US3859307A - Bis-basic esters and amides of xanthene and xanthone - Google Patents

Bis-basic esters and amides of xanthene and xanthone Download PDF

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Publication number
US3859307A
US3859307A US162716A US16271671A US3859307A US 3859307 A US3859307 A US 3859307A US 162716 A US162716 A US 162716A US 16271671 A US16271671 A US 16271671A US 3859307 A US3859307 A US 3859307A
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carbon atoms
bis
xanthene
xanthone
compounds
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US162716A
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Albert A Carr
Robert W Fleming
Arthur D Sill
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Richardson Vicks Inc
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Richardson Merrell Inc
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Priority to US162716A priority Critical patent/US3859307A/en
Priority to IL39725A priority patent/IL39725A/en
Priority to GB2959472A priority patent/GB1350520A/en
Priority to CA146,373A priority patent/CA976962A/en
Priority to DE2233223A priority patent/DE2233223A1/de
Priority to JP6829772A priority patent/JPS5725553B1/ja
Priority to CH1037072A priority patent/CH587838A5/xx
Priority to FR7225600A priority patent/FR2145717B1/fr
Priority to NL7209761A priority patent/NL7209761A/xx
Priority to US05/375,754 priority patent/US3957986A/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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • each A is alkylene of 2 to about 8 carbon atoms and separates its adjacent Y and amino nitrogen by an alkylene chain of at least 2 carbon atoms; and each Y is oxygen, or
  • R is hydrogen or (lower)alkyl of l to 4 carbon atoms; or a pharmaceutically acceptable acid addition salt thereof.
  • the compounds of this invention include both the base form and pharmaceutically acceptable acid addition salts of the base form wherein the base form can be represented by the formula R O O R N A Y t 7 it Y..t N m 3 2 4 Formula. I wherein:
  • Z is oxygen or H each of R and R is hydrogen
  • each A is alkylene of 2 to about 8 carbon atoms and separates its adjacent Y and amino nitrogen by an alkylene chain of at least 2 carbon atoms; and each Y is oxygen, or
  • R is hydrogen or (lower)alkyl of l to 4 carbon atoms; or a pharmaceutically acceptable acid addition salt thereof.
  • one of the groups can be linked to the tricyclic ring system by replacement of any of the four hyd rogens of the benzenoid ring to which such group is attached.
  • one of the groups will be in any positions of 1 through 4 of the tricyclic ring system and the other will be in any of the positions 5 through 8.
  • one of the basic side chains is in the 2-position and the other in the 7-position of the tricyclic ring system.
  • Each of the alkylene groups as represented by A in the above generic Formula I is an alkylene group having from 2 to about 8 carbon atoms which can be straight chained, or branched chained and which separates its adjacent Y from the amino nitrogen by an alkylene chain of at least two carbon atoms.
  • the Y group and the amino nitrogen are not on the same carbon atom of the alkylene group.
  • Each of the alkylene groups as represented by A can be the same or different. Preferably both of these groups are the same.
  • alkylene groups as represented by A there can be mentioned: 1,2-ethylene; 1,3-propylene; 1,4- butylene; 1,5-pentylene; 1,6-hexylene; 2-methyl-l,4- butylene; 2-ethyl'l,4-butylene; 3-methyl-l,5- pentylene; 2,2-dimethyl-l,S-pentylene and the like.
  • A is alkylene having from 3 to 6 carbon atoms.
  • R and R can be hydrogen, (lower)alkyl, cycloalkyl of 3 to 6 ring carbon atoms, alkenyl of 3 to 6 carbon atoms having the vinyl unsaturation in other than the l-position of the alkenyl group, or each set of R and R taken together with the nitrogen atom to which they are attached is a saturated monocyclic heterocyclic group.
  • cycloalkyl groups as represented by each of R and R there can be mentioned: cyclopropyl; cyclobutyl; cyclopentyl and cyclohexyl.
  • R and R represent alkenyl groups
  • the vinyl unsaturation is in other than the 1-position of said alkenyl group.
  • alkenyl groups as can be represented by each of R and R there can be mentioned: allyl; 3-butenyl; 4- hexenyl; and the like.
  • heterocyclic groups represented by R and R together with the nitrogen atom to which they are attached there can be mentioned various saturated monocyclic heterocyclic groups such as those generally equivalent to di(lower- )alkylamino groups in the pharmaceutical arts, e.g., pyrrolidino, piperidino, morpholino, N- (lower)alkylpiperazino such as N-methylpiperazino, N-ethylpiperazino, and the like.
  • R and R groups can be the same or different.
  • Preferably all of the R and R groups are the same.
  • the amino groups are preferably tertiary amino groups such as di(lower- )alkylamino, dialkenylamino or each set of R and R together with the nitrogen to which they are attached is pyrrolidino, piperidino, N-(lower)alkylpiperazino or morpholino.
  • Each Y group in Formula I can be oxygen or wherein R is hydrogen or (lower)alkyl of l to 4 carbon atoms. Preferably R is hydrogen.
  • (lower)alkyl or (lower)alkoxy as used herein relates to such groups having from 1 to 6 carbon atoms and preferably from 1 to 4 carbon atoms.
  • (lower)alkyls as can be represented by each of R and R there can be mentioned straight or branched chain alkyls such as: methyl, ethyl, n-propyl, isopropyl, n-butyl, secondary butyl, tertiary butyl, isoamyl, n-pentyl, n-hexyl, and the like.
  • the compounds of this invention can be (a) xanthene and xanthone esters or (b) xanthene and xanthone amides, which can be illustrated by the following formulas, respectively:
  • compounds of this invention there may be mentioned, for example, bis(3- diethylaminopropyl)-9-oxoxathene-2,7-dicarboxylate dihydrochloride, bis(3-diethylaminopropyl)xanthene- 2,7-dicarboxylate dihydrochloride, bis(3-di-nbutylaminopropyl)-9-oxoxanthene-2,7-dicarboxylate dihydrochloride, bis(3-di-nbutylaminopropyl)xanthene-2,7-dicarboxylate dihydrochloride, N,N -bis( 3-di-n-butylaminopropyl)-9- oxoxanthene-2,7-dicarboxamine, N,N-bis(3-di-nbutylaminopropyl)xanthene-2,7-dicarboxamide, bis(3- piperidinopropyl)-9-oxath
  • Pharmaceutically acceptable acid addition 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, propionic, glycolic, lactic, pyruvic, malonic, succinic, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic, salicylic, 2-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 with 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 the 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 mammalian origin.
  • 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 viruses in the presence of a host cell. Some of the viruses susceptible to replication inhibition by interferon are set forth in Horsfall and Tamm, Viral and Rickettsial Infections of Man," 4th Edition (1965), .l. 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); arbovirus, for example, Semliki forest; Herpes virus group, for example, herpes simplex; and poxviruses; for example, Vaccinia IHD.
  • picornavirus for example, encephalomyocarditis
  • myxovirus for example, Influenza A (lap/305)
  • arbovirus for example, Semliki forest
  • Herpes virus group for example, herpes simplex
  • poxviruses for example, Vaccinia IHD.
  • 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 about
  • a daily dosage of the active ingredients will generally range from less than about (H to over about 500 mg (milligram) per kg (kilogram) of body weight.
  • dosage levels of the administered active ingredient can be intravenous, 0.l to about 10 mg/kg; intraperitoneal, 0.1 to about 50 mg/kg; subcutaneous, 0.1 to about 250 mg/kg; oral, O.l
  • 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 from less than about 2.0 mg to over 3 grams of active ingredients in a significant quantity of a nontoxic 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.
  • oils there can be mentioned those of petroleum, animal, vegetable or synthetic origin, 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 the 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 will depend, 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.
  • animal feed concentrates can ordinarily comprise about 0.5 to about 95% by weight of the active ingredient compounded together with a finely divided solid, preferably flours, such as wheat, corn, soya bean and cottonseed.
  • 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, as well as the feed concentrates, can additionally contain other components of feed concentrates or animal feeds, as will be readily understood.
  • the active ingredients can be packaged in a pressurized aerosol container together with a gaseous or liquefied propellant, for example, dichlorodifluoromethane, carbon dioxide, nitrogen. propane, etc. with the usual adjuvants such as co-solvents, and wetting agents, as may be necessary or desirable.
  • a gaseous or liquefied propellant for example, dichlorodifluoromethane, carbon dioxide, nitrogen. propane, etc. with the usual adjuvants such as co-solvents, 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 emulsifying 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 polygly
  • 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 HLB (hydrophile-lipophile balance) of about 12 to 17.
  • HLB hydrophile-lipophile balance
  • Such formulations can be solutions, suspensions or emulsions in conventional 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 formulation can vary from about 5 to 15% by weight ofthe formulation.
  • the quantity ofa 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 20 by weight of the formula tion.
  • the 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 conventional excipients for injectable compositions.
  • the surfactant can be a single surfactant having the above-indicated HLB or a mixture of two or more surfactants wherein such mixture has the indicated l-lLB.
  • 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.
  • the compounds of this invention can be prepared by a variety of procedures including the following:
  • A The reaction of a xanthene or xanthone dicarboxylic acid or a reactive derivative thereof such as an acid halide, azolide, or ester of the formula wherein Z is oxygen or H W is hydroxy, halogen such as chlorine or bromine, azolide, or a lower alkoxy such as methoxy or ethoxy, with an aminoalkanol or aminoalkylamine of the formula wherein Y is oxygen or wherein R is hydrogen or (lower)alkyl of l to 4 carbon atoms,- A is alkylene of 2 to about 8 carbon atoms, either straight chain or branched, and each R and R is (lower)alkyl of l to 6 carbon atoms, cycloalkyl of 3 to 6 ring carbon atoms, or alkenyl of 3 to 6 carbon atoms having the vinyl unsaturation in other than the l-position of the alkenyl group, or together with the nitrogen to which they are attached form a heterocycl
  • the esterification can be achieved by allowing the xanthene or xanthone dicarboxylic acid, where W in the above formula is hydroxy, to react with the appropriate aminoalkanol in an inert solvent in the presence ofa catalyst and employing general methods for removing water from the reaction site.
  • Preferred solvents are chloroform, isopropanol, dioxane, toluene and the like.
  • the reaction may be catalyzed by the use of mineral acids including hydrochloric, sulfuric or certain organic acids such as p-toluenesulfonic acid.
  • Methods whereby water can be removed from the reaction include the use of water scavengers such as the carbodiimides or by the azeotropic removal of water.
  • the reaction will proceed at temperatures ranging from l0025 0C. over a period of 6 to 72 hours depending upon the solvent and catalyst.
  • the esterification can be achieved by allowing the acid halide, where W in the above formula is halogen, to react with the appropriate aminoalkanol.
  • the esters of this invention can be produced in a variety of inert solvents over a wide range of temperatures and reaction time.
  • the solvents of choice include methylene chloride, chloroform, dioxane, tetrahydrofuran, and the aromatic solvents such as benzene and toluene.
  • ln chloroform the reaction is generally complete within 1 hour at a temperature of from C. to the reflux temperature of the solvent, although the reaction time can range from 15 minutes to 3 days.
  • the amides of this invention can be prepared by allowing the xanthene or xanthone diacid halide to react with the appropriate aminoalkylamine.
  • the preferred reaction conditions are those which employ chloroform as the solvent and heating at the reflux temperature of said solvent for 2l8 hours.
  • the compounds of this invention may also be produced by a transesterification reaction in which a (lower)alkoxy ester of the xanthene or xanthone dicarboxylic acid, where W, for example, is methoxy or ethoxy in the above formula, is caused to react with the appropriate aminoalkanol under suitable conditions.
  • This type of reaction is catalyzed by alkaline or acid catalysts and is reversible.
  • the compounds of this invention may be produced by causing the equilibrium to be shifted by removing the lower alkanol component or by employing a large excess of the aminoalkanol.
  • the reaction is carried out by removing the lower alkanol component with the use of an alkaline catalyst.
  • the lower alkanol may be removed by direct distillation or distillation with a suitable solvent.
  • Suitable alkaline catalysts are alkali metals, sodium or potassium; alkali lower alkoxides, such as sodium methoxide or sodium ethoxide; alkali amides such as lithium or sodium amide; etc.
  • Suitable solvents are those forming an azeotropic distillation mixture with the lower alkanol, for example, benzene or toluene, or a solvent which boils sufficiently higher than the alkanol to permit removal of the alkanol by distillation at a temperature below that of the boiling range of the solvent.
  • the amides of thisinvention may also be produced by allowing the lower alkoxy ester of the xanthene or xanthone dicarboxylic acid to react with the appropriate aminoalkylamine under the conditions as for the esters.
  • the compounds of this invention may also be produced by reacting the xanthene or xanthone dicarboxylic azolide with a diamine or a tertiary aminoalcohol and a catalytic amount of an alkoxide at temperatures of from 25to C. with or without an aprotic solvent for l to 24 hours.
  • azolides which may be used are imidazolides, 1,2,3, -triazolides and the like.
  • the esters of this invention can be produced by allowing the xanthene or xanthone dicarboxylic acid, or an activated salt thereof, to react with an aminoalkyl halide in a suitable organic solvent such as chloroform or isopropanol.
  • the aminoalkyl portion of the reactant is the same as in IA, above.
  • the reaction conditions can vary from 6 hours to 72 hours over a temperature range of from room temperature to the reflux temperature of the solvent employed in the presence or absence of an activating moiety such as inorganic cations including sodium and silver or organic activators such as benzyltrimethylammonium chloride. These activators may be present in stoichiometric amounts or catalytic quantities. Since these activators considerably reduce the reaction time, the preferred conditions are to use a catalytic amount of benzyltrimethylammonium chloride and allow the reaction to proceed for 6-18 hours at the reflux temperature of isopropanol.
  • the compounds of this invention can be prepared by allowing a xanthene or xanthone m-haloalkyl diester or diamide, prepared by general methods, of the forwherein Z, Y and A are as previously defined and Hal is chlorine, bromine or iodine to react with an amine of the formula:
  • R and R are (lower)alkyl, or together with the nitrogen to which they are attached form a heterocyclic group such as that generally equivalent to a dialkylamino group.
  • the xanthene or xanthone w-haloalkyl diester or diamide may be prepared by the reaction of a xanthene or xanthone dicarbonyl chloride with an w-haloalkanol or an w-haloalkylamine in a suitable solvent to give the respective products.
  • the preferred halogen in the above formula is bromine or iodine.
  • the reaction is conducted in the presence of stoichiometric amounts of a material which will effectively remove the acid generated in the course of the reaction.
  • Suitable acid binding reagents are anhydrous sodium or potassium carbonate, potassium bicarbonate or extra equivalents of the amine.
  • the solvents of choice are nonprotonic organic liquids such as toluene, chloroform, diethyl ether and dioxane.
  • the preferred conditions are those in which components are allowed to react in ethanol at 50to 150C. for 3 hours to 72 hours in the presence of potassium iodide.
  • the secondary or primary amino derivatives of the compounds of this invention can be prepared by the various procedures under 1 above, if the amino group of the aminoalkanol is suitably blocked to reactivity by formation of a salt or, preferably, by substituting it with a readily removable blocking group such as trifluoroacetyl, carbobenzoxy or the like, followed by removal of the blocking group with a suitable technique such as mild acid hydrolysis or catalytic reduction.
  • a readily removable blocking group such as trifluoroacetyl, carbobenzoxy or the like
  • the primary amino derivatives of the compounds of this invention where R and R are hydrogen may be prepared by converting the corresponding diacids into cyanoalkyl do derivatives of the formula wherein Z, Y and A are as previously defined, and reducing these cyanoalkyl derivatives to primary amine derivatives, such as, by hydrogenation over a platinum oxide or Raney nickel catalyst at 25 to 75C. for 3 to 72 hours with a solvent such as ethanol or acetic acid, at a hydrogen pressure of about 60 psi or lower. Ammonia may be used with non-acidic solvents to suppress the formation of secondary or tertiary amine byproducts.
  • Other compounds of Formula I wherein Z is oxygen may be prepared by oxidation of the corresponding xanthene compounds.
  • the oxidation reaction may be carried out, for example, by air oxidation in pyridine solution containing a catalytic amount of Triton B (tetramethylammonium hydroxide) for a period of from 15 minutes to 12 hours.
  • Triton B tetramethylammonium hydroxide
  • Other compounds of Formula l wherein Z is H may be prepared by reduction of the corresponding xanthone compounds.
  • the reduction reaction may he carried out, for example, by hydrogenation of the xanthone compounds in the presence of a palladium catalyst.
  • This material was dissolved in methylene chloride and treated by the slow addition of 37.2 g (0.2 mole) of N,N-di-n-butyl propylenediamine. After stirring for five minutes, the solvent was removed at reduced pressure. The resulting material was partitioned between chloroform and sodium hydroxide solution. The separated chloroform layer and two chloroform washings of the aqueous layer were combined, washed with water, dried (anhydrous magnesium sulfate) and concentrated at reduced pressure to a solid residue.
  • dicarboxylate dihydrochloride bis(5-dimethylamino-2,2-dimethylpentyl)-9- oxoxanthene-2,7-dicarboxylate dihydrochloride, bis(3-dicyclohexylaminopropyl)-9-oxoxanthene-2,7-
  • EXAMPLE 7 An illustrative composition for hard gelatin capsules is as follows:
  • the formulation is prepared by passing the dry powders of(a) and (b) through a fine mesh screen and mixing them well. The powder is then filled into No. 0 hard gelatin capsules at a net fill of 235 mg. per capsule.
  • EXAMPLE 9 An illustrative composition for tablets is as follows:
  • Preparation A granulation obtained upon mixing lactose with the starch and granulated starch paste is dried, screened and mixed with the active ingredient and magnesium stearate. The mixture is compressed in tablets weighing 150 mg. each.
  • EXAMPLE 10 An illustrative composition for pills is as follows:
  • the pills are prepared by blending the active ingredient and starch and then adding the liquid glucose with thorough kneading to form a plastic mass. The pills are then cut and formed from the plastic pill mass.
  • a compound of the formula Z dihydrochloride can be prepared by the usual pharmall ceutical techniques according to the following formula: O
  • each A is alkylene of 2 to 8 carbon atoms and sepa- Bis( 3-diethylaminopropyl )-9-oxoxanthene-2,7- rates its adjacent Y and amino nitrogen by an alkyldicarboxylate dihydrochloride is mixed with soybean ene chain of at least 2 carbon atoms; meal to prepare an animal feed concentrate containing each Y is oxygen, or N-R wherein R is hydrogen or 10 grams of said oxoxanthene compound per pound of (lower)alkyl of l to 4 carbon atoms; the medicated feed.
  • each A is alkylthe medicated feed. ene of 2 to 6 carbon atoms; and each of the EXAMPLE 13
  • the following formulation is illustrative of a dusting powder: R2
  • the dusting powder is prepared by intimately admix- A Compound of claim 1 having the formula ing the ingredients. The mixture is then packaged in 40 dispensing containers.
  • the composition of Example 14 is prepared by diswherein the substituent groups solving 0.64 g. of sodium chloride in 100 ml. of water 60 for injection; mixing the polyoxyethylene sorbitan Rl monooleate with the oxoxanthene, adding a sufficient l solution of the sodium chloride in water to the active ingredient and polyoxyethylene sorbitan monooleate to make 20 ml, shaking the mixture, and then autoclaving it for 20 minutes at C. at 15 p.s.i.g. steam pressure.
  • the composition can be dispensed in a single ampule for multiple dosage or in 10 or 20 ampules for single dosages.
  • each of R and R is hydrogen, (lower)alkyl, cycloalkyl of 3 to 6 ring carbon atoms, alkenyl of 3 to 6 carbon atoms having the vinyl unsaturation in other than the 1-position of groups is a tertiary amino group selected from di(- lower)alkylamino, dialkenylamino, or each set of R and R together with the nitrogen to which they are attached is pyrrolidino, piperidino, N- (lower)alkylpiperazino or morpholino.
  • each of R and R is (lower)alkyl of l to 4 carbon atoms.
  • Z is oxygen or H each of R and R is hydrogen, (iower)-alkyl, cycloalkyl of 3 to 6 ring carbon atoms, alkenyl of 3 to 6 carbon atoms having the vinyl unsaturation in other than the l-position of the alkenyl group, or each set of R and R taken together with the nitrogen atom to which they are attached is pyrrolidino, piperidino, N-(lower)- alkylpiperazino, or morpholino; and
  • each A is alkylene of 2 to 8 carbon atoms and separates its adjacent amide nitrogen and amino nitrogen by an alkylene chain of at least 2 carbon atoms; each R is hydrogen or (lower)alkyl;
  • each R is hydrogen; each Ais alkylene of 3 to 6 carbon atoms; and each of the is (lower)alkyl of l to 4 carbon atoms.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Fodder In General (AREA)
  • Pyrane Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Hydrogenated Pyridines (AREA)
US162716A 1971-07-14 1971-07-14 Bis-basic esters and amides of xanthene and xanthone Expired - Lifetime US3859307A (en)

Priority Applications (10)

Application Number Priority Date Filing Date Title
US162716A US3859307A (en) 1971-07-14 1971-07-14 Bis-basic esters and amides of xanthene and xanthone
IL39725A IL39725A (en) 1971-07-14 1972-06-21 Bis-basic esters and amides of xanthene and xanthone
GB2959472A GB1350520A (en) 1971-07-14 1972-06-23 Bis-basic esters and amides of xanthene and xanthone
CA146,373A CA976962A (en) 1971-07-14 1972-07-05 Bis-basic esters and amides of xanthene and xanthone
DE2233223A DE2233223A1 (de) 1971-07-14 1972-07-06 Dibasische ester und amide des xanthens und xanthons
JP6829772A JPS5725553B1 (enrdf_load_stackoverflow) 1971-07-14 1972-07-10
CH1037072A CH587838A5 (enrdf_load_stackoverflow) 1971-07-14 1972-07-11
FR7225600A FR2145717B1 (enrdf_load_stackoverflow) 1971-07-14 1972-07-13
NL7209761A NL7209761A (enrdf_load_stackoverflow) 1971-07-14 1972-07-14
US05/375,754 US3957986A (en) 1971-07-14 1973-07-02 Antiviral compositions containing bis-basic esters and amides of xanthene and xanthone

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US162716A US3859307A (en) 1971-07-14 1971-07-14 Bis-basic esters and amides of xanthene and xanthone

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US05/375,754 Division US3957986A (en) 1971-07-14 1973-07-02 Antiviral compositions containing bis-basic esters and amides of xanthene and xanthone

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US3859307A true US3859307A (en) 1975-01-07

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Country Link
US (1) US3859307A (enrdf_load_stackoverflow)
JP (1) JPS5725553B1 (enrdf_load_stackoverflow)
CA (1) CA976962A (enrdf_load_stackoverflow)
CH (1) CH587838A5 (enrdf_load_stackoverflow)
DE (1) DE2233223A1 (enrdf_load_stackoverflow)
FR (1) FR2145717B1 (enrdf_load_stackoverflow)
GB (1) GB1350520A (enrdf_load_stackoverflow)
IL (1) IL39725A (enrdf_load_stackoverflow)
NL (1) NL7209761A (enrdf_load_stackoverflow)

Cited By (5)

* 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
EP0198798A3 (en) * 1985-04-11 1988-10-05 Ciba-Geigy Ag Light-sensitive polycondensates, process for their preparation, materials coated therewith and their use
US5597943A (en) * 1991-07-03 1997-01-28 Shionogi & Co., Ltd. Phospholipase A2 inhibitor
US20070019134A1 (en) * 2005-07-19 2007-01-25 Won-Sang Park Polarizing film assembly, method of manufacturing the same and display device having the same

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR102503934B1 (ko) 2017-11-21 2023-02-27 삼성전자주식회사 운동 보조 장치

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

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 (5)

* 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
EP0198798A3 (en) * 1985-04-11 1988-10-05 Ciba-Geigy Ag Light-sensitive polycondensates, process for their preparation, materials coated therewith and their use
US5597943A (en) * 1991-07-03 1997-01-28 Shionogi & Co., Ltd. Phospholipase A2 inhibitor
US20070019134A1 (en) * 2005-07-19 2007-01-25 Won-Sang Park Polarizing film assembly, method of manufacturing the same and display device having the same

Also Published As

Publication number Publication date
FR2145717B1 (enrdf_load_stackoverflow) 1975-06-20
CH587838A5 (enrdf_load_stackoverflow) 1977-05-13
IL39725A (en) 1976-04-30
GB1350520A (en) 1974-04-18
NL7209761A (enrdf_load_stackoverflow) 1973-01-16
DE2233223A1 (de) 1973-02-01
JPS5725553B1 (enrdf_load_stackoverflow) 1982-05-29
IL39725A0 (en) 1972-08-30
FR2145717A1 (enrdf_load_stackoverflow) 1973-02-23
CA976962A (en) 1975-10-28

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