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Патент USA US3074946

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United States Patent 0 F
Patented Jan. 22, 1963
3,074 937
Guido Cavallini and Elena Massarani, Milan, Italy, assign
ors to Francesco Vismara S;p.A., Casatenovo, ‘Como, 5
No Drawing. Filed Nov. 23, 1960, Ser. No. 71,166
Claims priority, application Italy Aug. 27, 1960
7 Claims. (Cl. 260-240)
This invention relates to a novel series of soluble
chemotherapeutic agents having substantial antiviral ac
tivity. More speci?cally these compounds are diphenyl
carbonylmethinylhydrazidoalkyl quaternary salts.
The novel compounds of this invention have been found
to have antiviral activity, either prophylactic or curative,
and dialltyl-Nalkylpiperazinium
against such viral infections as distemper virus, hepatitis
virus (MHV3), neurotropic virus (CLM), Coxsackie
virus, Echo virus, hemadsorption virus, adenovirus, New
castle disease virus, herpes simplex and, particularly, in
?uenza virus (A or PR8). The compounds are also very
Water soluble thereby lending themselves readily to var
ious routes of administration particularly subcutaneous
routes or topical applications, for instance under the form
of collyrium.
These compounds are represented by the ‘following
basic structural formulas:
A represents a moiety of the group consisting of oxygen,
sulfur, sulfonyl (S02), sul?nyl (SO), methylene, ethyl
ene, vinylene (C/H,=CH)' or a single valence ‘bond; IR and
R1 are hydrogen, halogen of atomic weight less than _80,
alkoxy, methyl or h'ydroxy.
Preferably the substituents on the diphenylnucleus are
in the‘para or 4-pos'itiofns relative to the connection of the
two‘phenyl rings."
Preferred and advantageous compounds are those ac
in which formulas X is a pharmaceutically acceptable
anion such as chloride, iodide or bromide; Y is a quater
nary ammonium radical of the group consisting of pyri
( QQ)
cording to the following formulas
in which A is oxygen, sulfur or a single bond and Y
is trimethylammonium, p'yridinium' or morpholinium and
X .is as described above.
The ‘compounds of this invention ‘are prepared by con
densing a diphenylyl mono or his glyoxal derivative iwith
an ‘alkanohydrazide ammonium halide having the follow
‘in which X and Y are as de?ned above for Formulas I
and II., The starting material glyoxalcan also be used
( 9/tiIryl > ‘
in the form of an addition compound such as a hydrate,
alcoholate for instance ethylate or'methylate or a bisul?te
70 addition product. These glyoxal starting materials are
all described in copending applications.’ An excess of
the hydrazide of Formula V is'usually employed.v The
phenylylcarbonyl)methinyl-hydrazidomethyl] pyridinium
solvent is any unreactive organic solvent in which the
reactants are mutually soluble. The lower alcohols,
preferably, methanol, ethanol or isopropanol have been
found to be very useful.
Example 7
Often a condensing acid such
A mixture of 3.02 g. of 4,4'-bisglyoxylylbiphenyl hy
drate, ‘6 g. of acethydrazide pyridinium chloride, 5 ml.
as acetic acid is advantageously present. Anhydrous
conditions are particularly desirable. A re?ux period of '
from 30 minutes to about three hours usually su?ices for
relatively complete reaction.
of acetic acid and 50 ml. of ethanol is heated at re?ux
‘for 30 minutes, cooled and concentrated. Trituration
The products are isolated by cooling or by evaporation
and trituration of the residue with ethyl ether. The de
sired quaternary products thereupon crystallize but be
of the residue gives a crystalline precipitate, biphenyl
yl-4,4’ - bis(carbonylmethinylhydrazidomethylpyridinium
10 chloride) .
Example 8
cause of their chemical and physical nature melting points
A mixture of 2.46 g. of biphenyl-4-glyoxal hydrate,
2.9 g. of acethydrazide methylmorpholinium iodide, 5 ml.
The term alkyl is used herein to de?ne straight or
branched saturated hydrocarbon residues of from 1 to 3 15 ‘of acetic acid and 25 ml. of methanol is heated at re?ux
for 2 hours. The cooled mixture is concentrated and
carbon atoms inclusive. Alkoxy groups are similarly
cooled to give the desired [(4-biphenylylcarbonyl)meth
comprised of 1 to 3 carbon atoms. The term “reactive
inylhydrazidomethyl] methylmorpholinium iodide.
halide” de?nes chloride, bromide or iodide anions. Of
course other conventional nontoxic, pharmaceutically ac
Example 9
ceptable anions can be substituted therefor. Other modi
A mixture of 2.3 g. of 4-phenylthiophenylglyoxal, 2.1
?cations in the structures outlined are obvious to those
g. of acethydrazide trimethylammonium chloride, 7 ml.
skilled in the art such as other substituents in the hen
of acetic acid and 30 ml. of ethanol is heated at re?ux
zene or heterocyclic portions of the chemical structures
for 4 hours, then worked up as above to give [(4-phenyl
or using larger alkyl moieties however the essential fea
tures of the compounds of this invention are described 25 'thiophenylcarbonyl)methinylhydrazidomethyl] trimethyl
ammonium chloride.
hereabove and the methods of preparing representative
compounds of this invention are described hereafter.
Example 10
A mixture of 2.4 g. of 4,4'-bis-glyoxylylstilbene hy
Example 1
cannot be obtained.
5.1 g. of acethydrazide triethylammonium bromide,
A mixture of 2.26 g. of 4-phenoxyphenylglyoxal, 1.97 30 drate,
5 ml. of acetic acid and 40 ml. of ethanol is reacted and
g. of acethydrazide pyridinium chloride, 5 ml.- of glacial
worked up as in Example 3 to give stilbene-4,4’-bis
acetic acid and 25 ml. of absolute ethanol is heated at
carbonylmethinylhydrazidomethyltriethylammonium bro
re?ux for 30 minutes. The mixture is cooled and evap
orated. "The residue is triturated with anhydrous ethyl
Example 11
ether to obtain a white crystalline product,
A mixture of 3.3 g. of 4,4'-bisglyoxylyldiphenyl- 4'
[ ( 4-phen oxyphenylcarbonyl) methinylhydrazidomethyl]
sulfoxide ethylate, 5.8 g. of a-ethylacethydrazide methyl
pyridinium chloride.
piperidinium bromide, prepared by quaternizing the
Example 2
hydrazide of Petrie and Horsley (US. Pat. No. 2,834,781),
A mixture of 2.2 g. of 4-glyoxylyldiphenylmethane hy 40 10 ml. of acetic acid and 50 ml. of isopropanol is heated
at re?ux for 5 hours. Cooling, evaporation and tritura
drate, 2.45 g. of acethydrazide pyridinium chloride, 5 ml.
‘tion with ether gives the desired diphenylsulfoxide-4,4’
of glacial acetic acid and 25 m1. of absolute methanol are
bis(carbonylmethinylhydrazidoisopropyl methylpiperidin
heated at re?ux for 3 hours. Cooling separates the de
sired product, [(4-benzylphenylcarbonyl)methinylhydra
zidomethyl] pyridinium chloride.
Example 3
ium bromide).
A mixture of 1 g. of diphenylethane-4-glyoxal, 1 g. of
Example 12
A mixture of 1.5 g. of 2-phenoxyphenylglyoxal hy
drate, 1.8 g. of acethydrazide trimethylammonium chlo
ride, 5 ml. of acetic acid and 25 ml. of ethanol is heated
at re?ux for 2 hours and worked up as in Example 1
acethydrazide pyridinium chloride, 2.5 ml. of acetic acid
and 15 ml. of ethanol is heated at re?ux for 3"hours, 50 to give [(2-phenoxyphenylcarbonyl)methinylhydrazido~
cooled and concentrated. The residue is triturated with
methyl] trimethylammonium chloride.
ether to give [(4-phenethylphenylcarbonyl)methinylhy
drazidomethyl]pyridinium chloride.
Example 4
Example 13
A mixture of 2.98 g. of 4,4’-bisglyoxylyldiphenylethane,
5.4 g. of acethydrazide pyridinium bromide, 5 ml. of
of acetic acid and 25 ml. of methanol is heated at re?ux
for several hours. Working up as described above
acetic acid and 25 ml. of methanol is heated at re?ux
for 3 hours. Cooling gives biphenylethane-4,4'-bis(car
bonylmethinylhydrazidomethylpyridinium bromide).
A mixture of 1.2 g. of 4-phenylsulfonylphenylglyoxal,
l g. of propionylhydrazide methylpyrrolidinium chloride,
prepared by quaternizing the hydrazide of Petrie, 5 ml..
gives [(4-phenyl-sulfonylphenylcarbonyl)methinylhydra60
zidoethyl] methylpyrrolidinium chloride.
Example 5
A mixture of 3.18 g. of 4,4’-bisglyoxylyldiphenylether, '
5.4 g. of acethydrazide pyridinium chloride, 5 ml. of
Example 14
A mixture of 2.5 g. of biphenyl-4-glyoxal, 2.8 g. of‘
acethydrazide N-methylpiperazinium dimethochloride,
acetic acid and 50 ml. of ethanol is heated at re?ux for 65 prepared as in Petrie, 10 ml. of acetic acid and 50 ml.
3 hours, then cooled vand concentrated. Trituration with
of ethanol is heated at re?ux for 4 hours, cooled and
ether gives diphenylether-4,4’-bis(carbonylmethinylhy
drazidomethylpyridinium chloride).
evaporated. Trituration with ether gives the desired di
quaternary salt.
Example 6
Example 15
A mixture of 2.56 g. of diphenylyl-4-glyoxal ethylate,
3 g. of acethydrazide pyridinium chloride, 5 ml. of acetic
of acethydrazide methyl-N-methylpiperazinium chloride,
acid and 25 ml. of ethanol is heated at re?ux for 30
v1O ml. of acetic acid and 40 ml. of isopropanol is heated
A mixture of 2.7 g. of 4-phenoxyphenylglyoxal, 2.5 g.
at re?ux for 2 hours, cooled and evaporated. Tritura
minutes, then cooled. The mixture is evaporated to dry;
ness in vacuo to give, upon tr'ituration with ether, [(4-bi 75 tion with ether gives [(4-phenoxy-phenylcarbonyl)
methinylidrazidomethyl] 1,4-dimethylpiperazinium chlo
Example 16
A mixture of 2.8 g. of 4'-methoxybiphenylyl-4-glyoxal,
2.5 g. of acethydrazide pyridinium chloride, 10 m1. of
acetic acid and 75 ml. of methanol is heated at re?ux
‘for 30 minutes and worked up as in Example 1 to give
8’ 6)
in which alkyl is of from 1 to 3 carbon atoms; X is a
reactive halide; Y is a quaternary ammonium radical
selected from the group consisting of pyridinium, tri
[(4’ - methoxy - 4 - biphenylylcarbonyl)methinylhydra
zidomethyl] pyridini'um chloride.
Example 17
alkylammonium, alkylpiperidinium, alkylpyrrolidinium,
alkylmorphollnium, alkyl - N - alkylpiperazinium and di
alkyl-N-alkylpiperazinium, each of said alkyi moieties is
A mixture of 1.5 g. of 3'-chloro-4'-1nethoxybiphenylyl
of from 1 to 3 carbon atoms; A represents a member se
4-glyoxal ethylate, 1.8 g. of acethydrazide trimethyl
lected from the group consisting of oxygen, sulfur, sul
ammonium bromide and 100 ml. of isopropanol is heated
Working up as described above 15 fonyl, sul?nyl, methylene, ethylene, vinylene and a direct
link; R is a member selected from the group consisting
[ (3'-chloro-4'-methoxy-4-biphenyly1carbonyl ) meth
at re?ux for 6 hours.
inylhydrazidomethyl] trimethylammonium bromide.
Example 18
of hydrogen, allroxy of from 1 to 3 carbon atoms, methyl,
chloro and hydroxy; and R1 is a member selected from
the group consisting of hydrogen and chloro.
2. A chemical compound of the formula:
Repeating Example 15 but using 1.2 g. of 4'-?uoro
biphenylyl-4-glyoxal gives the 4'-?uoro analogue; using
1.4 g. of the 4'-bromobiphenylyl-4-glyoxa1 gives the 4’~
bromo analogue; using 1.1 g. of the 4'-methylbipheny1-4
glyoxal gives the 4'-methyl quaternary.
Example 1 9
A mixture of 0.9 g. of 4’-hydroxybiphenylyl-4-glyoxal
hydrate, 1 g. of acethydr-azide pyridinium chloride, 5 ml.
in which X is a reactive halide.
3. [(4 - phenoxyphenylcarbonyl)methinylhydraztido
methyl] pyridinium chloride.
4. Diphenylether - 4,4’ - bis(carb.onylmethinylhydra
of ‘acetic acid and 20 ml. of ethanol is heated at re?ux
for 1 hour to give the desired 4'-hydroxy-pyridiniurn 30 zidomethyl pyridinium chloride) .
“chloride. Substituting the 4’-n-propoxyglyoxal gives the
5. Biphenyl - 4,4’ - bis(carbonylrnethinylhydrazrido
corresponding 4’-n-propoxy-pyridini1nn chloride.
Example 20
methylpyridinium chloride) .
6. [(3' - chloro - 4’-methoxy-biphenylcarbonyl)-meth
inylhydrazidomethyl] trimethylammonium bromide.
A mixture of 1.1 g. of 3.3'-bisglyoxylylbiphenyl is re
7. [(4 - biphenylylcarbonyl)methinylhydrazidomethyl]
acted With 2.2 g. of acethydrazide pyridinium chloride
as described in Example 7 to give the 3,3’-is0mer.
methylrnorpholinium chloride.
Example 21
A mixture of 1.6 g. of 4-(4'-chlorophenoxy)phenyl 40
glyoxal hydrate, 1.8 g. of acethydrazide triethylammoni
um chloride and 40 ml. of methanol is heated at re?ux
References Cited in the file of this patent
Gregory et a1. ________ _.. Feb. 23, 1954
Austria ____________ __ Mar. 25, 1958
for 4 hours. Cooling, concentration and trituration gives
the desired [(4’-chloro-4-phenoxyphenylcarbonyl) meth
inylhydrazidomethyl] .tr-iethylammonium chloride.
What is claimed is:
1. A quaternary salt selected from the group consist
Seligman 'et a1.: Chemistry and Industry, 1954, page
ing of compounds of the formulae:
Forss et al.: Nature, vol. 173, pages 401-2 (1954).
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