US3706768A - Xanthone derivatives - Google Patents

Xanthone derivatives Download PDF

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US3706768A
US3706768A US90444A US3706768DA US3706768A US 3706768 A US3706768 A US 3706768A US 90444 A US90444 A US 90444A US 3706768D A US3706768D A US 3706768DA US 3706768 A US3706768 A US 3706768A
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xanthene
oxo
acid
carboxylic acid
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David Edmund Bays
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Allen and Hanburys Ltd
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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

Definitions

  • X represents a carboxyl or 5-[lH1-tetrazolyl group; and R and R which may be the same or different each represent a hydrogen atom, an alkyl group containing from 1 to 4 carbon atoms, a nitro group, a halogen atom or a group of the formula -NR R or 0R or NR SO R (in which the groups R and R; which may be the same or different each represent a hydrogen atom, a phenyl group, a benzyl group or an alkyl group'which may optionally be substituted by an alkoxy group containing from 1 to 6 carbon atoms, a phenoxy group, phenyl group, an amino, alkylamino or dialkylamino group or by one or more hydroxy groups; and in which R, is a hydrogen atom or an alkyl group containing from 1 to 6 carbon atoms and R is an alkyl group containing from 1 to 6 carbon atoms); with the proviso that when X represents
  • R and R which may be the same or different each represent a hydrogen atom, an alkyl group containing from 1 to 4 carbon atoms, a nitro group, a halogen atom or a group of the formula NR R or 0R or NR SO R (in which the groups R and R, which may be the same or different each represent a hydrogen atom, a phenyl group, a benzyl group or an alkyl group which may optionally be substituted by an alkoxy group containing from 1 to 6 carbon atoms, a phenoxy group, phenyl group, an amino alkylamino or dialkylamino group or by one of more hydroxy groups; and in which R is a hydrogen atom or an alkyl group containing from 1 to 6 carbon atoms and R is an alkyl group containing from 1 to 6 carbon atoms
  • non-toxic salts according to the invention may for example be salts of the group X with alkali metals, e.g. sodium, or with organic bases, for example dimethylaminoethanol and morpholine. Where R or R contain basic substituents the invention also provides non-toxic salts with acids, e.g. hydrochlorides.
  • esters of the carboxylic acid function for example those with lower alkanols and glycerol.
  • R, or R represent alkyl are preferably those in which the alkyl groups contain from 1 to 4 carbon atoms.
  • R, or R represent NR R OR or NR SO R and R R R and R represent alkyl groups these are preferably ones which contain from 1 to 4 carbon atoms.
  • 6-phenoxy-9-oxo-xanthene-2-carboxylic acid 6-benzyloxy-9-oxo-xanthene-2-carboxylic acid. 6-methoxy-7-nitro-9-oXo-xanthene-2-carboxylic acid. 5-methoXy-9-oXo-xanthene-Z-carboxylic acid. 7-methyl-9-oxo-xanthene-2-carboxylic acid. 6,7-dimethoxy-9-oxo-xanthene-2-carboxylic acid. 7-methoXy-9-oxo-xanthene-2-carboxylic acid and sodium salt.
  • the xanthone derivatives according to the invention have been shown to inhibit release of spasmogens from antigen-antibody reactions such as occur in the rat during the PCA (passive cutaneous anaphylaxis) test described by Ogilvie (J. Immunol., 1967, 12, (2), 113).
  • PCA passive cutaneous anaphylaxis
  • Ogilvie J. Immunol., 1967, 12, (2), 113.
  • the compound of Example 24 when given intravenously was about 5-7 times more potent than sodium cromoglycate in inhibiting the PCA reaction in sensitised rats challenged with Nippostrongylis brasiliensis as antigen.
  • extrinsic antigen combination with a reaginic antibody is primarily responsible, for example extrinsic asthma, hay fever, urticaria, eczema or atopic dermatitis.
  • compositions which contain a xanthone derivative of general Formula I or a salt or ester thereof together with a pharmaceutically acceptable carrier, excipient or other formulatory agent.
  • the compositions may also contain supplementary medicinal agents, e.g. a bronchodilator, antihistamine, tranquilliser or anxio lytic.
  • supplementary medicinal agents e.g. a bronchodilator, antihistamine, tranquilliser or anxio lytic.
  • forms for oral administration include tablets, capsules, syrups or emulsions.
  • compositions according to the invention may be in the form of a powder or snuff or as an aerosol spray presentation.
  • the last may conveniently be a pressurised pack with a metering valve to deliver a fixed dosage unit or may be an aqueous solution that may be delivered via a nebuliser device.
  • the dosage at which the active ingredient is administered may vary within a wide range.
  • a suitable oral dosage range is generally from 20-1500 mg. and for inhalation is from 1-20 mg.
  • the invention also provides a process for the preparation of compounds of Formula I in which acids of general Formula II are cyclised to xanthones of general Formula 111 where R R and Z may be the groups R7 CO H R7 R R and X of Formula I as herein defined or are groups that can be subsequently converted thereto by standard methods of chemistry well known to those skilled in the art, e.g. Z may be a methyl group which can then be oxidised to the carboxylic acid, or may be a nitrile which can be hydrolysed to the acid or can be converted into the -[lH]-tetrazolyl function.
  • the cyclisation may be effected by heating with condensing agents such as sulphuric acid, phosphorus oxychloride, or polyphosphoric acid PPA), for example at temperatures between 60 and 100".
  • condensing agents such as sulphuric acid, phosphorus oxychloride, or polyphosphoric acid PPA
  • Z represents a nitrile group this is converted by -PPA under the cyclisation conditions into an amide and by sulphuric acid into a mixture of the amide and the acid.
  • the amide can then be hydrolysed to the carboxylic acid with mineral acids or with alkali or it may be reconverted into the nitrile with dehydrating agents, e.g. by warming with tosyl chloride and pyridine in dimethylformamide.
  • Conversion of compounds where Z represents a nitrile function into those where Z represents a 5-[1H]-tetrazolyl group can be effected by treatment with hydrazoic acid or its salts.
  • the reaction can conveniently be carried out with sodium or ammonium azide in an inert solvent, e.g. dimethylforrnamide, which may be warmed to about 100 C.
  • the intermediates of general Formula II may be prepared by an Ullman reaction of the halo acid (IV) and a phenol (V).
  • COzH -Z Hal HO Hal represents a halogen atom, e.g. chlorine or bromine.
  • the reaction can conveniently be carried out in the presence of an alkali metal carbonate such as potassium carbonate, cuprous iodide, and copper bronze at elevated temperatures, e.g. between and 180 C.
  • alkali metal carbonate such as potassium carbonate, cuprous iodide, and copper bronze
  • Inert highboiling solvents such as xylene or nitrobenzene may also be present.
  • Compounds of general Formula I wherein R and/or R represent amino groups may be prepared by reduction of the corresponding nitro compounds with, for example stannous chloride.
  • X is a protected carboxyl group, for example the group CO CH
  • the compounds of general Formula I in which R represents the group NHSO R may be prepared by reaction of the appropriate amine with a suitable sulphonyl chloride, for example methane sulphonyl chloride. Further alkylation may be effected with a suitable alkylating agent, for example dimethylsulphate.
  • R, and/or R represent a group 0R
  • R in the group OR represents an alkyl radical substituted with hydroxyl such radical may be provided by reaction of the corresponding compound in which R, and/or R represent OH with an alkylene oxide in particular ethylene oxide.
  • the compound in which R and/or R represent OH may be prepared from its corresponding compound in which R and/or R represent OCH by heating with hydrogen bromide in acetic acid or aluminum chloride in xylene.
  • EXAMPLE 1 7-nitro-9-oxo-xanthene-2-carboxylic acid 2-chloro-5-nitro-benzoic acid (20 g.), p-cresol (20 g.), anhydrous potassium carbonate (1.4 g.), copper bronze (0.2 g.), and cuprous iodide (0.2 g.) were ground together and heated for 1 hour at -175". The mixture was cooled, triturated with water, and filtered. The filtrate was acidified with dilute hydrchloric acid and the precipitate was recrystallised from aqueous methanol (1:1) to give 5-nitro-2-(p-tolyloxy)-benzoic acid (5 g.), M.P. 166-167".
  • EXAMPLE 4 6-methoxy-9-oxo-xanthene-2-carboxylic acid 6-nitro-9-oXo-xanthene-2-carboxylic acid (1 g.) from Example 3 in dimethylformamide ml.) was heated at 8090 for 1.75 hours with sodium methoxide [from sodium (0.25 g.) and methanol (10.5 ml.)] and then poured onto ice (300 g.) and extracted with ethyl acetate (350 ml.). The aqueous phase was acidified with concentrated hydrochloric acid and chilled. The bufl precipitate was filtered ofl" and recrystallised from glacial acetic acid to give 6-methoxy-9-oxo-xanthene-Z-carboxylic acid (0.45 g.), M.P. 331334.
  • 6-substituted-9-oxo-xanthene-2-carboxylic acids were prepared from the 6-nitro compound as described above by displacement with the appropriate alkoxide M.P. C. 6-propoxy- 285 6-(2-hydroxyethoxy)- 280 6- 2-hydroxypropoxy 240 6-(2-methoxyethoxy)- 260 6-(2-dimethylaminoethoxy)- 1 286 6-(isopropoxy)- 273 6- [2 (2-hydroxyethoxy)ethoxy1- 235 6-(2-phenoxyethoxy)- 287 6-(2-phenylethoxy)- 230 6-phenoxy- 198-201 6-benzyloxy- 291-293 1 Hydrochloride.
  • 6-methoxy-7-nitro 9 oxo-xanthene 2 carbonitrile (2.093 g.) was suspended in a solution of glacial acetic acid (20 ml.), water (220 ml.) and concentrated sulphuric acid (20 ml.) and the mixture was boiled under reflux for 6 hours. During this period the product separated as a white solid. Water (100 ml.) was added and the precipitated solid was collected, washed well with water and dried, M.P. 345.6-346 C. (dec.) (2.012 g.). Recrystallisation from dimethylformamide aflorded fine needles, M.P. 341343 (dec.) (1.863 g.).
  • EXAMPLE 6 5-methoxy-9-oxo-xanthene-2-carboxylic acid 2-chloro-S-methyl-benzoic acid (9.2 g.), 2-methoxyphenol (7.57 g.), copper bronze (l g.) were added to methanolic sodium methoxide [from sodium (2.78 g.) and methanol (50 ml.)]. The solvent was removed and the residue was placed in an oil bath at 140. The temperature was then raised to 185, nitrobenzene (25 ml.) added, and heating continued for 1.5 hours. The cooled mixture was treated with an excess of aqueous potassium carbonate and extracted with ether.
  • EXAMPLE 7 7-methyl-9-oxo-xanthene-2-carboxylic acid 2-(4-cyano-phenoxy)-5-methylbenzoic acid, M.P. 172, was obtained from 2-chloro-S-methyl-benzoic acid and 4- hydroxybenzonitrile using the method described in Example 6 for the preparation of 2-(2-methoxy-phenoxy)- S-methylbenzoic acid.
  • the cyano acid (4.7 g.) was refluxed for 1.5 hours with sulphuric acid (47 ml.), acetic acid (47 ml.), and water (47 ml.). The mixture was poured into water to give a precipitate of 5-methyl-2,4'-oxydibenzoic acid (4.5 g.), M.P. 263.
  • This di-acid (4.3 g.) was stirred at 90-100 for 2.5 hours with polyphosphoric acid (57.3 g.) and then treated with water (50 ml.). The precipitate was washed with water and recrystallised from ethanol and then from acetone to give 7-methyl-9-oxo-xanthene-Z-carboxylic acid (0.9 g.), M.P. 298 C.
  • EXAMPLE 8 6,7-dimethoxy-9-oxo-xanthene-Z-carboxylic acid 2-(4-cyanophenoxy)-4,5-dimethoxy-benzoic acid, M.P. 254-5 C., was prepared from the Ullman reaction between 2-bromo-4,S-dimethoxybenzoic acid and 4-hydroxy benzonitrile using the conditions described in Example 6 for the synthesis of 2-(2-methoxyphenoxy)-5-methyl-benzoic acid.
  • the cyano-acid (1 g.) was heated at 90-100 for 25.5 hours with polyphosphoric acid (6 g.) and then poured onto ice. The precipitate was recrystallised from acetic acid to give 6,7-dimethoxy-9-oxo-xanthene-Z-carboxamide (0.95 g.), M.P. 2l9-222 C.
  • EXAMPLE 9 7-methoxy-9-oxo-xanthene-Z-carboxylic acid
  • 2-chloro-5-nitro-benzoic acid (156 g.) in n-pentanol (600 ml.) and p-methoxyphenol (110 g.) were refluxed with stirring for 4 hours with anhydrous potassium carbonate (240 g.), copper bronze (0.8 g.) and cuprous iodide (0.8 g.).
  • the cooled mixture was treated with ether and water and the aqueous phase was further extracted with ether and then acidified with dilute hydrochloric acid.
  • This acid (75 g.) was cyclised with sulphuric acid by the method described in Example 1 for 5-nitro-2-(p-tolyloxy)-benzoic acid, to give 7-methoxy-2-nitro-xanthone (37.2 g.), M.P. 211-2l2.5 C. after crystallisation from ethyl acetate/ methanol.
  • This amine (1.8 g.), suspended in concentrated hydrochloric acid (5 ml.) and water (10 ml.), was treated dropwise at below 5 C. with 10% sodium nitrite (5 ml.). After ten minutes the mixture was added to a vigorously boiling solution of nickel chloride hexahydrate (3 g.) and sodium cyanide (3 g.) in water (30 ml.). After 0.5 hour reflux, the mixture was cooled and filtered. The filter cake was washed well with water and then refluxed for 5 hours with sulphuric acid (25 ml.), acetic acid (25 ml.) and water (25 ml.). The mixture was poured into water and filtered.
  • Method B 2-bromo-5-methoxybenzoic acid (924 g.), potassium carbonate (818 g.), copper bronze (16 g.), cuprous iodide (16 g.), and xylene (4 l.) were stirred at and 4-hydroxybenzonitrile (476 g.) was added over 10 minutes. The temperature was raised to C. for 3 hours during which time an azeotrope of water (200 ml.) and xylene was collected. The mixture was cooled to 100 C. and water (3 l.) was added. After filtration through Hyflo the xylene layer was washed with water (2 l.). The combined aqueous phases were slowly added to vigorously stirred concentrated hydrochloric acid 1200 ml.).
  • Method C 2 (4 cyanophenoxy)-5-methoxy-benzoic acid (400 g.) (Method B above) and polyphosphoric acid g.) was heated for 2 hours at 90-100 C. Acetic acid (150 ml.) was added and the mixture poured into water (4 1.), keeping the temperatures below 45 C. The solid was washed well with water and then with ethanol and dried at 60 to give 7-methoxy-9-oxo-xanthene-2-car boxamide (358 g.), M.P. 280-290 C. crystallisation from aqueous acetic acid gave material M.P. 301-3 C.
  • This nitrile (0.42 g.) was hydrolysed with watersulphuric acid-acetic acid, as described in Example 3 for 6-nitro-9-oxo-xanthene-Z-carboxylic acid, to give 7-dimethylamino-9-oxo-xanthene-2-carboxylic acid (0.37 g.), M.P. 280-281.5 C., after crystallisation from ethanol.
  • EXAMPLE 12 7-hydroxy-9-oxo-xanthene-2-carboxylic acid 7-methoxy-9-oxo-xanthene-2-carboxylic acid (0.6 g.), aluminum chloride (2.4 g.) and xylene (20 ml.) were heated at 65-75 C. for 5 hours and poured onto crushed ice (50 g.) and concentrated hydrochloric acid (15 ml.). The precipitate was filtered off, taken up in 8% sodium bicarbonate, refiltered and recovered by acidification with hydrochloric acid. The product was extracted into ethyl acetate and the extracts were washed and evaporated. Crystallisation of the residue from ethyl acetate gave 7- hydroxy-9-oxo-xanthene-Z-carboxylic acid (0.2 g.), M.P. 349 C. (d).
  • EXAMPLE 13 7-amino-9-oxo-xanthene-2-carboxylic acid methyl ester 7-amino-9-oxo-xanthene-2 carboxylic acid, hydrochloride (12.2 g.), from Example 2, was refluxed for 16 hours in methanol (1600 ml.) and sulphuric acid (61 m1.) and then poured onto crushed ice. The precipitate was filtered 01f, triturated with 2 N sodium hydroxide, refiltered, and dried to give the methyl ester (9.4 g.),
  • EXAMPLE 14 7-methanesulphonamido-9-oxo-xanthene-2-carboxylic acid 7-amino-9-oxo-xanthene-2 carboxylic acid, methyl ester (4 g.), from Example 13, pyridine (150 ml.), and methanesulphonyl chloride (1.28 ml.) were stirred for 6 days at room temperature and then for 24 hours at 40 C. A further portion (1.05 ml.) of methanesulphonyl chloride was added and heating continued for 5.5 hours.
  • EXAMPLE 15 7-dimethylamino-6-methoxy-9-oxo-xanthene-2- carboxylic acid 2 chloro 4 rnethoxy 5 nitro-benzoic acid (10 g.) and 4-hydroxybenzonitrile (11.6 g.) were condensed, using the method described in Example 1 for 5-nitro-2- (p-tolyloxy)benzoic acid, to give 2-(4-cyanophenoxy)-4- methoxy-S-nitrobenzoic acid (7.25 g.), M.P. 216-219", after crystallisation from aqueous ethanol.
  • This acid (2 g.) was cyclised with phosphorus oxychloride as described in Example 3 for 6-nitro-9-oxoxanthene 2 carbonitrile, to give 6-methoxy-7-nitro-9- oxo-xanthene 2 carbonitrile (1.7 g.), M.P. 339-340 C. (d), after crystallisation from dimethylformamide.
  • This amine (2 g.) was treated with formic acid and Formalin as described in Example 10 for 7-dimeth'ylamino-9-oxo-xanthene-Z-carbonitrile.
  • the reaction solution was concentrated and the precipitate was purified by elution from a column of alumina with 5-10% ethyl acetate/benzene to give 7-dimethylamino-6-methoxy-9- oxo-xanthene-Z-carbonitrile (0.94 g.), M.P. 224-7 C., after crystallisation from methylene chloride ethanol.
  • EXAMPLE 16 7-isopropoxy-9-oxo-xanthene-2-carboxylic acid 7 hydroxy 9 oxo-xanthene-2-carboxylic acid (7 g.) from Example 12 in dry ethanol (700 ml.) was refiuxed for 5 hours with dry hydrogen chloride, then cooled, and diluted with water (110 ml.). The precipitate was crystallised from ethanol to give the ethyl ester (4 g.), M.P. 230 C.
  • This ester (0.5 g.) and sodium hydride (50% dispersion in oil) (0.3 g.) were stirred in dimethylforrnamide for ten minutes and isopropyl iodide (3 ml.) was added. After a further ten minutes the excess of hydride was decomposed with water and the solution was allowed to stand for 1 hour. The mixture was acidified and the precipitate was crystallised from ethanol to give 7-isopr0p0xy-9-oxoxanthene 2 carboxylic acid (0.22 g.), M.P. 269-270 C.
  • EXAMPLE 17 7-(2-hydroxyethoxy)-9-oxo-xanthene-2-carboxylic acid 7 hydroxy 9 oxo-xanthene 2 carboxylic acid, ethyl ester (1 g.), from Example 16, dimethylformamide (10 ml.), ethylene oxide (5 ml.), and pyridine (one drop) were heated in a sealed tube at for 116 hours and then poured into water. The precipitate was refluxed for 2 hours with sodium hydroxide (l g.) ethanol (250 ml.), and water (10 ml.) and the solution was cooled and acidified. The solid was crystallised from ethanol to give 7 (2 hydroxyethoxy) 9 oxo-xanthene-Z-carboxylic acid (0.19 g.), M.P. 263-265 C.
  • EXAMPLE 1'8 7-chloro-9-oxo-xanthene-2-carboxylic acid 2,5-dichlorobenzoic acid (23.5 g.), potassium carbonate (23 g.), cuprous iodide (0.1 g.), copper bronze (0.1 g.), 4 hydroxybenzonitrile (21.6 g.), and nitrobenzene (105 ml.) were heated at 160 for 12 hours.
  • the mixture was diluted with water and ether and the organic phase was extracted with 2N sodium hydroxide.
  • the alkaline extracts were acidified with hydrochloric acid and the oil that separated was allowed to stand until the unchanged 4 hydroxybenzonitrile crystallised, leaving the crude 5-chloro-2-(4-cyanophenoxy)-benzoic acid.
  • the crude acid was cyclised with polyphosph-oric acid, as described in Example 9, Method C, for 7-mcthoxy- 9-oxo-xanthene-2-carboxamide, to give crude 7-chloro- 9 oxo-xanthene 2 carboxamide which was used in the next stage.
  • the 6-chl0ro compound may be prepared in a similar manner M.P. 164.8 C.
  • EXAMPLE 22 7-dimethylamino-2-( lH-tetrazol-S-yl -xanthone 7 dimethylamino-9-oxo-xanthene-2-carbonitrile (0.24 g.) (Example 10), sodium azide (0.06 g.), ammonium chloride (0.05 g.) and dimethylformamide (4 ml.) were heated at 100 for 40 hours and then evaporated to dryness. The residue was taken up in warm dilute sodium bicarbonate and filtered. The filtrate was acidified with concentrated hydrochloric acid and cooled to 0 C.
  • nitrile 0.5 g. was treated with sodium azide, as described in Example 22 for 7-dimethylamino-2-(IH-tetrazol-5-yl)-xanthone, to give 6,7-dimethoxy2-(lH-tetrazol-5-yl) xanthone (0.38 g.), M.P. 300, after crystallisation from aqueous dimethylformamide.
  • EXAMPLE 24 7-methoxy-2-( 1H-tetrazol-5 -yl) -xanthone 7-methoxy-9-oxo-xanthene-2-carboxamide (285 g.) (Example 9, Method C), tosyl chloride (304 g.), pyridine (1150 ml.), and dimethylformamide (1150 ml.) were heated at 100 for hours and then poured onto crushed ice (3 kg.). The slurry was acidified with concentrated hydrochloric acid. The precipitate was washed with water (2X 1 l.) and dried at 50 C. Crystallisation from dimethylformamide gave 7-methoxy-9-oxo-xanthene-2-carbonitrile (202 g.), M.P. 255-8 C.
  • the tetrazole (127.5 g.) was dissolved in water (450 ml.) containing morpholine (39.5 g.) by warming on the steam bath. Acetone (500 ml.) was added and the solid that crystallised was washed with acetone and dried to give the tetrazole, morpholine salt (99 g.), M.P. 285-8 C.
  • EXAMPLE 25 Mg. Active ingredient sodium salt, monohydrate 2.25 Emulsifier YN 0.075 Propellant 11 23.10 Propellant 12 59.30
  • the active ingredient sodium salt is micronised and mixed with the propellant 11 together with the Emulsifier YN.
  • the required quantity of this suspension is filled into an aerosol can and a suitable metering valve crimped in place.
  • the propellant 12 is filled into the can through the valve.
  • Example 26 Capsules: To prepare 5,000 capsules each containing mg. of the compound of Example 9 (active ingredient).
  • Aerosols An inhalation aerosol may be prepared containing in each metered dose 2 mg. of active ingredient made to the following formula:
  • the active ingredient sodium salt is micronised and mixed with the propellant 11 together with the Emulsifier YN.
  • the required quantity of this suspension is filled into an aerosol can and a suitable metering valve crimped in place.
  • the propellant 12 is filled into the can through the valve.
  • R and R are each H; alkyl of 1 to 4 C atoms; nitro; halo; hydroxy; phenoxy; alkoxy of 1 to 4 C atoms; alkoxy of l to 4 C atoms substituted by hydroxy, alkoxy of 1 to 6 C atoms, Z-hydroxyethoxy, phenoxy, phenyl or dialkylamino in which each alkyl radical is of 1 to 4 C atoms; monoalkylamino of 1 to 4 C atoms; dialkylamino in which each alkyl radical is of 1 to 4 C atoms; alkanesulphonoamido of 1 to 6 C atoms or N-alkyl-substituted alkanesulphonamido in which the N-alkyl substituent and alkane moiety are of 1 to 6 C atoms, at least one of R and R being other than H or a pharmaceutically acceptable non-toxic
  • a compound as claimed in claim 1 which is 7-nitro- 9-oxo-xanthene-Z-carboxylic acid.
  • a compound as claimed in claim 1 which is 6-nitro- 9-oxo-xanthene-Z-carboxylic acid.
  • a compound as claimed in claim 1 which is 6-methoxy-9-oxo-xanthene-2-carboxylic acid.
  • a compound as claimed in claim 1 which is 6-propoxy-9-oxo-xanthene-2-carboxylic acid.
  • a compound as claimed in claim 1 which is 6-(2- hydroxyethoxy)-9-oxo-xanthene-2-carboxylic acid.
  • a compound as claimed in claim 1 which is 6-(2- hydroxypropoxy)-9-oxo-xanthene-2-carboxylic acid.
  • a compound as claimed in claim 1 which is 6-(2- methoxyethoxy)-9-oxo-xanthene-Z-carboxylic acid.
  • a compound as claimed in claim 1 which is 6-(2-dimethylaminoethoxy)-9-oxo-xanthene 2 carboxylic acid, hydrochloride.
  • a compound as claimed in claim 1 which is 6-(isopropoxy)-9-oxo-xanthene-2-carboxylic acid.
  • a compound as claimed in claim 1 which is 6-[2 (2 hydroxyethoxy)ethoxy]-9-oxo-xanthene-2-carboxylic acid.
  • a compound as claimed in claim 1 which is 6-(2- phenoxyethoxy)-9-oxo-xanthene-2-carboxylic acid.
  • a compound as claimed in claim 1 which is 6-(2- phenylethoxy)-9-oxo-xanthene-2-carboxylic acid.
  • a compound as claimed in claim 1 which is 6- phenoxy-9-oxo-xanthene-Z-carboxylic acid.
  • a compound as claimed in claim 1 which is 6-benzyloxy-9-oxo-xanthene-2-carboxylic acid.
  • a compound as claimed in claim 1 which is 6-methoxy-7-nitro-9-oxo-xanthene-2-carboxylic acid.
  • a compound as claimed in claim 1 which is S-methoxy-9-oxo-xanthene-2-carboxylic acid.
  • a compound as claimed in claim 1 which is 7-methyl-9-oxo-xanthene-2-carboxylic acid.
  • a compound as claimed in claim 1 which is 6,7- dimethoxy-9-oxo-xanthene-Z-carboxylic acid.
  • a compound as claimed in claim 1 which is 7-methoxy-9-oxo-xanthene-2-carboxylic acid or its sodium salt.
  • a compound as claimed in claim 1 which is 7-dimethylamino-9-oxo-xanthene-Z-carboxylic acid.
  • a compound as claimed in claim 1 which is 7-(N- methylamino)-9-oxo-xanthene-2-carboxylic acid.
  • a compound as claimed in claim 1 which is 7-hydroxy-9-oxo-xanthene-2-carboxylic acid or its ethyl ester.
  • a compound as claimed in claim 1 which is 7- methanesulphonamido 9 oxo xanthene 2 carboxylic acid or its methyl ester.
  • a compound as claimed in claim 1 which is 7-dimethylamino-G-methoxy 9 oxo xanthene-Z-carboxylic acid.
  • a compound as claimed in claim 1 which is 7-isopropoxy-9-oxo-xanthene-Z-carboxylic acid.
  • a compound as claimed in claim 1 which is 7-(2- References Cited hydroxyethoxy)-9-oxo-xanthene-Z-carboxylic acid.
  • a compound as claimed in claim 1 which is 6-ch10- 5 Chemlcal Abstracts 33 (1939), P- 8025' ro-9-oxo-xanthene-Z-carboxylic acid.
  • a compound as claimed in claim 1 which is 7-(N- NORMA MILESTONE Pnmary Exammer ggaglyglc-gigianesulphonamido)-9-oxo-xanthene 2 car- Us. cl XR' 31.

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
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US3818042A (en) * 1972-01-12 1974-06-18 Syntex Inc Xanthone carboxylic acids and derivatives
US3818040A (en) * 1972-09-25 1974-06-18 Syntex Corp Alkenyl and alkynyl substituted xanthone carboxylic acid compounds
US3835157A (en) * 1972-05-17 1974-09-10 Syntex Inc Heterocyclic substituted xanthone carboxylic acid compounds
US3859442A (en) * 1971-08-23 1975-01-07 Syntex Inc A method of inhibiting symptoms of asthma
US3867407A (en) * 1971-08-23 1975-02-18 Jurg R Pfister Substituted xanthone carboxylic acid compounds
US3873714A (en) * 1971-07-14 1975-03-25 Syntex Inc Xanthone carboxylic acids and derivatives
US3879411A (en) * 1971-07-23 1975-04-22 Fisons Ltd Ditetrazolyl-benzodipyrans
US3885038A (en) * 1971-08-23 1975-05-20 Syntex Inc Method of using substituted xanthone carboxylic acid
US3886181A (en) * 1972-01-12 1975-05-27 Syntex Inc Disubstituted xanthone carboxylic acid compounds
US3887574A (en) * 1971-10-08 1975-06-03 Allen & Hanburys Ltd Carboxamido tetrazolo chromones
US3891766A (en) * 1971-08-23 1975-06-24 Syntex Inc Methods of using substituted xanthone carboxylic acid compounds
US3894049A (en) * 1972-06-05 1975-07-08 Syntex Inc Disubstituted xanthone carboxylic acid compounds
US3904647A (en) * 1972-07-19 1975-09-09 Syntex Inc Thioxanthone carboxylic acids and derivatives
US3905989A (en) * 1972-05-19 1975-09-16 Burroughs Wellcome Co (Tetrazolyl)thioxanthone-10,10-dioxides
US3910957A (en) * 1972-06-05 1975-10-07 Syntex Inc Xanthone carboxylic acids and derivatives
US3920826A (en) * 1974-07-01 1975-11-18 American Home Prod Method of treating antiarrhythmic activity with bis(2-(dialkylamino)ethoxy)xanthen-9-one antiarrhythmic agents
US3928379A (en) * 1972-03-03 1975-12-23 Mead Johnson & Co N-phenyl amidines
US3933845A (en) * 1970-08-26 1976-01-20 Fisons Limited Benzopyranyltetrazoles
US3939276A (en) * 1972-09-07 1976-02-17 Burroughs Wellcome Co. Cyclic carbonyl compounds
US3949084A (en) * 1972-03-03 1976-04-06 Syntex (U.S.A.) Inc. Novel substituted xanthone carboxylic acid compounds
US3950342A (en) * 1971-09-08 1976-04-13 Burroughs Wellcome Co. Acridone-dicarboxylic acids
US3951618A (en) * 1974-03-12 1976-04-20 Syntex (U.S.A.) Inc. Method of use of, and compositions containing, disubstituted xanthone carboxylic acid compounds
US3959482A (en) * 1971-09-08 1976-05-25 Burroughs Wellcome Co. Fluorenone carboxylic acids for the prevention of the symptoms of asthma and allergin rhinitis
US3963753A (en) * 1974-01-08 1976-06-15 Syntex (U.S.A.) Inc. Disubstituted xanthone carboxylic acid compounds
US3963752A (en) * 1974-01-08 1976-06-15 Syntex (U.S.A.) Inc. Disubstituted xanthone carboxylic acid compounds
US3965115A (en) * 1974-01-08 1976-06-22 Syntex (U.S.A.) Inc. Disubstituted xanthone carboxylic acid compounds
US3979414A (en) * 1975-03-13 1976-09-07 Syntex (U.S.A.) Inc. Disubstituted xanthone carboxylic acid compounds
US3988352A (en) * 1975-03-13 1976-10-26 Syntex (U.S.A.) Inc. Disubstituted xanthone carboxylic acid compounds
US3989721A (en) * 1975-03-13 1976-11-02 Syntex (U.S.A.) Inc. Disubstituted xanthone carboxylic acid compounds
US3989720A (en) * 1975-03-13 1976-11-02 Syntex (U.S.A.) Inc. Disubstituted xanthone carboxylic acid compounds
US4007205A (en) * 1976-03-16 1977-02-08 Warner-Lambert Company 7-Substituted-9-oxoxanthene-2-carboxaldehydes
US4012499A (en) * 1972-05-19 1977-03-15 Burroughs Wellcome Co. Cyclic sulphur compounds
US4025635A (en) * 1972-09-06 1977-05-24 Burroughs Wellcome Co. Cyclic sulphur compounds
US4035368A (en) * 1975-04-02 1977-07-12 Riker Laboratories, Inc. Substituted 3-(1H-tetrazol-5-yl)-quinoline compounds
US4039556A (en) * 1972-09-06 1977-08-02 Burroughs Wellcome Co. Substituted carbonyl compounds
US4061768A (en) * 1971-09-08 1977-12-06 Burroughs Wellcome Co. Certain cyclic carbonyl compounds used in the prophylaxis of allergic conditions
US4064256A (en) * 1970-08-26 1977-12-20 Fisons Limited Benzopyranyltetrazoles as antiasthma agents
US4094968A (en) * 1972-09-06 1978-06-13 Burroughs Wellcome Co. Treatment for allergy and method of composition thereof
US4103015A (en) * 1975-06-12 1978-07-25 Burroughs Wellcome Co. Antiallergic cyclic sulphur compounds
US4107172A (en) * 1974-03-01 1978-08-15 Abbott Laboratories Uricosuric diuretic composition
US4127573A (en) * 1972-09-06 1978-11-28 Burroughs Wellcome Co. Ditetrazole substituted acridone compounds
US4217361A (en) * 1978-05-22 1980-08-12 Syntex (U.S.A.) Inc. Disubstituted xanthone-2-carboxylic acid antiallergy agents
US4232040A (en) * 1978-03-08 1980-11-04 Syntex (U.S.A.) Inc. Compositions for and a method of preventing diabetic complications
US4250182A (en) * 1972-02-24 1981-02-10 Burroughs Wellcome Co. Pharmaceutical composition containing acridone compounds and method of using same
US4282365A (en) * 1978-11-24 1981-08-04 Merck & Co., Inc. Dibenz[b,e]oxepin compounds
US4333934A (en) * 1979-02-09 1982-06-08 Roussel Uclaf Imidazoquinoxalines and pyrroloquinoxalines
US4363812A (en) * 1978-11-30 1982-12-14 Kakenyaku Kako Co., Ltd. 3-(Tetrazol-5-yl), 4-methyl-8-alkoxy coumarins and anti-allergic compositions thereof
US4544557A (en) * 1982-07-29 1985-10-01 Merck & Co., Inc. 6-(1-Hydroxyethyl)-2-(2-aminoethylthio)-3-tetrazoly-1-carbadethiapen-2-em
US4626432A (en) * 1983-10-25 1986-12-02 Burroughs Wellcome Co. Storage of red blood cells
US4826996A (en) * 1980-10-21 1989-05-02 Groupement D'interet Economique Dit Centre International De Recherches Dermatologioues C.I.R.D. 1,8,-dihydroxy-9-anthrones substituted in the 10-position
US4902701A (en) * 1982-04-27 1990-02-20 Burroughs Welcome Co. Tetrazolyl substituted tricyclic compounds and pharmacological compositions thereof
US5310909A (en) * 1989-11-29 1994-05-10 Ciba-Geigy Corporation Photochromic compounds, a process for their preparation, and their use
CN102180858A (zh) * 2011-04-08 2011-09-14 华东师范大学 一取代或二取代呫吨酮化合物及合成方法

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GB1389827A (en) * 1971-07-23 1975-04-09 Fisons Ltd Tetrazolyl benzopyrans
BE793749A (fr) * 1972-01-12 1973-07-09 Syntex Corp Nouveaux composes d'acides xanthone-carboxyliques disubstitues
SE397825B (sv) * 1972-01-12 1977-11-21 Syntex Corp Nytt forfarande for framstellning av xanton-2-karbonsyraforeningar
BE793751A (fr) * 1972-01-12 1973-07-09 Syntex Corp Nouveaux composes d'acides xanthone-carboxyliques disubstitues
US3835158A (en) * 1972-05-17 1974-09-10 Syntex Inc Heterocyclic substituted xanthone carboxylic acid compounds
US3835139A (en) * 1972-07-19 1974-09-10 Syntex Inc N-substituted acridone carboxylic acids and derivatives
GB1452891A (en) * 1972-09-06 1976-10-20 Wellcome Found Tricyclic tetrazole derivatives their synthesis and compositions containing them
BE793864A (fr) * 1972-09-25 1973-07-10 Syntex Corp Derives d'acide xanthone-carboxylique substitues par un groupement ether non sature
US3919211A (en) * 1973-02-12 1975-11-11 American Home Prod 9-Oxoxanthene-N,N{40 -bis(substituted)-2,7-disulfonamides
NL7403583A (en)) * 1973-03-19 1974-09-23
JPS5516432B2 (en)) * 1974-05-28 1980-05-01
US4221800A (en) * 1977-12-23 1980-09-09 Miles Laboratories, Inc. Cycloalkenochromone
WO2018083635A2 (en) 2016-11-04 2018-05-11 Auckland Uniservices Limited Tricyclic heterocyclic derivatives and uses thereof
US11970505B1 (en) 2023-11-07 2024-04-30 King Faisal University Pyridino-2,16-dioxapentacyclo[7.7.5.01,21.03,8.010,15]henicosa3(8),10,12,14-tetraene-7,20-dione as an antimicrobial compound

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FR1417961A (fr) * 1961-01-19 1965-11-19 Cassella Farbwerke Mainkur Ag Procédé de préparation de dérivés d'hydroxy-xanthones

Cited By (58)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3933845A (en) * 1970-08-26 1976-01-20 Fisons Limited Benzopyranyltetrazoles
US4064256A (en) * 1970-08-26 1977-12-20 Fisons Limited Benzopyranyltetrazoles as antiasthma agents
US3933844A (en) * 1970-08-26 1976-01-20 Fisons Limited Benzopyranyltetrazoles
US3873714A (en) * 1971-07-14 1975-03-25 Syntex Inc Xanthone carboxylic acids and derivatives
US3879411A (en) * 1971-07-23 1975-04-22 Fisons Ltd Ditetrazolyl-benzodipyrans
US3859442A (en) * 1971-08-23 1975-01-07 Syntex Inc A method of inhibiting symptoms of asthma
US3867407A (en) * 1971-08-23 1975-02-18 Jurg R Pfister Substituted xanthone carboxylic acid compounds
US3885038A (en) * 1971-08-23 1975-05-20 Syntex Inc Method of using substituted xanthone carboxylic acid
US3891766A (en) * 1971-08-23 1975-06-24 Syntex Inc Methods of using substituted xanthone carboxylic acid compounds
US3959482A (en) * 1971-09-08 1976-05-25 Burroughs Wellcome Co. Fluorenone carboxylic acids for the prevention of the symptoms of asthma and allergin rhinitis
US3950342A (en) * 1971-09-08 1976-04-13 Burroughs Wellcome Co. Acridone-dicarboxylic acids
US4061768A (en) * 1971-09-08 1977-12-06 Burroughs Wellcome Co. Certain cyclic carbonyl compounds used in the prophylaxis of allergic conditions
US3887574A (en) * 1971-10-08 1975-06-03 Allen & Hanburys Ltd Carboxamido tetrazolo chromones
US3818042A (en) * 1972-01-12 1974-06-18 Syntex Inc Xanthone carboxylic acids and derivatives
US3886181A (en) * 1972-01-12 1975-05-27 Syntex Inc Disubstituted xanthone carboxylic acid compounds
US4250182A (en) * 1972-02-24 1981-02-10 Burroughs Wellcome Co. Pharmaceutical composition containing acridone compounds and method of using same
US3949084A (en) * 1972-03-03 1976-04-06 Syntex (U.S.A.) Inc. Novel substituted xanthone carboxylic acid compounds
US3928379A (en) * 1972-03-03 1975-12-23 Mead Johnson & Co N-phenyl amidines
US3835157A (en) * 1972-05-17 1974-09-10 Syntex Inc Heterocyclic substituted xanthone carboxylic acid compounds
US4012499A (en) * 1972-05-19 1977-03-15 Burroughs Wellcome Co. Cyclic sulphur compounds
US3905989A (en) * 1972-05-19 1975-09-16 Burroughs Wellcome Co (Tetrazolyl)thioxanthone-10,10-dioxides
US3910957A (en) * 1972-06-05 1975-10-07 Syntex Inc Xanthone carboxylic acids and derivatives
US3894049A (en) * 1972-06-05 1975-07-08 Syntex Inc Disubstituted xanthone carboxylic acid compounds
US3904647A (en) * 1972-07-19 1975-09-09 Syntex Inc Thioxanthone carboxylic acids and derivatives
US4094968A (en) * 1972-09-06 1978-06-13 Burroughs Wellcome Co. Treatment for allergy and method of composition thereof
US4127573A (en) * 1972-09-06 1978-11-28 Burroughs Wellcome Co. Ditetrazole substituted acridone compounds
US4025635A (en) * 1972-09-06 1977-05-24 Burroughs Wellcome Co. Cyclic sulphur compounds
US4039556A (en) * 1972-09-06 1977-08-02 Burroughs Wellcome Co. Substituted carbonyl compounds
US3939276A (en) * 1972-09-07 1976-02-17 Burroughs Wellcome Co. Cyclic carbonyl compounds
US3818040A (en) * 1972-09-25 1974-06-18 Syntex Corp Alkenyl and alkynyl substituted xanthone carboxylic acid compounds
US3963752A (en) * 1974-01-08 1976-06-15 Syntex (U.S.A.) Inc. Disubstituted xanthone carboxylic acid compounds
US3965115A (en) * 1974-01-08 1976-06-22 Syntex (U.S.A.) Inc. Disubstituted xanthone carboxylic acid compounds
US3963753A (en) * 1974-01-08 1976-06-15 Syntex (U.S.A.) Inc. Disubstituted xanthone carboxylic acid compounds
US4107172A (en) * 1974-03-01 1978-08-15 Abbott Laboratories Uricosuric diuretic composition
US3951618A (en) * 1974-03-12 1976-04-20 Syntex (U.S.A.) Inc. Method of use of, and compositions containing, disubstituted xanthone carboxylic acid compounds
US3920826A (en) * 1974-07-01 1975-11-18 American Home Prod Method of treating antiarrhythmic activity with bis(2-(dialkylamino)ethoxy)xanthen-9-one antiarrhythmic agents
US3988352A (en) * 1975-03-13 1976-10-26 Syntex (U.S.A.) Inc. Disubstituted xanthone carboxylic acid compounds
US3989720A (en) * 1975-03-13 1976-11-02 Syntex (U.S.A.) Inc. Disubstituted xanthone carboxylic acid compounds
US3989721A (en) * 1975-03-13 1976-11-02 Syntex (U.S.A.) Inc. Disubstituted xanthone carboxylic acid compounds
US3979414A (en) * 1975-03-13 1976-09-07 Syntex (U.S.A.) Inc. Disubstituted xanthone carboxylic acid compounds
US4035368A (en) * 1975-04-02 1977-07-12 Riker Laboratories, Inc. Substituted 3-(1H-tetrazol-5-yl)-quinoline compounds
US4103015A (en) * 1975-06-12 1978-07-25 Burroughs Wellcome Co. Antiallergic cyclic sulphur compounds
US4007205A (en) * 1976-03-16 1977-02-08 Warner-Lambert Company 7-Substituted-9-oxoxanthene-2-carboxaldehydes
US4232040A (en) * 1978-03-08 1980-11-04 Syntex (U.S.A.) Inc. Compositions for and a method of preventing diabetic complications
US4217361A (en) * 1978-05-22 1980-08-12 Syntex (U.S.A.) Inc. Disubstituted xanthone-2-carboxylic acid antiallergy agents
US4282365A (en) * 1978-11-24 1981-08-04 Merck & Co., Inc. Dibenz[b,e]oxepin compounds
US4363812A (en) * 1978-11-30 1982-12-14 Kakenyaku Kako Co., Ltd. 3-(Tetrazol-5-yl), 4-methyl-8-alkoxy coumarins and anti-allergic compositions thereof
US4333934A (en) * 1979-02-09 1982-06-08 Roussel Uclaf Imidazoquinoxalines and pyrroloquinoxalines
US4474784A (en) * 1979-02-09 1984-10-02 Roussel Uclaf Substituted imidazo 1,2-a-quinoxaline-4-(5H)ones, their compositions and method of use
US4826996A (en) * 1980-10-21 1989-05-02 Groupement D'interet Economique Dit Centre International De Recherches Dermatologioues C.I.R.D. 1,8,-dihydroxy-9-anthrones substituted in the 10-position
US4902701A (en) * 1982-04-27 1990-02-20 Burroughs Welcome Co. Tetrazolyl substituted tricyclic compounds and pharmacological compositions thereof
US4544557A (en) * 1982-07-29 1985-10-01 Merck & Co., Inc. 6-(1-Hydroxyethyl)-2-(2-aminoethylthio)-3-tetrazoly-1-carbadethiapen-2-em
US4626432A (en) * 1983-10-25 1986-12-02 Burroughs Wellcome Co. Storage of red blood cells
US4626431A (en) * 1983-10-25 1986-12-02 Burroughs Wellcome Co. Storage of red blood cells
US4791136A (en) * 1983-10-25 1988-12-13 Burroughs Wellcome Co. Pharmacologically active ketones and use
US5310909A (en) * 1989-11-29 1994-05-10 Ciba-Geigy Corporation Photochromic compounds, a process for their preparation, and their use
US5432049A (en) * 1989-11-29 1995-07-11 Ciba-Geigy Corporation Photochromic composition
CN102180858A (zh) * 2011-04-08 2011-09-14 华东师范大学 一取代或二取代呫吨酮化合物及合成方法

Also Published As

Publication number Publication date
IE34720L (en) 1971-05-27
FR2073425B1 (en)) 1974-06-21
CH557347A (de) 1974-12-31
CS172918B4 (en)) 1977-01-28
ZA707727B (en) 1971-08-25
NO133367B (en)) 1976-01-12
PH11097A (en) 1977-10-25
GB1312620A (en) 1973-04-04
FR2073425A1 (en)) 1971-10-01
IL35668A (en) 1973-08-29
FI56005B (fi) 1979-07-31
IL35668A0 (en) 1971-01-28
AT304547B (de) 1973-01-10
FI56005C (fi) 1979-11-12
NO133367C (en)) 1976-04-21
PL81223B1 (en)) 1975-08-30
SE382459B (sv) 1976-02-02
DE2058295A1 (de) 1971-06-03
NL7017336A (en)) 1971-06-01
ES385927A1 (es) 1973-12-01
DK130740C (en)) 1975-09-08
BE759292A (fr) 1971-05-24
HU162579B (en)) 1973-03-28
DE2058295B2 (de) 1979-10-04
DK130740B (da) 1975-04-07
CA930743A (en) 1973-07-24
DE2058295C3 (de) 1980-06-19
IE34720B1 (en) 1975-07-23
US3755319A (en) 1973-08-28

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