CA1076591A - Pharmaceutical compositions comprising substituted 3-cinnamoyl-2h-pyran-2,6(3h)-diones - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

Pharmaceutical compositions comprising a substituted 3-cinnamoyl-2H-pyran-2,6(3H)-dione and methods of inhibiting the antigen-antibody reaction by administering said composi-tions. Certain of the 3-cinnamoyl-2H-pyran-2,6(3H)-diones are novel compounds per se.

Description

659~

1 This invention relates to novel. pharmaceutical ~ompositions which inhibit certain antigen-antibody reac-tions and to methods of inhibiting such antigen-antibody reactions by administering said compositions. More specifi-cally9 the compositions of this invention comprise a sub stituted 3-cinnamoyl-2H-pyran-296(3H)-dione as th~ active medicament.
The novel pharmaceutical compositions o this invention comprise a nontoxic pharmaceutical carrier or diluent and a substituted 3-cinnamoyl-2_-pyran-296(3~-dione of the following general structural formula:
~H3 ~ R
o FORMULA I
~_ .
wherein R represents hydrogen9 methoxy9 dimethoxy9 hydroxy~
methyl9 carboxymethyleneoxyg acetamido or 3-acetamido-4-hydroxy.
Advantageously the compositions of this invention 2Q comprise a compound of ormula I above when R is hydroxy9 carboxymethyleneoxy or acetamido.
The compounds of formula I are generally pre-pared as shown in the following reaction schemP

CH ~ ~ ~ H ~ CH~ ~ ~ R
3 ll 3 + 1 ~R .~
HO ~ o, ~ ~/ C~ \o/bO

- in which R is as defined above. Thus3 395-diacetyl-49~-dihydroxy-2H-pyran-2-one and the benzaldehyde are usually heated at reflux in an inert orga~ic solvent such as :

- 2 -:':

765~9~L

l chloroform and in the presence of piperidine ~or from 4 to - -36 hoursO The pyran starting ma~erial is obtained by re-action of acetonedicarboxylic acid and acetic anhydride in sulfuric acid at elevated temperature.
Certain of the compounds of formula I above are novel compounds and as such form a part of this invention.
These compounds may be represented by the f~llowing formulaOo ~H

FORMWLA II
wherein R represents hydroxy9 carboxymethyleneoxy9 acetamido or 3-acetamido^4-hydroxyO
The compositions of this invention inhibit the release and/or formation of pharmacologically active media- ;
tors from effector cells triggered by the interaction o~
a~tigen and a specific antibody fixed to the cell surface.
Thus the compositions are valuable ln the treatment of allergic diseases such as asthma9 rhinitis and urticaria.
The inhibitory activity of ~he compositions of this invention on mediator release in sen~itized tis~ues ii measured by ~he ability uf the active medicament to inhiblt the passive cutaneous anaphylaxis (PGA) reaction in rats. In this test 5ystem9 titered and appropriately diluted serum ~from rats previously immunized by the intra-peritoneal in~ection of ovalbuminaluminum hydroxide or ovalbumin-i.mO~Bordatella pertussis UOSoPo iOpO-and No Brasiliensis iop~ ) containing reaginic antibodies directed against ovalbumin i5 in~ect~d intradermally at four sites : . .

~ 7 ~ ~9 ~
1 on the shaved backs of normal adult male rats, Forty eight hours later the animals are injected intravenously with 005 ml~ of isotonic saline solution containing 5 mgO
of the ovalbumin antigen and S mgO of Evans blue dye.
S Chemical mediators such as histamine and serotonin which are released at the ~ensitized sites as a result of a local cellular a~aphylaxis 9 cause an increase in capillary perme~
ability with resultant leakage of plasma and formation of a whealO The wheal is visualized by the plasma protein~
bound Evans blue dyeO Under conditions of the test9 the avPrage control wheal is approxima~ely 12x12 mm~ Thirty minutes ollowing antigen challenge 9 the animals are killed the dor~al skin is reflected and the diameter of the wheals recordedO A test compound is administer~d intravenously9 initially at 005 minu~es prior to antigen challenge (longer pretreatment times and other routes of drug administration3 i~e, oral or intraperitoneal 9 may be employed)~ Percent inhibition is calculated from the differenc~ in mean average wheal diameter between a treated group and sali~e or appropriate diluent controlsO
The compounds of formula 1 admi~iætered intra-venously to rats at doses o from 0.5 to lO mglk~ producs marked inhibit~on of the PCA reactionO ~A preferred c~m-pound9 5-acetyl-3-(p-hydroxycinnamoyl~4~hydroxy-2H-pyran-Z'5 296(3~ -dione9 produced 48~/o inhibition of the rat PCA wheal at 105 mg/kg iovo Another preferred compound9 5~acety~-3 [p-(carboxymethYlene~xY)Cinnamoyl~-4-hydroxy-2H~pyran~2 9 6-(3~dione 9 produced 50% inhibition of the r~t PCA wheal at 0,5 mg/kg~ i.v. In te~ting for mechanism of a~tion~ the compounds of formula I were fou~d not to provide compar~ble :

~765g~

1 inhibition of wheals of approximately equal severity pro-duced in rats by the intracutsneous administration of his-tamine and serotonin following i.v. administratlon of the test compound at the same dose and pretreatment time which exhibited significant inhibition of the rat 48 hour PCA
reactionO
Upon oral administration~ 5-acetyl-3-(m-~hydroxy-cinnamoyl~ 4Ohydroxy-2H-pyran-296~3~-dione produced 29%
inhibi~ion in the rat 48 hour PCA system at 25 mg/kg and a pretreatment time of 15 minutes~
The pharmaceutical compositions of this inventio~
comprise an appxopriate amount of a substituted 3-cinnamoyl-2H-pyran-296(3~-dione as ~et orth in ormu~a I in associa-tion with a pharmaceutical carriler or diluent. The nature of the composition and the pharmaceutical carrier or diluen~ will of course depend up~n the intended route of administration9 i.e. orally9 parenterally or by inhalation.
Preferably the active medicament is administered to an animal in a composition comprising an amount suficient to produce an inhibitioQ of the consequences of the antigen-an~ibody reactionO When employed in this manner~ the do~-age of composition is such that from 5 mgO to 500 mgO 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 about 5 mg. to about 2000 mg.
In genexal~ particularly for the prophylactic treatment of asthmag the compositions will be in a form suitable for administration by inhalation. Thus the com~
positions will comprise a suspen~ion or solution of the ~3765~

1 active ingredient in water for administration by means of a conven~ional nebulizerO Alternatively the compositions will c~mpri~e a suspension or solution of the active ingre-dient in a conventional liquified propellant such as di~
chlorodifluoromethane or chlorotrifluoroethane to be administered from a pressurized container. The compositions may also comprise the solid active ingredient diluted with a solid diluent 9 eOgO lactose 9 for administration from a powder inhalation deviceO In the above compositions 9 the amount of carrier or diluent will vary but preferably will be the major proportion of a su~pension or solution of the active ingredientO When the dilue~t is a solid9 it may be present in less 9 equal or greater amounts than the solid active ingredient.
As a specific embodiment of a useful composition9 the active ingredient such as 5~ac~yl-3-(p~hydr~xycinna-moyl~ 4 hydroxy-2H-pyra~2 96(3~ ~dio~e9 i9 dissolved in sterile water at a concentration of 005% and aer~soliæed rom a nebul~zer operating at an air 10w ad~u~ted to deliver the desired aerosolized weight of drugO ~-A wide variety of other pharmaceutical forms can be employed. Thus9 if a solid carrier i~ used the prepara- -tion can be tableted9 placed in a hard gelatin capsule in powder or pellet orm9 or in the form of a troche or lozenge or oral administratio~ The amount of ~olid carrier will vary widely but preferably will be about 25 mgO
to about 1 g. I~ a liquid carrier is used9 the preparation will be in the form of a syrup9 emulsion~ soft gelati~
capsule9 sterile injectable liquid such as an ampul9 or an aqueous or nonaqueous liquid suspensionO

.L~7659~L
1 Exemplary of sol~d carriers are lactose 9 terra alba9 sucrose3 talc9 gela~ 5, agar9 pectin9 acacia9 mag-nesium stearate~ stearic acid and the like~ Exemplary of liquid carrierg are syrup 9 peanut oil~ olive oil 9 water and the likeO Similarly the carrier or diluent can include any time delay material well known to the art~ such as glyceryl monostearate or glyceryl distearate alone or with a waxO
The method in accordance with this lnvention also ~ . .
includes inhibiting the effects of the antigan-antibody reaction which comprises the prior application to the area of the antigen~antibody mechanism a therapeutically effec-tive amount of a substitu~ed 3~cinnamoyl~2H~pyran-2 9 6~3 dione as defined in formula Io A particular application 15 i5 a me~hod of relieving or preventing allergic airway obstruction which comprises administering to an animal a ~herapeutlcally effective amount at sui~able intervals~
The pharmaceutical preparations are made follow-ing the conventional techniques of the pharmaceutical ~0 chemist involv~ng mixing9 granulating and compressing when neceæsary9 or variou~ly mixing and dissolving the ingredi- .
ents as appropriate to the desired e~d product.
The accompanying examples illustrate the prepara-tion of compounds of formula I and their incoxporation i~to pharmaceutical compositions of this invention and as such are not to be considered as limiting the invention set forth in the claims appended hereto.
Kiang9 Ao Ko et alO J. Chem. Soc. (c~ ppO ~721r6 (1971) have ques~ioned the structure assigned by previous authors such as Wiley~ Ro H. et al.

1~ 7 ~ 5~

l 210686 688 (19569 to the reaction product of acetonedicar-boxylic acid and acetic anhydride 9 designated 5-carbo~y-dehydroacetic acid Thus~ Kiang et alO supra reported that the reaction of aceto~dicarboxylic acid with acetic anhy-dride gave the compound of structure III
OH
CH~CO ~ COCH3 FORMULA III
~ . .
Wiley et al~ supra have also reported condensation products of "5~carbo~ydehydroacetic acid" with p-dimethyl-amino-and 2 ~3~dimetho~ybenzaldehyde snd assigned the fol-lowing structure to the productsO
:.
pH : .
H02C3~0C'H~CHAr

3 0 Upon investigation which has incIuded 13C nuclear magnetic resonance spectral studies 9 we have concluded that the reaction of acetondicarboxylic acid with acetic anhy-dride gives a product having the tautomeric structure as shown belowJ
~ H ~ OH ~ ~ ~H
CH ~ ~ ~CH CH3/ ~ `CH ~ H3/ ~ H3 HO~o i O ~------ o~o ~ H

For convenience this product i8 ~esignated herein as 395 d~acetyl~496 dihydroxy~2H;pyran-2~oneO Thi9 agrees with Klang et al~8 gross ~tructure i~dlcated by formula III

~ 8 ~

3L~7659~
1 aboveO The rate of tau~omerization represented by ~ above is affected9 among other factors3 by the solvent used in the 13C spectral studyO Accordingly9 the reaction o~ this pro- ;
duced with a benzaldehydeD ~C6H4CHO9 gives a product having S the tautomeric structures as shown belowO

CH3~C ~ \ ~ C~3 C
E~O O o O

OH

lS in which R is a~ defined above for formula Io For conveni~
ence~ one tautomeric form ha~ been cho~enD namely the intermediate pyran-296-dione ~tructwre9 to represent the compounds formed by reaction of ~ with a benzaldehyde9 --RC6H4CHO9 as indicated by formula I abov~O
EXA~PLE 1 __ A mixture of 8048 gO ~0004 mO) of 395~diacetyl 496-dihydroxy-2H~pyran-2one9 4.88 g. (0,04 m.) of p-hy d~oxybenzaldehyde in 100 mlO of chloroform and 20 drops of piperidine is refluxed for 12 hoursO The cooled reaction mixture is filtered and the filtrate is concentrated to give the starting pyranO The original solid is treated with acetone/water to yield S-acetyl~3-(p-hydroxycinnamoyl)o4 hydroxy~2H~pyran~2 9 6~3~dio~e~ m.p0 235o237Co SimilarlyD 8048 gO of 3D5-diacetyl~4960dihydroxy~ ~ -2H~pyran-2~oneg 4090 g. ~f m~hydroxybenzaldehydep 35 drop~

_ 9 .0 .
.. . . . .

7 ~
of piperidine and 200 mlO of chloroform is refluxed for 12 hour~ and the resulting precipitate ls removed by fil-tration ~o give 5-acetyl 3~m-hydroxycinnamoyl~4 hydroxy-2H~pyran~2~6~3~dione 9 m~p0 194~196C.
S ~XAMPLE 2 Following the procedure of Example 1D a mixture of 8048 gO ~OOO4 mO~ of 3D5~diacetyl-4~6-dihydroxy-2H~
pyran2~0ne9 4O8 g, (0O04 mO~ of p~methylbenzaldehyde in 100 mlO of chloroform and 20 drops of piperidi~e is reflux-ed for 10 hours~ concen~rated and iltered to yield 5-ace~yl

4 hydroxy~3~p~methylcinnamoyl~ 2H pyran2 9 6(3~3~dione 9 mOpO 188~190Co ~XAMPLE 3 A mix~ure of 4024 gO of 395-diacetyl~4J6~dihydroxy 2H~pyran~2~one~ 2012 gO of be~zaldehyde3 20 drops of plperi~
dine and 75 mlO o chloroform i~ refluxed for eight hoursO
The water liberated during the reaction i9 removed by a receiverO The r~action mixture is conce~trated and tritura~
ted with ethanol to afford 5 ac~tyl~3 cinnamoyl-4~hydroxy-2~ 2H~pyran~296~3~dione9 m.pO 154 1S5C~

395~Diacetyl 4~6~dihydroxy~2Hpyran-2~one (8O48 g;9 0.04 m~ 6065 gO (0O04 m~ of 295-dimethoxybenzaldehyde in 50 mlO o~ chloroform and 20 drops cf piperidine are re fluxed for eight hoursO The reaction mixture is cooled and filtered to glve 5-acetyl-3~2g5 dimethoxycinnamoyl~-4-hydroxy-2H~pyran~2~6(3~-dione9 m.pO 194-195C~
Similarly~ equimolar amounts of 3g5 diacetyl~496-dihydroxy~2H-pyran-2-one and 3D4-dimethoxybenæaldehyde or 293~d~methoxybellzaldehyde are reacted as above to yield - 1 û ~

~ 76S~l ~

1 the productsg 5nacetyl~3nn(3D4~dimethoxycinnamoyl~n4-hydroxy~2H~pyran~296~3~dione9 mOpO 223 225Cog a~d 5-acetyl-3~(2~3 dimethoxycinnamoyl~ 4~hydroxy~n2H~pyran~296~3~ n dione~ m.pO 17S~176Co ~ respectively, Following the procedure of Example 19 equimolar amounts of 3~5ndiacetyln4~6 dihydroxy2H~pyran~2none and pnmethoxyb~nzaldehyde or mnmethoxybenzaldehyde are reacted to ~urnish 5~acetyl~4nhydro~y~3<n(pnmethoxycinnamoyl)-2H~;pyr~n~
2~6(3~-dione~ m~pO 182~184Co ~ and 5wacetyln4nhydroxy-3~
~m-met:hoxycinnamoyl~2Hepyran~2D6~3~dioneg m~pO 180-182Co 9 respectively, ~ .
A mixture of 402 g, (0002 m,) of 395~diacetyl~
496-dihydroxy-2Hnpyrannn2none~ 306 g. ~0.02 mO~ of 4-formyl phenoxyacetic acid~ 200 ml. of c!hloroform and 30 drops of piperidine is azeo~roped under rleflux for 24 h wrs. The reactlon mixture. is fil$ered to give S~acetyl~3n[pn~car~
boxymethyleneoxy~cinnamoyl]-4 hydroxy-2Hnpyran-2D6~3H~-dione9 m~pO 218~5-221Co To a mixture vf 2,11 gO ~0~0~ m,~ of 395-diacetyl~
496-dihydroxy-2H~pyran--2~one and 1063 g. (OoOl mO) o:E
p-acetamidobenzaldehyde in 200 mlO of chloroform is added with stirring 25 drop~ of piperidineO The resulting ~olu~
tion is refluxed and azeotroped for 12 hoursg iltered hot and the ~olid i~ washed wi~h dilute hydrochloric acid~
water and ether to give 3~(p~acetamidocinnamoyl~5~acetyl~
4~hydroxy~2H-pyran-2~6~3~ ~dioneg m.pO 230~231C, -; :
. ~ .

Similarly, 4.2 fg. (0.02 m.) of 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one, 3.2 g. (0.02 m.) of m-acetamido-benzaldehyde, 200 ml. of chloroform and 0.5 ml. of piperi-dine is azeotroped for four hours and the reaction mixture is filtered to yield 3-(m-acetamidocinnamoyl)-5-acetyl-4-hydroxy-2H-pyran-2,6(3H)-dione, m.p. 222-224°C.

A mixture of 2.96 g. (0.014 m.) of 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one, 2.5 g. (0.014 m.) of 3-acet-amido-4-hydroxybenzaladehyde (prepared frin 3-amino-4-hydroxybenzaladehyde by reaction with acetic anhydride/
sodium acetate), 200 ml. of chloroform and 35 drops of piperidine is refluxed, stirred and azeotroped for 36 hours.
Filtration gives a solid which is washed with dilute hydro-chloric acid and chloroform. The dried solid is placed in a Soxhlet apparatus and extracted with acetone for several hours. The acetone extract is evaporated and the solid is washed with chloroform, then triturated with ether to fur-cish 3-[(3-acetimido-4-hydroxy)cinnamoyl]-5-acetyl-4-hydroxy-2H-pyran-2,6(3H)-dione, m.p. 237-239°C.

For oral administration, compositions such as the following can be prepared:

The above ingredients are screened through a #40 mesh screen, mixed and filled into #0 hard gelatin capsules.

Claims (7)

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

1. A process for the preparation of chemical compounds of the formula:

wherein R is hydrogen, methoxy, methyl, hydroxy, carboxy-methyleneoxy, acetamido or 3-acetamido-4-hydroxy, which comprises reacting 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one with a benzaldehyde, RC6H4CHO, in which R is as defined above.

2. The process according to claim 1 in which the reactants are heated at reflux in an inert organic sol-vent and in the presence of piperidine for from 4 to 36 hours.

3. The process for the preparation of 5-acetyl-3-(p-hydroxycinnamoyl)-4-hydroxy-2H-pyran-2,6(3H)-dione which comprises reacting 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one with p-hydroxybenzaldehyde.

4. The process for the preparation of 5-acetyl-3-[p-(carboxymethyleneoxy)cinnamoyl]-4-hydroxy-2H-pyran-2,6(3H)-dione which comprises reacting 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one with p-formylphenoxyacetic acid.

5. A compound represented by the formula:

wherein R is hydrogen, methoxy, methyl, hydroxy, carboxy methyleneoxy, acetamido, or 3-acetamido-4-hydroxy, whenever prepared by the process of claim 1 or an obvious chemical equivalent thereof.

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

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