Note: Descriptions are shown in the official language in which they were submitted.
~6~691
The present invention relates to novel tetra-
substituted ben~ene compounds, a process for the
preparation thereof and antiviral agents containing same.
More particularly, the present invention relates
to nGvel tetra-substituted benzene compounds of the
general formula
~2 ~ ~3
Y ~ R4
Rl X
wherein X represents an oxygen or sulphur atom or
hydroxyimino; Y represents methylene or imino;
R1 represents a hydroxy, phosphonooxy, glycosyloxy,
acylated glycosyloxy,acyloxy or lower alkoxycarbonyl-
oxy; R represents lower alkoxy, lower alkenyloxy
or lower alkylthio; R represents lower alkoxy;
R represents lower alkyl, p-lower-alkoxy benzoyl
or a phenyl, benzyl,
pyridylmethyl, furfuryl, tetrahydrofurfuryl, thenyl,
tetrahydrothenyl, pyrrolylmethyl~pyrrolinylmethyl
or pyrrolidinylmethyl g~oup, with the proviso that
when R represents alkyl, a phenyl,
benzyl or p-hydroxybenzyl, Y does not represent a
,
il;369Gi~
-- 2 --
methylene radical; and with the further proviso that
when R represents p-methoxybenzyl and Y represents
methylene, R2 and R àre different,
and pharmaceutically acceptable salts thereof.
Preferred examples of glycosyloxy and acylated
glycosyloxy are ~-D-glucopyranosyloxy and tetra-O-acetyl-
~-D-glucopyranosyloxy. The acyloxy radicals are preferably
derived from aliphatic acids containing from 2 to 13
carbon atoms or from aromatic acids, preferred acyloxy
radicals being acetoxy, propionyloxy, butyryloxy, iso-
butyryloxy, pivaloyloxy, stearoyloxy and benzoyloxy. The
lower alkoxycarbonyloxy radicals contain preferably
up to 7 carbon atoms, a preferred alkoxycarbonyloxy
radical being ethoxycarbonyloxy. The lower alkoxy radicals
contain preferably from 1 to 6 carbon atoms, especially
from 1 to 4 carbon atoms, such as methoxy, ethoxy,
propoxy, isopropoxy or butoxy. The lower alkylthio radicals
contain preferably 1 to 6 carbon atoms especially from
1 to 4 carbon atoms, such as methylthio. The lower alkyl
radicals contain preferably from 1 to 6 carbon atoms,
especially from 1 to 4 carbon atoms, such as methyl,
ethyl, propyl and butyl. The lower alkenyloxy radicals
contain preferably from 2 to 7 carbon atoms, especially
from 2 to a carbon atoms, such as allyloxy and 3-methyl-
2-propenyloxy. Preferred examples of such phenyl, benzyl
and pyridylmethyl radicals are phenyl, or loweralkoxy
phenyl such as p-methoxyphenyl; benzyl which is substituted by
~6~1G9L
-- 3 --
one or more substituents such as hydroxyl, halogen, lower
alkyl, lower alkoxy, lower alkylthio, amino, dialkylamino,
allyloxy, benzyloxy and alkylenedioxy, especially
p-hydroxybenzyl, m-hydroxy-p-methoxybenzyl, p-chloro-
benzyl, p-methylbenzyl, p-methoxybenzyl, m-methoxybenzyl,
m,p-dimethoxybenzyl, p-butoxybenzyl, p-(methylthio)benzyl,
p-(dimethylamino)~benzyl, p-(allyloxy)benzyl, p-(benzyl-
oxy)benzyl, and m,p-(methylenedioxy)benzyl. An exemplary
pyridylmethyl radical is 4-pyridylmethyl. Preferred
examples of substituted furfuryl, thenyl and pyrrolyl-
methyl radicals and saturated derivatives thereof are
furfuryl, 5-methyl~urfuryl, tetrahydro-S-methylfurfuryl,
2-thenyl, tetrahydro-2-thenyl, and 2-pyrrolylmethyl.
A preferred group of compounds of formula I are
those wherein R2 is lower alkoxy or lower alkylthio and
R1, R3, R4, X and Y are as defined above~
Also preferred are compounds of formula I wherein
R is hydroxy, lower alkanoyloxy, benzoyloxy, phosphonooxy,
lower alkoxycarbonyloxy; R is lower alkoxy or lower
alkenyloxy; R3 is lower alkoxy; R4 is substituted phenyl;
and X is a oxygen or sulfur atom and Y is methylene or
imino, especially those wherein Y is imino. Compounds of
particular interest are 4-ethoxy-2-hydroxy-5-methoxy-N-
(p-methoxybenzyl)-benzamide, 2-[(p-anisylamino)carbonyl]-
5-ethoxy-3-methoxyphenyl dihydrogen phosphate and the
disodium salt thereof.
12~;9G~
- 4
According to the process provided by the present
in~ention, the novel tetra-substituted benzene compounds
of formula I and their pharmaceutically acceptable salts
are prepared by
S (a) hydrogenating a compound of the general
formula
R ~ R41 II
wherein X, Rl, R2, R3 are as
defined in formula I, and R41 represen~s pyridyl,
furyl, tetrahydrofuryl, thienyl, tetrahydrothienyl, pyrrolyl,
pyrrolinyl or pyrrolidinyl, in the presence of a catalyst in
a solvent~ or
(~) reacting a,reactive derivative of a
carboxylic acid of the general formula
R2 , R3 III
COOH
Rl '
;9b;4
,5
j,
wherein R2 and R3 are as defined
in formula I and R represents a
protected hydroxyl radical,
with a compound of the general formula
R4 - NH2 IV
wherein R4 is as defined in
formula I,
and then removing the protecting moiety of the
protected hydroxyl radical,0 or
tc) reacting an acetophenone of the
general formula
R2 ~3 V
' ~C~ 3
Rl o
~2~6g6~
wherein Rl, R2 and R3 are as
defined in formula I,
with iodine in a tertiary amine and reacting a resulting
salt with an amine of formula IV hereinbefore,
or
(d) subjecting an ester of the general
formula
~2~ R3
~J~ CH 3 VI
d
O ~ 1 - R~
wherein R2, R and R4 are as
defined in formula I,
to rearrangement in the presence of a base in a solvent,
or
(e) reacting a ketone of the general formula
R3 VI~
~C~ 2~RI~
OH
wherein R2, R3 and R4 are as defined
in formula I,
with a salt of hydroxylamine in a solvent,
or
' 12~696~
~7 _
(f) reacting a carbonyl compound of the general
formula
R2 ~ , R3
Y ~ R4 VIII
OH
wherein Y R2 R3 and R4 are
as defined in formula I,
with phosphorus pentasulphide in the presence of a
base in a solvent,
or
. (g) reacting a phenol of the general formula
~ IX
. ~ ~ R4
t~
696~
_ 8,, _
.
wherein Y, R2, R3 and R4 are as
defined in formula I and X' represents
an o~ygen or sulphur atom,
with an acylating agent in the presence of a base,
S . o~
(h) reacting a phenol of formula IX hereinbefore
with phosphorus oxychloride or dibenzylphosphoro-
chloridate in the presence of a base in a solvent
followed by hydrolysis or hydrogenolysis as the case
may require and, if necessary, convertirlg a resulting
compound into a salt,
o~
(i) reacting a phenol of formula IX hereinbefore
with a glycosyl halide which may be acylated in the
presence of a catalyst in a solvent, followed, i
necessary, by removal of the acyl radicals.
The hydrogenation in accordance with embodiment
(a) of the process can be carried out by treating a
compound of formula II with hydrogen in the presence
of a catalyst such as palladium black, palladium-on-
charcoal and the like in a solvent such as chloroform.
:~2~69~4
9.
-
The reaction in accordance with embodiment (b~of the process can be effected by reacting a reactive
derivative of a carboxylic acid of formula III with an
amine of formula (IV) followed by removal of the
protecting moiety of the protected hydroxyl radical
in the resulting compound. Prsferred examples of
such reactive derivatives of carboxylic acids of
formula III are acyl halides such as acyl chlorides,
acyl bromides and the like and active esters such as
the N-hydroxysuccinimide ester, p-nitrophenyl ester
and the like. The removal of the protecting moiety
of the protected hydroxyl radical can be performed
by a method known per se.
~he reaction in accordance with embodiment (c)
of the process is a novel reaction. In carrying out
this reaction, an acetophenone of formula V is reacted
with iodine in a te~tiary amine such as pyridine,
lutidine or the like at an elevated temperature and
subsequently a resulting salt is reacted with an amine
of formula IV.
~2~6964
lp
The base-catalized rearrangement in accordance
with embodiment (d) of the process can be carried out
by subjecting an ester of formula VI to rearrange~ent
in the presence of a base such as potassium carbonate,
sodium hydride, sodium amide or the like in a solvent
such as benzene, toluene, tetrahydrofuran, dioxan or
the like.
The oximation in accordance with embodiment (e)
of the process can be effected by reacting a ketone o~
formula VII with a salt of hydroxylami.ne in a solvent
such as dimethyl sulphoxide.
The reaction in accordance with embodiment ~f)
of the process can be caxried out by reacting a carbonyl
compound of formula VIII with phosphorus pentasulphide
in the presence of a base such as triethylamine in a
solvent such as carbon disulphide.
The acylation of the hydroxyl radical in a phenol
of formula IX in accordance with embodiment tg) of the
~2~964
process can be carried out~in a manner known per se
by treatment with an acylating agent such as acetic
anhydride, ethoxycarbonyl chloride, stearic anhydride,
benzoyl chloride or the like in the presence of a base
such as sodium acatate, pyridine, triethylamine,
4-(dimethylamino)pyridine or the like,
The phosphorylation of the hydroxyl radical in a
phenol of formula IX in accordance with embodiment (h)
of the process can be effected in a manner known per se
by treatment with phosphorus ox~chloride or dibenzyl-
phosphorochloridate in the presence of a base such as
triethylamine, N,N-diisopropylamine or the like in a
solvent such as benzene, toluene, triethylamine or the
like. When phosphorus oxychloride is used, the resulting
compound is hydrolyzed. When dibenzylphosphorochloridate
is used, the resulting compound is subject to hydrogen-
olysis. The phosphate of a compound of formula IX thus
obtained may be converted into a salt by a process known
per se.
~2~6~;4
- 12 -
.
The glycosidation of the hydroxyl radical in a
phenol of formula IX in accordance with embodiment (i)
of the process can be carried out in a manner known per
se by treatment with a glycosyl halide in which ~he
hydroxyl radicals are protected by protecting radicals
such as acetyl, benzyl and the like. Preferred glycosyls
are glucosyl, mannosyl, glucosaminyl and the like.
The compounds of formula I provided by the present
inuention exhibit an antiviral activity and, in particular,
inhibit the replication of human rhinoviruses in Hela
cell culture at 0.001 to 2.7 ~g/ml.
.
The present invention also relates to antiviral
agents containing a compound of formula I or a
pharmaceutically acceptable salt thereof. The c.ompounds
of formula I are particularly effective against certain
viruses of the Picorna group. However, the following
compounds have particularly strong antiviral activity:
:~26~69~4
- 13 -
1-~4-Ethoxy-2-hydroxy-6-methoxyphenyl)-3-(4-methoxy-
phenyl)-1-propanone,
5-ethoxy-3-methoxy-2-~3-(p-methoxyphenyl)-
propionyl]phenyl acatate,
5 , 4-ethoxy-2-hydroxy-6-methoxy-N-(p-methoxy-
benzyl)benzamide,
2-hydroxy-4,6-dimethoxy-N-[p--(methylthio)benzyl]-
benzamide,
2-{~ [p-(allyloxy)benzyl]amino 7carbonyl}-3 r 5~
-dimethoxyphanyl benzoate,
1-(4-ethoxy-2-hydroxy-6~methoxyphenyl)-3-
-(4-methoxyphenyl)-1-propanethione,
5-ethoxy-3-methoxy-2-[3-(4-methoxyphenyl)-
propionyl]phenyl ethyl carbonate,
2-[(p-ani.sylamino)carbonyl]-5-ethoxy-3-
-methoxyphenyl dihydrogen phosphate,.:_ ~
disodium 2-[(p-anisylamino)carbonyl]-5-ethoxy-
-3-methoxyphenyl phosphate~
2-hydroxy-6-methoxy-4-propoxy-N-(p-methoxybenzyl)
benzamide,
4-(allyloxy)-2-hydroxy-6-methoxy-N-(p-methoxy-
benzyl)benzamide,
2-hydroxy-6-methoxy-4-(3-methyl-2-butenyloxy)-N-
(p-methoxybenzyl)benzamide and
disodium 2-[(p-anisylamino)carbonyl]-3-methoxy-
5-propoxyphenyl phosphate.
6~
1~ --
Antiviral Activity
A suspension o~ HeLa cells (6 x 104) was mixed
with rhinovirus HGP (3 x 103 plaque-forming units, PFU)
and was plated in a microtest p7ate containing the
compounds to be tested serially diluted. The cells
were then cultured with Eagle's minimum essential medium
containing 2% calf serum, 1~ tryptose phosphate ~roth,
100 ~g/m~ of streptomycin and 20 units/m~ of penicillin
G. The viral C.P.E. (cytopathogenic efect) and
cytotoxicity were observed by a microscope after 2 days
culture at 33C. The antiviral activity (IC50) of the
test compounds is expressed by the concentration
inhibitlng the viral C.P.E. by 5Q% when compared with
the control culture. ~he cytotoxicity is expressed as
the minimum concentration at which toxic symptoms were
observed (cytotoxic dose).
The results are shown in Table 1 and demonstrate
~ ' .
~2696'~6~
- 15 _
that the compounds provided by the present invention
exhibit anti-rhinovirus activity at concentrations
which are lO to lO,OOO times lower than their cytotoxic
doses.
In addition, the antiviral spectra of l-(4-
-ethoxy-2-hydroxy-6-methoxyphenyl)-3-14-methoxyphenyl)-
-l-propanone (compound ~) and 4-ethoxy-2-hydroxy-~-
-methoxy-N-(p-metho~ybenzyl)benzamide (compound B)
against various serotypes of rhinovirus are shown in
Table 2.
~2~g~
~ 16~ -
Table 1
. ~ ,
. Compound IC50 Cytotoxicity
(~g/~Q~ (~g/mQ)
_ . ,~., , _ ~
1-(2-Hydroxy-4,6-dimethoxy-
phenyl)-3-[3,4-(methylene-
dioxy~phenyl]-l-propanone 0.03 - 0.1 >8
1-(2-Hydroxy~4,6~dimethoxy-
phenyl)-3-[4-methylthio)-
phenyl]-l-propanone 0.01 - 0.03 8
1-(2-Hydroxy-4,6-dimethoxy-
phenyl)-3~(4-methylphenyl)-
-l-propanone 0.01 - 0.03 >8
l-(4-Ethoxy-2-hydroxy-6-
-methoxyphenyl)-3-(4-
-methoxyphenyl)-l-propanone O.002 >8
S-Ethoxy-3-methoxy-2-[3-(p-
-methoxyphenyl)propionyl]-
phenyl dihydrogen phosphate 0.3 - 0.8 >10
5-Ethoxy-3-methoxy-2-[3-(p-
-methoxyphenyl)propionyl]
phenyl acetate 0.001 >8
1-(2-Hydroxy-4,6-dimethoxy-
phenyl)-3-(4-methoxyphenyl)-
-l-propanone oxime (Z-isomer) 0.03 >lO
1-(2-Hydroxy-4~6-dimethoxy-1
phenyl)-3-(4-methoxyphenyl)- 0.3 - 0.9 >lO
-l-propanone oxime (E isomer)
2-Hydroxy-4,6-dimethoxy-
-N-(p-methoxybenzyl)-
benzamide 0.002 8
3-(4-Chlorophenyl)-l-(2-
-hydroxy-4,6-dimethoxy-
phenyl)-l-propanone 0.1 lO
,
12¢~69i64
- i7
Table 1 (cohtinued)
~ . . , _
Compound IC50 Cytotoxicity
. ~yg/mQ) (~g/mQ)
,,, _
1-~2-Hydroxy-4,6-dimethoxy-
phenyl)-3-(5-methyl-2-furyl)-
-l-propanone 0.9 >8
1-(2-Ethoxy-6-hydroxy-4-
-methoxyphenyl)-3-(4-
-methoxyphenyl)-l-
-propanone 0.01 - 0.03 0.9
1-(2~Hydroxy 4,6 dimethoxy-
phenylt3-(4-methoxyphenyl)-
-1,3-propanedione 0.01 - 0.03 8
1-(2-Hydroxy-6-methoxy-4-
-propoxyphenyl)-3-(4-
-~ethoxyphenyl)-l- . .
-propanone 0.004 - 0.01 2.7
1-(2-Hydroxy-4-isopropoxy- .
-6-methoxyphenyl)-3-(4-
-methoxyphenyl)-l-propanone O.03 - O.1 8
4-Ethoxy-~-hydroxy-6-
methoxy-N-(p-methoxy-
benzyl)benzamide 0.002 >10
1-(2-Hydroxy-4,6-dimethoxy-
phenyl) 3-(tetrahydro-5
-methyl-2-uryl)-1-
-propanone 0.9 >8
2-Hydroxy-4,6-dimethoxy-N-
-~4-me~hoxyphenyl)benzamide O.03 - O.1 >10
N-Benzyl-2-hydroxy-4,6-
-dimethoxybenzamide O.03 - 0~1 8
,
. ,
6~
_ 181 -
3~_
. ~ r , __
I 50 Cytotoxicity
Compound (~g/mQ) (~g/mQ)
2-Hydroxy-4,6-dimethoxy-
-N-[m,p-(methylenedioxy)-
benzyl]benzamide 0.003 - OoOl >8
2-Hydroxy-4,6-dimethoxy-
-N-(m-methoxybenzyl)-
benzamide O.002 >8
2~Hydroxy-4,6-dimethoxy-
-N-(p-methylbenzyl)-
benzamide O.Ol - 0-03 8
N-(p-Chlorobenzyl)-2-
-hydroxy-4,6-dimethoxy-
benzamide O.Ol - O.03 ~2.4
N-Furfuryl-2-hydroxy-4,6-
-dimethoxyb~nzamide 0.03 - O~l ~8
2-Hydroxy-4,6-dimethoxy-N-
-methylbenzamide 0.9 ~8
2-Hydroxy-N-(m-hydroxy-p-
-methoxybenzyl)-4,6-
~dimethoxybenzamide O.l - 0.3 2.7
N-(m,p-Dimethoxybenzyl)-2-
-hydroxy-4,6-dimethoxy-
benzamide 0.3 8
2-Hydroxy-4,6-dimethoxy-N-
-[~(4-pyridyl)methyl]- I
benzamide I0.9 8
.
` ~26~6g6~
-- 19 --
Table 1 (cantinued)
, ~ . , ~ . _ .
Compound IC50 Cytotoxicity
(~g/mQ) (~g/mQ)
. ,.,~,_ , _, , .... __ .. ..... _
N-(p-Butoxybenzyl)-2-
-hydroxy-4,6-dimethoxy-
benzamide 0.3 8
2-Hydroxy-N-(p-hydroxy-
benzyl)-4,6-dimethoxy-
ben2amide 0.3 '8
N-~p-Dimethylamino~benzyl]-
-2-hydroxy-4,6-dimethoxy-
henzamide O.01 >~
2-Hydroxy 4,6-dimethoxy-N-
-~p-(methylthio)benzyl]-
benzamide 0.002 >8
N-[p-(Benzyloxy)benzyl]-2- .
-hydroxy-4,6-dimethoxy-
benzamide O.3 ~ 0.9 '8
2-Hydroxy-4,6-dimethoxy-N-
-(2-thenyl)benzamide 0.03 8
~-~p-(Allyloxy)benzyl]-2-
-hydroxy-4,6~dimethoxy-
benzamide 0.01 8
2-Hydroxy-4,6-dimethoxy-N-
-(tetrahydro-2-thenyl)-
benzamide O.004-0.01 8
2-Hydroxy-4,6-dimethoxy-N-
- [ (2-pyrrolyl)methyl]~ !
benzamide 2.7 '8
964
- 20 _
Table 1 (co~ntinued)
IC __ !
Compound 50 Cytotoxicity
(~g/m~) (~g/m~)
_~ .~ . .
2-~(p-Ani~ylamino)-
carbonyl]-5-ethoxy-3-
-methoxyphenyl acetate 0.3 >8
2-[~[p-(Allyloxy)benzyl]-
amino]carbonyl]-3,5-
-dimethoxyphenyl benzoate 0.002 2.7
2-~ [~-(allyloxy)benzyl]-
amino /carbonyl}-3,5-
-dimethoxyphenyl octa-
decanoate 0.3 '8
1-(4-Ethoxy-2-hydroxy-6-
-methoxyphenyl)-3-(4-methoxy-
phenyl)l propanethione 0.002 2.7
4-Ethoxy-2-hydroxy-6-methoxy-
-N-(p methoxybenzyl)thio- .
benzamide 0.01 >8
1-~2-~ydroxy-6-methoxy-4-
-(methylthio)phenyl]-3-
-(4-methoxyphenyl)-1
-propanone 0.1
5-Ethoxy 3-methoxy-2-[3-(4-
-methoxyphenyl)propionyl]-
phenyl ethyl carbo~ate 0.002 8
5-Ethoxy~3-methoxy 2 ~3 (4-
-methoxyphenyl)propionyl]-
phenyl octadecanoa~e 0.9 1 >8
i
~Z~696~L
- 21 -
. .
Table l (continued)
, _ _ _
Compound I~50 Cytotoxicity
(~g/m~)(~g/mQ)
. . . _ .................... . _~_ .
5-Ethoxy-3-methoxy-2-~3-
-(4-methoxyphenyl)-
propionyl]phenyl benzoate 0.01
2-~(p-Anisyli~mino)carbonyl]-
-3,5-dimethoxyphenyl ethyl
carbonate 0.1 >8
2-~(p-Anisylamino)carbonyl]-
-3,5-dimethoxyphenyl benzoate O.03 >8
2~(p-Anisylamino)carbonyl]-
-3,5-dime~hoxyphenyl
octadecanoate 0.3 - 0.9 >8
2-~(p-Anisylamino)car~onyl]-
-3,5-dimethoxyphenyl tetra-O-
-acetyl ~-D-glucopyranoside 2.7 '10
2-~(p-Anisylamino)carbonyl]-
-3,5-dimethoxyphenyl ~-D-
~glucopyranoside 2.7 >lO
S-Ethoxy-3-methoxy-2-~3-(4-
-methoxyphenyl)propionyl]-
phenyl ~-D-glucopyranoside 2.7 ~10
Disodium 5-ethoxy-3-methoxy-
-2-~3-(4-methoxyphenyl)-
propionyl~phenyl phosphate 0.03 - 0.1 >lO
,,
~2~691~4
_ 2~ _
.
Table 1 (continued)
. _
Compound IC50 Cytotoxicity
(~/mQ) (~g/mQ)
_ . .__
2-[(p-Anisylamino)carbonyl]-
-3,5-dimethoxyphenyl
dihydrogen phosphate 0.006-O.Ol ~8
2-[~p-Anisylamino)carbonyl]-
-5-ethoxy-3-methoxyphenyl
dihydrogen phosphate O.Ol -0.03 >8
Disodium 2-[(p anisylamino~-
carbonyl]-5 ethoxy-3-
-me~hoxyphenyl phosphate O.Ol -0.03 ~8
2-Hydroxy-6-methoxy-4- .
propoxy-N-(p-methoxy-
benzyl)benzamide 0.001-0.003 ~20
4-(Allyloxy)-2-hydroxy-6-
methoxy-N-(p-methoxy
benzyl)benzamide 0.002 >8
2-Hydroxy-6-methoxy-4-
(3-methyl-2-butenyloxy)- .
N-(p-methoxybenzyl)-
benzamide 0.001-0.002 ~8
.
Disodium 2-~(p-anisylamino)-
carbonyl]-3-methoxy-5-
propoxyphenyl phosphate 0.01 -0.02 >200
_ _
~lZ~9~4
_ 23
Table 2
IC 50 ( ~g/mQ )
Virus Strain . .
Compound A Compound B
Rhinovirus lA O . 03 - O ~ 09 O . 009 - O . 02 7
lB 0.03 - 0.09 0.003 - 0.009
2 0.001 0.001
9 0.012 - 0.037 0.003
~4 0 0 1 - 0 . 30 . 009 - 0 . 027
16 _ 0. 003
21 cO. 001 ~0. 001
23 0.004
2g 0.01 - 0.03
0.01 - 0.09
_ 0.001- 0.00
31 0.03 - 0.09 0.081- 0.24
32 _ 0.003 - 0.009
36 . ~ 0.009 - 0.0~7
39 0.012 - 0.037 1 0.003
44 _ 1i 0.003
0.037 - Ooll
47 _ 0 . 003
0 . 004 - 0 . 012 0 . 01
0. 009
, . , , ,, ~
Cytotoxic doses inhibiting He~a cells growth by 50~6 are
60 ,ug/m~ ~A) and 40 llg/Ir~ (B), respectively.
~l2~96~
_ 2~ _
As mentioned earlier, the compounds of formula I
and their pharmaceutically acceptable salts can be used
as medicanents against viral diseases, especially in the
common cold, in the form of pharmaceutical preparations.
The pharmaceutical preparations contain at least
one of said antiviral compounds or pharmaceutically
acceptable salts thereof in association with a compatible
pha~maceutical carrier material and they may also contain
other pharmaceutically active compounds such as a febrifuge,
an anodyne, an anti-inflammatory, an anti-histamine, an
interferon-inducer or the likeO The pharmaceutical
preparations include solid forms for oral administration
such as tablets, capsules, pills, powders or granules,
liquid forms for nasal or oral administration such as
solutions, suspensions, syrups or elixers, forms or
parenteral administration such as sterile solutions,
suspensions or emulsions and forms for topical
administration such as solutions, emulsions, micronized
powders, ointments, gargles, troches or aerosols.
~L2~696~
- 25' -
The pharmaceutical preparations can be administeredso that the concentration of active ingredient is greater
than the minim~m inhibitory concentration for the
particular viral in~ection being treated.
The dosage for treatment depends on the route of
administration, the age, weight and condition of the
patient and the particular disease to be treated, In
general, for adults a suggested dosage for use in the
common cold is about 100 to 2,000 mg three to six times
daily in the case of oral treatment and about 0.1 to
100 ~g/cm2 three to six times daily in the case of
topical administration.
12~9~
- 2'6 _
The following Examp~es illustrate the present
in~ention:
~.~
A solution of 328 mg of 4'-ethoxy-2'-hydroxy-4,6'-
-dimethoxychalcone in 10 mQ of chloroform was hydrogenated
in the presence of 30 mg of 10% palladium-on-charcoal at
room temperature under atmospheric pressure for 3 hours.
The catalyst was removed by filtration and washed with
30 m~ of chloroform. The filtrate and the washing were
combined and evaporated under reduced pressure to give a
crystalline residue. Recrystallization of the residue
from methanol yielded 302 mg of 1-(4-ethoxy-2-hydroxy-6-
-metho~yphenyl)-3-(4-methoxyphenyl)-1-propanone as
colourless needles of melting point 100.5 - 101C.
In a manner analogous to that described in Example 1,
the products listed in Table 3 were obtained from the
corresponding chalcones listed in Table 3.
~2tL~964
- 27 _
Table` 3
., ~ ~
Chalcones Products
. . .
2'-Hydroxy-4,4',6'- l-(2-Hydroxy-4,6-dimethoxy-
-~rimethoxychalcone phenyl)-3-(4-methoxyphenyl)-1-
-pxopanone; melting polnt
110C trecrystallized from
methanol)
2'-Hydroxy 4'-6'- 1-(2-Hydroxy-4,6-dimethoxy-
-dimethoxy-4-(methylthio)- phenyl)-3-~4~(methylthio)-
chalcone phenyl]-l-propanone; melting
point 84 - 85C (methanol)
2'-Hydroxy-4',6'-dimethoxy- 1-(2-Hydroxy-4,6-dimethoxy-
-3,4-(methylenedioxy)- phenyl) 3-~3,4-(methylenedioxy)-
chalcone phenyl]-l-propanone; melting
point 124.5C (methanol)
2'-Hydroxy-4',6'- 1-(2-Hydroxy-4,6-dimethoxy-
-aimethoxy-4 phenyl)-3-(4-methylphenyl)-l-
-methylchalcone -propanone; melting point
128 - 129C (methanol)
4-Chloxo-2'-hydroxy- 3-(4-Chlorophenyl)~l-(2-hydroxy-
-4',6'-dimethoxychalcone -4,6-dimethoxyphenyl)-1-
-propanone; melting point
104.5C (benzene/hexane)
2'-Ethoxy-6'-hydroxy- 1-(2-Ethoxy-6-hydroxy~4-
-4,4'-dlmethoxychaIcone -methoxyphenyl)-3-(4-methoxy-
phenyl)-l-propanone; melting
. point 108 - 109C ~benzene/
hexane)
_ , . . ~
~2~g~
_ 28 -
. .
Exam~le 3
A solution of 400 mg of 2'-hydroxy 4',6'-dimethoxy-
-3-(5-methyl-2-furyl)acrylophenone in 25 mQ of chloroform
was hydrogenated in the presence of 40 mg of 10%
palladium on-charcoal at room temperature under
atmospheric pressure for 4 hours. After removal of the
catalyst by fil~ration, the filtrate was evaporated to
give an oily residue which was dissolved in a small amount
of benzene. The solution was applied to a column of
silica gel and the column was eluted with hexane/ethyl
acetate (5:1, v/v), giving two fractions, A (Rf 0.29)
and B (Rf 0.16), when monitored by silica gel thin-layer
chromatography using cyclohexane/ethyl acetate (4:1, v/v)~
Removal of the solvent from fraction A and recrystallization
from benzene/hexane gave 192 mg of 1-(2-hydroxy-4,6-
-dimethoxyphenyl)-3-(5-methyl 2-furyl)-1-propanone as
colourless crystals of melting point 92 - 93C.
Similar working-up of fraction B gave 25 mg of
1-~2-hydroxy-4,6-dimethoxyphenyl)-3-(tetrahydro-5-
-methyl-2-furyl)-1-propanone as colourless needles of
9~;4
_ 29~ _
melting point 67.5C (recrystallized from petroleum
ether).
Exam~le_4
85 mg of 2'-hydroxy-4,6'-dimethoxy~4'-
-propoxychalcone were hydrogenated in a manner analogous
to that described in Example 1. There were obtained
69 mg of 1-(2 hydroxy-6 methoxy-4-propoxyphenyl)~3-
-(4-methoxyphenyl)-1-propanone as colourless needles of
melting point 85 - 86C.
- The 2'-hydroxy-4,6'-dimethoxy-4'-propoxychalcone
used as the starting material was prepared as follows:
A mixture of 182 mg of 2'~ 4'-dihydroxy-6'-
-methoxyacetophenone, 187 mg of propyl iodide and 276 mg
of anhydrous potassium carbonate in 5 mQ of aceto~e was
heated under reflux for 16 hours. After cooling, the
mixture was diluted with 30 mQ of water and extracted
three times with 30 mQ of dichloromethane each time.
~2a~s~4
_ 30 _
The combined dichloromethàne extracts were washed with
water~ dried over sodium sulphate and evaporated to give
crude 2'-hydroxy-6'-methoxy-4'-propoxya~etophenone as a
pale yellow oiL.
The foregoing oil was dissolved in 5 mQ of ethanol
con aining 120 mg of p-methoxybenzaldehyde, to which 4 mQ
of 15~ aqueous sodium hydroxide were added. .After
stirring at room temperature for 2 days, the mixture
was adjusted to pH S - 6 with hydrochloric acid and
extracted with three 30 mQ portions of ethyl acetate.
The combined ethyl acetate extracts were washed with water,
dried over sodium sulphate and evaporated to give.an oily
residue. Recrystallization of the residue from methanol
gave 110 mg of 2'-hydroxy-4,6'-dimetho~y-4l-propoxy-
chalcone as yellow needles of melting point 95 - 96C.
Example 5
In a manner analogous to that described in Example
1, from 2'-hydroxy-4'-isopropoxy~4,6'-dimethoxychalcone
there was obtained 1-(2-hydroxy-4-isopropoxy-6-methoxy-
phenyl)-3-(4-methoxyphenyl)-1-propanone of melting point
96.5C (recrystallized from methanol).
~Z~g64
_ 31 _
The starting materiàl was prepared in a manner
analogous to that described in Example 4, except that
lsopropyl iodide was used instead of propyl iodide,
120 mg of 2'-hydroxy-4,6'-dimethoxy-4'-(methylthio)-
chalcone were dissolved in 10 mQ of chloroform. The
solution was hydrogenated in the presence of 180 mg of
10~ palladium-on-charcoal a~ room temperature under
atmospheric pressure for 33 hours. After removal of
the catalyst by filtration, the filtrate was e~aporated
to give a pale yellow residue which was recrystallized
from methanol. There were obtained 103 mg of l-[2-
-hydroxy-6-methoxy-4-(methy~thio)phenyl]-3-(4-methoxy-
phenyl)-l-propanone as cream coloured needles of melting
lS point 127 - 127.5C.
The starting material was prepared as follows:
To a solution of 120 mg of 2'-hydroxy-6'-methoxy-
g6~
_ 3~ _
-4'-(methylthio)acetophenone and 92 mg of p-methoxy-
benzaldehyde in 6 mQ of ethanol were added 4 mQ of
15% aqueous sodium hydroxide. After stirring at room
temperature for 24 hours, the mixture was diluted
with 10 mQ of water and acidified with lN hydrochloric
acid. The resulting crystalline precipitate was
collected by filtration, washed with a small amount
of 50% methanol and recrystallized from methanol to
give 144 mg of 2'-hydroxy-4,6'-dimethoxy-4'-(methylthio)-
chalcone as yellow needles of melting point 145 - 147C.
ExamPle ?
1 g of 2-(benzyloxy)-4,6-dim~thoxybenzoic acid was
dissolved in 5 mQ of thionyl chloride and the solution
was stirred at room temperature for l hour. Removal of
excess thionyl chloride by repeated evaporation with the
aid of benzene gave an oil which dissolved in 5 mQ of
benzene. The solution was added dropwise to an ice-cold
solution of 1.8 ml of p-methoxybenzylamine in 5 mQ of
~IZ~6969L
_ 33 -
benzene. After stirring àt room temperature for 17hours, the mixture was diluted with 50 mQ of ethyl
acetate, washed successlvely with dilute hydrochloric
acid and water, dried over sodium sulphate and
evaporated under reduced pressure to give 1.66 g of an
oil.
The foregoing oil was dissolved in 2 mQ of benzene
and the solution was applied to a column of silica gel
(60 g in hexane). The column was eluted with 600 mQ
of hexane/ethyl acetate (1:1, v/v). Removal of the
solvent from the eluate followed by recrystallization
frsm ethyl acetate gave 700 mg of 2-~benzyloxy)-4,6-
-dimethoxy-N-(p-methoxybenæyl)benzamide as colourless needles
of melting point 123 - 124C.
A solution of 700 mg of the foregoing benzamide in
~0 mQ of chloroform was hydrogenated for 4.5 hours in the
presence of 140 mg of 10% palladium-on-charcoal at room
temperature under atmospheric pressure. Removal of the
catalyst by filtration followed by evaporation of the
i2~6~6'~
_3~, -
filtrate gave a crystalline residue. Recrystallizationof ~he residue from methanol yielded 475 mg of 2-hydroxy-
-4,6 dimethoxy-N-(p-methoxybenzyl~benzamide as colourless
needles of melting point 108 - 109C.
The 2-~benzoyloxy)-4,6-dimethoxybenzoic acid used
as the starting material was prepared as follows:
To a stirred suspension of 39.75 g of methyl 2-
-hydroxy-4,6-dimethoxybenzoate and 207 g of anhydrous
potassium carbonate in 2000 mQ of acetone was added
dropwise a solution of 22.3 mQ of benzyl bromide in
300 mQ ~f acetone. After stirring at room temperature
for 78 hours, the mixture was filtered. The filtrate
was evaporated under reduced pressure to give an oil
which was dissolved in 500 mQ of chloroform. The
solution was washed with 400 mQ of water, dried over
sodium sulphate and evaporated to give 78.7 g of crude
methyl 2-~benzyloxy) 4,6-dimethoxybenzoate as a
colourless oil.
~Z~ 6~
_ 35 _
78.7 g of the ~oregoing crude ester were dissolved
in 2200 mQ of dioxan/methanol (4:1, v/v). To this
solution were added 900 mQ of 2.4N sodium hydroxide,
the mixture was heated under reflux for 16 hours, cooled
and then acidified with hydrochloric acid. The resulting
crystalline precipitate was collected by filtration and
washed with ethyl acetate to yield 48 g of 2-(benzyloxy)-
-4,6-dimethoxybenzoic acid as colourless needles of
melting point 167 - 168C.
~
In a manner analogous to that described in Example 7,
the products listed in Table 4 were obtained from 2-
-(benzyloxy)-4,6-dimethoxybenzoic acid (prepared as the
starting material in Example 7) and the respective amines
listed in Table 4.
~6969L
- 3~ _
Tablè 4
¦ Amines c ~
p-Methoxyaniline 2-Hydroxy-4,6-dimethoxy-N (4-
-methoxyphenyl)benzamide; melting
point 131 - 132C (recrystallized
from methanol)
Benzylamine N-Benzyl-2-hydroxy-4,6-dimethoxy-
benzamide; melting point 96C
(me~hanol)
m,p-(Methylenedioxy)- 2-Hydroxy-4,6-dimethoxy-N-(m,p-
benzylamine -methylenedioxybenzyl)benzamide;
melting point 116 - 117C
(methanol)
. m-Methoxybenzylamine 2-Hydroxy-4,6-dimethoxy-N-(m-
-methoxybenzyl)benzamide; melting
. . point 95 - 96C (methanol)
p-Methylben2ylamine 2-Hydroxy-4,6-dimethoxy~N-(p-
-methylbenzyl)benzamide; melting
. point 100 - 100.5C (methanol)
p-Chlorobenzylamine N-(p-Chlorobenzyl)-2-hydroxy-
-4,6-dimethoxybenzamide; melting
point 131 - 132C (methanol)
i 2-(Aminomethyl)furan N-Furfuryl-2-hydroxy r4 r 6-
; . -dimethoxybenzamide; melting
point 74 - 75C(methanol)
Methylamine . 2-Hydroxy-4,6-dimethoxy-M-
-methylbenzamide; melting
point 144 - 145.5C (methanol)
.
1~696~
- 37~ _
Table 4 (continued)
Amines Products
m-(Benzyloxy~ p- 2-Hydroxy-N (m-hydroxy-p-methoxy-methoxybenzylamine benzyl)-4,6-dimethoxybenzamide;
melting point 144 - 145C (methanol)
m,p-Dimethoxybenzyl- 2-Hydroxy-4,6-dimethoxy N-
amine -(m,p-dimethoxybenzyl)benzamide;
melting point 115 - 116C (methanol~
-Butoxybenzylamine N-(p-Butoxybenzyl)-2-hydroxy-
-4,6-dimethoxybenzamide; melting
point 88 - 89C (methanol)
p-Hydroxybenzylamine 2-Hydroxy-N-(p-hydroxyben2yl)-
-4,6-dimethoxybenzamide; melting
poin~ 170 - 171C (methanol)
p-(Dimethylamino)- N-~p-(Dimethylamino)benzyl]-2-
benzylamine -hydroxy-4,6-dimethoxybenzamide;
melting point 79 - 82C (methanol)
p-(Methylthio)- 2-Hydroxy-4,6-dimethoxy-N-[p-
benzylami.ne -(methylthio)benzyl]benzamide;
melting point 119 - 120C
(methanol)
p (Benzyloxy)- N-~p-(Benzyloxy)benzyl]-2-
benzylamine ~hydroxy-4,6-dimethoxybenzamide;
. . melting point 109 - 110C
(methanol)
2-Thenylamine 2-Hydroxy-4,6-dimethoxy-N-(2-
-thenyl)benzamide; melting
point 60C (methanol)
Tetrahydro-2- 2-Hydroxy-4,6-dimethoxy-N-
-thenylamine -(tetrahydro-2-thenyl)benzamide;
melting point 81 - 82C
(methanol)
. .. _
12~69~4
-38
Exam~e 9
To a cooled suspension of 2-tbenzyloxy)-4,6~
-dimethoxybenzoic acid ( 1 g), prepared as the starting
material in Example 7, and 400 mg of N-hydroxysuccinimide
in 20 mQ of dioxan were added 858 mg of dicyclohexyl-
carbodiimide. The mixture wa~ stirred at room temperature
for l9 hours and then filtered. Removal of the solvent
from the filtrate gave an oil which was chromatographed
on 50 g of silica gel eluting with hexane - ethyl
acetate (4:1, v/v). The eluate was evaporated to give
a syrup which upon standing in a cool place solidified
as a crystalline mass.
225 mg of the solid obtained according to the
preceding paragraph were dissolved in 5 mQ of dimethyl-
ormamide. To the resulting qolution were added 88 mgof p-methoxybenzyla~ine and the mixture was stirred at
room temperature. After 18 hours, the mixture was
diluted with 20 mQ of lN hydrochloric acid and extracted
twice with 50 mQ of ethyl acetate each time. The
` lZ~i69~4
39. -
combined ethyl acetate extracts were washed with water,dried over sodium sulphate and evaporated to give a
crystalline residue. Recrystallization of the residue
from ethyl acetate/hexane yielded 228 mg of 2-(benzyloxy)-
-4,60dimethoxy-N-(p-methoxybenzyl)benzamide as colourless
needles of melting point 123 - 124C.
R~moval of the benzyl group from the foregoing
benzamide by hydrogenolysis following the procedure
described in Example 7 yielded 2-hydroxy-4,6-dimethoxy-
N-(p-methoxybenzyl)benzamide of melting point 108 -
109 C
. .
~10
~o a solution o 980 mg of 2'-hydroxy-4',6'-
-dlmethoxyacetophenone in 2 mQ of pyridine were added
15 . 1.27 g of iodine. ~he mixture was heated at 100C for
1 hour to give a solid m ss. Afker cooling, the solid
was washed successively with 50 mQ of ether and a small
amount of cold water and then dried under reduced pressure
~IZ~6~6~
40 -
to give 2 g of crude l-~(2-hydroxy-4,6-dimethoxybenzoyl)-
methyl]pyridinium iodide as a brown powder.
1 g of the foregoing pyridinium salt was added to
514 mg of p-methoxybenzylamlne and the mixture was heated
S at 80C for 72 hours. After cooling, the mixture was
poured into 20 m~ of lN hydrochloric acid. The resulting
suspension was extracted twice with lO0 mQ of
dichloromethane each time. The combined dichloromethane
extracts were washed with water~ dried over sodium
sulphate and evaporated to give 945 mg of an oily residue
which was purified by silica gel chromatography using
he~ane/ethyl acetate (3:1t V/V) for the elution.
Removal of the solvent from the eluate followed by
recrystailization of the residue from methanol gave
316 mg of 2-hydroxy-4,6-dimethoxy-N-(p-methoxybenzyl)-
benzamide of melting point 108 - 109C.
.
Exam~le 11
In a manner analogous to that described in Example
10, the products listed in Table 5 were obtained from the
~Z~ Ei9~4
~1
pyridinium salt prepared in Example 10 and the respective
amines listed in Table 5.
Table 5
, _ _ . ~
Amines Products
. . ~_ _ _ _
4-(Aminomethyl)pyridine 2-Hydroxy-4,6-dimethoxy-N-[(4-
. -pyridyl)methyl]benzamide;
melting point 114 - 115C
(recrystallized from ether)
p-(Allyloxy)benzylamine N-Cp-(Allyloxy)benzyl]-2-
-hydroxy-4,6-dimethoxybenzamide;
melting point 93 - 94C
(methanol)
2-(Aminomethyl)pyrrole 2-Hydroxy-4,6-dimethoxy-N-(2-
-pyrrolylmethyl)benzamidP;
melting point 116 117C
~ . .
Example 12
A solution of 9.8 g of 4'-ethoxy-2'-hydroxy-6'-
-methoxyacetophenone and 12 g of iodine in 22 m~ of
pyridine was heated at 100C for 1 hour. The resulting
lZ(~69~
_ 42
slurry was cooled, tr}t~ated and again heated at
lOO~C for 1 hour. After cooling, the mixture was filtered
and the solid residue was washed successively with 100 mQ
of ether and 100 mQ of water and then dried at 60C for
3 hours under reduced pressure. There were obtained 18.2 g
of l-t~4-ethoxy-2-hydroxy-6-methoxybenzoyl)methyl]
pyridinium iodide as a pale brown solid.
15.4 g of the foregoing pyridinium salt were added
to 10 mQ of p-methoxybenzylamine and the stirred mixture
was heated at 80C for 18 hours under nitrogen. After
cooling, the mixture was treated with 200 mQ of ethyl
acetate and 150 mQ of water. The ethyl acetate phase was
separated and the aqueous phase was extracted with 150 mQ
of ethyl acetate. The combined ethyl acetate solutions
were washed successively with two 150 mQ portions of
dilute hydrochloric acid, 150 mQ of aqueous sodium
bicarbonate and brine, dried over sodium sulphate and
then evaporated to give 15 g of an oil which was purified
by silica gel chromatography using hexane/ethyl acetate
for the alution. Removal of the solvent from the eluate
~2~696~
~ ~3 _
ollowed by recrystallization of ~he residue from methanol
yielded 6.3 g of 4-ethoxy-2-hydxoxy-6-methoxy-N-(p~
-methoxybenzyl)benzamide as colourless needles of melting
point 87 - 88C.
~ æ~
A mixture of 336 mg of 2-acetyl-3,5-dimethoxyphenyl-
-4-methoxybenzoate and 735 mg of anhydrous potassium
carbonate in 5 mQ o~ toluene was heated at 100C for 17
hours, cooled and then filtered. After washing with
benzene, the filtered cake was treated wi~h 50 mQ of
di~hloromethane and 50 mQ of water. The dichloromethane
phase was separated~ dried over sodium sulphate and
evaporated to give a crystalline residue. Recrystallization
of the residue from methanol gave 77 mg of 1-(2-hydroxy-
-4,6-dimethoxyphenyl)-3-(4-methoxyphenyl)-1,3-propanedione
as yellow prisms o melting point 136 - 136.5C.
~ 6~;4
~`~
.
Ex~æle 14
~ o a stirred suspension of 580 mg of 1-(2-hydroxy-
-4,6-dimethoxyphenyl)-3-(4-methoxyphenyl)-1-propanone,
obtained as described in Example 2, and 482 mg of sodium
acetate in 9 mQ of dimethyl sulphoxide were added 204 mg
of hydroxylamine hydrochloride. The mixture was h~ated
at 80C for 15.5 hours, cooled, diluted with 30 m~ of
ethyl acetate, washed successively with dilute hydrochloric
acid and water, dried over sodium sulphate and than
evaporated to give ~10 mg of a yellow oil which was
dissolved in 1 mQ of benzene.
The solution obtained according to the preceding
paragraph was applied to a column of 25 g of silica gel
and the column was eluted with hexane/ethyl acetate
(3:1, v/v) with ~ractionation (each fraction 15 m~).
Fractions 5 to 8 we~e combined and evaporated to give
43S mg of a pale yellow oily residue. Recrystallization
of the residue from ethyl acetate/hexane yielded 301 mg
of ~he E isomer of 1-(2-hydroxy-4,6-dimethoxyphenyl)-3-
-(4-methoxyphenyl)~l-propanone oxime as colourless
crystals of melting point 82 - 83.5C.
lZ~g6~
- 4$ -
The corresponding Z isomer of the oxime was also
obtained as colourless crystals (melting point 102 -
104C) from fractions 20 to 30 after removal o~ the
solvent and subsequent recrystallization from ethyl
acetate/hexane (yield 95 mg).
A mixture of 500 mg of 4-ethoxy-2-hydroxy-6-methoxy-
-N-~p-methoxybenzyl)benzamide, obtained as described in
Example 12, 673 mg of phosphorus pentasulphide and 259 mg of
triethylamine in 10 mQ of carbon disulphide was stirred
at room temperature for 3 days. There were then added
100 m~ of ethyl acetate and lO0 mQ of water and the mixture
was shaken. The ethyl acetate phase was separated and the
aqueous phase was extracted with 100 mQ of ethyl acetate.
The combined ethyl acetate solutions were washed with
brine and evaporated. The residue was chromatographed
on silica gel using benzene/ethyl acetate (10:1, v/v)
for the elution~ Removal of the solvent from the eluate
and recrystallization from methanol yielded 4-ethoxy-2-
-hydroxy-6-methoxy-N-(p-methoxybenzyl)thiobenzamide as
- ~L2~169~;4
_ 46 _
pale yellow needl.es of melting point 98 - 99C.
Example 16
In a manner analogous to that described in Example lS
but using l-(4-ethoxy-2-hydroxy-6-methoxyphenyl~-3-(4-
-methoxyphenyl)-l-propanone (obtained as described in
Example 1) in place of 4-ethoxy-2-hydroxy-6 methoxy-N-
-(p-methoxybenzyl)benzamide, there was obtained 1-(4-
-ethoxy-2-hydroxy-6-methoxyphenyl)-3-(4-methoxyphenyl)-1-
-propanethione as orange needles of melting point 69 -
70C (recrystallized from methanol).
. .
Example 17
A mixture of 165 mg of 1-(4-ethoxy-2-hydroxy-6-
-methoxyphenyl)-3-(4-methoxyphenyl) l-propanone, 0.2 mQ
. of acetic anhydride.and 5 mg of sodium acetata in a sealed
tube was heated at 140C for 3 hours. After cooling, the
mixture was poured into 20 mQ of water. The mixture was
extracted with 50 mQ of chloroform and the extract was
6;1~ 6
- 4?-
washed with water, dried over sodium sulphate andevaporated to give 178 mg of an oily residue.
Rec~ystallization of the residue from methanol gave
138 mg of 5-ethoxy-3-methoxy-2-[3-(4-methoxyphenyl)-
propionyl]phenyl acetate as colourless needles ofmelting point 58 - 59C.
Exam~le 18
To a solution of 200 mg of 4-ethoxy-2-hydroxy-6-
-methoxy-N-(p-methoxybenzyl)benzamide, obtained as
described in Example 12, in 2 mQ of pyridine was added
0.~7 mQ of acetic anhydride. The mixture was stirred at
room temperature for 18 hours and then evaporated under
reduced pressure to give an oily residue. Recrystallization
of the residue from methanol gave 60 mg of 2-C(p-
anisylamino)carbonyl]-5-ethoxy-3-methoxyphenyl acetate
as colourless needles of melting point 121 - 122C.
9~4
_ 4~
To a solution of 317 mg of 2 hydroxy-4,6-dimethoxy-
-N-(p-methoxybenzyl)benzamide, obtained as described in
Example 7, 0.14 mQ of triethylamine and 24 mg of 4
-(dimethylamino)pyridine in 20 mQ of dichloromethane was
added 0.1 mQ of ethoxycarbonyl chloride. The mixture was
stirred at roo~ temperature for l hour, washed
successively with dilute hydrochloric acid and water,
dried over sodium sulphate and then evaporated to give
480 mg of a yellow oil. The oil was chromatographed
on silica gel using hexane/ethyl acetate (3:1, v/v) for
the elution. Removal of the solvent from the eluate and
recrystallization from ether/petroleum ether gave llO mg
of 2-~(p-anisylamino)carbonyl]-3,5-dimethoxyphenyl ethyl
carbonate as colourless crystals of melting point 123 -
124. 5Co
In a manner analogous to that described in Example
l9j but using 1-(4-ethoxy-2-hydroxy-6-methoxyphenyl)-3-
-(4-methoxyphenyl)-1-propanone in place of 2-hydroxy-4/6-
.
i2~f~964
- 49 -
-dimethoxy-N-(p-methoxybenzyl)benzamide, there was
obtained 5-ethoxy-3-methoxy-2-~3-(4-methoxyphenyl)propionyl]-
phenyl ethyl carbonate; H-nmr spectrum tin CDCL~):
~ 1.38 (3H), 1.40 (3~), 3.00 (4H), 3.76 (6H), 4.02 (2H),
4.34 (2H), 6.32 (2H), 6.80 (2H) and 7.13 ppm (2H).
Exam~le 21
To a solution of 200 mg of 2-hydroxy-4,6-dimethoxy-
-N-(p-methoxybenzyl)benzamide, obtained as described in
Example 7, in 5 mQ of pyridine were added 347 mg of
stearic anhydride. The mixture was heated at 60C ~or
22~5 hours and then evaporated under reduced pressure
to give an oily residue which was dissolved in 30 mQ
of ethyl acetate. The solution was washed successively
with dilute hydrochloric acid and brine, driad over
sodium sulphate and evaporated. Recrystallization of
the residue from ethyl acetate yielded 92 mg of 2-[(p-
-anlsylamino)carbonyl] 3,5-dimethoxyphenyl octadecanoate
as colourless needles of melting point 88~ - 89C.
964
- 50; -
In a manner analogous to that described in
Example 21, but using N-~p-(allyloxy)benzyl3-2-hydroxy-
-4,6 dimethoxybenzamide in place of 2-hydroxy-4,6-
-dimethoxy-N-(p-methoxybenzyl)benzamide, there was
obtained 2-{~ ~p-(allyloxy)benzyl]amino_7carbonyl}-3,5-
-dimethoxyphenyl octadecanoate as colourless crys~als
o~ melting point 88 - 89C (recrystallized from ethanol/
hexane).
Example 23
. .
In a manner analogous to that described in
Example 21, but using 1-(4-ethoxy-2-hydroxy-6-methoxy-
phènyl)-3-(4-methoxyphenyl)-1-propanone in place of
2-hydroxy-4,6-dimethoxy-N-(p-methoxybenzyl)benzamide,
there was obtained $-ethoxy-3-methoxy-2-[3-(4-methoxy-
phenyl)propionyl]phenyl octadecanoate of melting point
40 - 41C (recrystallized from methanol).
6964
-
.
Example 24
In a manner analogous to that described in Example
19, but using benzoyl chloride in place of ethoxycarbonyl
chloride, there was obtained 2-[~p-anisylamino)carbonyl]-
-3,5-dimethoxyphenyl benzoate as colourless crystals of
melting point 124.5 - 125.5C (recrystallized from ethyl
acetate/hexane).
Example 25
In a manner analogous to that described in Example
19, but using N-~p-(allyloxy)benzyl]-2-hydroxy-4,6-
-dimethoxybenzamide (obtained as described in Example 11)
and benzoyl chloride in place of 2-hydroxy-4,6-dimethoxy-
-N-(p-methoxybenzyl)benzamide and ethoxycarbonyl chloride,
respectively, there was obtained 2-{/ [p-(allyloxy~benzyl]-
amino_7carbonyl}-3,S-dimethoxyphenyl benzoate as colourless
crystals of melting point 105 - 106C (recrystallized
from methanol).
964
- 52 -
Exa~_~ 6
In a manner analogous to that described in
Example 19, but using 1-(4-ethoxy-2-hydroxy-6-methoxy-
phenyl)-3-(4-methoxyphenyl)-1-propanone and benzoyl
chloride in place of 2-hydroxy-4,6-dimethoxy-N-(p-
-methoxybenzyl)benzamide and ethoxycarbonyl chloride,
r~spectively, there was obtained 5-ethoxy-3-methoxy-2-
-~3-(4 methoxyphenyl)propionyl]phenyl benzoate; H nmr
spectrum: ~ 1.42 (3H3, 2.65 3.35 (4H), 3.75 (3H), 3.80
(3H), 4.06 (2H), 6.40 (2~I), 6.75 (2H), 7.11 (2H) and
7.42 - 7.70 ppm (3H).
Exam~le 27
To a solution of 990 mg of 1-(4-ethoxy;2-hydroxy-
6-methoxyphenyl)-3-(4-methoxyphenyl)-1-propanone,
15 . obtained as described in Example 1 and 2 mQ of N,N-
-diisopropylethylamine in 20 mQ of toluene were added
in one portion 10 mQ of phosphorus oxychloride. The
,
J 2~ 64~
- 53 -
mixture was stirred at roo`m temperature for l.S hours and
then evaporated under reduced pressure at a bath
temperature of below 40C to give an oily residue which
was dissolved in 10 m~ of toluene. After removal of
the solvent by evaporation under reduced pressure, the
resulting oily residue was dissolved in 40 mQ o tetra-
hydrofuran/water (1:3, v/v). The solution was vigorously
stirred at room tempPrature for 50 minutes and
concentrated under reduced pressure at a bath temperature
of 30 - 40C to an aqueous solution which was then
extracted three times with 50 mQ of chloroform each
time. The co~bined chloroform extracts were washed with
a small amount of water, dried over sodium sulphate and
evaporated to give an oily residue which was dissolved
in 100 mQ of O.lN potas~ium carbonate. The solution
was washed twice with 30 mQ of ethyl acetate each time,
acidified with hydrochloric acid and extracted three
times with 50 mQ of ether each time. The combined ether
extracts were washed with a small amount of water, dried
over sodium sulphate and evaporated to give an oily
residue. Recrystallization of the residue from ether
6g~
- s~ -
yielded 930 mg of 5-ethoxy-3-methoxy-2-[3-(4-methoxy-
phenyl)propionyl]phenyl dihydrogen phosphate as
colourless needles of melting point 122 - 125C
(decomposition).
~3~æ~
410 mg of 5-ethoxy-3-methoxy-2-[3-(4 methoxyphenyl)-
propionyl]phenyl dihydrogen phosphate, obtained as
described in Example 27, were dissolved in 15 mQ of
O.lN sodium hydroxide. After carefully adjusting the
pH to 8.0 with O.lN sodium hydroxide, the solution was
lyophilized to give a white solid. Recrystallization of
the solid from water/acetonitrile yielded 380 mg of
disodium 5-ethoxy-3-methoxy-2-[3-(4 methoxyphenyl)-
propionyl]phenyl phosphate as colourless needles of
melting point 138 - 139C.
.
Exam~le 29
To a stirred solutlon of 380 mg of dibenzyl-
phosphorochloridate in 10 mQ of benzene was added a
i2C~K~6~
- _ 5S _
solution containing 350 mg of 4-ethoxy-2-hydroxy-6-
-methoxy N-(p-me~hoxyben2yl)benzamide, obtained as
described in Example 12, and 51 mg of 60% sodium hydride
in 10 mQ of dimethylformamlde. After stirring at room
temperature for 14.5 hours, the mixture was diluted with
50 mQ of ethyl acetate, washed three times with 50 mQ
of water each time, dried over sodium sulphate and
evaporated to give 1.25 g of a yellow oil. The oil
was chromatographed on 37.5 g of silica gel using ethyl
acetate/hexane (1:1, v/v) for the elution. Removal
of the solvent from the eluate gave 237 mg of dibenzyl
2-~(p-anisylamino)carbonyl]-5-ethoxy-3-methoxyphenyl
phosphate as a colourless syrup which was dissolved in
20 mQ of chloroform.
~he solution obtained according to the preceding
paragraph was hydrogenated for 34 hours in the presence
of 47 mg of 10% pal~adium-on-charcoal at room temperature
under atmospheric pressure. Removal of the catalyst by
iltration followed by evaporation of the filtrate gave
94 mg of a white residue. Recrystallization o the
~Z~6~364
- - 56 -
residue from methanol yielded 79 mg of 2{(p~anisylamino)-
carbonyl~-5-ethoxy-3-methoxyphenyl dihydrogen phosphate
as colourless crystals of melting point 162 - 16305C.
The compound thus obtained was con~erted into
disodium 2-~(p-anisylamino)carbonyl]~5-ethoxy-3-methoxy-
phenyl phosphate of melting point 126 - 127C in a
manner analogou.s to that described in Example 28.
Exam~le 30
In a manner analogous to that described in
Example 29, but using 2-hydroxy-4,60dimethoxy-N-(p-
~methoxybenzyl)benzamide in place of 4-ethoxy-2-hydroxy-
-6-methoxy-N-(p-methoxybenzyl)benzamide, there was
obtained 2-[(p-anisylamino)carbonyl]-3,5-dimethoxyphenyl
dihydrogen phosphate as colourless crystals of melting
point 160.5 ~ 162.5C.
~'Z~g64
_ s7 _
To a stirred solution of 300 mg of 2-hydroxy-4,6
-dimethoxy-N-(p-methoxybenzyl)benzamide, obtained as
described in Example 7~ and 50 mg of 60% sodium hydride
in 3 mQ of dimethylformamide were added 600 mg of 2,3,4,6-
-tetra-0-acetyl-a-D~glucopyranosyl bromide. The mixture
was stirred at room temperature for 18 hours and then
treated with 50 mQ of ethyl acetate and 30 mQ of water.
The ethyl acetate phase was separated, washed with water,
dried over sodium sulphate and evaporated to give an
oily xesidue. The residue was chromatographed on 10 g
of silica gel using ethyl acetate for the elution.
Removal of the solvent from the eluate followed by
recrystallization from methanol gave 135 mg of 2-~(p-
-anisylaminolcarbonyl]-3,5-dimethoxyphenyl tetra-0-
-acetyl ~-D-glucopyranoside as colourless cxystals of
melting point 73 - 76C.
~6g6~
~ 5.8 -
To a suspension of 100 mg of 2-[tp-anisylamino)-
carbonyl]-3,5 dimethoxyphenyl tetra-0-acetyl-~-D-
-glucopyranoside, obtained as des~ribed in Example 31,
in 30 mQ of methanol were added 0.09 mQ of water and
O.o9 m~ o~ triethylamine. After stirring at room
temperature for 3 days, the mixture was evaporated to
give a solid residue. The residue was chromatographed
on 10 g of silica gel using ethyl acetate/methanol
(10:1, v/v) for the elution. Removal of the solvent
from the eluate followed by recrystallization from
ethanol/hexane yielded 40 mg of 2-[tp-anisylamino)-
carbonyl]-3,5-dimethoxyphenyl ~-D-glucopyranoside as
colourless needles of melting point 132 - 133C.
~ Y~
To a stirred solution of 330 mg of 1-(4-ethox~-2-
-hydroxy-6-methoxyphenyl)-~4-methoxyphenyl) l-propanone,
ob ained as described in Example 1, and 44 mg of 60%
~'~06~64
-59
sodium hydride in 5 mQ of dimethylformamide was added
tetra,O-acetyl-a-D-glucopyranosyl bromide. The mixture
was stirred at room temperature for 18 hours, diluted
with 30 mQ of cold water and extracted with three 30 mQ
portions of ethyl acetate. The combined extracts were
washed with water, dried over sodium sulphate and
evaporated to give 700 mg o~ crude 5-ethoxy-3-methoxy-
-2-[3-(4-methoxyphenyl)propionyl]phenyl tetra-O-acetyl-
-~-D-glucopyranoside.
The foregoing crude material was puri~ied by silica
gel chromatography using hexane/ethyl acetate (3:1, v/y)
for the elution and then saponi~ied following the,,procedure
described in Example 32 to give 5-ethoxy-3-methoxy-2-~3-
-(4-methoxyphenyl)propionyl]phenyl ~-D-glucopyranoside;
H nmr: ~ 1.35 (3H), 2.6 - 3.2 (4~), 3.2 - 4.6 (6H),
3.72 (3H), 3.78 (3H), 4.05 (2H), 4.87 (lH), 6.26 (lH),
6.45 (lH), 6.78 (2H) and 7.15 ppm (2H).
lZ1~69~i4
~ 60 -
Example 34
In a manner analogous to that descri~ed in Example 12
but using 2'-hydroxy~6~-methoxy-4~-propoxyacetophenona in
place of 4~-ethoxy-2'-hydroxy-6'-methoxyacetophenone, theré
was obtained 2-~ydroxy-6-methoxy-4-propoxy-N- ~-methoxybenzyl~
~enzamideas colourless crystals of melting point ~6.5 -
97.5C trecrystallized from methanol).
~Examp:le~35
In a manner analogous to that descri~ed in Example 12
but using 2~-hydroxy-6'-methoxy-4~-(2.propenyloxy)acetophenone
in place of 4'-ethoxy-2'-hydroxy-6'-methoxyacetophenone,
there ~as obtained 4-~allyloxy~-2-hydroxy~~-methoxy-N-
(p-methoxybenzyl~benzamide as colourless crystals o~ melting
point 6~.5 - 70C (recrystallized from methanol).
Example~36
In a manner analogous to that described in Example 12
but using 2'-hydroxy-6'-methoxy-4'-(3-meth~1-2-butenyloxyl
acetophenone in place of 4'-ethoxy-2'-hydroxy-6'-methoxyaceto-
phenone, there was obtained 2-hydroxy-6-methoxy-4-~3-methyl-
2-butenyloxy~-N-(p-methoxybenzyl)benzamide as colourless
crystals of melting point 48.0 - 48.5C (recrystallized from
petroleum ether).
.
l'Z~6964
- 61---
Example 37
In a manner analogous~ to that descri.bed in Example 29
but using 2-hydroxy-6-methoxy-4-propoxy-N-(p-methoxybenzyl)
benzamide, obtained as described in Example 37. in place of
4-ethoxy-2-hydroxy-6-methoxy-N-(p-methoxybenzyl)benzamide,
there was obtained disodium 2-~(p-anisylamino)carbonyl~-3-
methoxy-5-propoxyphenyl phosphate as colourless crystals of
melting point 116 - 119C (recrystallized from ethyl acetate).
.
696~
-62 _
Ex2m~1e_ A
Tablets containing the following ingredients can
be prepared by conventional procedures:
Active ingredient (i.e. a compound
of ~ormula I) 300 mg
Dried lactose 200 mg
Cellulose (microcrystalline) 30 mg
Polyvinylpyrrolidone 5 mg
Magnesium stearate 4 mg
Example B
. . .
Drops for intranasal administration containing the .
~ollowing ingredients per 1 mQ can be prepared using
methods known per se:
Active ingredient (i.e. a compound
of formula I) 0.1 mg
Surfactant 0.05 mg
Propyleneglycol/water (1:1, v/v) ~. s . ad 1 mQ
..
1~6g~4
- 63 -
An acceptable range of concentration of the active
ingredient is 0~001 to 1 mg~m~.
~.
Troches containing the following ingredients can
be prepared using methods known per se:
Acti~e ingredient (i.e. a compound
of formula I) 0.1 g
Powdered sucrose 1.6 g
Acacia 0.2 g
Dextrin 0.1 g
Flavor . 0.001 g
