GB1565813A - Creación de Inventos y Patentes con Inteligencia Artificial

GB1565813A – Substituted 2h – pyran – 2,6(3h)-dione derivatives
– Google Patents

GB1565813A – Substituted 2h – pyran – 2,6(3h)-dione derivatives
– Google Patents
Substituted 2h – pyran – 2,6(3h)-dione derivatives

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Publication number
GB1565813A

GB1565813A
GB50051/76A
GB5005176A
GB1565813A
GB 1565813 A
GB1565813 A
GB 1565813A
GB 50051/76 A
GB50051/76 A
GB 50051/76A
GB 5005176 A
GB5005176 A
GB 5005176A
GB 1565813 A
GB1565813 A
GB 1565813A
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Prior art keywords
compound
hydrogen
compound according
pyran
pharmaceutical composition
Prior art date
1975-12-03
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GB50051/76A
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GlaxoSmithKline LLC

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SmithKline Corp
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1975-12-03
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1976-12-01
Publication date
1980-04-23

1976-12-01
Application filed by SmithKline Corp
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SmithKline Corp

1980-04-23
Publication of GB1565813A
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patent/GB1565813A/en

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C—CHEMISTRY; METALLURGY

C07—ORGANIC CHEMISTRY

C07D—HETEROCYCLIC COMPOUNDS

C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings

C07D309/34—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members

C07D309/36—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms

C07D309/38—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms one oxygen atom in position 2 or 4, e.g. pyrones

A—HUMAN NECESSITIES

A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE

A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

A61P11/00—Drugs for disorders of the respiratory system

A—HUMAN NECESSITIES

A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE

A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

A61P37/00—Drugs for immunological or allergic disorders

A61P37/08—Antiallergic agents

Description

PATENT SPECIFICATION
( 11) 1 565 813 Application No 50051/76 ( 22) Filed I Dec 1976 Convention Application No 637428 Filed 3 Dec 1975 in United States of America (US)
Complete Specification published 23 April 1980
INT CL 3 C 07 D 309/00 A 61 K 31/35 Index at acceptance C 2 C 1670 1671 200 215 220 227 22 Y 253 25 Y 281 290 292 29 X 29 Y 30 Y 321 322 328 32 Y 332 342 34 Y 351 352 355 364 365 369 36 Y 385 510 51 X 531 591 601 620 621 623 624 62 X 630 633 643 645 660 661 662 672 710 761 802 80 Y AA KH KR LK LW LY MG SJ ( 54) SUBSTITUTED 2 H-PYRAN-2,6 ( 3 H)-DIONE DERIVATIVES ( 71) We, SMITHKLINE CORPORATION, of 1500 Spring Garden Street, Philadelphia, Pennsylvania 19101, United States of America, a corporation organized under the laws of the Commonwealth of Pennsylvania, one of the United States of America, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:-
This invention relates to substituted 2 H pyran 2,6 ( 3 H) dione derivatives which are useful for inhibiting the symptoms of an allergic response resulting from an antigenantibody reaction More specifically, the compounds of this invention are believed to be effective by inhibiting the release and/or formation and release of pharmacologically active mediators such as histamine, serotonin and slow-reacting substance of anaphylaxis (SRS-A) from effector cells which are produced and/or released as a result of the interaction of antigen and specific antibody fixed to the cell surface (allergic reaction) These properties make the subject compounds particularly useful in the treatment of various allergic diseases such as asthma, rhinitis and urticaria.
The compounds of this invention are represented by the following general structural formula:
0 o R CH 3 0 O NAe, Ck 3 k FORMULA I wherein R represents hydrogen, methylsulfonyl, or straight or branched chain alkanoyl of from 2 to 5 carbon atoms, preferably acetyl or propionyl; and R 1 represents hydrogen or lower alkyl of from 1 to 4 carbon atoms, preferably methyl.
The advantageous compounds of this invention are represented by formula I when the OR, substituent is in the 4-position and R 1 is hydrogen, and the NHR substituent is in the 3-position.
The compounds of formula I wherein R is alkanoyl are prepared as shown in the following scheme:
o OH O » O ‘ 11 O OH C C 4 X CH 3 -lp +H 3 CN 3 A c \ 1, ‘oi N 1 R N RW O 71 1 N -1 MHR in which R’ is straight or branched chain alkanoyl, of from 2 to 5 carbon atoms and R 1 is hydrogen or lower alkyl of from 1 to 4 carbon atoms Thus, 3,5 diacetyl 4,6 di hydroxy 2 H pyran 2 one and the appropriately substituted aniline are preferably heated at reflux in an inert organic solvent such as benzene, toluene or methanol for from one to twelve hours to give the desired products It will be noted that at room temperature, the reactants form a complex which results in the desired product upon reflux.
To prepare the compounds of formula I wherein R is hydrogen, an OR, substituted nitroaniline is reacted as above with the ( 21) ( 31) ( 32) ( 33) ( 44) ( 51) ( 52) 2 1,565,813 2 pyran-2-one to give the corresponding nitrosubstituted derivative which is hydrogenated catalytically, for example with palladium-on-carbon, to obtain the corresponding free amino products.
To prepare the compounds of formula I wherein R is methylsulfonyl, the appropriate free amino compound (R is hydrogen) is conveniently reacted with methane sulfonyl chloride, for example in pyridine solution.
Mono-and di-alkali metal salts of the compounds of formula I, such as the monoand di-sodium or potassium salts are readily obtainable by reaction with an appropriate alkali metal alkoxide, for example methoxide, in an alkanol solvent such as methanol Similarly, the free amino compounds (R is hydrogen) can be used in the form of a pharmaceutically acceptable acid addition salt, for example those formed with either an inorganic or organic acid, e g.
maleic, fumaric, methanesulfonic, acetic, hydrochloric, hydrobromic or sulfuric acids.
The pyran-2-one starting material of formula II above is obtained by the reaction of acetonedicarboxylic acid with acetic anhydride in sulfuric acid at elevated temperature The reaction product has the tautomeric structure as shown below:
o 110 O O OH O Zto CH 3 I s Cl tl»C 9 11 IJ J 0 on O O NII0 Ok I ‘0 O However, for convenience it is designated herein as 3,5-diacetyl 4,6 dihydroxy2 H pyran 2 one Accordingly the 0 CH 3 O ON c «C C 13 ( in which R and R, are as defined above for formula I For convenience, we have chosen to use one tautomeric form, namely the intermediate enamine pyran-2,6-dione structure, to represent all of the compounds formed by reaction of () with the aniline,.
as with formula I above It will be apparent, however, to one skilled in the art that the more complete representation of the compounds of formula I is shown by the tautomerization of Q.
The alkanamido substituted aniline starting materials of formula III, such as 4 amino 2 nitrophenol are conveniently prepared by acylation of the appropriate nitroaniline followed by reduction of the nitro group to the aniline.
Wiley, R H et al J Org Chem 21:686688 ( 1956) has reported the reaction of amines with the reaction product of acetonedicarboxylic acid and acetic anhydride, the latter being designated as 5carboxydehydroacetic acid Similarly, Kiang, A K et al J Chem Soc (c) pp 2721-6 ( 1971) has described such reaction products with amines However there is no reaction of this compound with an aniline as shown above gives a product having the tautomeric structures as shown below:
description of products represented by formula I.
The inhibitory activity of the compounds of this invention on mediator release in sensitized tissues, thereby inhibiting the effects of the allergic reaction, is measured by the ability of a compound under test to inhibit the passive cutaneous anaphylaxis (PCA) reaction is rats In this test, titered and appropriately diluted serum (from rats previously immunized by the intraperitoneal injection of ovalbuminaluminum hydroxide or ovalbumin-i m -Bordatella pertussis U.S P i p -and N-Briasiliesis i p) containing reaginic antibodies directed against ovalbumin is injected intradermally at four sites on the shaved backs of normal adult male rats Forty-eight hours later the animals are injected intravenously with 0 5 mol of isotonic saline solution containing 5 mg of the ovalbumin antigen and 5 mg of Evans blue dye Chemical mediators such as histamine and serotonin which are released at the sensitized sites as a result of a local cellular anaphylaxis, cause an increase in capillary permeability with resultant 1,565,813 1,565,813 leakage of plasma and formation of a wheel.
The wheal is visualized by the plasma protein-bound Evans blue dye Under conditions of the test, the average control wheal is approximately 12 x 12 mm Thirty minutes following antigen challenge, the animals are killed, the dorsal skin is reflected, and the diameter of the wheals is recorded A test compound is administered intraveously, initially at 0 5 minutes prior to antigen challenge (longer pretreatment times and other routes of drug administration, i e.
oral or intraperitoneal can be employed).
Percent inhibition is calculated from the difference in mean average wheal diameter between a treated group and saline or appropriate diluent controls.
The interruption by a test compound of the sequence of events triggered by reaginic anitbody-antigen interaction on the surface of sensitized cells is indicative of utility in inhibiting the symptoms which result from an immediate-type allergic response.
The compounds of formula I administered intraveously to rats at doses of from 0 1 to 10 mg/kg produce marked inhibition of the PCA reaction For example, 5 acetyl 3 lI ( 3 amino 4 hydroxyphenylamino)ethylidenel 4hydroxy 2 H pyran 2,6 ( 3 H) dione produced 64 inhibition of the rat PCA wheal at 0 5 mg/kg, i v Another compound, 3 l 1 ( 3 acetamido 4 hydroxphenylamino)ethylidenel 5 acetyl 4 hydroxy 2 H 2 pyran 2,6 ( 3 H) dione, produced 45 % inhibition of the rat PCA wheal at 0 1 mg/mg, i e.
Similarly 5 acetyl 4 hydroxy 3 lI ( 3 propionamido 4 hydroxy phenylano)ethylidenel 2 H pyran 2,6 ( 3 H) dione produced 44 W inhibition of the rat PCA wheal at 0 5 mg/mg, i v.
In testing for mechanism of action the compounds of formula I, following i v.
administration at the same dose and pretreatment time which exhibited significant inhibition of the rat 48-hour PCA reaction, do not provide comparable inhibition of wheals of equal severity produced in rats by the intracutaneous administration of histamine and serotonin.
Upon oral administration, 5 acetyl 3 lI ( 3 amino 4 hydroxyphenylamino)ethylidenel 4 hydroxy 2 H pyran 2,6 ( 3 H) dione produced approximately 80-85 % inhibition in the rat 48-hour PCA system at 12 6 mg/kg and a pretreatment time of 15 minutes The compounds 3 lI ( 3 acetamido 4 hydroxyphenylamino)ethylidenel 5 acetyl 4 hydroxy 2 H pyran 2,6 ( 3 H) dione produced 51 ‘ inhibition of the rat PCA wheal after oral administration of 25 mg/mg at a pretreatment time of 15 minutes Similarly 5 acetyl 4 hydroxy 3 lI ( 3 propionamido 4 hydroxphenylamino)ethylidenel 2 H pyran 2,6 ( 3 H) dione upon oral administration produced 60 % inhibition in the rat 48-hour PCA system at 1 mg/kg and a pretreatment time of 15 minutes.
The compounds of this invention can be administered in conventional pharmaceutical compositions comprising an appropriate amount of a compound of the invention, preferably in as the sole active ingredient with R is hydrogen, association with a pharmaceutical carrier or diluent.
The nature of the composition and the pharmaceutical carrier or diluent will, of course, depend upon the intended route of administration, i e orally, parenterally or by inhalation Preferably a compound is administered to an animal in a composition comprising an amount sufficient to produce an inhibition of the symptoms of an allergic response When employed in this manner, the dosage of the composition is preferably such that from 0 5 mg to 600 mg of active ingredient are administered at each administration Advantageously equal doses will be administered 1 to 4 times daily with the daily dosage regimen being 0 5 mg to 2400 mg.
In general, particularly for the prophylactic treatment of asthma, the compositions will be in a form suitable for administration by inhalation Thus the compositions can be in the form of a suspension or solution of the active ingredient in sterile water for administration by means of a conventional nebulizer.
Alternatively, the compositions will be in the form of a suspension or solution of the active ingredient in a conventional liquified propellant, such as dichlorodifluoromethane, or chlorotrifluoroethane, to be administered from a pressurized container The compositions can also be in the form of the solid active ingredient diluted with a solid diluent, e g lactose, for administration from a powder inhalation device In the above compositions, the amount of carrier or diluent will vary but preferably will be the major proportion of a suspension or solution of the active ingredient When the diluent is a solid, it can be present in less, equal or greater amounts than the solid active ingredient.
A wide variety of other pharmaceutical forms can be employed Thus, if a solid carrier is used, the compositions can be tableted, placed in a hard gelatin capsule in powder or pellet form, or in the form of a troche or lozenge for oral administration.
The amount of solid carrier can be varied widely but preferably it will be 25 mg to I g.
If a liquid carrier is used, the compositions can be in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable liquid such as in an ampoule, or an aqueous or nonaqueous liquid suspension.
Examples of solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid Examplesof liquid carriers are syrup, peanut oil, olive oil, and water.
Similarly, the carrier or diluent can include a time delay material, such as glyceryl monostearate or glyceryl distearate, alone or with a wax.
The pharmaceutical compositions thus described can be made following the conventional techniques of the pharmaceutical chemist involving mixing, granulating and compressing when necessary, or variously mixing and dissolving the ingredients as appropriate to the desired end product.
The symptoms of an allergic response resulting from an antigen-antibody reaction can be inhibited by administering to an animal a therapeutically effective amount or a compound of the invention for producing said inhibition formula I, preferably in the form of a pharmaceutical composition The administration can be carried out using dosage units at suitable intervals or in single doses as needed Preferably administration of a compound of the invention is effected when relief of allergic symptoms is specifically required However, continuous or prophylactic treatment can also be given.
A preferred method of relieving or preventing allergic airway obstruction comprises administering to an animal a therapeutically effective amount of a compound of the invention at suitable intervals Routine experiment can be used to determine the effective dosage to be administered from the dose range set forth above, taking into consideration such factors as the degree of severity of the allergic condition being treated, and so forth.
The following Examples illustrate the preparation of compounds of formula I and their incorporation into pharmaceutical compositions.
EXAMPLE I
A mixture of 10 g ( 0 065 mol) of 2 amino 4 nitro phenol, 125 ml of dry toluene, and 25 ml of glacial acetic acid is heated to effect solution Acetic anhydride ( 7.57 g 0 074 mol) is added dropwise over a period of twenty minutes, and the resulting mixture is heated at about 80 C for two hours The reaction mixture is filtered, and the solid is washed with toluene and then recrystallized from methanol to give 2acetamido 4 nitrophenol, m p 283284 C.
The 2 acetamido 4 nitrophenol, thus prepared ( 6 6 g, 0 034 mol), in 200 ml of methanol and 5 65 ml of concentrated hydrochloric acid is hydrogenated with 0 50 g of 10 % palladium-on-carbon in a Parr apparatus for about one hour The reaction mixture is filtered and the methanol is removed in vacuo to yield 2 acetamido 4 aminophenol hydrochloride The latter ( 4.8 g, 0 0236 mol) is dissolved in a minimum amount of methanol and it is treated with a solution of sodium bicarbonate ( 1 98 g 0.0236 mol) in about 25 ml of water This solution is added to a solution of 5 0 g ( 0.0236 mol) of 3,5 diacetyl 4,6dihydroxy 2 H pyran 2 one in refluxing methanol and the mixture is refluxed for 2 5 hours under nitrogen The resulting mixture is stirred at room temperature overnight, and then it is filtered The solid is washed with ether, boiled with a large excess of dioxane, and filtered The solvent is reduced to about 150 ml, 100 ml of acetonitrile are added, and after cooling overnight the product is obtained, 3 l 1 I( 3 acetamido 4 hydroxyphenylamino)ethylidenel 5 acetyl 4 hydroxy 2 H pyran 2,6 ( 3 H) dione, m p 248-250 C (dec).
Both the mono and di-sodium salts are prepared upon treatment of the dione with sodium methoxide in methanol.
EXAMPLE 2
Following the procedure of Example 1, 3 g ( 0 0195 mol) of 4 amino 2nitrophenol are added to a refluxing solution of 4 1 g ( 0 0195 mol) of 3,5 diacetyl 4,6 di hydroxy 2 H pyran 2 one in methanol, and the mixture is refluxed for about two hours Filtration of the reaction mixture yields 5 acetyl 4 hydroxy 3 l 1 ( 3 nitro 4hydroxyphenylamino)ethylidenel 2 H pyran 2,6 ( 3 H) dione, m p 236-237 C (dec).
The nitroenamine ( 4 1 g, 0 0118 mol) is hydrogenated in a mixture of 200 ml of ethanol and 0 4 g of 10 % palladium-oncarbon using a Parr apparatus at room temperature The precipitate is filtered, dissolved in tetrahydrofuran, and filtered again The resulting solution is treated with ethereal hydrogen chloride to give 5acetyl 3 l 1 ( 3 amino 4hydroxyphenylamino)ethylidenel 4 hydroxy 2 H pyran 2,6 ( 3 H) dione hydrochloride, dec > 240 C.
EXAMPLE 3
To a mixture of 82 ml of dry toluene, 20 ml of isobutyric acid, and 5 g ( 0 0324 mol) of 2 amino 4 nitrophenol, are added 5 2 ml of isobutyric anhydride The resulting suspension is refluxed for two hours, filtered, and the solid is air-dried overnight 4 1,565,813 1,565,813 to give, 2 isobutyramido 4 nitrophenol, m p 239-240 C (dec).
The nitrophenol prepared above ( 1 0 g, 0.0045 mol) is hydrogenated at room temperature in a mixture of ethanol and ‘%, palladium-on-carbon using a Parr apparatus, until the calculated amount of hydrogen is absorbed The catalyst is removed by filtration, and the solvent is evaporated in vacuo to leave 4 amino 2 isobutyramidophenol.
This phenol ( 0 86 g, 0 0045 mol) is refluxed with 3,5 diacetyl 4,6 dihydroxy 2 H pyran 2 one ( 0 96 g) in 50 ml of methanol for ten hours The reaction mixture is filtered and the solid is recrystallized from ethanol to furnish 5 acetyl 4 hydroxy 3 lI ( 3 isobutyramido 4 hydroxyphenylamino)ethylidenel 2 H pyran 2,6 ( 3 H) dione, m p 208-209 C (dec).
EXAMPLE 4
Following the procedures of Example 1, 4.0 g ( 0 0204 mol) of 4 acetamido 2 nitrophenol (prepared by acetylation of the corresponding amine) is hydrogenated in a mixture of 150 ml of ethanol, 3 3 mol of concentrated hydrochloric acid, and 0 5 g of % palladium-on-carbon in a Parr apparatus at room temperature Filtration of the reaction mixture gives a powder which is dissolved in a minimum amount of water and filtered This aqueous solution of 4 acetamido 2 aminophenol hydrochloride is added to a mixture of 3,5 diacetyl 4,6 dihydroxy 2 H pyran 2 one ( 3 42 g, 0 0162 mol) and 1 36 g ( 0.0162 mol) of sodium bicarbonate in 130 ml of methanol After 18 hours at reflux, the reaction mixture is filtered and the solid is recrystallized from dioxane-acetonitrile to give 3 l 1 I ( 5 acetamido 2 hydroxyphenylamino)ethylidenel 5 acetyl 4 hydroxy 2 H pyran 2,6 ( 3 H) dione, m p 253-254 C (dec).
Similarly reaction of 5 acetamido 3 aminophenol hydrochloride with 3,5 diacetyl 4,6 dihydroxy 2 H pyran 2 one as described above furnishes 3 l 1 ( 5 acetamido 3 hydroxyphenylamino)ethylidenel 5 acetyl 4 hydroxy 2 H pyran 2,6 ( 3 H) dione.
EXAMPLE 5
Following the procedures of Example 3, 2 g ( 0 0096 mol) of 4 nitro-2propionamidophenol (prepared from propionic acid and 2 amino 4 nitrophenol) are hydrogenated in a mixture of 100 ml of ethanol, 0 3 g of 10 % palladiumon-carbon and 1 34 ml of concentrated hydrochloric acid in a Parr apparatus.
Filtration and evaporation of the solvent gives 4 amino 2 propionamidophenol hydrochloride The latter ( 2 1 g, 0 0096 mol) in a methanol solution is treated with I equivalent of triethylamine under nitrogen atmosphere The solution of the free amine is added to a refluxing mixture of one equivalent of 3,5 diacetyl 4,6 dihydroxy 2 H pyran 2 one and 30 ml of methanol under nitrogen The reaction mixture is refluxed for 18 hours, filtered and the solid is recrystallized from ethanol to yield 5 acetyl 4 -hydroxy 3 l 1 ( 4 hydroxy 3 propionamido phenylamino)ethylidenel 2 H pyran 2,6 ( 3 H) dione, m p 228-229 C (dec).
EXAMPLE 6
Employing the procedures of Example 1, 1 g ( 0 0048 mol) of 2 methoxy 5 nitroacetanilide (prepared by acetylation of the corresponding amine) is hydrogenated in 100 ml of ethanol in the presence of 0 3 g of 10 % palladium-on-carbon in a Parr apparatus at room temperature Filtration and evaporation of the solvent gives 3 acetamido 4 methoxyaniline.
The aniline thus prepared ( 0 8 g, 0 0045 mol) is added to a hot suspension of 3,5 diacetyl 4,6 dihydroxy 2 H pyran 2 one in 50 ml of methanol The mixture is refluxed for one hour and is filtered to obtain 3 l 1 ( 3 acetamido 4methoxyphenylamino)ethylidenel 5 acetyl 4 hydroxy 2 H pyran 2,6 ( 3 H) dione, m p 252-253 C (dec).
As a specific embodiment of a useful composition of this invention, an active ingredient such as 3 l 1 ( 3 acetamido 4 hydroxyphenylamino)ethylidene J 5 acetyl 4 hydroxy 2 H pyran 2,6 ( 3 H) dione is dissolved in sterile water at a concentration of 0 5 % and aerosolized from a nebulizer operating at an air flow adjusted to deliver th’e desired aerosolized weight of drug.
For oral administration, compositions such as those of the following Examples can be prepared.
EXAMPLE 7
Ingredients acetyl 3 l 1 ( 3 amino 4 -hydroxyphenyl amino) ethyl idenel 4 hydroxy 2 Hpyran 2,6 ( 3 H) dione (employed as the hydrochloride salt) Calcium sulfate, dihydrate Sucrose Starch Talc Stearic acid Mg./ Tablet
The sucrose, calcium sulfate and active 125 1,565,813 ingredients are thoroughly mixed and granulated with hot 10 % gelatin solution.
The wetted mass is passed through a No 6 mesh screen directly onto drying trays The granules are dried at 120 F and are passed through a No 20 mesh screen, mixed with the starch, talc and stearic acid, and compressed into tablets.
EXAMPLE 8
Mg / Ingredients Capsule acetyl 4 hydroxy 3 lI ( 4 hydroxy 3 propionamidophenylamino) ethylidenel 2 H pyran 2,6 ( 3 H)dione 50 Magnesium stearate 5 Lactose 350 The above ingredients are screened through a No 40 mesh screen, mixed and filled into No 0 hard gelatin capsules.
EXAMPLE 9
To a cold solution of 1 6 g ( 0 005 mol) of acetyl 3 lI ( 3 amino 4 hydroxyphenylamino)ethylidenel 4 hydroxy 2 H pyran 2,6 ( 3 H) dione (free base prepared as in Example 2) in 10 ml of pyridine is added 0 89 g ( 0 0077 mol) of methane sulfonyl chloride The reaction mixture is stirred in an ice bath for ten minutes, then at room temperature for 30 minutes, and poured into a cold mixture of dilute hydrochloric acid and water The resulting solid is filtered and washed with water and ethanol to give 5 acetyl 4 hydroxy 3 lI ( 4 hydroxy 3 methylsulfonamidophenylamino)ethylidenel 2 H pyran 2,6 ( 3 H) dione, mp 223224 5 C.
EXAMPLE 10
To a solution of 18 12 g ( 0 12 mol) of 3 acetamidophenol dissolved in 300 ml of acetic acid is added 9 2 g ( 0 132 mol) of sodium nitrite, portionwise, followed by 12 ml of concentrated nitric acid The reaction mixture is stirred at room temperature for 1.5 hours, and the insoluble 3 acetamido 4 nitrophenol is filtered off The filtrate is poured onto ice-water, and the resulting solid is filtered off The crude 5 acetamido 2 nitrophenol is recrystallized from ethanol to give pure crystals melting at 218 5-220 C.
A suspension of 5 g ( 0 026 mol) of 5 acetamido 2 nitrophenol in 25 ml of dilute hydrochloric acid is heated under reflux for 45 minutes The solution is cooled and the precipitate is filtered.
Recrystallization from water gives 5amino 2 nitro phenol, m p 163 C.
A solution of 2 12 g ( 0 01 mol) of 3,5 diacetyl 4,6 dihydroxy 2 H pyran 2 one and 1 54 g ( 0 01 mol) of 5 amino 2 nitrophenol in 120 ml of warm methanol is heated under reflux for one hour The resultant solid is filtered and washed with hot methanol to yield 5 acetyl 4acetyl 4 hydroxy 3 l 1 ( 3 hydroxy 4 nitrophenylamino) ethylidenel 2 H pyran 2,6 ( 3 H) dione, m.p 200-203 C (decomp).
The above-prepared nitroenamine ( 2 g, 0.0057 mol) is hydrogenated over 0 6 g of % palladium-on-carbon in 15 ml of dimethylformamide The catalyst is removed by filtration and the filtrate is diluted with ice water to give 5 acetyl 3 l 1 ( 4 amino 3hydroxyphenylamino)ethylidenel 4 hydroxy 2 H pyran 2,6 ( 3 H)dione, m.p 220-221 C (decomp).
The aminoenamine ( 1 4 g, 0 0044 mol) is dissolved in a mixture of 170 ml of tetrahydrofuran and 25 ml of dimethylformamide, and gaseous hydrogen chloride is bubbled into the solution until a precipitate appears The product is filtered and washed with ether to furnish 5 acetyl 3 l 1 ( 4 amino 3 hydroxyphenylamino)ethylidenel 4 hydroxy 2 H 2,6 ( 3 H) dione hydrochloride, m p 258-259 5 C (decomp).

Claims (27)

WHAT WE CLAIM IS:-

1 A compound represented by the formula:
o o H CH 3 OO O o I 11 N ow where R is hydrogen, methylsulfonyl or straight or branched chain alkanoyl from 2 to 5 carbon atoms; and R, is hydrogen or lower alkyl of from I to 4 carbon atoms; a mono or di-alkali metal salt of said compound or a phamaceutically acceptable acid addition salt of said compound when R is hydrogen.

2 A compound according to Claim 1, where OR, is in the 4-position and NHR is in the 3-position.

3 A compound according to Claim I or Claim 2, where R, is hydrogen.

4 A compound according to any one of the preceding claims, where R is hydrogen or straight or branched chain alkanoyl of from 2 to

5 carbon atoms.
A compound according to any one of the preceding claims, where R is hydrogen.

6 A compound according to any one of Claims I to 4, where R is acetyl.
1,565,813

7 A compound according to any one of Claims I to 4, where R is propionyl.

8 A compound according to any one of Claims 1 to 3, where R is methylsulfonyl.

9 A compound according to any one of Claims I to 5 in the form of a hydrochloride salt.

A process for the preparation of a compound according to Claim 1 which process comprises:
(a) to prepare a compound where R is alkanoyl, reacting 3,5 diacetyl 4,6 dihydroxy 2 H pyran 2 one with an aniline of the formula:
(where R’ is straight or branched chain alkanoyl of from 2 to 5 carbon atoms and R 1 is hydrogen or lower alkyl of from 1 to 4 carbon atoms), or (b) to prepare a compound where R is hydrogen, reacting, 3,5 diacetyl 4,6 dihydroxy 2 H pyran 2 one with a nitroaniline of the formula:
Hok (where R 1 is hydrogen or lower alkyl of from I to 4 carbon atoms) and hydrogenating catalytically the nitro-derivative produced, or (c) to prepare a compound where R is methylsulfonyl, reacting the free amino substituted product obtained in (b) above with methane sulfonyl chloride; and optionally forming a salt of the product of formula I with an alkali metal or an acid.

11 A process according to Claim 10 (a) in which the pyran-2-one and aniline reactants are heated at reflux in an inert organic solvent for from one to twelve hours.

12 A process according to Claim 10 (b), in which the hydrogenation catalyst is palladium-on-carbon.

13 A process according to Claim 10 (c) in which the reaction is effected in pyridine.

14 A process according to Claim 10 in which the salts are formed by reaction of the compound of formula I produced with an alkali metal alkoxide to give a corresponding mono or di-alkali metal salt.

A process according to Claim 10 (b), in which the compound of formula I produced is treated with an acid to form a pharmaceutically acceptable acid addition salt of said compound.

16 A process according to Claim 10 (b), in which the nitroaniline reactant is 4 amino 2 nitrophenol.

17 A process for the production of a compound according to Claim 1 substantially as hereinbefore illustrated in any one of Examples 1 to 6, 9 and 10.

18 A compound according to Claim 1, whenever prepared by a process according to Claim 10.

19 A compound according to Claim 1, whenever prepared by a process according to Claim 17.

A pharmaceutical composition for inhibiting the symptoms of an immediatetype allergic response comprising a pharmaceutical carrier or diluent and an amount sufficient to produce said inhibition of a compound according to any one of Claims 1 to 9 and 18 and 19.

21 A pharmaceutical composition according to Claim 20, comprising as sole active ingredient a compound according to Claim 5.

22 A pharmaceutical composition according to Claim 20, in a form suitable for administration by inhalation.

23 A pharmaceutical composition according to Claim 22, comprising a solution or suspension of the active ingredient in sterile water.

24 A pharmaceutical composition according to Claim 22, in the form of an aerosol formulation.

A pharmaceutical composition according to Claim’ 22, in which the pharmaceutical carrier or diluent is a solid.

26 A pharmaceutical composition according to Claim 20, in a form suitable for oral administration.

27 A pharmaceutical composition according to any one of Claims 20 to 26, in dosage unit form and in which the active ingredient is present in an amount of from 0.5 mg to 600 mg per dosage unit.
G H HARGREAVES, Chartered Patent Agent, Printed for Her Majesty’s Stationery Office, by the Courier Press, Leamington Spa, 1980 Published by The Patent Office, 25 Southampton Buildings, London WC 2 A l AY, from which copies may be obtained.
OP.1 «I NR R?

GB50051/76A
1975-12-03
1976-12-01
Substituted 2h – pyran – 2,6(3h)-dione derivatives

Expired

GB1565813A
(en)

Applications Claiming Priority (1)

Application Number
Priority Date
Filing Date
Title

US05/637,428

US4025642A
(en)

1975-12-03
1975-12-03
Substituted 2H-pyran-2, 6(3H)-dione derivatives

Publications (1)

Publication Number
Publication Date

GB1565813A
true

GB1565813A
(en)

1980-04-23

Family
ID=24555892
Family Applications (1)

Application Number
Title
Priority Date
Filing Date

GB50051/76A
Expired

GB1565813A
(en)

1975-12-03
1976-12-01
Substituted 2h – pyran – 2,6(3h)-dione derivatives

Country Status (27)

Country
Link

US
(1)

US4025642A
(en)

JP
(2)

JPS5911594B2
(en)

AT
(1)

AT348522B
(en)

AU
(1)

AU501748B2
(en)

BE
(1)

BE848352A
(en)

CA
(1)

CA1070319A
(en)

CH
(1)

CH624400A5
(en)

DD
(1)

DD127642A5
(en)

DE
(1)

DE2649855A1
(en)

DK
(1)

DK489776A
(en)

ES
(1)

ES453883A1
(en)

FI
(1)

FI60864C
(en)

FR
(1)

FR2333503A1
(en)

GB
(1)

GB1565813A
(en)

GR
(1)

GR62008B
(en)

HU
(1)

HU176158B
(en)

IE
(1)

IE44268B1
(en)

IL
(1)

IL50786A
(en)

LU
(1)

LU76301A1
(en)

MX
(1)

MX4457E
(en)

NL
(1)

NL175995C
(en)

NO
(1)

NO145059C
(en)

PH
(1)

PH12397A
(en)

PT
(1)

PT65811B
(en)

SE
(1)

SE426489B
(en)

SU
(1)

SU679142A3
(en)

ZA
(1)

ZA766279B
(en)

Families Citing this family (3)

* Cited by examiner, † Cited by third party

Publication number
Priority date
Publication date
Assignee
Title

US4165365A
(en)

1977-04-29
1979-08-21
Smithkline Corporation
Substituted 2H-pyran-2,6(3H)-dione derivatives

US4160021A
(en)

1977-05-23
1979-07-03
Smithkline Corporation
Substituted 2H-pyran-2,6(3H)-dione derivatives

DE4419622A1
(en)

1994-06-03
1995-12-07
Cassella Ag

Monoazo dyes, their production and use

Family Cites Families (7)

* Cited by examiner, † Cited by third party

Publication number
Priority date
Publication date
Assignee
Title

US3864493A
(en)

1967-08-17
1975-02-04
Fisons Ltd Felixstowe
Compositions and methods for the prevention of asthmatic symptoms

GB1223690A
(en)

1967-10-17
1971-03-03
Fisons Pharmaceuticals Ltd
Substituted chromon-2-carboxylic acids

US3885038A
(en)

1971-08-23
1975-05-20
Syntex Inc
Method of using substituted xanthone carboxylic acid

BE790802A
(en)

1971-11-04
1973-04-30
Takeda Chemical Industries Ltd

NEW CHROMONE DERIVATIVES AND THEIR MANUFACTURING

US3849446A
(en)

1972-01-17
1974-11-19
Warner Lambert Co
Chromone-3-carboxylic acids

US3883653A
(en)

1972-10-24
1975-05-13
Pfizer
Method of preventing asthmatic symptoms

US3879544A
(en)

1973-05-09
1975-04-22
Carter Wallace
Method for suppressing histamine release

1975

1975-12-03
US
US05/637,428
patent/US4025642A/en
not_active
Expired – Lifetime

1976

1976-10-21
ZA
ZA766279A
patent/ZA766279B/en
unknown

1976-10-27
IL
IL50786A
patent/IL50786A/en
unknown

1976-10-29
DE
DE19762649855
patent/DE2649855A1/en
active
Granted

1976-10-29
DK
DK489776A
patent/DK489776A/en
not_active
Application Discontinuation

1976-11-01
NO
NO763717A
patent/NO145059C/en
unknown

1976-11-02
CA
CA264,674A
patent/CA1070319A/en
not_active
Expired

1976-11-04
SE
SE7612288A
patent/SE426489B/en
unknown

1976-11-04
JP
JP51134001A
patent/JPS5911594B2/en
not_active
Expired

1976-11-05
DD
DD195634A
patent/DD127642A5/xx
unknown

1976-11-09
PT
PT65811A
patent/PT65811B/en
unknown

1976-11-15
AT
AT849676A
patent/AT348522B/en
not_active
IP Right Cessation

1976-11-16
BE
BE172366A
patent/BE848352A/en
not_active
IP Right Cessation

1976-11-17
NL
NLAANVRAGE7612770,A
patent/NL175995C/en
not_active
IP Right Cessation

1976-11-19
FI
FI763325A
patent/FI60864C/en
not_active
IP Right Cessation

1976-11-26
PH
PH19170A
patent/PH12397A/en
unknown

1976-11-30
HU
HU76SI1554A
patent/HU176158B/en
unknown

1976-11-30
FR
FR7636077A
patent/FR2333503A1/en
active
Granted

1976-12-01
GB
GB50051/76A
patent/GB1565813A/en
not_active
Expired

1976-12-01
LU
LU76301A
patent/LU76301A1/xx
unknown

1976-12-01
IE
IE2636/76A
patent/IE44268B1/en
unknown

1976-12-02
ES
ES453883A
patent/ES453883A1/en
not_active
Expired

1976-12-02
CH
CH1522276A
patent/CH624400A5/de
not_active
IP Right Cessation

1976-12-02
SU
SU762424502A
patent/SU679142A3/en
active

1976-12-03
MX
MX765188U
patent/MX4457E/en
unknown

1976-12-03
AU
AU20250/76A
patent/AU501748B2/en
not_active
Expired

1976-12-03
GR
GR52311A
patent/GR62008B/en
unknown

1981

1981-05-12
JP
JP56072876A
patent/JPS5943953B2/en
not_active
Expired

Also Published As

Publication number
Publication date

BE848352A
(en)

1977-05-16

DE2649855A1
(en)

1977-06-16

FR2333503B1
(en)

1980-08-29

LU76301A1
(en)

1977-06-09

ES453883A1
(en)

1977-11-01

SE426489B
(en)

1983-01-24

NO145059B
(en)

1981-09-21

JPS5911594B2
(en)

1984-03-16

FI763325A
(en)

1977-06-04

NL175995C
(en)

1985-02-01

AT348522B
(en)

1979-02-26

FI60864B
(en)

1981-12-31

US4025642A
(en)

1977-05-24

GR62008B
(en)

1979-02-15

IE44268L
(en)

1977-06-03

SU679142A3
(en)

1979-08-05

NL7612770A
(en)

1977-06-07

IL50786A
(en)

1980-01-31

ATA849676A
(en)

1978-07-15

CH624400A5
(en)

1981-07-31

NL175995B
(en)

1984-09-03

SE7612288L
(en)

1977-06-04

FI60864C
(en)

1982-04-13

JPS5268183A
(en)

1977-06-06

PH12397A
(en)

1979-02-01

NO763717L
(en)

1977-06-06

IL50786A0
(en)

1976-12-31

AU2025076A
(en)

1978-06-08

JPS5943953B2
(en)

1984-10-25

ZA766279B
(en)

1977-09-28

MX4457E
(en)

1982-05-12

NO145059C
(en)

1982-01-04

JPS5726679A
(en)

1982-02-12

FR2333503A1
(en)

1977-07-01

HU176158B
(en)

1980-12-28

DE2649855C2
(en)

1987-01-22

DK489776A
(en)

1977-06-04

PT65811A
(en)

1976-12-01

AU501748B2
(en)

1979-06-28

IE44268B1
(en)

1981-09-23

CA1070319A
(en)

1980-01-22

DD127642A5
(en)

1977-10-05

PT65811B
(en)

1978-05-12

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