Note: Descriptions are shown in the official language in which they were submitted.
~ ~57~
l Thi~ invention relates to novel pharmaceutical
compositions which inhibit certain antigen-antibody re-
actions and to methods of inhibiting such antigen-antibody
reactions by administering ~aid compositions. More ~pecifi-
S cally3 the compositions of this invention comprise a sub
stituted 496-dihydroxy-2H-pyran-2-one as the active
, medlcamentO
: The novel pharmaceutlcal compositions of this in~
, .
; vention comprise a nontoxic pharmaceutical carrier or : ;.
diluent and a substituted 4,6-dihydroxy-2H-pyran-2-one of
the following general structural formula: `:
. HO O ~` ;
1 5 ' '' "~~ FORMULA I ~ `
`i wherein R represents lo~er alkyl9 straight or branched :~
chaing of from l to 6 carbon atoms9 the R9s being identical. ~ :~
: Advantageously the compositions of this inventlon
comprise a compound of ~ormula I above when R is methyl.
The compounds of formula I are generally prepared
by the reaction of acetonedicarboxylic acid and an appro- ` :
i1 priate acid anhydride of the formula ~RCO)209 where R is
as defined above. The reacta~ts are usually heated in
. ~I
i, 25 sulfuric acid at an elevated temperat~re up to about 90C.
~¦ The compositions of thls invention inhibit thP.
release 2nd/or formation of pharmacologically active media- ;
tors from effector cells triggered by the ~nteraction of :
;.1 an~igen and a specific antibody fixed to the cell surface~
:~ 30 Thus the compositions are valuable in the treatment of
'~ ~
:~ allergic diseases ~uch as asthma9 rhinitis and urticaria. :~
2 -
.
~ ~5'~
1 The inhibitory ac~ivity of the compositions oE
this invention on mediator release in sensitized tissues
is measured by the ability of the active medicament to
inhibît the passive cutaneous anaphylaxis (PCA`~ reaction
S in rats. In this test system~ titered and approprlately
; diluted serum (from rats previously immunlzed by the intra~
-~ peritoneal injection of oval~umlnaluminum hydxo~ide or
ovalbumin-i.m.-Bordatella pertussls ~SOPo i.p.~and N.
Brasiliensis i.p~ containing reagînic antibodies directed `~
against ovalbumin is injected intradermally at four sites
on ~he shaved backs of normal adult male rats. Forty-eight
.. .
hours later the anlmals are injected intravenously with
0.5 ml. of isotonic saline solution containing 5 mg. of
the ovalbumin antigen and 5 mg. of Evans blue dye. Chemi~
15 cal mediators such as histamine and serotonin which are~
released at the sensitized sites as a result of a local
cellular anaphylaxis9 cause an increase in capillary per~
li~ meability with resultant leakage of plasma and formation
of a wheal~ The wheal is visualized by the plssma protein-
~, 20 bound Evans blue dye. Under condition~ of the test~ the
average control wheal is approximately 12x12 mmO Thirty
,;1 minutes following antigen challengeg the animalfq are Icilled~
l the dorsal skin i9 reflected and the diameter of the wheals
1l~ recor~ed. A test compound is administered intravenouslyg
`1 25 initially at 0.5 min~tes prior to antigen challenge ~longer
pretreatment times and other routes of drug administration9
i.e. oral or intraperitoneal 9 may be employed)O Percent
¦ inhibition is calculated from the dif~erence in mean aver-
¦ age wheal diameter between a treated group and saline or
:., 30 appropriate diluent controls. ;
~ ~ 3 ~
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~0576~
l The compounds o~ ormula I administered in~ra-
venously to rats at doses of from S to 15 mg/kg produce
marked inhibition of the PCA reaction. A preferred com-
pound9 3~5-diacetyl-496-dihydroxy-2H-pyran-~-one~ produced ;
62% inhibitlon of the rat PCA wheal at 15 mg/kg l.v. ~n
testing for mechanism of action9 the compounds of formula I
were found not to provide comparable inhibition of wheals
of approximately equal ~everity produced in rats by the
intracutaneous administration of hi~tamine and serotonin
following i,v. administration o~ the test compound at the
same dose an~ pretreatment time which exhibited slgnificant
inhibition of the rat 48 hour PCA reaction.
Upon oral administration~ 395-diacetyl~496-dihy-
droxy-2H~pyran-2-one produced 83% inhibition in the rat
48 hour PGA system at 150 mg/kg and a pretreatment time of
.
15 minutes. This compound is also active in vitro for
inhibition of antigen induced mediator release from monkey
~ , . . .
-3~ lung and skin and rat lung sys~ems at concentrations of - ;
1.2 x lV 3M to 5.9 x 10 4M.
,~ 20 The pharmaceutical compositions of this invention ~ ~`
, comprise an appropriate amount of a substituted 4~6-dihydroxy-
¦ 2H-pyran-2-one as set forth in formula I in as~ociation
with a pharm~ceutical carrier or diluent. ~le nature of
3 the composition and the pharmaceutical carrier or diluent
will o course depend upon the intended rnute of adminis
'1 tratio~9 L.e. orally~ parenterally or by inhalation. Pre-
l, ferably the active medicament is administered to an animal
i in a compo~ition comprising an amount sufficien~ to produce
an inhibition of the antigen antibody reaction. When em~
ployed in ~his manner~ the dosage o~ compoæitivn is such
~ .
: I
~ ~7 6 ~ ~
l that from 25 mg. to 750 mg. of active ingredient are
administered ~t each adminis~ration Advan~ageous1~ ~ual
doses will be administered l to 4 times daily wlth the daily
dosage regimen belng about ~5 mg. to about 3000 mg.
In generalg particularly for the prophylactic
`~ treatment of asthma9 the compositions wll~ be in a form
suitable for administration by ~nhalation. Thus the compo-
sitions will comprise a suspenslon or solution of the active
ingredient in water for administration ~y means of a CO''l-
ventional nebulizer. Alternatively the compositions will
comprise a suspension or solution of the active ingredient
in a conventional liqui~ied propellant such as dichlorodi-
fluoromethane or chlorotrifluoroethane to be administered
from a pressurized container. The compositions may also
; .
lS comprise the solid active ingredient diluted with a solid
diluent, e.g. lactose, for administration from a powder -
inhalatio~ device. In the above compositions 9 the amount
of carrier or dLluent will vary but preferably will be the
major proportion of a suspension or solution o the active
ingredient. When the diluent is a solid9 it may be present
in less~ equal or greater amoun~s than the solid active
ingredient.
A wide variety of other pharmaceutical forms
can be employedO Thus9 if a solid carrier is used the
;l 25 preparation ca~ be tableted9 placed in a hard gelatin cap~
I sule in powder or pellet form9 or in the form o a troche ;~
.~ , . ~.
-i or lozenge for oral administration. The amoun~ o~ solid
~ carrier will vary t~idely but preferably will be about 25 mg.
;~ to about l g. If a liquid carrier is u~ed9 ~he preparation
~ 30 will be in the form of a syrup9 emulsion, so~t gelatin cap-
.~ ! .
' ' '` ~'' ~"
.' ' .
5 7
l sule, sterile injectable liquid such as an ampul~ or an :~
aqueous or nonaqueous liquid suspension. ~ ~
Exemplary of solid carriers are lactose~ terra ~ :
alba~ sucrose~ talc3 gelatin9 agar~ pectln~ acacia9 magnes~
ium stearate9 stearic acid and the like. Exemplary o~
liquid carriers are syrup9 peanut oilg olive oil9 water :.
. and the likei. Similarly the carrier or diluent can include
any time delay material well known to the art 9 such as
glyceryl monDstearate or glyceryl distearate ala~e or with
0 a wax. ~ ~
`~ The method in accordance with this invention also ..
includes inhibiting the efects of the antigen-antibody
reaction which comprises the prior application ~o the area
l of ~he iantigen-antibody mechanism a therapeu~ically
~, 15 effective amount of a substituted 4,6-dihydroxy-2H-pyran- ;
:l 2-one as defined in foxmula I. A particular application is
I a method or relieving or preventing allergic airway ~ :
¦: obætruction which comprises administering to an animal a
the~apeutically ~ectiv~i amount at suitable i~tervals.
~ The pharmaceutical preparations are made follow- ~;
~,~ ing the conventional techniques o the pharmaceutical chem-
I ist involving mixi~g~ granulating and compressing when
necessary, or variously mixing and disso~ving the ingredi-
~, enits as appropriate to the desired end produc~
~ $ The accompanying examples illustrate the prepara~
:~ tion of compounds of ormula I and their incorporation into
1 pharmaceutical compoæitions o~ this:invention and as such
~,
~: are not ~o be considered as limiting the invention set :
; forth in the claims appended here~o.
930 -
,
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~0S76~
1 Kiang~ A. K. et al. J. Chem. Soc. ~c3 pp. 2721-6
(1971) have questioned the structure assigned by previous
authors such as Wiley~ R. H. et al. ~ 21:686-
688 (1956) to the reaction product of acetonedicarboxylic
acid and acetic anhydride.9 designated 5-carboxydehydro-
acetic acid. Thusg Kiang et al. supra reported that the
reaction of acetonedicarboxylic acid with acetic anhydride
gave the compound of structure IIo -
OH ` ;~
CH3CO ~ X 3
FORMULA II
M. Mamike et al.g J. Org _5~ Japan
25:472-6 (1951) and C. A. Salemink~ Rec. Trav. Chim. 80
422-30 (1961) have also reported "2-pyrone-5-carboxylic
acids".
Upon investigation which has included l3C nucl~a~
ma~netic resonance spectral studies~ we have concluded
that the reaction of acetonedicarboxylic acid with acetic
anhydrlde gives a product having the ~automeric structure
as shown b~low:
CH3~ ~ C~,H CH3/C ~ c\c CH /C ~ C~C
~5 HO O ~o O OH
For convenience this product~ designated herein as 3~5-
diacetyl-4,6-dihydroxy-2H-pyran-2-one~ and the analogous
,
. products from reaction with other acid anhydrides are
, ~
j represented by formula I above. ThiS agrees with Kiang
~l 30 e~ al's gross structure indicated by form~la II~ The :
)
.~ .
. 7
:.
~L~)5'76~
l rate of tautomerization represented by ~ is afected~
among other factors~ by ~he sol~ent used in the 13C spectral
study.
~EXA~LE 1
To a mixture o~ 12050 g~ ~116 ml~g 1~2 mO~ of
~, acetic anhydride and 5 mlO of concentra~ed sulfuric acidat 10-20Co is added slowly 36,5 gO ~0025 m.~ o~ acetonedi~
carboxylic acid. The resulting mix~ure is heated on a ~team
bath at 90-95C. for 30 m~nutes and then poured into about
500 ml. of ice-water. The solid removed by filtration and
r recrystallized from benzene to give 39S-dlacetyl-496-dihy-
droxy-2H~pyran-2~one9 mJpu 153~155Co
EXAMPLE 2
Acetonedicarboxylic acid ~703 gO 9 0005 m.) i9
added 510wly to 32.1 ml. (3205 g.g 0025 m,) of propionic
. j .
j anhydride with 1 mlO of concentrated sulfuric acid at
10-20C.~ me resulting mi~:ture is heated on a Bteam bath
at 90~95~C0 or~ 45~minutes and then poured into about
100 ml. of ice-waterO The solld is ~iltered and recry~
.1 ~
~ 20 stall~zed from methanol to yield 3D5-bis~propionyl)~4D6-
.1 dihydroxy-2H pyran-2~oneD m~pO 114-115Co
EXAMPLE 3
~ ~,
i, To a mixture of 39,55 g, (0.25 m.) of n-butyric
;!: anhydride with 1 ml, o concentrated sulfuri:c acid at
, 25 10-20C. is added 910wly 7~3 gO ~0005 m.) of acetonedicax~
.. ~.
! boxylic acid and the resulting mixture i~ heated on a steam
~1 - , . . : . , '~ '
bath at 90-95C0 ~or one~hour. The reaction mix~ure is
poured into ice-water9 the solid is fileered and recry-
stallized from methanol to ~urnish 395-bis(butyryL)~496-
dihydroxy-2H-pyran-2-one9 mOp~ 80~82C~
. : ,
, ~ - 8 ~ ~
.
~5'7~
}~`
~X~*PLE 4
Following the procedure of Example 1~ acetonedi~
carboxyllc acid ~703 gO 9 0~05 mO 3 i5 addP.d s13wly to 46c6 gO
~0.25 mO ) o n~valeric anhydri.de with 1 mlO of concentrated
sul~uric acid at 10~20~C~ The resultlng mixture i~ heated -
on a ~team ba~h at 90-95Co ~or one hour and then po~red
into ice~water. The fil~red solid is recrystallized ~rom
methanol to give 395-bis~valer~1~-4~6~dihydro~y;2H~pyran-2
one~ m.pO 84-85G~
EY~ E 5
To a mixture of 53~6 gO ~00~5 ~.~ of n~heganoic
anhydride with 1 mlO of concen~rated sulfuric acld at
10-20Co i~ added slowly 703 gO (0005 m. ) of acetonedicar-
~: 15 boxylic acid and the resulting mixture is heated on a ~team `~
bath for 30 minutes. The reac~ion mixture is poured in~o
ice~water9 filtered and the ~olid recrystallized from
: methanol to yield 3~5 bis~hexanoyl)-4 9 6~dihydroxy-2H;-pyran~ 2~0ne9 m~p~ 87~88C.
!: 20 : Simi-larly9 reaction of 65.5 g~ (7004 ml.9 0025 mO~
of n-hep~anoic anhydride with acetonedicarboxylic acid as
described above gives the corresponding product 3~5~;bis~
eptanoyl)-496-dihydroxy-2H~pyran~2~one9 m.p~ 88~90Co `~;
~i As a specific embodiment o~ a useful composition
of thi~ inventionD an active i~gredient such as 395~bis~
(hexanoyl~ 496-dihydroxy-2H~pyran-2~one i8 dissolved in :
~i sterile water at a concentra~ion of 0~5% aerosolized from
~ a nebulizer operating a~ an aîr ~low adjusted to deliver ;~
`j the desir2d aerosolized weight of drug.
For oral administra~ion9 composi~ions such as
those in the following examples can be preparedO ~
~ :
~57~1~61
EXAMPLE 6
let
35,5-diacetyl~45,6-dihydroxy~2H~ 25
pyran-2~one
Calcium sulfate9 dihydra~e 12S
S
Sucrose ~5
Starch 15
' Talc 5
Stearic acid 3 ~ ~
10The sucrose~ calcium sulfate and the active ingredient are: ~;
~, thoroughly mi~ed and granulated wi~h hot ~0% gelatin solu--
tion~ The wetted mass is passed through a ~6 mesh screen ~ :
directly onto dryi~g trays. me granules are dried at ~::
'! 120F, and passed through a #20 me~h screen9 mixed with
i 15the starch~ talc and stearic acid9 and compressed into
:' tablets~
.~
EXAMPLE 7
l ~ ,
il~ 3 9 5:-diacetyl-4 9 6-dihydroxy-2~I~ 100
pyran~2-one
: 20 Magnesium stearate ~ 5
Lactose 300
The above ingredients are screened through a ~40 mesh
~ screen9 mixed and illed into ~tO hard gelatin cap~ulesO
;1 , ' -
~ :.
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',
.
~ - 10 ~
~, ~
, :
