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Патент USA US2121207

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Patented June 21, 1938
UNITED STATES
PATENT @FFEQE
2,121,207
NEW BASIOALLY SUBSTITUTED ACRIDHNE
COMPOUNDS
Fritz Mietzsch, Wuppertal-Elberfeld, and Hans
Mauss, Wuppertal-Barrnen, Germany, assign
ors to Winthrop Chemical Company, l'na, New
York, N. Y” a corporation of New York
N0 Drawing.
Application .l'une 3, 1935, Serial
No. 24,775.
In Germany June 7, 1934
10 Claims.
This invention relates to new basically sub
stituted acridine compounds and is a further de
velopment of the invention described and claimed
in our co-pending application for Letters Patent
Ser. No. 534,460, filed May 1, i931, and Ser. No.
I726,866, ?led May 21, 1934. The new acridine
compounds same as the acridine compounds de
scribed in the said (so-pending applications are
distinguished by a considerable e?icacy on blood
10
parasites.
.
-
In accordance with the present invention the
new acridine compounds displaying the said
anti-parasitic properties particularly against
malaria parasites are obtainable by the manu
facture of acridine compounds of the general
formula:
halogen derivatives as starting materials the re
action sometimes takes place with the formation
of acridines, containing the radical of the solvent
used in ether- or thioether-like linkage in the
9-position, as intermediate products. The reac—
tion is complete after heating for about one to
several hours. The new base formed may be sepa— 10
rated off by rendering the reaction mixture alka
line and taking up the base precipitated in an
organic solvent, such as ether, methylene chlo
ride or the like.
The aliphatic polyamine containing a primary 15
A
uents, for example, the hydrcxyl group and
ether- or thioether-like linkages. Suitable amines
are, for instance, diethylaminoethylmethylamine,
_R.
0.1)
dimethylaminoethylamine, l-diethylamino-Z-hy
droxypropyl - 3 - ethylamine,
methyl, ethyl, butyl, methoxy, lSODI'QpYlOX“, hy
droxypropyloxy, methylthio, ethylthio group and
the like. The saidalkyl, alkoxy and alkylthio
groups in the 2- and 7-position of the new acri
dine compounds have proved to be of essential
importance as to the anti-parasitic properties of
the new products and are equivalent in this
respect.
dimethylaminoethoxy-ethylamine, and the like.
The new acridine compounds are in the form
of the free bases light yellow substances which 25
are soluble in the usual organic solvents, for ex
ample, ether, alcohol, acetone, benzene and
methylene chloride. They may be dissolved in
water in the form of their salts with acids, such
as hydrochloric, hydrobromic, sulfuric, acetic, 30
citric, tartaric, lactic acid and the like. These
salts are obtained in the customary manner by
neutralizing the free base with the acid. Two
equivalents of the acid neutralize one mol. of the
base. Of course, the free bases are soluble in 35
dilute mineral acids and organic acid with the
formation of the water-soluble salts.
said new acridine compounds are prepared by
The invention is further illustrated by the
following examples without being restricted
reactingupon such acridine substitution products
thereto:—
In accordance with the present invention the
as contain in the 9-position a replaceable sub~
situent and in the 2- and 7-position an alkyl,
alkoXy or alkylthio group, with aliphatic poly
amines containing a primary or secondary amino
145 group. Replaceable substituents in the 9-posi
tion are, for instance, ether and ester like groups,
such as halogen, aryloxy, alkoxy, aryl- and alkyl
mercapto groups; The reaction is preferably
carried out in phenolic solution while heating, ad
vantageously on the water-bath.
20
1 - diethylamino—4~
pentylamine, diethylaminoethylthio-propylamine,
in which R1 stands for hydrogen or alkyl, such
as methyl or ethyl, R2 stands for an aliphatic
~"' radical, such as a methylene, ethylene, propylene,
hydroxypropylene group, or for alkylene groups
which are interrupted by ether-like bound oxyn
gen or sulfur atoms, and R3 and R4 stand for
alkyl, alkoxy or alkylthio groups, such as the
30
about 130° C. when using these substances as
solvents. If necessary the reaction is performed
in closed vessels. Presumably when using the 9
or secondary amino group may contain substit
’
R._
(Cl. 260-36)
Also other or
ganic substances, containing hydroxyl or sulf
hydryl groups, have proved to be suitable sol
vents, for instance, ethyl alcohol, glycol, amyl
alcohol, cresol, naphthol, thiophenol, and the like.
(55 The reaction temperature is advantageously at
Example 1.—2’l.4 grams of 2.7-dimethoxy-9
40
chloro-acri-dine are melted in the Water-bath
with 100 grams of phenol and 16 grams of u
diethylamino - delta - aminopentane
are
added
While stirring and heating for 1 hour to 90—100° C. 45
The reaction mixture is then introduced into
1009 cos. of 2-normal caustic soda solution and
the 2.‘l-dimethoxy-9-a~diethylamino-delta-pen- ,
tylaminoacridine formed is taken up in ether. It
is puri?ed by way of its acetic acid salt and 50
separated as yellow dihy-drochloride which is
readily soluble in water and decomposes at
245-250" C.
The 2.T-dimethoxy-9-chloroacridine (yielding
yellow crystals from benzene, which melt at 228
55
2
2,121,207
229° C.) is obtained from the 4.4'-dimethoxy
the 2-1nethylmercapto-'l-methoxy-Q-chloro-acri
diphenylamine-6~carboxylic acid (yielding yellow
dine (from benzene yolk-like colored needles
melting at 181-183° C.) is obtained by subjecting
crystals from alcohol, melting at 167-168° C.) by
subjecting it to ring closure and chlorination.
The dihydrochlorides of 2.7-dimethoxy»9~(e
the former to ring closure and chlorination.
dimethyl-amino-?-ethylamino)-acridine, 2.7--di
dine is prepared in an analogous manner. When
methoxy-9-(a-diallylaminow‘proplyamino) - ac
reacting thereupon with a-diethylamino-delta—
aminopentane the Z-butylmercapto-‘l-methoxy
ridine,
2.7-dimethoxy-9~(a-diethylamino~delta
butylamiho)-acridine, are obtained in the form
of yellow crystal powders when using in the
above example instead of a-diethylamino-delta~
aminopentane
a - dimethyl - amino - ,6 ~ aminoeth
ane, a-diallylamlnow-aminopropane, a-diethyle
amino-delta-aminobutane, respectively. Their
15 properties correspond to those of the above de—
scribed dihydrochloride.
When using a-diethylaminoethylthio-'y-amino
propane (boiling at 135-136° C. under 12 mm.
pressure),
or dimethyl-aminoethoXy-p-amino
ethane (boiling at 88-92° C. under 11 mm. pres
sure) the dihydrochlorides of 2.7-dimethoXy-9
(a - diethylaminoethylthio - 'y - propylamino) -acri—
dine, and of 2.7-dimethoxy-9-(or-dimethylamino
ethoxy-e-ethylamino) -acridine are obtained in
The 2-butylmercapto-'l-methoxy~9-chloroacri
9-(a-diethylamino-delta- pentylamino) - acridine
is obtained. It forms a lactate which is readily
soluble in water.
Example 5.—The 2-methyl-7-methoxy-9-(a
diethylamino-delta~pentylamino> -acridine is ob
tained from 2-methyl-'7—methoxy-9-chloroacri
dine and a-diethylamino-delta--amino-pentane.
It forms a citric acid salt which is readily soluble
in water with yellowish-green ?uorescence.
The
2-methyl-7 - niethoxy - 9 - chloroacridine
(from ligroin pale-yellow needles melting at 161
1620 C.) is obtained from the 4’~methyl-4-meth
oXydiphenylamine-ti-carboxylic acid (from alco
hol yellow prisms melting at 160-161° C.) by sub
jecting the latter to ring closure and chlorination.
The 2-ethyl-7-methoxy-9-ch1oroacridine is pre
25 the form of yellow crystals which are-soluble in
pared in an analogous manner.
water.
Instead of the dihydrochlorides the salts with
other acids, for instance, hydrobromic acid, sul
furic acid, nitric acid, acetic, lactic, tartaric acid
30 and the like may be prepared in an analogous
with a-diethylamino-delta-aminopentane it is
transformed into the 2-ethyl-7-methoxy-9-(a
diethylamino-delta-pentylamino)-acridine. It is
readily soluble in water in the form of its salts,
for instance, with lactic, citric and tartaric acid. 30
Example 6.—The 2.7-dimethyl-9-(or-diethyla—
manner.
Example 2.—33.1 grams of 2.7-dimethoxy-9
phenoxy-acridine are treated with 15 grams of
35
a-diethylamino-c-hydroXy-y-aminopropane
in
accordance with the directions indicated in Ex—
ample 1. The dihydrochloride of the 2.7-dimeth
oxy-9- (a-diethylamino - @- hydroXy-'y~propylami
no)-acridine is obtained as yellow dihydrochlo
ride which is readily soluble in water with yellow»
.40 ish-green ?uorescence and decomposes at 240° C.
Also the dihydrobromide, the sulfate and the
dinitrate are readily soluble in water.
The 2.7-dimethoxy-Q-phenoxyacridine pre
45
pared from 2.7-dimethoxy-9-ch1oroacridine by
treatment with phenol, the two components being
melted at water-bath temperature, crystallizes
from alcohol in thin lea?ets melting at MHZ-148°
C. Its hydrochloride forms yellow~ glittering leaf
lets which are di?icultly soluble in water and de
50 compose at 225° C.
Example 3.--On treating 2-isopropyloxy-'7
methoxy-Q-chloroacridine with a-diethylamino—
delta-aminopentane the 2-isopropyloxy-7-meth
55
oxy-9-(a-diethylamino-de1ta-pentylamino) - acri
dine is obtained. It is isolated as a yellow citrate
which is readily soluble in water with yellowish
green ?uorescence.
From
When reacted 25
4 - methoxy - 4' - isopropyloxydiphenyla
mino-delta-pentylamino)-acridine is obtained
from 2.7-dimethyl-9-chloroacridine and a-dieth
ylamino-delta-aminopentane. Its yellow dihy
drochloride is readily soluble in water and melts 35
at 245-250“ C. with decomposition.
The 2.7-dimethyl-9-chloroacridine (from lig
roin pale-yellow crystal powder melting at
154-155" C.) is obtained from 4.4'-dimethyldi
phenylamine-6-carboxylic acid (from alcohol or 40
benzene yellowish crystals melting at 187-188” C.)
by subjecting it to ring closure and chlorination.
Example 7.-—The 2.7-dimethyl-9-(a-diethyl
amino-54%dimethyl-'y-propylamino) -acridine is
obtained from 2.7-dimethyl—9-chloroacridine and 45
a—diethylamino~?.?- dimethyl — v - aminopropane.
Its dihydrochloride decomposes at 238-240° C.
Example 8.—From 2-n-butyloxy-7-methoxy-9
chloroacridine and a-diethylamino-s-aminopen~
tane the 2-n-butyloxy-7-methoxy—9 - (a-diethyl
in accordance with the methods indicated in
Example 1. It yields a citric acid salt which is
soluble in water with yellowish-green ?uorescence
55.
and decomposes with foaming at 100° C.
In an analogous manner the 2-n-butyloxy-7
methoxy-9-.(a-diethylamino-p -hydroxy - 'y - pro
pylamino)-acridine is obtained from 2-n-butyl
oxy-‘l-methoxy-9-chloroacridine and a-diethyl
mine-G-carboxylic acid (yielding thin yellow nee
dles from ligroin, melting at 156-15'7° C.) the 2
amino-,e-hydroxy-v-aminopropane.
isopropyloxy-7-methoXy-9-chloroacridine (yield
The 2-n-butyloxy-7—methoxy-9-chloroacridme
(from ligroin thin, yellow needles melting at
ing yellow crystals from ligroin, melting at 129
130° C.) is obtained by subjecting the former
65 product to ring closure and chlorination.
Example 4.—On treating 2-methylmercapto-7~
methoxy-Q-chloroacridine with a-diethylamino
delta-aminopentane the Z-methylmercapto-‘l
methoxy-9- (a-diethylamino-delta-pentylamino) -
70 acridine is obtained which as citrate or tartrate
forms a deep-yellow colored powder which is
readily soluble in water.
From the 4-methoxy-4’-methylmercapto-di
phenylamine-G-carboxylic acid (from, alcohol
.26 yolk-like colored needles melting at 175-17 6° C.)
50
amino-delta-pentylamino)-acridine is obtained
Its hydro
60
chloric acid salt melts at 201-202° C.
133° C.) is obtained from 4-methoxy~4'-n-butyl
oxy-diphenylamine-?-carboxylic acid (from alco 05
hol yellow crystals melting at 130-131° C.) by sub
jecting it to ring closure and chlorination.
Example 9.-—By reacting the Z-n-butyloxy-‘l
ethoxy-9-chloroacridine with a-diethylamino
delta-aminopentane in the above described man 70
ner the 2-n-butyloxy-7-ethoxy-9-(u-diethyla
mino-delta-pentylamino) -acridine is obtained. It
forms as citric acid salt a yellow powder which
is readily soluble in Water.
The Z-n-butyloxy-‘l-ethoxy-Q- (or-diethylamino
3
2,121,207
p-hydroxy - 7 - propylamino) - acridine, obtained
wherein R.2 stands for an aliphatic radical, and
when using a-diethylamino-,3-hydroxy-’y-amino
R3 stands for a substituent of the group consist
propane and the 9-chloroacridine compound re
ing of the alkyl, alkoxy and alkylthio groups,
which compounds in the form of the free bases
ferred to above, yields a yellow hydrochloric acid
salt melting at 230-231° C.
The 2-n-butyloxy-‘7 - ethoxy - 9 - chloroacridine
(from benzene white, crystalline powder melting
at 147° C.) is obtained from 4-ethoxy-4’-n-butyl
oxydiphenylamine-6-carboxylic acid (from alco
10 hol yellowish-green crystals melting at 136-137°
C.) by subjecting it to ring closure and chlorina
tion.
are soluble in organic solvents and in the form of
their salts with acids are soluble in water.
4. Acridine compounds of the general formula:
10
R
0--alkyl
Example 10.—'I'he 2-n-hexyloxy-7-methoxy-9
(u-diethylamino-delta-pentylamino) - acridine is
N
15 obtained from 2-n-hexyloxy-‘7-methoxy-9-chlo
roacridine and a-diethylamino-delta-aminopen
tane in accordance with the methods indicated
in Example 1.
It is isolated as a citric acid salt
which is readily soluble in water.
20
The 2-n-hexyloxy-7-methoxy-9- (u-diethylam
ino-5-hydroxy-»y-propylamino)-acridine is
ob
tained when reacting a-diethylamino-p-hydroxy
'y-aminopropane with 2-n-hexyloxy-7-methoxy
15
wherein R3 stands for a substituent of the group
consisting of the alkyl, alkoxy and alkylthio
groups, which compounds in the form of the free
bases are soluble in organic solvents and in the
form of their salts with acids are soluble in 20
water.
5. Acridine compounds of the general formula:
Q-chloroacridine. Its yellow hydrochloric acid
25 salt melts at 189-190“ C. while decomposing.
25
The 2-n-hexyloxy-7-methoxy-9-chloroacridine
is obtained as yellowish-green powder melting at
'74-75° C. after subjecting the 4-methoxy-4'-n
hexyloxydiphenylamine-G-carboxylic acid (from
30 ligroin yellow scales melting at 102-103° C.) to
ring closure and chlorination.
We claim:
_ 1. Acrldine compounds of the general formula:
HN—'R1'-—N(alkyl)2
85
N
30
wherein R.2 stands for an aliphatic radical,
which compounds in the form of the free bases
are soluble in organic solvents and in the form
of their salts with acids are soluble in'water.
35
6. Compounds of the group consisting of the
2.7-dialkoxy-9-dialkylaminoalkylamlno-acridines
40 wherein R2 stands for an aliphatic radical and
R3 and R4 each stand for a substituent of the
group consisting of the alkyl, alkoxy and alkyl
thio groups, which compounds in the form of the
free bases are soluble in organic solvents and in
the form of their salts with acids are soluble in
water.
2. Acridine compounds of the general formula:
and. their salts, which compounds in the form of
the free bases are soluble in organic solvents and
in the form of their salts with acids are soluble
in water.
7. Compounds of the group consisting of the 2.7
dialkoxy-Q-diethylaminoalkylamino-acridines and
their salts, which compounds in the form of the
free bases are soluble in organic solvents and
in the form of their salts with acids are soluble
in water.
8. Compounds of the group consisting of the
2.7-dialkoxy- 9 - (a - diethylamino - delta - pentyla
mino) -acridines and their salts, which compounds
50
in the form of the free bases are soluble in or
ganic solvents and in the form of their salts with
acids are soluble in water.
wherein R3 and R4 each stand for a substituent
55 of the group consisting of the alkyl, alkoxy and
alkylthio groups, which compounds in the form
of the free bases are soluble in organic solvents
and in the form of their salts with acids are
soluble in water.
60
65
3. Acridine compounds of the general formula:
9. 2.7-dimethoxy-9-(u-diethylamino-delta-pen
tylamino) -acridine, which compound in the form 55
of the free base is soluble in organic solvents and
in the form of its salts with acids is soluble in
water.
101. 2.7 - dimethoxy - 9 - (a — diethylamino -.-delta
pentylamino) - acridine - dihydrochloride which
forms a water-soluble yellow crystal powder de
composing at 245-250° C.
FRITZ MIETZSCH.
HANS MAUSS.
65
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