CA1045550A - Antiviral 5-(substituted benzal)hydantoins - Google Patents

Abstract

ABSTRACT

An antiviral, therapeutic composition presented by conventional pharmaceutical techniques in a form adapted to secure on its administration to mammals a dosage at the rate of 1 to 500 milligrams per kilogram of body weight per day, in single or multiple doses, of a substance of the following formula conveyed by a pharmaceutically acceptable carrier.

I

in which the hydantoin moiety is partially N-acetylated, and wherein:
Formula I includes individual geometrical isomers and mixtures thereof, R1 is hydrogen or methoxy;
R2 is hydrogen, methoxy or acetoxy;
R3 is hydrogen, methoxy, or acetoxy; and R4 is hydrogen or methoxy; with the provisos that:
R2 and R3 together may be - OCH2O provided that R1 and R4 are hydrogen;
when R3 is acetoxy R1 and R4 are hydrogen and R2 is methoxy or acetoxy; and no more than two of R1, R2, R3 and R4 are methoxy.

Description

~L3~55~
The present in~ention relates to therapeutic compositions having anti-viral activity and comprising certain partially acylated 5~(substituted benzal) hydantoins.
It was previously reported by Deulofeu and Mendivelzua, Z. physiolO Chem. 219, 233 (1933) that the condensation of vera-traldehyde (3,4-dimethoxybenzaldehyde) with hydantoin in acetic - anhydride in the presence o~ fused anhydrous sodium acetate gave 5-(3',4'-dimethoxybenzal) hydantoin. we have now found, however, that this reaction leads to the formation o a corresponding -acetylated product.
Similarly, other acylated-5-(substituted benza:L) hydantoins can be prepared, as described by G. Billek~ Monatsh. Chem., 92, 352(1961), by heating the appropriately substituted benzaldehyde and an anhydrous alkali metal alkanoate together with hydantoin and the corresponding acid anhyaride. The reaction is generally conducted at an elevated temperature until the reaction is substantially complete. For example, in the reaction of benzal-dehydes with hydantoin in the presence of anhydrous sodium acetate and acetic anhydride, the reaction is generally carried out at about 125-140 & . It has also been found that potassium bicar-bonate can be used in place of the anhydrous alkali metal alkanoate wi~h similar results being obtained. After the condensa-tion is complete, the reaction mixture is cooled, usually over-night, treated with water and then refrigerated for several hours.
~he crystalline product is then filtered, ~ashed with water and dried. The major portion of the product appears to be mono-acylated compound, together with small amounts of di-acylated compound. Where the aromatic aldehyde starting material contains phenolic hydroxylic groups, it has been found that the~se are ---` 104SSS~
acylated under the conditions of the reaction. Thus proto- -catechualdehyde, hydantoin, anhydrous sodium acetate, and acetic anhydride gave acetylated 5-(3',4'-diacetoxybenzal) hydantoin.
We have found the partially acylated compounds thus produced to be highly effective as antiviral agents, in particular against ~he Picorna group of viruses. The Picorna viruses are a group of small RNA viruses comprising enteroviruses (poli-omyolitis, coxsackie, and echo viruses), rhinoviruses, and viruses of nonhuman origin such as foot-and-mouth virus of cattle.
The outstanding characteristics of the compounds of ~he present invent~on are their high degree of inhibition against ~e above vixu~e3, even at concentrations below 1~ g/ml, coupled with their low order of toxicity.
Accordingly, the invention relate~ to an antiviral, therapeutic composition presented by conventional pharmaceutical techniques in a form adaptea to secure on its administration to mammals a dosage at the rate of 1 to 500 milligrams per kilogram of body weight per day, in single or multiple doses, of a substance of the following ~Eormula conveyed by a ~h~rmQc~ic~
~a~cceptable carrier:
:

'Rt -

2~--~CH=r~

~: ` R4 : ~ :

in which the hydantoin moiety is partially ~-acetylated, and ~wherein:
- :

55S~

Formula I~includes individual geometrical isomers and mixtures thereof, Rl is hydrogen or methoxy;
R~ is hydrogen, methoxy or acetoxy;
R3 is hydrogen, methoxy, or acetoxy; and ~ 4 is hydrogen or methoxy; with the provisos that:
R2 and R3 together may be - OCH20 provided that R
and R4 are hydrogen;
when R3 is acetoxy Rl and ~4 are hydrogen and R2 is methoxy or acetoxy; and no more than two oE Rl, R , R3 and R~ are m~thoxy.
The in vitro activity of representative compounds includi~g those of the present invention are set forth below.
In preparing the compounds for testing, they were handled aseptically throughout. The compounds were dissolved in a minimum amount of a suitable solvent, and the final dilutions were made up to the required volume in a complete ~ulture medium in a concentratlon not exceeding the predeter~ined maximum non-cytotoxic levels. All materials were tested by weight, first at three concentrations, 100 - 10 - 1~ g/ml and those which showed an inhibiting activity in that range were carefully retested at several concentrations below the maximum non-cytotoxic level.
The cell cultures used in all primary in vi~ro anti-picorna virus screening tests were an established cell line of the African green monkey kidney (VERO), a primary cell culture of the Cercopythecus monkey kidney, or human embryonic lung diploid cells WI-38.
The cytotoxic studies were performed on each of the compounds to determine the level of response of the cellc; used

- 3 -~0~555~
to the potentially toxic action of the substances. Cytotoxic levels were expressed as a 50% inhibition of the cell growth as compared to the appropriate controls (CTD50) or as a maximal non-toxic concentration (CTDo) which does not produce any morphologically detectable inhibition of cell growth.
Standard batches of the vixuses were made by growing the virus in an appropriate cell culture and then making a pool which was dispersed in ampoules and kept frozen at -76C until usedO
The titer of each virus was determined in the cell cultures used.
The cells were grown in test tubes in a suitable medium.
Immediately before use the initial medium was replaced with the one which contained the test compound in an appropriate concen-trationO A~ter the virus was added, the infected culture was i~cubated at 37C for a number of days and the cytopathic effect of the virus observed and xecorded. The results were read every day in all of the tubes and the destruction of cells assessed in percentage of the cell sheet destroyed: 0-25-50-75-lOO~o As controls, cells with only virus ~for cytopathic ef~ect) or with only the compound (for cytotoxic effect) were ussd as well as the normal, uninfected cells (no cytotoxic - no cytopathic effects).

Degree o~ a speci~ic cytopathic effect or its inhibition ~
~ . .. .
was calculated at the tLme when the cell virus-control tubes showed complete destruction of the cell monolayer sheetO ~et dif~erence in cytopathic effect between treated and control tubes expressed in percentage give the extent of the inhibitory acti vity of the substance. From these data a dose-response curve was then calculated and plotted~ -~
The TCID50 represents the tissue culture infective dose of virus that will destroy 50~ of the cellsO

- 4 -.. . .. .

~45SS~

5- ( 3 , 4 -DIMETHOXYBENZAL ) HYDANTOIN

Pollo I., Primary Monkey Kidney Cells 316 TCID50 Concentration of Compound % Inhibition 100 micrograms/ml 45 50 .......................... 34 - . . - ~ _ ~, - . -ACETYLATED 5-(3',4'-DIMETHOXYBENZAL) H~DANTOI~ .
~ - , . .

(A) Prepared according to the method of Deulofeu and Mendivelzua (loc. cit.) (Example 14) .
10Polio I, Vero Cells; 316 TCID50 Concentration of Compound ~ Inhibition ':' 10 micrograms/ml 100 -5 " 100 1 ........................... 100 . ' .
005 " .

Coxsackie B3, Vero Cells, 173 TCID50 -- --Concentration of Compound ~ Inh-bition 10 micrograms/ml 100 5 " 100 . 20 1 " 97 ~5 " 88 ~ ~:

' , . ~ .

L~ i~ ':

SS5~ ~
}:cho 9, Vero Cells; 31.6 TCID50 -, Cytotoxicity Concentration % Inhlbition ¦
CTD50 ¦ 0 of Compound ( ilg/ml ( llg/ml ) 1 ~lg/ml ) .. ..
100 ~ 10 10.0 100 0~3 29 Ool 8 . . _.__ ,'. .

Echo 11, Primary Monlcey Kidney Cells, 178 TCID50 -_ ... .. -- . - - - - __ Cytotoxicity Concentration~ Inhibition ~ o~ Compound (llg/ml) ~ g/ml) (Il~/ml) , . ~ ................ _ , , . . ,: ' 100 ~ 100 100 100 . ~ .

~00 ~:

loO - 68 :
0 7 32 :
, , . _ 0.1 _ .~ ' : ~ .
Rhino 2, WI-38 Cells, 316 TCID
- ~_ ,5 ~:
Cytotc Concentration% InhibitLon CTD50 CTDo of Compound ( llg/ml ) ( llg/ml ) ( llg/ml ) .
_ . . . ..... ~... ~
~ 100 ~100 10 100 .'. ,: ' .

6 7 100 l-0 743 ..... , _ 0~ 1 .. .... ,.. ~
____~__ 1~4555~

(B) Prepared by acetylation of 5-(3',4'-dimethoxybenzal) hydantoin with acetic anhydrideO
Coxsackie B3, Vero Cells; 562 TCI~50 ~ . . _ . . .... _ . , . ,__ Concentration of Compound ~ Inhibition ~ _. _ . _ _ _.
1.0 micrograms/ml 100 -5 " 95 0.1 " 75 .
0005 " 50 :~
0~01 '! 20 .. .. . ... . _ _ . _ - :. .
(C) Prepared by acetylation of 5-(3',4'~
dimethoxybenzal) hydantoin with sodium acetate-acetic anhydride.
Cox~ackie B3, Vero Cells; 562 TCID50 -- -- .................................................. . .
..... .. . . , . , , Concentxation of Compound % Inhibition 1.0 micrograms/ml 100 .
5 " 100 . : :
Oo 1 ~ 100 . . .
0 05 '' . 5 . ~ . ~ . . _ .__ _. , ACETY _TED 5-(~'-METHOXY-4'-ACETOXYB_NZAI~ HYDANTOIN
(Example 15) Polio IJ Vero Cells: 56.2 TCID50 . ~ . . ~. .... . . .. .
Cytotoxicity Concentration % Inhibition CTD~o CTDo of Compound (~g/ml) (~g/ml) (~g/ml) ~ .
'-~i00 ~10 . ~_ . 1~0 ~ ~ .

3o _ ~ 0 1 ~ 19 ~(~45S51~
Coxsackie B39 Vero Cells; 562 TCID50 . - :
... , ., . _ .
Cytotoxicity ¦ Concentration % Inhibition CTD50 CTDo of Compound (~g/ml) (~g/ml) (~g/ml) , . .. __ _ . -- _ : . .
' 100 ~ 10, 10 680 .__ - . , _ . . _ .. . , ~.

ACETY1ATED ~-(BENZAL~ H~D~TOIN (Example 16) ; :

Polio I, Vero Cells; 56.2 TCID50 ~ ~
., 10Cytotoxioity Concentration ~ Inhibition 5 O of Compound . :- :

. (~g/ml) (~g/ml) ~g/ml) _ _ ~ 19 ' :. . ' : Coxsackie B3, ~ero Cellsg 562 TCID50 ~ `
.... . - - _ -q t~n~l~itv Concentration ~ Inhibition . .
CTD50 CTDo of Compound ~ :
(~g/ml) (~g/ml) (~g/ml) .
_ . .- ., .
3 1~ 10 25 .. - .

~, . .. . .

5SS~

AChTYL~TED 5-(2'~4`,5'-TRIMETHOXYBENZAL) HYDANTOIN
(Example 22) Polio I~ Vero Cells; 100 TCID50 Cytot x_ itY Concentration % Inhibition CTD50CTDQ o~ Compound (~g/ml) _ (~g/ml) 100 0.3 9 . 0 07 55 _ - . _ _ Polio I, Vero Cells; 10 TCID50 ,, _ Cytotoxici~y CoAacntraCIon % Inhlbition CTD50CTDo of Compound (~g/ml) (~g/ml) (~g/ml) . , . .. ...
. 1 007 100 0 3 94 :

_ . - , 003 27 Coxsackie B3, Vero Cells; 178 TCID50 Cytotox LCity Concentxation ~ Inhibition CTD50 CTDo ~ Compound .~g/ml) (~g/ml) (~g/ml) _-r ~ . ~ ~ 1 ~ 100 1 1 9 ~ 0.3 88 0~07 37 0 03 ~ 12 10~L555~
Coxsackie B3, Vero Cells; 56.2 TCID50 ~ :
:
- . .
CytotoxicityConcentration ~ Inhibition CTD50 CTDo ¦f Compound - (~/ml) (~g/ml)(~/ml) _ _ _ . ~ 100 1 003 100 .

_ OoOl 19 ACET~LATED 5-~',4',5'-TRIMETHOXYBENZAL)H~DANTOIN
(~xample 23) .'- '~
Polio I, Vero Cells; 316 TCID50 :

.. .. . . . . . . .-- . .
Cvtoto XlCityConcentration~ Inhibition CTD50 CTDo of Compound .
.(~g/ml) (~g/ml) ~g/ml) _ _ _ ~0 L 10 ~ ~

Polio I~ Vero Cells; 1708 TCID50 -- -- _ .
Cytotoxiciky Concentration % Inhibition CTD50 CTDo of Compound .(~g/ml) (~g/ml) (~g/ml) .. _ 3~ . ~ 1,, ~ ~

-- ~ . -,- ' -': -- 10 -- . ", " , : . -. ~.

~)45S~ia9 Coxsackie B3, Vero Cells, 316 TCID50 ~ , . . ~
Cytotoxicity Concentration % Inhibition CTD~o CTDb of Compound (~g~ml) (~g/ml) (~g!ml) --- - ~ - ~ -50 ~ 10 10 97 ~ . . ~ . ........... . . _ O : . .

Coxsackie B3, Vero Cells; 178 TCID50 , .,~_ . . . . _ Cytotoxicity Concentration- % Inhibition CTD50 CTDo f Compound (~g/ml) (~/ml) (~g/ml) .

loO 88 00 7 . 62 _..... . - 0~3 _ 15 .
ACETYLA ~ ',5'-DIMETHOXYBE~ZAL) HYDANTOI~ .
(Example 21) ~ .
Polio I, Vero Cells; 100 TC__~o _ . . _ ~ , .
Cytotoxicity Concentration ~ Inhibition .5 O of Compound (~q/ml ! ( ~q/ml) ~g~ml L - . ~ ~
~100 100 10 100 ' __ ___ 0'9_ '~ ~ -. . .

11 - :: ., ., , . ~'"

... . . .

~09~555~

Polio I, Vero Cells; 10 TCID50 CytotoxicityConcentration5~ Inhibition CTD50 CTr)o of Compound ( llg/m 1 ) ( llg/m 1 ) ( llg/ml ) ~ _ .
~ 100 100 10 100 O. 5 . _ Coxs ack ie B3 , Ve ro Ce l ls; 3 16 TC ID50 , Cytoto KiC ityConcentrat ion% Inh ib it ion CTD5n CTDo o:E Compound ( llg/m~ )( llg/m 1~ ( ~lg/m 1 ) . . .. . . . ~ .. _ __ .
100 I ~ ~ 100 . . .., ~
.

Coxsackie B3, Vero Cells; 17.8 ~CID50 ,~ ,.. - ..... . - .... , .. ' ~ytotoxicity__ Concentration ~ Inhibition CTD50 CTDoo~ Compound (llg/m~ g/~ml )( ~lg/ml ) . . - ~ . ., .. 100 100 10 ' 100 . . ._ 005 21 .: ' .

, . .: "
PURE MONOACETATE OF 5-(3' ,~ DIM~THOXYBE~ZAL) HYDA~OIN
___ ~ . _ --_-- - - . .: .
.
' ~'. : ' . , , ~:;'' ' ' ' 1(~4S5~ :

Coxsackle B3, Vero Cells; 1000 TCID50 Cvtotoxlcity Concentration ~ Inhibition CTD50 CTDoof Compound ( ~lg/ml ) ( llg/ml )( tl~/ml ) , - . . . _ Coxs ack ie B3 ~ Ve ro Ce lls; 100 TC ID50 _ . . ~ .. . .. .
CYto,toxicitYConcentration ~ Inhibition CTD50 CTDoOf Compound ( llg/ml )( llg/ml( llg/ml ) . . ~ ....

.. . 1 . . _ ., .
Polio I~ Vero Ce}ls; 3I6 TCID50 Cytotoxicity Concentxation % Inhibition CTD50 CTDo~f Compound .
( ~g/ml ) ( ~g~ml) (~J/ml) - . .... ~ . . _.
loo lo 5 84 ::
. . _ 0 -~ -.~ ,:
.:

..

' :

. ' ~
.

. ~. .: ~ . . . . .. . - .. . : .

555~

PURE DIACETATE OF 5 - (3 ~, 4 ~ -DIMETHOXYBENZAL) :~.
HYDANTOIN. (Example 3? ) Coxsackie B3, Vero Cells; 1000 TCID50 .. ~
Cytoto xi.clty Concentration ~ Inhibltion CTD50 CTDo~ Compound (~g/ml) (~g~ml) (~/ml) . .

. . _ . ~- ~

Coxsackie B3, Vero Cells; 100 TCID50 _ xici~y Concentration ~ Inhib~ti~
CTD50 CTDo of Compound (~g/ml) (~g/ml) (~g/ml) _ . -,-33 lo 50 loo o 1~5 ';
Polio I, Vero Cells; 316 TCID50 Cytoto~ l~icity Concentra l:ion ~ Inhibition CTD50 CTDoo~ Compound (~g/ml) (~g/ml) (~g/mL) . ~ , . . _ ~ . .
33 1 l 5 ~

~.

.: :, _ 14 - ~:

~5L0~5~i5¢~
Polio I, Vexo Cells; 5602 TCID50 ~ .. . . , _ _ __ .
Cytot ~xicity Concentration S~ Inhibition CTD50 CTDo of Compound ( llg/ml ) ( llg/ml ) ( ~g/ml ) 33 10 5 _ _ 10 _86 _ CYTOTOXICITY OF ACE:TYLATED_~' ,4'-DIMETHOXY13ENZAL) YDAN~OIN AGAINST VERO CEL~S A~D PRIMARY MONKEY
KID~EY CEL~S

Concentration Toxicity (~) 0 iD micrograms/ml . - . :

300 100 100 ~: :

200 25 ~5 ::
150 10 10 : ~
100 10 O ,:
6607 10 0 ~: :

0 :~
O

3~3 O O
loO O O :
0~7 0 0 0.3 0 0 .~ _ . .. , _. . _. ~ , .. _ . ':
:-.' ' -.~ . ~'' When acetylat~d 5-(3',4'-di~ethoxybenzal) h~dantoin (Exam ple 14) was injected intraperitoneally into mice the sub-acute Ln5o during 16 days by daily injection was 400 500 mg/kg.
Oral administration showed an ~D50 of greater than 1,300 mg/kg in m.ice.

:

5~S~
Acetylated 5-(3',4'-dimethoxybenY.al) hydantoin (Example 14) was tested in Cynomolgus monkeys, weighing from 2-4 kg7 that were in~ected with the Mahoney strain of Polio virus~ at ~
a dosage of 25 mg/kg per day initially for six days by the intraperitoneal route and thereafter subcutaneously fox an additional 8 daysO The co~pound was administered in a 005~
saline solution containing a small amount of dimethylsulfoxide and emulsifierO The solution was subjected to ultra~onic irradiation in order to disintegrate and disperse the compound throughout the solution., The results obtained in the monkey tests and set forth in the table below indicated that acetylated 5-(3~,4~, dimethox~-benzal) hydantoin was e~fective against the Mahoney Polio virus ~tra~n in the in~ected animal~

' : ' .
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m m ~ o u~ o ~ rLl _ _ E~ Z
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:~ ~ , . ~ ., ,~ U~ . ~o U~ ~ U~ ~ ~ \
~i ~ ~ _ Zi ,1 ~__ O ' ,'~' :
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Ll~ ~ O ' ' ': ' Fl ,_~ ~ ~ ~I ~
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W ~ H _ ~ ` .
~ t-o ~ ~ ~ ~ o o o x ~ ~ m H 1:~ Lf~ U~
æ ~, O O ~ ~ _ ~ ~ ~ ~-E-l~1 ,C~ ~ H 00 ~ 03 a~ LS~ ::
~ . C) 1~3 O ~ ~ ~ .: -H ~ ~ l -- O
_ ~ i O ~ ~t trl ~:
_-~ ~ C) >1 ~D CO .
~ ~ :2; ~: . . . _ " "
L~ ~ ' ~ ::1 ~25 ~ ~ ~
1~ c~ _ . .

~ ::1 _ - ~r _ _ ____ W .~ ~0 ~ ~ O ., ~ O U~ S~ ~ ~ ~ l :-~; O ' ~ ~ ~ ~1 ~1 ,.
' 11~ ~ ~ O ._ .,,,-,-,~,.
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h h ~ S~ ~ ~
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The compounds of the present invention formulated wi~h a suitable liquid or solid carrier can be used to control3 iOeO, treat or prevent, viral infection in vertebratesO The routes of administration include intranasal, oral and parenteral adminis-trationO The first mode of administration can be conveniently effected by means of aerosol formulations employing the widely~
known and used ~ropellants in a suitable dispenser. An injectible composition or formulation may comprise a suspension or solution .
of the acive compound in a mixture of normal saline solution and a pharmaceutically acceptable solvent~ at a concentration of from about 0O05 to 0 o 10%o Oral administration may be in the form of tablets, pills, capsules, granule~, powders, syrups and the likeO ~ :
Suitable pharmaceu~ically acceptable solid carriers in~ ~
clude starches, sugarsJ various stearates and carbona~es, : :
kaolin, talc, dicalcium phosphate, calcium sulfate, and gums.
Pharmaceutically acceptable liquid carriers include water oils : .
and watex-oil emulsions which advantageously include suitable dis-persing or suspending agents such as tragacanth, alginates, dextran, methyl cellulose, polyvinylpyrrolidone, gelatin, and mixtures thereofO Suitable oils for solutions and water-oil emulsions include vegetable oils such as cottonseed oll, coconut oil, peanut oil and the li~eO For injectible solutions the liquid carrier, eOgO normal saline, may include a solubilizer, such as N~-dimethylacetamide or N,N-dimethylformideO
The compounds are administered in effective, but non-toxic dosages, for example, about 1 to 500 mg per kg of body weight per day, preferably about 1-100 mg/kg per day administered in one dose or in a series of doses : .

, . ~ . .

5~
The following examples are provided to illustrate the preparation ~ substances used of the compositions whose activity was tested above, including compounds used in the compositions o~ the invention. The melting points are in C.

5-(3',4'-D~ roxybenzal) hydantoin A mixture of 3,4-dihydroxybenzaldehyde (2.072 g.) and hydantoin (1.50 g.) in water (15 ml) was heated to 70 to give a clear solution. To this was added monoethanolamine (1.38 g.) o and the magnetically stirred mixture was heated (90-92 , bath temperature) for 4 hours. Within 10 minutes crystalLization occurred. The product was allowed to cool to room temperature and was stored overnight. After immersing in an ice-bath~ the mixkure was acidified with HCl, refrigerated 5 hours, filtered, washed with cold (-10 ) l:L methanol-water and driedO The title compound was obtained as a pale brown solid: 2.776 g, m.p.
300-310 . (Trituration with hot absolute ethanol gave a pale brown solid in ca 65% recovery, m.p. 320 decomp.
EXA~PLE 2 5-~3'-Methoxy-4'-Hydroxybenzal) ~dantoin vanillin (3.04 g.) and hydantoin (2.0 g.~ in water (20 ml~were heated on the skeam-bath for a few minutes until 0 ;7~ - ' dissolution occurred. Ethanolamine (~h~ g.~ was then added and the solution heated at 85-90 (bath temperature) ~or 4.5 hours.
The solution deposited crystals and solidi~ied within 0.5 hours.
Concentrated HCl (5 ml) was added, the mixture was refrigerated overnight 518 hours)0 filtered, water washed and dried. I'he title compound was obtained as a yellow solid (4.18 g, 93%), m op . 266-271 decomp.
' - 19 - ' ' ~ ' ', - ~0~5SS6) A portion (4.122 g.) was crystallized from aqueous ethanol at -10 overnight. Weight of yellow solid~ 3.420 g., m.p. 267-271 . (T. B. Johnson and R. Bengis, ~ .. C~
Soc., 35, 1611 (1913) give m.p. 264-265 .) ..
5-~2'-chlorobenzal) hydantoin A mixture of o-chlorobenzaldehyde (2.50 g~ and h~dan-toin (1.78 g., 1 molar ratio) was treated with water (15 ml) and heated to 70 . Monoethanolamine (1.63 g., 1.5 molar ratio) was ~ -added and the mixture was stirred magnetically at gO-92 (bath temperature) for 4~25 hours. The mixture was cooled in an ice-bath, acidified with concentrated HCl, refrigerated ovexnight, ilte~ed, washed with water and dried at 55 /lOmm. The title compound was obtained as a pinkish solid ~2.63 g.), m.p~ 266-270 decomp.

5~(4'-Nitrobenzal~ hydantoin A mixture of ~-nitrobenzaldehyde (2.510 g.) and hydantoin tl.671 g., 1 molar ratio) in water (15 ml) was heated to 70 . Monoethanolamine (1.53 g., l.S molar ratio) was added and the~mixture was stirred magnetically and heated at 90-92 (bath tamperature) or 4 1/4 hours. The mixture was cooled in an ice-bath and acidified with Hcl~ ~fter refrigeration over-night the mixture was filtered, washed with water and dried at s: . . ,~
55 ~10 mm~ The title compound was obtained as a brown solid (3.258 g.), m.p. 252-253 decomp. ;

__ 5-(3',4'-Methylenedioxxbenzal? hydantoin .:::
A mixture o 3,4~methylenedioxybenzaldehyds (2~515 g.) :. : ' .:
, , ~ , . . ~ . :.. :

45~Sa~
and hydantoin (1.668 g., L molar ratio~ in water (15 ml~ was heated to 70 and monoethanolamine (1.40 gO, 1.5 molar ratio) was added. This 2 layer liquid mixture was stirred magnetically and heated at 90-92~ (bath temperature) for 4 hoursO The title compound was obtained as a pale yellow solid (3O440 gO), mOpO 248.
Crystallization of the crude materia]L from dioxane gave a colorless solid in 90% yield, mOp. 251-252~o ~-(2' 5'-Dimethoxy~benzal) hYdantoin A mixture of 2,5-dimethoxybenzaldehyde (2.504 g ) and hydantoin ~1.507 g., 1 molar ratio) in water ~15 ml) was heated to 70. To this 2 layer liquid was added monoethanolamine ~1,38 g., 1.5 molar ratio). The mixture was heated 4 hours at 90-92 (bath temperature) with magnetic stirring/ The title compound was isolated in the usual manner and obtained as a yellow solid (3.288 g.), m.p. 250-252. Crystallization from dioxane (86%
recovery) gave mOp. 251-252.
EXAMPLE ~
5-(3'.5'-Dimethox~benzal ~hydantoin A mixture of 3,5-dimethoxybenzaldehyde (2.550 g.) and hydantoin (1.505 g., 1 molar ratio) in water (15 ml) was heated : .
to 70. Monoethanolamine (1038 g., 105 molar ratio) was added and the 2 layer li~uid mlxture was magnetically stirred at 90-92 (bath temperature) ~or 4 hours. Isolation in the usual manner gave the title compound as a beige solid (2.870 g.), m.p. 285-287. ;

5-(2'~4'J5'-T
A mixture of 2~4,5-trimethoxybenzaldehyde (2.503 gO) and ;:.
hydantoin (1~275 g., 1 molarratio in water (15 ml) was heated to ., . ,............... . . . ~ - : . . .

1(~3455S~
70. Monoethanolamine (1.17 g.) was added and the suspension was stirred and heated at 90-92 (bath temperature) for 4 hoursO
Isolation in the usual manner gave the title compound as a yellow solid t3O306 g.), m.pO 276-277 decompO Crystalli~ation from dioxane did not raise the melting point.

5-(3',4',5 -Trimethoxybenzal) hydantoin :
A mixture of 3,4,5-trimethoxybenzaldehyde (2.497 gO) and hydantoin (1.276 g., 1 molar ratio) in water (15 ml) was heated ~`
to 70O Monoethanolamine (1.17 gO, 1.5 molar ratio) was added, followed by magnetic stirring and heating (90-92, bath temperature) for 4 hoursO Usual workup gave the title compound as a yellow solid (2.950 gO), m.p. 266-268. Crystallization from dioxane (o0% recovery) gave m.p. 268-270.
XAMP~E 10 5-(2'-Methoxybenz_l~ hydantoin A mixture of o-methoxybenzaldehyde (2000 gO, 14.7 mmoles) and hydantoin (1.47 g., 1 molar ratio) in water (12ml) was heated to 70; monoethanolamine (1035 g., 1.5 molar ratio) was then added.
20 The mixture was heated in an oil bath ~9Q-92) and stirred magne-tically ~or 4 hours. Usual workup gave the title compound as an orange solid (2.90 gO), m~p. 174-179.
E~AMPLE 11 5-(3'-Methoxybenzal) hydantoin A mixture of m-methoxybenzaldehyde (2.00 g., 14.7 mmoles) and hydantoin (1.47 gO) in water (12 ml) was heated to 70;
monoethanolamine (1.35 g.~ 105 molar ratio) was then added and the mixture was heated in an oil bath at 90-92 for 4 hours with magnetic stirring. Isolation in the usual manner gave the title ~5550 compound as a ~eige solid (2.56 gO), m.pO 229-231.

5-(4'-Methoxybenzal~ hydantoin A mixture of ~-methoxybenzaldehyde (2.00 g., 14 7 mmoles) and hydantoin (1.47 g., 1 molar ratio) in water (12 ml) was heated to 70; monoethanolamine tl 35 g., 105 molar ratio) was then added. The mixture was stirred magnetically and heated in an oil bath at 90-92 or 4 hoursO usual workup furnished the title compound as a pale yellow solid (2.74 gO), m.p. 250-252.

i EXAMPLE 13 5-~3'~4'~Dimethoxybenzal) hydantoin A magnetically stirred mixture o~ veratraldehyde (9O00 gO, 93~ pure), hydantoin (5.00 gO), fusedJ anhydrous sodium acetate (10 g.) and glacial acetic acid (20 ml) was refluxed (bath temperature 160-165) or 1.5 hours (solution within 5 minutes, crystallization during heating period). On cooIing, water was addedO The mixture was stirred for 1 hour, refrigerated 2 hours, filtered, washed with water and dried overnight at 55/10 mm. The title compound was obtained as a yellow solid:

20 4~72 g~ (38~ yield) mOp- 280-282o EX~M E 14 Acetylated 5-~3',4'~Dimethoxybenzal) hydantoin . . .
`- A mixture of pure 3,4-dimethoxybenzaldehyde (4.20 g. ~-99 9~ pure by vpc), hydantoin (2080 g~ )~ potassium bicarbonate (3.20 g.) and acetic anhydride ¢10 ml) was stirred magnetically and heated in an oil-bath at 130-140 (bath temperature) for 30 ~-minutesO After allow~ng the solution tostand overnight ~during which time crystallization occurred) water (100 ml) was added, ~ '," '.
. ' , .
. . .: ~. . . ;. . ; . : . . -~5i55~ ~
over 30 minutes, wlth stirringO The product was isolated by filtration, washed with hot water (250 ml) and dried overnight at 50/10 mm~ Wt. of yellow solid: 3~90 g., m.pO 183-218.
Acetyl value: 15.5 (theoretical for monoacetylation is 14~8)o A similar result was obtained when fused anhydrous sodium acetata was used in place of potassium bicarbonate.
EX~MPLE 15 Acetylate~d 5-(3'-methoxy-4'-acetoxybenzal) hydantoin A mixture of vanillin (1.900 g~), hydantoin 11v4 g.) and fused anhydrous sodium acetate (1.3gu) in acetic anhydride (5 ml) was heated under a reflux condenser at 125-i30 ~bath temperature) with magnetic stirring or 30 minutes. On standing overnight, the solution solidified completelyO Water (50 ml) was added and the mixture was stirred at room temperature for about one hour, then refrigerated 5 hours, filtered, washed with boiling water (ca.200 ml) and dried at 50/10 mm overnight ~:
(13 hours)O The crude title compound was obtained as yellow ;
solid: 20950 g. (86% yield) m.pO 188-191OJ
EX~MP~E 16 cetyLated 5-benzalhydantoin A magnetically stirred mixture of benzaldehyde (2.60 g.), hydantoin (2.80 gO), fused anhydrous sodium acetate (2060 g.) and acetic anhydride (10 ml) was heated at 125-135 (bath tem-perature) under a reflux condensar for 30 minutesO Dissolution and crystallization occurred during this time. On gradual cooling to room temperature (~ a 5 hours), water was addPcl, the : mixture was refrigerated o~ernight (18 hours), filtexed~ washed with hot water (150 ml) and with light petroleum ether. The product was dried 50~0 mm for 24 hrs. The title compollnld was .. ~ .,, . ~ . . . .

5S~a~
obtained as a beige solid: 4076 g., ~ p- 214-217 EX~MPLE 17 Acetylated ~-(2'-methoxybenzal) hydantoin A mixture of o-methoxybenzaldehyde (2058 gO), hydantoin (1.95 gO), fused, anhydrous sodium acetate (1~95 gO) and acetic an~ydride (705 ml) was stirred magnetically and heated in an oil bath (125-130) for 30 minutes (solution after 2 minutes). The mixture was removed from the bath and kept at xoom temperature (crystallization on cooling overnight)O Water was then added, follcwed by refrigeration for 6 hoursO The crystal~ were filtered off, washed with hot water and dried at 55/10 mm4 The tikle compound was obtained as a yellow solid (3.80 g.).

A mixture of m-methoxybenzaldehyde (2058 gO), hydantoin ;
(1095 g.), fused, anhydrous æodium acetate (1.95 g.) and acetic anhydride (7.5 ml) was stirred magnetically and heated in an oil bath at 125-130 for 30 minutes, (solution withln 10 minutes, crystallization on cooling). The mixture was kept at room tem~
perature overnight, treated with water, refrigerated 6 hours, filtered, washed with hot water and driedO The title compound was obtained as a pale yellow solid (4.12 g.)~
EX~MPLE~

Acetylated 5-(4'-methoxyben~al~ hydantoin :~, A mixture of p-methoxybenzaldehyde (2.58 gO)~ hydantoin (1.95 gO), fused, anhydrous sodium acetate (1.95 gO) and acetic anhydride (705 ml3 was stirred magnetically and heated in an oi} bath at 125-130 for 30 minutes. The mixture was stored at room temperature overnight, treated with water, refrigerated for 6 hours, filtered, washed with hot water and driedl The 10~;i5S~t title compound was obtained as a pale yellow solid (3D61 g.) mOp.

218-223 decomp.
EXAMPLE ?
Acetylated 5-(2',5'-dimethoxybenzal) hydantoin A m~xture of 2,5-dimethoxybenzaldehyc3e (2010 g~)~ hydan-toin (1040 g.) and fused~ anhydrous sodium acetat:e (1030 g.~ in ~ -acetic anhydride (5 ml) was heated at 125-130 (bath temperature) for 30 minutes with magnetic stirring (solution within 10 minutes)0 During overnight standing at room temperature, solidification occurred. Water (15-20 ml) was added and the mixture waC; stirred 1-1.5 hours. More water (60-70 ml) was added folIowed by re-frigeration overnight. The product was filtered, washed with hot water (caO 150 ml)0 The title compound was obtained as a tacky solid (3.35 g.).
The crude material (20893 gO) was crystallized from acetic acid to give a yellow solid (10977 g.)O
EX~MPLE 21 cetylated 5-(3',5'-dimethoxybenzal~ hydantoin ~ -A mixture of 3,5-dimethoxybenzaldehyde (2.10 g.), hydantoin (1040 g.) and fused, anhydrous sodium acetate (1.30 g.) in acetic anhydride (5 ml) was heated, with magnetic stixring, at 125-130 (bath temperature) for 30 minutes~ After ~anding at room tem-perature overnight (crystallization), water (15-20 ml) was added9 ;~
the mixture was stirred for 1-105 hours and then diluted with more water (60-70 ml) followed by refrigeration overnight~ The mixture was filtered, washed with water and dried. The title compound was obtained as a pale yellow solid (3O24 g.)O

- . - . ~ . . . ~
.

Ac tylated_ 5- (? ~, 4 ~ =trimethoxybenzal) hydantoin ~r/~e~x~ a6/~ 7/e A mixture of 2,4,5- ~e-~ ch~-e-(2.10 g.), hydantoin (1 40 gO) and fused, anhydrous sodium acetate (1030 g.) in acetic anhydride (5 ml) was magnetically stirred and heated at 125-130 (bath temperature) for 30 minutes. During storing at room temperature, solidification took place. Water (15-20ml) was added, the mixture was stirred 1-1.5 hours, followed by addition of more water (60-70 ml), and refrigeration overnight.
The product was ~iltered, washed with hot water and dried 20 hours, 50/10 mm. ~he title compound was obtained as a yellow solid (2.417 g.).
EXAMPL~
~cetylated ~ hydantoin A mixture of 3J4,5-trimethoxybenzaldehyde (2010 gO~
hydantoin (1.40 gO) and fused, anhydrous sodium acetate (1.30 g.) in acetic anhydride (5 ml) was heated at 125-130 (bath tempera-ture)for 30 minutes with magnetic stirring (solution after 5 minutes. During storage at room temperature ove~night solidifi-cation took place. Water (15~20 ml) was added, the mixture wasstirred 1-1.5 hours, followed by more water addition (60-70 ml).
After refrigeration ov~rnight, the crystals were filtered of~
w~shed with hot water (__150 ml) and dried 20 hours9 50/10 mm~
The title c~mpound was obtained as a yellow solid (2060 g~) m.p. 185 195. Crystallization from acetic acid gave the product :::
an 81% yield, m.p. 190-201o Acetylated 5-(3',4'-methylenedioxybenæal) hydantoin A mixture of piperonal (2.199 g.), hydantoin (1~60 g.) ~ :.
... . . . ....
.

4555a~
and fused, anhydrous sodium acetate (1.50 g ) in acetic anhydride ~5 ml) was stirre~ ma~netically and heated in an oil bath at :
130 + 2 (bath temperature) for 30 minutes, (solution and cry--stallization within 5 minutes)O After keeping the product at room temperature for 16 hoursJ water was added and the mixture was stirred for 005 hours followed by addit:ion of more water and refrigeration for 6.5 hoursO The mixture was ~iltered, the residue washed with hot water (150 ml) and dried 20 hours at 50/lOmm. The title compound was obtained as a yellow solid (3.105 gO), m.p. 260-262 decomp.

Acetylated 5-(3',4'-diacetoxybenzal) hydantoin -A mixture o protocatechualdehyde (2050 g.), hydantoin (2.50 g.) and fused, anhydrous sodium acetate (1.25 ~0) in acetic anhydride (12.5 ml) was stirred magnetically and heated at 105-110 (bath temperature) for 0.75 hours (solution within 10 minutes). Water (12.5 ml) was added to the hot solution and the precipitating mixture was refrigerated overnight, filtered, :.
water washed and dried 5 hours at 55/10 mmO The title compound was obtained as a colorless solid (1064 g.), m.pO 200-210~ :
A portion (o.958 gO) of the latter compound was crystal-lized from acetic acid at room temperatureO Weight of colorless ~ ;`
solid: 0~703 g.9 m.p. 233-239~o Acetylated 5-~2'-chlorobenzal) hydan~oin - A mixture of o-chlorobenzaldehyde (2010 gO)~ hydantoin (1.80 gO) and fused, anhydrous sodium acetate (1050 g.) in acetic anhydride (5 ml) was heated at 125-130 (oil bath temperature) for 30 minutes with magnetic stirring (solution after 5 minutes).

' ~

5S5~
On cooling to room temperature solidification took place. The mixture was left at room temperature overnight~ treated with water (caO 25 ml), stirred for 1-1.5 hours and refrigerated 5 ~ a~
hoursO Tha solid~ filtered off, washed with hot water and dried 18 hours at 55/lOmm.. The title compound was obtained as a yellow solid (3.61 g.)O

Acetylated 5-~4'-nitrobenzal) hydantoin .:
A mixture of p-nitrobenzaldehyde (2000 gO), hydantoin (1.40 g.) and fused, anhydrous sodium acetate (1030 g.) in acetic anhydride (5 ml) was stirred magnetically and heated at 125-130 (bath temperature) for 30 minutes (soluti~n within 5 minutes)4 On cooling to room temperature solidification took place. The material wa~ left overnight, treated with water (ca. 25 ml) and stirred for 1l5 hours. More water (caO 75 ml) was added followed by refrigeration for 40 hours. Filtration of the somewhat sticky solid, washing with hot water (ca. 50 ml) and drying at 50/10 mm over th~e weekend a~forded the title com-pound as a brown solid (3059 g.), m.p. > 300.
EXAMPhE 28 Propionated 5 (3',4'-dimethoxybenzal) hydantoin A mixture of pure veratraldehyde (2.10 g., 99.98% pure, by VPC), hydantoin ~1.40 g.) and potassium bicarbonate ¦1,60 g.
in propionic anhydride (6 ml) was magnetically stirred and heated in an oil bath at 125-130 (bath temperature) for 30 minutes ;
(clear solution after 5 minutes, then gradual crystallization)O
The mixture was then left at room temperature overnight (20 hours)O Water was added3 followed by magnetic stirring ~or 45 minutes to decompose residual anhydrideD The mixture was re-, i5S~
frigerated for 8.5 hours, filt~red, washed with hot water (25-35 ml) and dried overnight at 55/10 mmO The crude title compound was obtained as a yellow solid (3.07 gO)~ Substantially the same results are obtained when the benzaldehydes described in the preceding examples are similarly treated.

Mono- and Diacetylation of 5-(3'q4'-dimethoxYbenzal)_hy~dantoin A mixture of 5-(3',4'-dimethoxybenzal) hydantoin (1.00 gO, m.p. 280-281) and acetic anhydride (10 ml) was refluxed at 150 ~ 5 (bath temperature) for 6 hours (crystallization on cooling). The mixture was refrigerated over the weekend~ filtered and the solid dried overnight at 50/10 mm. Weight of yellow solid ~0.416 g.), m.pO 2oll-2o8oco A portion (0.375 g.) of the latter solid was crystalliæed from glacial acetic acid to give 0.298 g., m.p. 207-211. Acetyl value 1601. (Theoretical for ~ -monoacetylation: 14~8%) The filtrate from the above first crop (0.416 gO~ wa~
treated with water ~precipitation) and refrigerated. The pre-cipitated solid was filtered and dried at 50/10 mmO Weight o~
yellow solid: 0.530 g., m.p. 152-154. Crystallization from glacial acetic acid (76% recovery) gave m.pO 150-155~ Acetyl value: 2200~ (Theoretical for diacetylation: 2509~)o When the reaction time was extended to 16 hours, similar results were obtainedO
EXAMP~E 30 Acetylation of 5-(3',4'-dimethoxybenzal) hydantoin wil:h sodium acetate - a`cetic anh dride A mixture of 5-(3',4'-dimethoxybenzal) hydant:o:in (1.04 g.), prepared by sodium hydroxide hydrolysis of product clescLibed 555~
in Example 14, and fused ~nhydrous sodium acetate (0.44 g.) in acetic anhydride (6 ml) was heated with magnctic stirring at 125-130C (bath temperature) for about 30 mi.nutes. After storage at room temperature overnight, during which time crystallization had taken place, water was addedO Isolation of the product by filtration gave a yellow solid (1049 gO)O The product was crystallized from acetic acid to give a crystalline yellow solid (acetyl value 1501~)o This product is highly e~fective against Picorna group of virusesO
10Substantially the same results are obtained when the 5~ ;
(substituted benzal) hydantoins in the preceding exa~ples are similarly treated.

Preparation of pure monoacetate of 5-(3',4'-dlmethoxybenzal hydantoin Crude monoacetate of 5-(3'~4'-dimethoxybenzal) hydantoi~
(110 g.), prepared as described in Example 30, was dissolved in dimethylsul~oxide (180 m~) by h~ating to 90. Crystallization -~
occurred on standing overnight. The crystals were filtexed off and dried to give 9208 g. of product. This wa~ recrystalli.zed ~rom dimethylsulfoxide (150 ml) under similar conditions, the crystals were ~iltered off, washed with ethanol and driedO The product was finely ground, slurried with ethanol (250 ml)9 filtered, and dried to yield 77.7 gO of pure monoacetate~ m.p~
223-225. M~MoR~ showed the presence of one acetate group per - moleculeO '':' Pr~paration of pure diacetate o~ 5-~3',4'-dimethoxybenzal)hydantoln . ~
The filtrate as ob-tained in Example 30, containing the diacetate of 5-(3'4'-dimethoxybenzal) hydantoin, was evaporated ~1145S5~

to dryness and the residue (128 g.) was dissolved in dimethyl-acetamide (250 ml) by heating to 100. Overnight crystalli~ation yielded 69 g. of product which was recrystallized from dimethyl-acetamide (100 ml) under similar conditions. The dried crystals (55.1 gO) had mOpO 181-183. NoM~R~ showed the presence of two acetate groups per moleculeO

Separation of Pure Mono- and Di-acetates of 5-(3',4'-dimethoxy- ~ :
benzal) hydantoin and isomers .
The crude reaction product, derived from the acetylation of 5-(3',4'-dimethoxybenzal) hydantoin with fused anhydrous sodium acetate and acetic anhydride as descrihed in Example 30~ :
was crystallized fractionally rom dimethylsulfoxide~ The fractions then were recrystallized repeatedly from dimethyl- .:
sulfoxide to yield the following ive compounds:
a) Monoacetate A
This compound had m.pO 254-256. N~M~Ro showed the presence of one acetate group per molecule. ..
b) Monoacetate B
.
This compound had m.p. 221-224o N~M~Ro ~howed the presence of one acetate group per molecule.
c) Monoacetate C
This compound was ldentical with that described in Example 31 o d) Diacetate A
.~ .. , This compound ha~ m.p. 134-137. NoM ~ R~ showed the presence of two acetate groups per mo:Lecule.
e) Diacetate B

This compound was idantical with that described 3o in Example 32 ~

.

1~9L5S51~) EXAMPLE ~4 Preparation of pure mono- and di-acetates of 5-~2'~4'~5'-Tri-methoxybenzal) hydantoin and isomers thereof :
5-(2',4',5'-Trimethoxybenzal) hydantoin, prepared as described in Example 8, was acetylated with refluxing acetic anhydride in the manner outlined in Example 290 Fractional crystalliæation of the crude reaction product from dipolar aprotic solvents such as dimethylsulfoxide and dimethylacetamide provided four puxified compounds:
a) Monoacetate A
This compound had m.p. 195-197 after several recrystallizations from dimethylsulfoxide. N.M.R. ~;
showed the presence of one acetate group per molecule~ ;
b) Monoacetate B
This compound had mOpO 223~226 after recrystal-lization from dimethylacetamideO N~MoRo showed - the presence of one acetate group per molecule.
c) Diacetate A
This compound had mOpO 187-189 after crystallization first from dLmethylsulfoxide and then from dimethyl-acetamideO N~M~Ro showed the presence of two acetate groups per molecule.
d) Diacetate B
This compound had m.p. 175-177 after r~crystal-lization from dimethylacetamide. NoMoRo showed the presence of two acetate groups in this molecule.

. ' ' . . '. ~ ' . ' : ' .

~14555~ -Acetylation of 5-(3',4'-Dimethoxybenzal) hydantoin in Dimethylacetamide-Pyridine A solution of the above mentioned hydantoin (005 g~) in anhydrous dimethylacetamide (5 ml) and anhydrous pyridine (0.6 ml) ;
was treated with acetyl chloride(0.5 ml), when there was im-mediate p~ecipitation o~ a yellow solid, with slight evolution ~ :
of heat. After allowing the mixture to stand at room temperature overnight (17 hours), the product (0.53 g.) mOpO 204-208C was isolated as a yellow solid by precipitation into waterO Crystal-lization from dimethylsulfoxide as described in Example 31 gave yellow crystals (0.170 g.), showing identical NoMoRo spectrum to that o~ the monoacetate of 5-(3',4'-dimethoxybenzal) hydantoin described in Example 31.

Pivaloylation of 5-53'~4'-Dimethoxybenzal) hydantoin To a solution of the hydantoin (0.5 g.) in dimethyl-acetamide (5 ml) and anhydrous pyridine (2 ml)9 pivaloyl chloride (2 ml) was added and the resultant pale yellow solution left at room temperature over the weekend (67 hours)~ The solution was poured into water, extracted with methylene chloride and the methylene chloride extract washed once with NaHC03 solution, then with dilute hydrochloric acid and finally with water.
Evaporation of the dried ~Na2S04) extract let a yellow solid (005 g.), mOpO 153-158. Crystallization ~rom methylene chloride-light petroleum (bp 30-60C) gave the mono-pivalate as yellow crystals (0027 g.), mOp. 177-178.
EX~MPLE 37 Palmitoylation of 5-(3'~4'-Dimethoxybenzal) hydantoin To a solution of the above mentioned hydantoin (0.5 g) in - 34 ~

~55sal dry dimethylacetamide (5 ml) and anhydrous pyridine (1.0 ml) palimtoyl chloride (2.75 g) was added, resul~ing in formation of a yellow precipitateO After allowing the mixture to stand at room temperature for 64 hours water was added and the resultant solid was filtered off and washed first with water and then repeatedly with hexane. The resulting beige solid (1.5 g.), m.p. 75~78 was crystallized from a mixture of chloroform and light petroleum to give the dipalmitate as a nearly colorless solid (0.9 g) m.p. 87-88.
The compounds of the present invention formulated with a suitable liquid or solid carrier can be used to control, i.e., treat or prevent, viral infection in vertebrates. The term "vertebrate" as used herein is intencled to include mammals and birds, both of ~hich are subject to infectîon with viruses of the Picorna group.
The routes of administration include intranasal, oral and parenteral administration. The first mode of adminis~rQT;on can be conveniently effected by means of aerosol formulations employing the widely-known and used propellants in a suitable dispenser. An injectible composition or formulation may comprise a suspension or solution of the active compound in a mixture of normal saline solution and a pharmaceutically acceptable solvent, at a concentration of from about 0.05 to 0.10%.
Oral administration may he in the form o tablets, pills, capsules, granules, powders, syrups and the like~
Suitable pharmaceutically acceptable solid carriers include starches0 sugars, various steaxates and carbonates, kaolin, talc, dicalcium phosphate, calcium sulfatle, and gums .. ..

A.~ `

~555~D
Pharmaceutically acceptable liquid carriers include water oils and water-oil emulsions which advantageously :include suitable dispersing or suspending agents such as tragacanth, alginates, dextran, methyl cellulose, polyvinylpyrrolidone, gelatin, and mixtures thereof. Suitable oils for solul:ions and water-oil emulsions include vegetable oils such as cottonseed oil, coconut oil, peanut oil and the like. For in~ectible solutions the liquid carrier, e.g. normal saline, may include a solubilizer, such as N,N-dimethylacetamide or N,N-dimethylformide.

- 36 - ;

`, ' .

Claims (9)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. An antiviral, therapeutic composition presented by conventional pharmaceutical techniques in a form adopted to secure on its administration to mammals a dosage at the rate of 1-500 milligrams per kilogram of body weight per day, in single or multiple doses, of a substance of the following formula conveyed by a pharmaceutically acceptable carrier:

I

in which the hydantoin moiety is partially N-acetylated, and wherein Formula I includes individual geometrical isomers and mixtures thereof, R1 is hydrogen or methoxy;
R2 is hydrogen, methoxy or acetoxy;
R3 is hydrogen, methoxy, or acetoxy; and R4 is hydrogen or methoxy; with the provisos that:
R2 and R3 together may be - OCH2O provided that R1 and R4 are hydrogen;
when R3 is acetoxy R1 and R4 are hydrogen and R2 is methoxy or acetoxy; and no more than two of R1, R2, R3 and R4 are methoxy.

2. The composition of claim 1 wherein the compound is partially N-acetylated 5-(3'-methoxy-4'-acetoxybenzal) hydantoin.

3. The composition of claim 1 wherein the compound is partially N-acetylated 5-(3',4'-methylenedioxybenzal) hydantoin

4. The composition of claim 1 wherein the compound is partially N-acetylated 5-(2'-methoxybenzal) hydantoin.

5. The composition of claim 1 wherein the compound is partially N-acetylated 5-(3'-methoxybenzal) hydantoin.

6. The composition of claim 1 wherein the compound is partially N-acetylated 5-(4'-methoxybenzal) hydantoin.

7. The composition of claim 1 wherein the compound is partially N-acetylated 5-(3',4'-dimethoxybenzal) hydantoin.

8. The composition of claim 1 wherein the compound is partially N-acetylated 5-benzalhydantoin.

9. The composition of claim 1 wherein the compound is partially N-acetylated 5-(3',4'-diacetoxybenzal) hydantoin.