic, salicylic, 2- phenoxybenzoic and sulfonic acids such as methane sulfonic acid and 2-hydroxyethane sulfonic acid.
  • Either the mono or the di-acid salts can be formed, and such salts can exist in either a hydrated or a substantially anhydrous form.
  • the acid addition salts of these compounds are crystalline materials which are soluble in water and various hydrophilic organic solvents and which in comparison to their free base forms, generally demonstrate higher melting points and an increased chemical stability.
  • Dehydration can be achieved by dissolving the 2,7-bis basic alkanol (l l l) in a high boiling solvent, as for example, ethylene glycol or ethylene glycol monoethyl ether, adding the dehydrating agent and heating thene (l l), which serve as starting materials for the compounds of the present invention are also prepared in a two-step process.
  • the first step involves the Friedel-Crafts acylation of xanthene or thioxantheneuto form a 2,7-bis (w-haloalkanoyl) derivative.
  • the second step involves amination of these derivatives to form the corresponding 2,7-bis basic ketones of xanthene and thioxanthene.
  • the aminaticn can take place under a variety of conditions.
  • the w-haloalkanoyl derivatives can be heated with a large excess of an amine, the excess amine serving as both the reaction medium and hydrohalide acceptor.
  • the compounds may be heated with an amine in a suitable solvent such as toluene, dioxane or dimethylformamide to effect condensation.
  • suitable solvent such as toluene, dioxane or dimethylformamide
  • Treatment of the 2,7-bis basic-ketones of xanthene and thioxanthene (II) with a reducing agent results in the reduction of the a-ketone to that of a secondary alkanol, i.e., the 2,7-bis basic alkanols of xanthene and thioxanthene (III)
  • a suitable solvent using sodiumborohydride as the reducing agent at temperatures which range from about 20 to about 100C for periods of time which range anywhere from about minutes to about 24 hours.
  • solvents can be suitably employed, including tetrahydrofuran, methanol, ethanol and water.
  • a base such as sodium hydroxide is utilized in order to minimize the rate at which the sodium borohydride reagent decomposes.
  • the reduction of the 2,7-bis basic ketones of xanthene and thioxanthene is accomplished by dissolving the ketones in tetrahydrofuran and adding solid sodium borohydride in small increments with continued stirring.
  • concentrated hydrochloric acid or sulfuric acid is employed as the dehydrating agent.
  • the minimum time required for dehydration can be ascertained by monitoring the reaction medium by means of conventional procedures, e.g., observing the disappearance of the OH-stretching frequency in the infrared spectrumj
  • the isolation of the 2,7 -bis basic vinylene derivatives of xanthene and thioxanthene l so prepared is achieved using methods known to the art.
  • the reaction mixture can be made alkaline and the product extracted with ether; alternatively, any unreacted starting material can be separated from the final product by passage through a chromatographic column.
  • the compounds of the present invention are antiviral agents. Preferably, they are administered to an animal host to prevent or inhibit viral infections.
  • the term host refers to any viable biological material or intact animal including humans which is capable of inducing the formation of interferon and which serves as a support means for virus replication.
  • the host can be of animal or mammalian origin. lllustratively such hosts include birds, mice, rats, guinea pigs, gerbils, ferrets, dogs, cats, cows, horses and humans. Other viable biological material such as used in the production of vaccines may also act as a host.
  • tissue cultures prepared from organ tissues, such as mammalian kidney or lung tissue, as well as tissue cultures prepared from embryo tissue, such as obtained from amniotic cells or chick allantoic fluid have been found to be useful hosts.
  • the treatment of virus infections for purposes of the present invention encompasses both the prevention and the inhibition of characteristic disease symptoms in a mammalian host susceptible to invasion by a pathogenic virus.
  • mammalian virus infections which can be prevented or inhibited by the administration of the compounds of the presentinvention are infections caused by picomaviruses, such as encephalomyocarditis virus; myxoviruses, such as influenza A (lap/305) virus; arboviruses; such as Semliki forest virus; the herpes group of viruses, including herpes simplex; and the poxvi'ruses, as for example vaccinia IHD.
  • the compounds of the present in vention when administered orally or subcutaneously to mice in-varying doses either shortly prior or subsequent to a fatal inoculation of aneurotropic virus such as encephalomyocarditis virus, having a LD anywhere from 5 to 50, delay or prevent completely the onset of death.
  • Salts of these compounds are generally administered in compositions containing a 0.15 percent aqueous hydroxyethylcellulose vehicle, whereas the free base compounds are generally administered in compositions containing a 10 percent surfactant vehicle in order to help solubilize the compound.
  • aneurotropic virus such as encephalomyocarditis virus
  • mice are used for each treated group with an additional ministration the test virus is titrated in order to determine the potency or LD for the particular virus pool used as a challenge.
  • the control animals are given a placebo containing the identical volume of vehicle without, of course, the active ingredient. Because of the lethal nature of the test system employed, the antiviral nature of the test compound is dramatically illustrated by a side by side comparison of the survival time of treated animals with the untreated control group of animals.
  • Respiratory viruses such as influenza A (Jap/305) virus, which are also lethal to the test animals employed, are administered via intranasal instillation. Animals infected in this manner have the active ingredients administered in the same manner as the test virus, and again a side b side comparison is made of the survivors of the anima 8 treated with the untreated control animals.
  • a mouse treated with a normally fatal infection of encephalomyocarditis or influenza virus occasionally survives without further treatment. This may be the result of a prior, interferon-induced infection in the mouse, or perhaps due to some genetic factor or other natural defense mechanism not presently understood. For this reason the control group selected is of sufficient size as to statistically reduce to a negligible amount the influence of such a chance survivor upon the test results.
  • the vaccinia test virus is typical of the dermatotrophic type viruses which respond to treatment with compositions containing the compounds of the instant invention.
  • the vaccinia virus generally produces a nonfatal infection in mice, producing characteristic tail lesions when the virus is subcutaneously administered to the tail of the mouse.
  • the instant compounds are administered either orally or subcutaneously either prior to or subsequent to the vaccinia infection.
  • Tail lesions are subjectively scored on the eighth day following infection against untreated animals which serve as a control group.
  • the compounds of the present invention have been found to be effective in varying degrees against one or all of these test virus systems. u
  • the mode of activity of the active ingredients of the present invention is not rigirously defined. lnter alia, the compounds of the present invention may induce the formation of interferon in a viable host.
  • Interferon is a biological substance of unknown chemical structure, presumably proteinaceous in nature, which is produced by host cells in response to a viral infection. The interferon so produced acts to induce a virus inhibiting substance, which inhibits in some yet unknown manner the intracellular replication of the virus without appearing to have any inactivation effect per se upon the virus itself.
  • a few of the viruses susceptible to interferon replication inhibition are described in Horsfall and Tamm, Viral and Rickettsial Infections of Man 4th Edition (1965), J. B. Lippincott Company, pp. 328-9.
  • the compounds of the present invention may be prophylactically administered in order to prevent the spread of contagious viral diseases or they may be therapeutically administered to a host already infected intended for their curative effect.
  • the administration be made within to 96 hours prior to the infection of the host animal with a pathogenic virus.
  • the compounds of the present invention are administered for their curative effect, it is preferred that they are administered within about 1 or 2 days following infection of the host in order to obtain the maximum therapeutic effect.
  • the dosage to be administered will be dependent upon such parameters as the particular virus for which either treatment or prophylaxis is desired, the species of animal involved, its age, health, weight, the extent of infection, concurrent treatment,if any, frequency of treatment and the nature of the effect desired.
  • a daily dose of the active ingredients will generally range from about 0.1 mg to about 500 mg per kg of body weight.
  • dosage levels of the administered active ingredients for intravenous treatment range from about 0.1 mg to about 10 mg per kg of body weight; for intraperitoneal administration range from about 0.1 mg to ab0ut 50 mg per kg of body weight; for subcutaneous administration range from about 0.l to about 250 mg per kg of body weight; for oral administration may be from about 0.1 mg to about 500 mg per kg of body weight; for intranasal instillation range from about 0.1 mg to about 10 mg per kg of body weight; and for aerosol inhalation therapy, the range is generally from about 0.1 mg to about 10 mg per kg of body weight.
  • novel compounds described herein can also be administered in various different dosage unit forms, e.g., oral compositions such as tablets, capsules, dragees, lozenges, elixirs, emulsions, clear liquid solutions and suspensions; parenteral compositions such as intramuscular, intravenous or intraderrnal preparations; and topical compositions, such as lotions, creams or ointments.
  • oral compositions such as tablets, capsules, dragees, lozenges, elixirs, emulsions, clear liquid solutions and suspensions
  • parenteral compositions such as intramuscular, intravenous or intraderrnal preparations
  • topical compositions such as lotions, creams or ointments.
  • the amount of active ingredientcontained in each dosage unit form will, of course, vary widely according to the particular dosage unit employed, the animal host being treated, and the nature of the treatment, i.e., whether prophylactic or therapeutic in nature.
  • a particular dosage unit may contain
  • Suitable solid excipients include gelatin, lactose, starches, magnesium stearate and petrolatum.
  • Suitable liquid excipients include water and alcohols such as ethanol, benzyl alcohol and the polyethylene alcohols either with or without the addition of a surfactant.
  • the preferred liquid excipients particularly for injectable preparations include water, saline solution, dextrose and glycol solutions such as an aqueous propylene glycol or an aqueous solution of polyethylene glycol.
  • Liquid preparations to be used as sterile injectable solutions will ordinarily contain from about 0.5 percent to about 25 percent by weight, and preferably from about 1 per cent to about 10 percent by weight, of the active ingredient in solution.
  • various oils are utilized as carriers or excipients.
  • oils are mineral oils, glyceride oils such as lard oil, cod liver oil, peanut oil, sesame oil, corn oil and soybean oil.
  • a suitable method of administration for the compounds of the present invention is orally either in a solid dose form such as a tablet or capsule, or in a liquid dose form such as an elixir, suspension, emulsion or syrup.
  • the active ingredient comprises from about 0.5 percent to about 10 percent by weight of an oral liquid composition.
  • the pharmaceutical carrier is generally aqueous in nature, as for example, aromatic water, a sugar-based syrup or a pharmaceutical mucilage.
  • suspending agents may be added as well as agents to .control viscosity, as for example, magnesium aluminum silicate or carboxymethylcellulose. Bnffers, preservatives, emulsifying agents and other excipients can also be added.
  • the proportion of active ingredient ranges from about 0.05 percent to about 20 percent by weight, and preferably from about 0.1 percent to about 10 percent by weight of the liquid composition.
  • such composi tions may contain a non-ionic surfactant having a hydrophile-lipophile balance (HLB) of from about 12 to about 17.
  • HLB hydrophile-lipophile balance
  • the quantity of surfactant in such formulations ranges from about 5 percent to about 15 percent by weight.
  • the surfactant can be a single component having the above identified l-lLB, or a mixture of two or more components having the desired HLB.
  • surfactants useful in parenteral formulations are the class of polyoxyethylene sorbitan fatty acid esters as, for example, sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol.
  • Theconcentration of active ingredient contained in these various parenteral dosage unit forms varies over a broad range and comprises anywhere from about 0.05 percent to about percent by weight of the total formulation, the remaining component or components comprising liquid phar maceutical excipients previously mentioned.
  • the active ingredients of the present invention can also be admixed directly with animal feeds or incorporated into the drinking water of animals. For most purposes, an amount of active ingredient is used which provides from about 0.0001 percent to about 0.1 percent and preferably, from about 0.001 percent to about 0.02 percentby weight of the active ingredient based upon the total weight of feed intake.
  • the active ingredients can be admixed in animal feed concentrates, suitable for use by farmers or livestock growers for incorporation in appropriate amounts with the final animal feeds. These concentrates ordinarily comprise from about 0.5 percent to about 95 percent by weight of the active ingredient compounded with a finely divided solid carrier or flour, such as wheat, corn, soybean or cottonseed flour.
  • nutrients and fillers may'also be added such as ground cereal, charcoal, fullers earth, oyster shells and finely divided attapulgite or bentonite.
  • the active ingredients of the present invention can be packaged in a suitable pressurized container together with an aqueous or volatile propellant for use as an aerosol.
  • a suitable discharge valve is fitted to an opening in the container from which the active ingredients may be conveniently dispensed in the form of a spray, liquid, ointment or foam. Additional adjuvants such as co-solvents, wetting agents and bactericides may be employed as necessary.
  • the propel lant used is a liquified gaseous compound, preferably a mixture of low molecular weight fluorinated hydrocarbons. These haloalkanes are preferred because of their compatibility with the active ingredients of the present invention, and because they are non-irritating when applied to skin surfaces.
  • Other useful propellants include ethylene oxide,'carbon dioxide, propane and nitrogen gas.
  • EXAMPLE lll 2,7-Bis( 4-piperidinobutyryl )xanthene A mixture of 19.6 (0.05 mole) of 2,7-bis(4- chlorobutyryl)xanthene, 34.0 g (0.4 mole) of piperidi'ne, 16.6 g (0.1 mole) of potassium iodide and 200 ml of butanone is refluxed with stirring for a period of .60 hours. The reaction mixture is cooled and poured into 1 liter of water.
  • the residue 50 obtained is dissolved in a minimum of ethanol, treated withethanolic HCl to form the dihydrochloride salt and diluted with diethyl ether.
  • the product which forms is filtered, crystallized from a methanol-diethylether solution and hydrated in a constant humidity chamber to give the desired 2,7- bis[3-(diethylamino)propionyl1thioxanthene as the dihydrochloride dihydrate having a m.p. of 13740C.
  • the solid product is dissolved in a 10 percent hydrochloric acid solution, filtered and the filtrate made alkaline with a 10 percent sodium hydroxide solution.
  • the alkaline filtrate is extracted with methylene chloride.
  • the organic extract is then washed with water, followed by a wash of saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated to dryness in vacuo.
  • the residue containing the desired a, a'-bis(- 3-piperidinopropyl)xanthene-2,7-dimethanol is recrystallized twice from benzene to yield a product having a m.p. of l45-6C.
  • EXAMPLE VI 2 ,7-Bis( 4-piperidino l -hutenyl )xanthene A solution of 17.4 g (0.035 mole) of a,a-bis(3- piperidinopropyl)xanthcne-2,7-dimethanol is dissolved in a mixture of 25 ml of ethylene glycol monoethyl ether and 25 ml of concentrated hydrochloric acid and heated on the steam bath for 5 minutes. The solution is diluted with an equal volume of water and made alkaline with a 20 percent sodium hydroxide solution.
  • EXAMPLE VII The following Example is illustrative of the antiviral activity for the compounds ofthe present invention. 7
  • mice Thirty mice each weighing approximately l2-l5 gms are divided into two groups, a control group containing 20 animals and a test group of 10 animals. All of the animals are challenged with a fatal dose (8LD of encephalomyocarditis virus.
  • the test group of animals are treated both prophylactically and therapeutically using a parenteral composition containing 2,7-bis(4- piperidino-l-butenyl)xanthene as the active ingredient dissolved in a 10 percent solution of sorbitan monooleate.
  • the composition contains the active ingredient in an amount such that each dosage contains 0.25 ml which is equivalent to a dose level of 50 mg per kg.
  • the control group receives a subcutaneous placebo containing the same volume of vehicle without, of course, the active ingredient. Observations over a ten day period show a termination of all the control animals within a period of from 4 to 5 days, with the treated group of animals surviving for a statistically longer period of time. Y
  • a soft gelatin capsule is prepared in which the talc is omitted.
  • the dry 2,7-bis[4- (dimethylamino l -butenyl ]xanthene dihydrochloride powder can be filled as a granulation, slug or compressed tablet directly into the rotary dye or plate mold in which the soft gelatin capsule is formed.
  • the granulation obtained upon mixing lactose starchand granulated starch paste is dried, screened and mixed-with the active ingredient and magnesium stearate. The mixture is compressed into tablets weighing 150 milligrams each.
  • Each ml Contains Ingredients Amount 50 mg 2,7-bis[4-(diethylamino)- l-butenyllxanthene 1.000 g 100 mg Polyoxyethylene sorbitan monooleate 2.000 g 0.0064 Sodium chloride 0.128 g Water for injection, q.s. 20.000 ml
  • EXAMPLE Xll Preparation of dusting powder formulation 7 The following formulation illustrates a dusting powder for topical use:
  • Y is oxygen or sulfur;
  • A is a straight or branched alkylene chain having from one to four carbon atoms;
  • R and R are each selected from the group consisting of hydrogen, lower alkyl having from one to six carbon atoms, cycloalkyl having from three to six carbon atoms, alkenyl having from three to six carbon atoms in which the unsaturation is in a position other than in the l-position of the alkenyl group, and when R and R are taken together with the nitrogen atom to which they are attached represent the pyrrolidinyl, morpholino or piperidino radical; and the pharmaceutically acceptable acid addition salts thereof.
  • each R and R is a lower alkyl group having from one to six carbon atoms.
  • a process of preparing a compound of claim 1 which comprises reacting a 2,7-bis basic alkanol of xanthene and thioxanthene having the general formula:
  • Y is oxygen or sulfur
  • A is a straight or branched alkylene chain having from one to four carbon atoms
  • R and R are each selected from the group consisting of hydrogen, lower alkyl having from one to six carbon atoms, cycloalkyl having from three to six carbon atoms, alkenyl having from three to six carbon atoms in which the unsaturation is in a position other than in the l-position of the alkenyl group, and when R and R are taken together with the nitrogen atom to which they are attached represent the pyrrolidinyl, morpholino or piperidino radical; reacting said alkanol in solution with a dehydrating agent; and isolating the resulting 2,7-bis basic vinylene derivative of xanthene and thioxanthene therefrom.

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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US00317128A 1972-12-21 1972-12-21 Xanthene and thioxanthene derivatives Expired - Lifetime US3817992A (en)

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Application Number Priority Date Filing Date Title
US00317128A US3817992A (en) 1972-12-21 1972-12-21 Xanthene and thioxanthene derivatives
ZA738215*A ZA738215B (en) 1972-12-21 1973-10-23 Xanthene and thioxanthene derivatives
AU61884/73A AU476380B2 (en) 1972-12-21 1973-10-26 Xanthene and thioxanthene derivatives
CA184,442A CA1018973A (en) 1972-12-21 1973-10-29 Xanthene and thioxanthene derivatives
IL43665A IL43665A (en) 1972-12-21 1973-11-21 2,7-bis(dialkyl aminoalkenylene)xanthene and thioxanthene derivatives
DE2362695A DE2362695A1 (de) 1972-12-21 1973-12-17 Neue 2,7-bis basische vinylenderivate von xanthen und thioxanthen, verfahren zu ihrer herstellung sowie diese enthaltende pharmazeutische zusammensetzungen
GB5825873A GB1416749A (en) 1972-12-21 1973-12-17 Xanthene and thioxanthene derivatives
FR7345509A FR2211233B1 (de) 1972-12-21 1973-12-19
JP48141917A JPS4988874A (de) 1972-12-21 1973-12-20

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JP (1) JPS4988874A (de)
AU (1) AU476380B2 (de)
CA (1) CA1018973A (de)
DE (1) DE2362695A1 (de)
FR (1) FR2211233B1 (de)
GB (1) GB1416749A (de)
IL (1) IL43665A (de)
ZA (1) ZA738215B (de)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BE776535A (fr) * 1970-12-11 1972-04-04 Richardson Merrell Inc Cetones bis-basiques derivees du xanthene et de la xanthene-9-one, leurpreparation, et leurs utilisations therapeutiques

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3856789A (en) * 1971-04-23 1974-12-24 Richardson Merrell Inc Bis-basic ketones of thioxanthene

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BE776535A (fr) * 1970-12-11 1972-04-04 Richardson Merrell Inc Cetones bis-basiques derivees du xanthene et de la xanthene-9-one, leurpreparation, et leurs utilisations therapeutiques

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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

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GB1416749A (en) 1975-12-03
IL43665A (en) 1977-05-31
FR2211233A1 (de) 1974-07-19
AU6188473A (en) 1975-05-01
CA1018973A (en) 1977-10-11
AU476380B2 (en) 1976-09-16
FR2211233B1 (de) 1977-01-28
ZA738215B (en) 1974-08-28
IL43665A0 (en) 1974-03-14
DE2362695A1 (de) 1974-06-27

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