CA1057661A - Pharmaceutical compositions comprising substituted 4,6-dihydroxy-2h-pyran-2-ones - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
Pharmaceutical compositions comprising a substituted 4,6-dihydroxy-2H-pyran-2-one and methods of inhibiting the antigen-antibody reaction by administering said compositions.

Description

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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~
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; 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. :~

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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. ;

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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

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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-.~ ! .

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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.

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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 :

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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 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~
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~ 20 stall~zed from methanol to yield 3D5-bis~propionyl)~4D6-.1 dihydroxy-2H pyran-2~oneD m~pO 114-115Co ~ ~, 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~

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~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 ~

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~57~1~61 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~
.~

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
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Claims (10)

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

1. A pharmaceutical composition which inhibits the antigen-antibody reaction comprising a pharmaceutical carrier and an effective amount of a chemical compound of the formula:

wherein R is lower alkyl, straight or branched chain, of from 1 to 6 carbon atoms, the R's being identical.

2. A pharmaceutical composition according to claim 1 in a form suitable for administration by inhalation.

3. A pharmaceutical composition according to claim 1 comprising a solution or suspension of the active ingredient in sterile water.

4. A pharmaceutical composition according to claim 1 in the form of an aerosol formulation.

5. A pharmaceutical composition according to claim 1 comprising the solid active ingredient diluted with a solid diluent.

6. A pharmaceutical composition according to claim 1 in which R is methyl.

7. A pharmaceutical composition according to claim 1 in which R is n-pentyl.

8. A pharmaceutical composition in dosage unit form comprising a pharmaceutical carrier and a chemical compound of the formula:

wherein R is lower alkyl, straight or branched chain, of from 1 to 6 carbon atoms, the R's being identical, said compound being present in an amount of about 25 mg. to about 750 mg. per dosage unit.

9, A pharmaceutical composition according to claim 8 in which R is methyl.

10. A pharmaceutical composition according to claim 8 in which R is n-pentyl.