Note: Descriptions are shown in the official language in which they were submitted.
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.
, . .
: 30 : : : ~ :
:: . ...
~ ~ ~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
: ~ .
3 0
~ ~ :
5 -
~ 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 ~
: ;
S~)~
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.
,:
~ ~ .
~ - 8 -
.~ .
., .. ... , , .. , . . , . ... . . . . . , . . . ~ . .. . . . . . ... . . . .
~ ~ 6 ~
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.
EXAMPLE 2
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.
,
EXANPLE 3
~ 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.
- 11 -
.
~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.
EXAMPLE 5
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.
EXAMPLE 6
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 -
EXAMPLE 7
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.
EXAMPLE 8
,
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.
EXAMPLE 9
~ ~ ~ ; 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.
- 13 -
, .
.
, ~::'. .:
.
6~50~
EXAMPLE 10
.
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.
EXAMPLE 12
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 - `
: . ~ ~ . , . . .. .. - .
5~
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,
~ '
:
16 -
,,
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.
1 0
'
,.
:, '"' ',
~ .
:
::
.. . .
~ :20~
: ~: : ' .:
:~: .
: 2S
,~ . . . .
, :
~ : ,
,: , : '
: ~ 30
.
~' : :
17 -
;
: :
: ~; . ,
