CA1064509A - Substituted 2h-pyran-2,6(3h)-dione derivatives - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
Substituted 2H-pyran-2,6(3H)-dione derivatives, pharmaceutical compositions comprising such derivatives and methods of inhibiting the antigen-antibody reaction by admin-istering said compositions. The active ingredients are the products formed by the reaction of acetonedicarboxylic acid with acetic anhydride followed by reaction with an appropriate amine. Certain of the dione derivatives are novel compounds per se.

Description

l This invention relates to substituted 2H-pyran-

2,6t3~-dione derivatives, pharmacue~ical compositions com-prising such derivatives which inhibit the antigen-antibody reaction an~ to methods of inhibiting the antigen-antibody S reaction by administering said compositions.
The substituted 2H-pyran-2,6(3H)-dione derivatives which comprise the active ingredient of the pharmaceutical compositions of this invention, in association with a non-toxic p~armaceutical carrier or diluen~, are represented by the following general structural formula: :

8 OH C~3 CH3~ ~ ~ HR
O .~.
FO~M~LA I
wherein R represents lower alkyl, straight or bra~ched chain, of~from 3 to 6 carbon atoms, phenyl, halophenyl such as chlorophenyl, bromophenyl or ~luorophenyl, hydroxyphenyl, -methoxyphenyl~ alk noyloxyphenyl, the alkanoyl moie~y having 20~ from 2 to:7 car~on atomsj carbamoyloxyphenyl, N-methylcar- :
bamoyloxyphenyl, N-benzylcarbamoyloxyphenyl, N,N-dimethyl-carbamoyloxyphenyl,~ p~mercaptophenyl, aminophenyl or ureido-phenylO
:, :
Atvantageously the composltions of this invention 2S ~ oomprise a compound of formula I above when R is n-propyl, p-~ercaptophenyl, hydroxyphenyl, p-acetoxyphenyl~ p panta-.:
noyloxyphenyl, p-aminaphenyl or p-ureidophenyl. Pre~erably R i9;p-hydroxyphenyl.
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: 30 : : : ~ :
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~ ~ ~7 : ~ 2 . :

4SO~

Kiang, A.K. et al, J. ChemO Soc. ~c) pp. 2721-6 tl971~ have questioned the structure of a 5~substituted carbamyldehyro-acetic acid as~igned by previous authors such as Wiley, RqH. et al. ~ _5~
21:686-688 (1956) to the react:ion product of acetonedicar-boxylic acid and acetic anhydr:ide, designated 5-carboxyde-hydroacetic acid, and the carbamyl dexivatives thereof.
Thus, Kiang et al. supra reported that the reaction of acetonedicarboxylic acid with acetic anhydride gave the compound of structure II and that the latter reacted with aniline to form the compound of structure III:

p OH ~OI O ~H CIH3 ~ CH3 H ~ o H ~
FORMULA II FORMULA III
__ .
In view of thesP facts -we could not discount that the 5-substituted carbamyldehydroacetLc acids could have the isomeric struc-.
: ~ture~ indicated by Kiang:et al.
Upon subsequent investigation which has included 3C nuclear magnetic resonance spectral and x-ray crystallo- . :
..
graphic studies, we have now arrived at the following con-clusions. The reaction of acetonedicarboxylic acid with :~
acetic anhydride gives a product having the tautomeric ~ .
tructux~ a~ shown below:

: OH ~ g OH g ~ OH o CH3 CH3 ~ ~CH3 CH3/ y~ ~ CH3 30~ H~o ~o o~u'b ~o~ ~OH

3 -.

~645~

1 For convenience this product is de~ignated herein as 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one. This agrees with Kiang et al's ~ross structure indicated by formula II above.
The rate of tautomerization represented by ~ above is affected, arnong other factors, by ~he solvent used in the ~3C spectral study. Accordingly the reaction o this pro-duct with an amine, RNH2, gives a product having the tauto-meric structures as shown below:

~ ~H CH3 ~ pH C~3 ~3 ~H C~3 CH3~ ~C ~ CH3/ C~XX NHR ~H3 G~C~-R

O O
in which R i9 a8 de~ined above for ~ormula I. This also agrees with Kiang et al'~ grosæ ~truc~ure indica~ed by formula III above. :
Although we have not been able to identify by 13C
nmr the exact tautomer represented by ~ in ~olution~ an X-ray cry~tallographlc study in solid form of the co~pound .
wherein R is p-hydroxyphenyl showed that because of exten~
20 ~ : ~sive conjugation the carbon-carbon bonds throughout the molecule are hybridiæed and therefore the bond length~ lie :~ somewhere between the value~ ~or double and single bonds.
However~ since one of the exchangeable hydrogens in this compound i9 located on the ni~rogen, for convenience we :~
have chosen to ~se one tautorneric form, namely the inter-: mediate enamirle pyran-2,6-dione ~tructure~ ~o represent all of the compound~ f~rmed by reaction of ~ with an amine, RNH29 as indic:ated by ormula I above. It will be apparent .:
:however to one s~illed in the art that the more complete repre~entation of the compound3 of formula I i9 shown by the tautomeri~ation ~ 0 .,.

4 - ~ ~

.. ... .

5~ ~
AS indicated above the starting material xepresented by ~ is obtained by reaction o~ acetonedicarboxylic acid and acetic anhydride, carried out in sulEuric acid at elevated temperature. This material and the amine, RNH2, are usually heated at re~lux in an inert organic sol~ent such as benzene, toluene or methanol for from two to twelve hours to give the products of formula I. Mono-and di-alkali metal salts of the compounds of formula I, such as the mono-and di-sodium or potassium salts are readily obtainable by treatment with the appropriate alkali metal alkoxide, for example methoxide, in an alkanol solvent such as methanol~ 7 Several products of the reaction o~ 1l 5-carboxy- ~ i dehydroacetic acid", now known to be the structure represented by ~ , with amines have been reported by Wiley et al. supra and similarly r Kiang et al. supra has disclosed such reaction products as "anils". However no biological utility has been described for any of these products.
Certain of the compounds of formula I are novel compounds and as such form a part of this invention. These 20~ ;~ compounds may be represented by the following formula:

3 ~ X
o o ,, FO:E~MIJI~ IV
. . .
whereln; R~repre~ie~ts lower alkyl, stralght or brànahed chain,~ of ~rom 3 to 6 carbon atoms, hydroxyphenyl, alkanoyl-: :
~ ~ oxyphenyl, the alkanoyl moiety having ~rom 2 to 7 carbon : ~ .

~ ~ :

~ 9 1 atoms, carbamoyloxyphenyl, N-meth~lcarbamoyloxyphenyl, N-benzylcarbamoyloxyphenyl, N,N-dimethylcarbamoyloxyphenyl, p-mercaptophenyl, p-aminophenyl or ureidophenyl.
The compoun~s wherein R is alkanoyloxyphenyl are co~veniently prepared from the corresponding hydroxyphenyl derivative by reaction with the appropriate alkanoyl chloride, preferably in an orgclnic ba~e ~uch a~ triethyl amine and a nonreactive solvent ~uch a~ tetrahydrofuran.
The pharmaceutical compositions of thi~ invention 1 inhiblt the release and/or formation of pharmacologically active mediators from effectox cells triggered by the inter-action of antigen and a speciic antibody fixed to the cell ~urface. Thu~ the compositions are valuable in ~he ~reat-m2nt of allergic dlsease~ such a~ a~thms9 rhlnitis and urti- -~
caria, ~. ,., ,!`, ~. : The inhib~tory activity of the compositions of this~invention on mediator release in sen~itized tissues ~ i is measured by the ab~lity of the active medicament to inhibit the pa~ive cutaneous anaphylaxis ~P~A~ reaction in ao rat~. In this test sys~em, titered and appropri~tely diluted erum (from ra~ previou~ly immunized by th~ intra-perltoneal injection of ovalbuminaluminum hydroxlde or ovalbumin~i.m.-Bordatella pertussis U.S~P. i.p.-and N-., .
Brasilien~is i.p.) containi~g reaginic an~ibodies directed ~gainst ovalbumin i9 in; ected intrad~rmally at four sites on the ~haved backs of normal adult male rats. Forty-eight hours later the animals :are injected intravenously with ::
O.S ml. o i~otonic ~aline solutlon containing 5 mg. o the ovalbumin anti~en and 5 mg. of Evan~ blue dye. Chemical medL&tors such ns hist&&ine and serotonin wbich sre rele&sed . ~ .
.
,~

~ 6 ~5~
l at the sen~itized sites as a result of a local cellular anaphylaxis, cause an increase in capillary permeability with resultant leakage of plasima and formation of a wheal.
The wheal is visualized by the plasma protein-bound Evans blue dye. Under conditions oi- the test, the average control wheal i~ approximately 12x12 mm. Thirty minuteB following antigen challenge, the animal~ are killed, the dorsal skin is reflected and the dlameter of the wheals recorded. A
test compound is admlnistered in~ravenously, initially at 0.5 minutes prior to antigen challenge (longer pretreatment times and other routes of drug adminis~ration, i~e. oral or intraperitoneal, may be employed)~ Percent lnhibition 1s calculated from the difference in mean average wheal diameter between a treated group and saline or appropriate diluent controls.
The comRounds of formula I administered intra-venously to rats at doses of from 0.5 to 10 mg/kg produce ~-.
marked inhibition of the PCA reaction. A pr~ferred compound, 5-acetyl-4-hydroxy-3~ (p-hydroxyphenylamino) ethylidene]-?.0 2H-pyran~2,6(3~)~dione, produced 73% inhibition of the rat PCA wheal at 5.0 mg/kg, i.v. Another preferred compound, 5-acetyl-4-hydroxy-3~ (p~mercaptophenylamino)~ethylidPneJ-2-H-pyran-2,6(3~dione, produced 100% lnhibition of the rat PCA wheal at 5.0 mg/kg, i.v. Similarly 5-acetyl-3 ~5 ~p-aminophenylamino)ethylidene]-4-hydroxy-2H-pyran-2,6(3H)-dione produced 58% inhibitlon of the rat PCA wheal at 0O5 mg/kgJ i.v. -In testing for mechanism o~ ~ction, the compounds o~ formula I were found not to provide comparable inhibition 3() o wheal~ of equal sieverlty produced in ~ats by the intra-.
- 7 ~
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cutaneous administratinn of histamine and serotonin fol-lowing i.v. administration of the test compound at the same dose and pretreatment time which exhibited significant i.nhibition of the rat 48-hour PCA reaction.
Upon oral administraltion, 5-acetyl-4-hydroxy-3-[l-(p-hydroxyphenylamino)ethylidenel-2H-pyran-2,6(3H~-dion~
produced 58% inhibition in the rat 48 hour PCA ~ystem at 25 mg/kg and a pretreatment time of 15 minutes. This com-pound is also active in vitro for lnhibition o~ antigen induced mediator release rom monkey lung and ~kin and rat lung systems at concentrations of 3.3 x 10 4M to 3.3 x - 10 6M. Similarly 5-acetyl-3-[1-(p-aminophenylamino)ethyli-dene~-4~hydroxy-2H-pyran-2,6(3~-dione upon oral administra-tion produced 32% inhibition in the rat 48 hour PCA ~ystem lS at 25 mg/kg and a pretreatment time of 5 minute~. ~
- .:
The pharmaceutical composition~ of this invention compri~e an appropriate amount of a substituted 2H-pyran 2,6(3H)-dione derivative as set forth in formula I in as~ociation with a pharmaceutical carrier or diluent. The nature o the composition and the pharmaceutical carrier or diluent will of course depend upon the intended route of admini~tratlo~, i.e. orally, parenterally or by inhalation.
Preferably the active medicament i9 administered to an animal in a composition comprising an amount ~u~icient to ~5 produce an inhlbition o~ the antigen-antibody reaetion. ~;¦
When employecl in thls manner, the dosage of composition is such that from 0.5 mg to S00 mg o~ active ingredient are administered at each admini~tration. Advantageously equal doses will be ~dministered 1 to 4 times daily with the daily do~age regimen being about 0.5 mg to about 2000 mg.
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l In generalg par~icularly for the prophylactic treatment of a~thma, the composit~ons will be in a form 3uitable for administration by lnhalation. Thu8 the compo-sitions will comprise a suspen~ion or solution o~ the active ingredient in wa~er for administration by means of a conven~ional nebullzer. Alternatively the compo~ition~
will comprise a su~pension or ~Dlution of the ac~ive ingre-dlent in a convention~l liquifiled propellant ~uch ~ di-chlorodi1uoromethane or chlorot~ifluoroethane to be admin- :
i~tered from a pres9urized con~ainer~ The compo~itions may a~so compri~e the ~olid ac~ive ~ngredient diluted with a solid diluent, e.g. lacto8e, for admini~tration rom a powder inhalation device. In th~ above compositions, the amount of carrier or dil!uent will vary but preferably will be the major proportion of a suspenslon or ~olution of the active lngredient. When the dlluent i~ a ~olid, it may be : present in Iess, equal or greater amounts than the ~olid active ingxedient. ~ ~-A wide variety of other pharmaceutical form~ can be employed. Thus ,: if a ~olid carrier is used the prepara~
~: ~ tion can be tableted/ placèd in a hard gelatin capsule in . ~ powder or pellet form) or in the form of a troche or lozenge or oral admini~tration. The amount of ~olid carrier will vary widely but preferabl~ will be abou~ 2S mg to abo~t 1 g.
If a liquid c~rrier is us~dg the prep~ratlon will be in ~he form of a ~yrup, em~l~ion, sot gelatin capsule, sterile in3~ctabl~ liquld such a8 an ampuleJ or an aqueou~ or non-~queou~ liquid ~u~pen8ion.
: : Exemplarg o~ 301id carriers ar~ lacto~el terra 3Q . albag ~ucro~e, talc, gel~t~n, agar, pec~inJ acacia ~ 9 -, ':

~ . . .. .. . . . . . .. . .. . . . . .. . . . .

~69t5~9 1 magnasium s~earate, stearic aoid and the like. Exemplary of liquid carriers are syrup, peanut oil, olive oil, water and the like. Similarly the carrier or diluent can include any ~ime delay material well known to the art, such as glyceryl mono~teara~e or glyceryl distearate ~lone or wlth a wax.
The method in accordance with this invention al~o includes inh~bitlng the effects of the antigen-~ntibody reaction which comprises the prior application t~ the area of the antigen-antibody mechanism a ther~peutically effec-tive amount of a sub~itu~ed 2H-pyran~-2~6(3~dlone a8 :
defined in ~ormula I. A par~icular application 18 a method of r~lieving or preven~ing allergic airwa~ obstruc-tion which compri.se8 admini~tering ~o an animal a therapeu-tically effective amount at suitable intervals.
The pharmaceutical preparation~ are made following the conventional technique~ of the pharmaceutical chemist involving mixing, gxanulatLng and compr~ing wh~n neces-sary) or variously mixing and dis~olving tha ingredien~s - ~ ~:.
a~ appropxia~e to the desired end produc~
The accompanying examplesiillu~trate the prepara~
: tion~of compounds of formula I and their incorporation into pharmaceutical compo~ition~ of thi~ invention ~nd a~ such are not to be con~idered a~ limitin~ the inven~i.on set forth in the clai~s appented hereto. :.
. EXAMPLE 1 To ~I boiling ~olutio~ of 4.2 g. (0.02 m.) of 3,5-di~cetyl-4,6 dlhydroxy-2H-pyran-2-one in 150 ml. of ben-zene/mothanol i8 added 1.2 g. ~0.02 m.) of n-propylamine : 30 and the resul~:ing mixture i~ refluxed overnight. The re-" '. ' - 10 - '~ 'i'''' ~
.~ . ,~".

j45C~

1 action mixture is concentrated, filtered and the xolid treated with water to give pure 5-acetyl-4-hydroxy-3-[1-(n-propylamino)ethylidene~-2H-pyran-2,6(3~-dione, m. p . 145 -148C .
Similarly, 1.8 g. (0.025 m.) of n-butylamine and 5.3 g. (0.025 m.) of 3,5-diace~yl-4,6-dihydroxy-2H-pyran-2-one are refluxed overnight in 50 ml. of benzene and the resulting solid filtered to give 5-acetyl-3-[1-(n-butyl-amino)ethylidene]-4-hydroxy-2H-pyran-2,6(3~-dion~, m.p.
112-114C.

To a boiling solution of 4.2 g. (0.02 m.) of 3,5-diacetyl-4J6-dihydroxy-2H-pyran-~-one in 150 ml. of benæene i~ added 2.0 g. (0.02 m.) of n-hexylamine and the mixture is concentrated and the oily re~idue is tritura~ed with petroleum-ether to give 5-acetyl-3-[1-(n-hexylamino)-ethylidene~-4-hydroxy-2H-pyran-2,6(3H)-dione, m.p. 80-82C.
, ~ 3,5-Diacetyl-4,6-dihydroxy-2H-pyran-2-one (5.3 g.) ; 20 is dissolved in 200 ml. o~ boiling toluene and an equimolar amoun~ o~ p-chloroaniline is added. The mixture is reflux-ed for 12 hours, cooled and ~iltered to yield 5-acetyl-3-[l-(p~chlorophenylamino)ethylidene~-4-hydroxy-2H-pyran-2,6(3a~-dionel m.p. 205-206C.
EXAMPLE_ o~Chloroaniline (2.55 g., 0.02 m.) is added to 4.24 g. (0.02 m.) of 395-diacetyl-4,6-dihydro~y-2H-pyran-2-one in 150 mt. of methanol and the mixture i~ refluxed over-night. The re~ction mixture is concentrated, cooled and flltered to give 5-acetyl-3-~1-(o-chlorophenylamino) -ethylidene]-4-hydroxy-2~-pyran-2,6~3~-dlone, m.p. 143-145C.

.

~6~5al~
Similarly, equimolar amounts of m-chloroaniline and 3,5-diacetyl~4,6-dihydroxy-2H-pyran-2-one are refluxed in methanol to afford, a~ter workup, 5-acetyl-~3 [1-(m-chloro-phenylamino)ethylidene]-4-hydroxy-2H-pyran-2,6(3H)-dione, m.p. 163 164C.

To a boiling solution of 4.24 g. (0.02 m.) oE
3,5-diacetyl-4,6-dihydroxy-2~1-pyrcln-2-one in 200 ml. of methanol is added 2.18 g. (0.02 m.) of p-hydroxyaniline.
The resulting mixture is refluxed overnight and filtered to yield 5-acetyl-4-hydroxy-3-[1-(p-hydroxyphenylamino)-ethylidene]-2H-pyran-2,6(3H)-dione, m.p. 223-225C. Both the mono-and di-sodium salts are prepared upon treatment of the dione with sodium methoxide in methanol.
Similarly, m-hydroxyaniline and o-hydroxyaniline are reacted with an equimolar amount of 3,5-diacetyl-4,6-dlhydroxy-2H-pyran-2-one in methanol to give the respective products, 5-acetyl-4-hydroxy--3-[1-(m-hydroxyphenylamino)-ethylidene]-2H-pyran-2,6(3H)-dione, m.p. 213-216C., and 20~ 5-acetyl-4-hydroxy-3[1-(o-hydroxyphenylamino)ethylidene]-2H-pyran-2;6~3H)-dione, m.p. 210-212aC.

p-Fluoroaniline (2.2 g., 0.02 m.) is added to a hot solution o~ 4.24 g (0.02 m.~ of 3,5-diacetyl-4,6-di-hydroxy-2H-pyran-2-one in 150 ml. of methanol. The mixture is refluxed overnight and filtered to give 5-acetyl-3-[1-(p-fluorophenylamino)ethylidene]-4-hydroxy-2H-pyran-2,6-(3H)-dione, m.p. 199-201C.

'' ..'' '' ~ ~ 12 -A mixture of 2.12 g. of 3,5-diacetyl-4,6-dihy-droxy-2H-pyran-2-one, 1.25 g. of p-aminothiophenol and 75 ml.
of methanol is refluxed for two hours, cooled and filtered to yield 5-acetyl-4-hydroxy-3[1-(p-mercaptophenylamino)-ethylidene]-2H-pyran-2,6(3H)-dione, m.p. 207-210C.

, To a boiling solution of 3.0 g. (0.014 m.) of 3,5-diacetyl-4,6~dihydroxy 2H-pyran-2-one in 25 ml. of benzene is added 1.4 g. (0.015 m.) o aniline and the re-sulting mixture is refluxed overnight. The reaction mixture is cooled and filtered to give 5-acetyl-4-hydroxy-3[1-phenylamino)ethylidene] 2H-pyran~2,6(3H)-dione, m.p. 184-185C.
Similarly, equimolar amounts of p-methoxyaniline and 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one are refluxed in methanol to give, upon workupl 5-acetyl~4-hydroxy-3[1-(p-methoxyphenylamino)ethylidene]-2H-pyran-2,6(3H)-dione, m.p. 212-214C.

~ ~ ~ ; o-Phenylenediamine (2.1 g., 0.02 m.) is added to a , !, hot solution of 4.2 g. (0.02 m.) of 3,5-diacetyl-4,6-dihydroxy-2H-pyran-~2-one in methanol and the resulting mix-ture is re~luxed for two hours. The reaction mixture is cooled and filterecl to yield 5-acetyl-3-[1-(o-aminophenyl-amino)ethylidene]-4-hydroxy-2H-pyran-2,6(3H)-dione, , m.p. 179-181C.

Similarly, reaction of an equimolar amount of ., , ; p-phenylenediamine as described above gives the correspond-~ing 5-acetyl-3-[l(p-aminophenylamino)ethylidene]-4-hydroxy-~;30 ~ 2--pyran-2,~(3H)-dione, m.p. 215-218C.

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.
To a solution of 3.03 g. (0.01 m.) of 5-acetyl-4-hydroxy-3 [1-(p-hyroxyphenylamino)ethylidene]-2H-pyran-2,6(3H)-dione, 1.0 g. (0.01 m.) of triethylamine in 150 ml.
of tetrahydrofuran is added 0.78 g. (0.01 m.) of acetyl chloxide. The resulting mixture is refluxed for two hours, cooled and filtered. The solid is recrystallized to give i 3-[1-(p-acetoxyphenylamino)ethylidene]-5-acetyl-4-hydroxy-2H-pyran-2,6(3H)-dione, m.p. 199-201C.
Similary, equimolar amounts of 5-acetyl-4-hydroxy 3-[1-(p hydroxyphenylamino)ethylidene]-2H-pyran-2,6-(3H)-dione and an appropriate alkanoyl chloride are reaated as described above to give the following alkanoyloxy derivatives.
5-acetyl-4-hydroxy~3[1-(p-propionyloxyphenyl-amino) ethylidene~-2H-pyran-2,6(3H)-dione, m.p. 168-170C;
5-acetyl-3-[1-(p-butyryIoxyphenylamino)ethylidene]-.
4-hydroxy-2H-pyran-2~6(3H)-dione, m.p. 158-160C.;
5-acetyl-4-hydroxy-3-Cl-(p-pentanoyloxyphenyl-amino) ~-ethylidene]-2H-pyran-2,6(3H)-dione, m.p. 155-157C;
5-acetyl-3-[1-(p-hexanoyloxyphenylamino)ethylidene]-4-hydroxy-2H-pyran-2,6(3H)-dione; m.p. 148-149C.; y S acetyl-3-[1-(p-heptanoyloxyphenylamino)ethylidene~-4-hydroxy-2H-pyran-2,6(3H)-dione, m.p. 147-148C. i ,;
E~AMP
To a boiling solution of 2.1 g. (0.01 m.) o~ 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one in 150 ml. of methanol ~ i ,. ..
is added 2.4 g. (0.01 m.) o~ p-(N-benzylcarbamoyloxy~
aniline and the resulting mixture is refluxed for one hour.
:', '''` ' ', ' ' ; ~ ' !

~ 6 4~

1 The cooled reaction mixture is filtered and the ~olid i8 recrystallized to furnish 5 acetyl-3-[1-(p-N-benzylcar-bam~yloxyphenylamino)ethylldene]-4-hydr~xy-2H-pyran-2,6-(3~-dione, m.p. 195-197C.

A solution o~ 1.88 g, ~0.01 m.) o p-carbamoyl oxyaniline hydrochloride and 1.0 g. (0.01 m.) of triethyl-amine ln 50 ml. of methanol i8 added ~o a hot solutlon of 2.21 g. (0.01 m.) of 3,5-diacetyl-4,6-dihydroxy-2H-pyr~n-2-one in lS0 ml. of methanol. The resulting rrixture ls re-1uxed for two hours, cooled and the filtered 801id recry-stallized to give 5-acetyl~3-[1-(p-carbamoyloxyphenylamino~-e~hylidene]-4-hydroxy-2H-pyran-2~6(3~-dione, m.p. 213-215C.
Similarly, reaction with p; (N-methylcarbamoyloxy)-.
aniline or p-(N,~-dimethylcarbamoyloxy)-aniline a~ de~cribed above or in Example ll:yields the corresponding products, namely 5-acetyl-4-hydroxy-3-[1-(p-N-methylcarbamoyloxy-: phenylamino)ethylidene]-2H-pyran-2,6~3~-dione and 5-ace~yl-3-[1-(p-N,N-dimethylcarbamoyloxyphenylamino)ethylidene]-4-?.0 ~ hydroxy 2H-pyran-2,6(3H)-dione.
.
~ . ~ EXAMPLE 13 _.
: ~ ~ A solution of 1.5 g. (0.01 m.) of p-ureidoaniline in 50 ml, o~ melthanol i8 added to a solution of ~.1 g.
~0.01 m.) of 3,5-diacetyl-4~6-dihydroxy 2H~pyran-2-one in 2S 150 ml. o~ methanol. A solid i9 ~ormed lmmediately and the mixture i,5 refluxed for 12 hours. The ~iltered ~olid lx recry8t~11Lzed to give S-acetyl-4-hydro~y-3-[1-(p-ureidoph~nyl~nino~thylidene]-2H-p~ran-2,6(3~3-dione, . m.p. 2S0-253~C.

.
. - 15 - `

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1 A~ a specific embodiment of a u~eful composition of this invention, an active ingredient such as 5-acetyl-4 hydroxy-3-[1-(n-propylamino)etlhylidene3-2H-pyran-2,6(3H~
dione is dissolved i.n s~erile water at a concen~ration of 0.5% and aerosolized from a nebulizer operating at an air flow adju~ted to deliver the desired aerosolized wei~ht of drug.
For oral administrat:ion, compositions such a~
thvse in the ollowing example~ can be prepared.
EXA~PLE 14 ~L~
S-Acetyl-4-hydroxy-3-[1-(p- 10 hydroxyphenylamino~ethyli- . ;
denel-2~-pyran-2,6(3H)-dione . .
Calcium sulfate, dihydrate 150 ~
lS~ Sucrose 25 ., ~,1, .
Starch 15 Talc 5 :
Stearic acid 3 The sucrose, ca1cium sulfate and active ingredient are : ~.
?~0 thoxoughly mixed and granulated with hot 10% gelatin solu- ::
: .
tion. :The wetted mass i8 pas~ed through a ~6 mesh screen directly onto drying tray~. The granules are dried a~
120F. and passed through a ~20 me~h screen~ mixed with the ~tarch, talc and ~tearic acid, and compre~scd into ~ . ;
tablets.
..
EXAMPLE lS .

5-Acetyl-4-hydroxy-3~ (p- S0 hydroxyphenylamino)ethyli- . :
dene]~2H-pyr2n-2,6(3~ -dione ~0, ~ ' :

,, 1g3 6~

L 15 (cont~d) ~ M~./Capsule Magnesium stearate 5 Lactose 350 The above ingredients are screened through a #40 mesh screen~ mixed and filled into #l) hard gelatin capsules.

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Claims (6)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process for the preparation of compounds represented by the formula:

wherein R is lower alkyl, straight or branched chain, of from 3 to 6 carbon atoms, hydroxyphenyl, alkanoyloxyphenyl, the alkanoyl moiety having from 2 to 7 carbon atoms, car-bamoyloxyphenyl, N-methylcarbamoyloxyphenyl, N-benzylcar-bamoyloxyphenyl, N,N-dimethylcarbamoyloxyphenyl, p-mercapto-phenyl, aminbphenyl or ureidophenyl, which comprises react-ing 3.5-diacetyl-4,6-dihydroxy-2H-pyran-2-one with an amine, RNH2, in which R is as defined above.

2. The process of claim 1 in which the reactants are heated at reflux in an inert organic solvent for from two to twelve hours.

3. The process of claim 1 in which the products are treated with an alkali metal alkoxide to give the corresponding mono-and di-alkali metal salts.

4. The process for the preparation of 5-acetyl-4-hydroxy-3-[1-(p-hydroxyphenylamino)ethylidene]-2H-pyran-2,6(3H)-dione which comprises reacting 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one with p-hydroxyaniline.

5. A compound represented by the formula:

wherein R is lower alkyl, straight or branched chain, of from 3 to 6 carbon atoms, hydroxyphenyl, alkanoyloxyphenyl, the alkanoyl moiety having from 2 to 7 carbon atoms, car-bamoyloxyphenyl, N-methylcarbamoyloxyphenyl, N-benzylcar-bamoyloxyphenyl, N,N-dimethylcarbamoyloxyphenyl, p-mercapto-phenyl, aminophenyl or ureidophenyl, whenever prepared by the process of claim 1 or an obvious chemical equivalent thereof.

6. The compound 5-acetyl-4-hydroxy-3-[1-(p-hydroxyphenylamino)ethylidene]-2H-pyran-2,6(3H)-dione, whenever prepared by the process of claim 4 or an obvious chemical equivalent thereof.