Note: Descriptions are shown in the official language in which they were submitted.
10~ 0~,
SUMMARY OF THE INVENTION
This invention describes a novel composition incorpo-
rating substituted phenylamidinourea compounds. This invention
further provides valuable pharmaceutical preparations which
contain substituted phenylamidinourea compounds which possess
an effective degree of antihypertensive properties and exert
activities on the cardiovascular system. A method for the
treatment of hypertensive disorders by the administration of a
substituted phenylamidinourea compound is also described.
BACKGROUND OF THE INVENTION
The pharmaceutical compositions which have been used
as antihypertensive agents have included such as the thiazides,
reserpine, hydralazine, ~-methyl dopa, guanethidine and the
like. These compounds, however, while being effective produce
undesirable side effects such as electrolyte inbalance, ortho-
static hypertension, and gastric secretory and spasmolytic
properties.
I have unexpectedly found that amidinourea compounds
exhibit valuable pharmacologic properties.
I have unexpectedly found that the amidinoureas of
this invention are useful antihypertensive agents.
: I have further found that the amidinoureas compounds
of this invention are novel and can easily be prepared.
I have also found that the compounds of this
invention have a minimum of the side effects which accompany
antihypertensive agents.
I have still further found a simple and effective
; method for the treatment of cardiovascular disorders such as
hypertensive disorders.
~' .
-
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DESCRIPTION AND PREFERRED EMBODIMENT
This invention describes a class of novel composition
which contains a substituted phenyl radical which is further
attached to an amidinourea chain. This results in urea type
compounds having a substituted phenylamidino group attached at
one of the nitrogen atoms. This invention also describes the
non-toxic pharmaceutically acceptable salts and the method of
preparing these substituted phenylamidinourea compounds.
The invention compounds which are useful for the
treatment of cardiovascular disorders and which are amidinourea
compounds of formula I:
R 4~ N H - C - N H - e N H z
R5 R6
where:
R2, R3, R4, R5 and R6 may be the same or different and are
hydrogen (provided at least one of R2, R3, R4, R5 and R6
is other than hydrogen),
halo,
trifluoromethyl,
nitro,
loweralkoxy or
loweralkyl; and
the non-toxic acid addition salts thereof.
The preferred compounds which are useful in the
treatment of cardiovascular disorders are exemplified by those
compounds of formula II:
.. . ~ .
.. .
o~
xl
r ~N H - C N H - C - NH 2 I I
where:
X', Y' and Z' may be the same or different and are
hydrogen (provided at least one of X', Y' and Z' is
other than hydrogen),
halo,
haloloweralkyl,
nitro,
cyano,
loweralkylsulfonyl,
loweralkoxy or
loweralkyl. :
The more preferred compounds which are useful in the
treatment of cardiovascular disorders are shown in formula II
~ where: ~ .
X', Y' and Z' are
hydrogen (provided at least one of X', Y' and Z' is
other than hydrogen),
halo,
haloloweralkyl or
loweralkyl.
The most preferred compounds are described by
formula II
where:
X' is hydrogen,
chloro,
bromo or :
- fluoro;
. .
-- 3
. ; . .
~(~4~Q~
Y' is hydrogen,
chloro,
- methyl or
trifluoromethyl
Z' is chloro,
bromo,
fluoro,
methyl or
trifluoromethyl.
It is well known in the pharmacological arts that
non-toxic acid addition salts of pharmacologically active amine
compounds do not differ in activities from their free base.
; The salts merely provide a convenient solubility factor.
The amines of this invention may be readily converted
to their non-toxic acid addition salts by customary methods in
the art. The non-toxic salts of this invention are those salts
the acid component of which is pharmacologically acceptable in
the intended dosages; such salts would include those prepared
from inorganic acids, organic acids, higher fatty acids, high
molecular weight acids, etc., and include such as:
hydrochloric acid, succinic acid,
hydrobromic acid, glycolic acid,
sulfuric acid, lactic acid,
nitric acid, salicylic acid,
phosphoric acid, benzoic acid,
methane sulfonic acid, nicotinic acid,
benzene sulfonic acid, phthalic acid,
acetic acid, stearic acid,
propionic acid, oleic acid,
malic acid, abietic acid, etc.
~U~l~O~
Representative compounds of this invention which are
particularly useful are as follows:
o-chlorophenylamidinourea
m-chlorophenylamidinourea
p-chlorophenylamidinourea
(2,3-dichlorophenylamidino)urea
(2,4-dichlorophenylamidino)urea
(2,5-dichlorophenylamidino)urea
(3,4-dichlorophenylamidino)urea
10 (3,5-dichlorophenylamidino)urea
p-bromophenylamidinourea
(2-chloro-4-bromophenylamidino)urea
p-fluorophenylamidinourea
(2,4-difluorophenylamidino)urea
(2,6-difluorophenylamidino)urea
p-trifluoromethylphenylamidinourea
(2-methyl-4-chlorophenylamidino)urea
(2-methyl-4-bromophenylamidino)urea
(2,6-dimethylphenylamidino)urea
20 (2-trifluoromethyl-4-methylphenylamidino)urea `
(4-iodo-2-methylphenylamidino)urea nitrate
(2-trifluoromethyl-4-fluorophenylamidino)urea nitrate
(2-ethyl-6-methylphenylamidino)urea nitrate
(4-methoxy-2-methylphenylamidino)urea
(4-chloro-2-methoxyphenylamidino)urea
(2-methoxy-6-methylphenylamidino)urea
(2,5-difluorophenylamidino)urea
(3-chloro-4-fluorophenylamidino)urea
(pentafluorophenylamidino)urea
(2-chloro-6-fluorophenylamidino)urea
(2,4,6-trimethylphenylamidino)urea
~. .
. ~ :-~ .
. . .
~o~i~o~
The compounds useful in the invention may be prepared
by the following general synthesis:
Condensation of cyanamide and a substituted aniline
results in the corresponding substituted phenylguanidine.
The reaction is preferably carried out on the aniline
salt either in a polar medium or neat and using increased
temperatures. The salt used may be any acid addition amine
salt but preferably the salt of a mineral acid. The polar
medium may be aqueous, partially aqueous or a non-aqueous
solution. It is convenient to choose a solvent that will
reflux at the desired reaction temperature. The more preferred
solvents are water or alcohol but other solvents may be used
such as DMS0, diethyleneglycol, ethyleneglycol, tetrahydro-
furan, dimethylformamide, etc. The most preferred solvent is a
mildly acidic solvent which is non-nucleophilic such as phenol,
cresol, xylenol, etc. The reaction should also be carried out
- at a temperature which is high enough so that condensation
takes place readily, but not sufficient to decompose the
guanidine formed. The reaction temperature can vary from room
temperature to about 250C. although it is preferable to run
the reaction at temperatures from about 50C. to 150C. The
guanidine salt which is formed can be converted to the free
base with a metal hydroxide or alkoxide solution. The iso-
lation of the desired guanidine can be carried out by any
method known in the art.
When the substituted phenylguanidine is reacted with
t-butylisocyanate then the product formed is a l-substituted
phenylamidino-3-t-butylurea. This reaction is preferably
carried out in a non-polar medium using solvents such as
benzene, toluene, xylene, etc. The reaction is also carried
out as above at raised temperatures.
- 6 -
~`,i
.
~(~4~90~
Treatment of the l-substituted phenylamidino-3-t-
butylurea with acid results in the desired l-substituted
phenylamidinourea. This reaction is carried out preferably as
a 10% solution in a 1:1 mixture of conc. hydrochloric acid and
glacial acetic acid at increased temperature. The resultant
product is isolated as a salt by any method known in the art.
The followin~ reaction equations illustrate this
synthesis:
~ R2 N
R4 ~ O ~ NH2 HX + C-NH2
1~
R5 R6
j~R2
R4 ~ O ~ NH-C-NH2 HX'
~ t-but NCO
\ / .'
R4 ~ NH-C-NH-C-:H-I-CH3
H+ CH3
R5 R6 /
~ 2
R4~NH-c-NH-c-NH2
R5 R6
~04~
where:
! HX' is a mineral acid.
Appropriately desired end products having various X',
Y'and Z'substituents may be prepared at various steps of
synthesis using suitable reactions in order to convert one
- group to another.
The starting anilines are either known, may be pre-
pared by known techniques or reference to the preparation is
shown. Thus, chlorination or bromination of an acetanilide or
aniline may be carried out in acetic acid, or in the presence
of a small amount of iodine dissolved in an inert solvent such
as carbon tetrachloride. A solution of chlorine or bromine is
then added while the temperature is held near 0C. Iodination
may also be carried out by known methods using iodine mono-
- chloride (ClI).
Alkylation may be carried out on an acetanilide using
an alkyl halide and aluminum chloride under Friedel-Crafts
conditions to obtain desired alkyl substitution.
Nitration may be carried out using fuming nitric acid
at about 0C.
A nitro compound may be hydrogenated to the corre-
sponding amine which may then be diazotized and heated in an
alcohol medium to form the alkoxy compound.
An amino compound may also be diazotized to the
diazonium fluoroborate which is then thermally decomposed to
the fluoro compound. Diazotization followed by a Sandmeyer
type reaction may yield the bromo, chloro or iodo compound.
Diazotization of an amino compound followed by
addition of cuprous cyanide may result in the desired cyano
compound.
When an amino compound is diazotized followed by
8 -
. .
~o'~
reaction with potassium ethylxanthate and then hydrolyzed, the
mercapto compound results. This in turn may be alkylated to
the alkylthio group which is then oxidized to the corresponding
alkylsulfonyl substituent.
A halo compound in which halo is chloro or bromo or
iodo may be reacted with cuprous cyanide in guanidine at about
150C. to produce a cyano compound.
A chloro, bromo or iodo compound may also be reacted
with trifluoromethyliodide and copper powder at about 150C. in
dimethylformamide to obtain a trifluoromethyl compound
~etrahedron Letters:47, 4095 (1959 ~.
A halo compound may also be reacted with cuprous
methanesulfinate in quinoline at about 150C. to obtain a
methylsulfonyl compound.
Of course the above reactions may also be carried out
on acetophenone in order to direct substitution. Formation of
an oxime followed by Beckmann Rearrangement results in the
acetamide which is then deacylated to the aniline.
Reactions may also be carried out on the substituted
anilines which would result in di- and tri- substituted
anilines.
Reactions may also be carried out at other stages of
synthesis depending on the substituents present and the substi-
tuents desired and various combinations of the foregoing
reactions will be determined by one skilled in the art in order
that the desired product results. Thus, a phenylguanidine may
be halogenated or nitrated as above, etc.
The compounds of this invention exert activity on the
cardiovascular system. They possess blood-pressure lowering
effects and are useful as antihypertensive agents.
For these purposes, the amidinoureas of this
g
: ' . ~ . - . ' ' '
iO4~0~
invention can be normally administered orally or parenterally.
Orally they may be administered as tablets, aqueous or oily
suspensions, dispersible powders or granules, emulsions, hard
or soft capsules, or syrups or elixirs.
Compositions intended for oral use may be prepared
according to any method known in the art for the manufacture of
pharmaceutical compositions and such compositions may contain
one or more agents selected from the group consisting of
sweetening agents, flavoring agents, coloring agents, pre-
serving agents and the like, in order to provide a pharmaceuti-
cally elegant and palatable preparation.
The dosage regimen in carrying out the methods of
this invention is that which insures maximum therapeutic
response until improvement is obtained and thereafter the
minimum effective level which gives relief. Thus, in general,
the dosages are those that are therapeutically effective in the
alleviation of hypertensive disorders. In general, the daily
dose can be between about 0.05 mg/kg/day and 70 mg/kgtday
(preferably in the range of 1-25 mg/kg/day), bearing in mind,
of course, that in selecting the appropriate dosage in any
specific case, consideration must be given to the patient's
weight, general health, age, and other factors which may
influence response to the drug.
Various tests in animals have been carried out to
show the ability of the compounds of this invention to exhibit
reactions that can be correlated with activity in humans.
One such test is the ability of the compound to
lower blood pressure in the spontaneous hypertensive rat (Ryo
Tabei, et al., Clin. Pharm. & Therap. 11: 269-274, 1970).
Blood pressure measurements are recorded by both the tail cuff
method and by direct cannulation of a common carotid artery.
- 10 -
.
104~L90~
Compounds that are effective antihypertensives in man have been
shown to be active in lowering blood pressure in this animal
model. In view of the results of this test, the amidinoureas
of this invention can be considered to be active antihyper-
tensive agents.
The following are detailed examples which show the
preparation of the compounds of this invention. They are to be
; construed as illustrations of said compounds and not as limi-
tations thereof.
10EXAMPLE 1
2,6-Dichlorophenylguanidine
To 51 9. (0.315 mole) of 2,6-dichloroaniline is added
0.4 moles of etherial HCl and 200 ml of m-cresol. The mixture
is then stirred and heated on a steam bath to drive off the
ether and excess hydrogen chloride. To the resultant mixture
is then added 13.3 g. (0.315 mole) of cyanamide then heated for
2 hours on a steam bath. The reaction mixture is then cooled,
added to 150 ml of conc. sodium hydroxide solution, cooled and
extracted with 2 liters of ether. The ether layer is washed
with 2 x 1 liter of water, dried over sodium sulfate, charcoal-
ed and evaporated. The residue is triturated with hexane and
the precipitate is filtered off and washed with ether and dried
to obtain 2,6-dichlorophenylguanidine.
The free base is prepared by dissolving 2,6-dichloro-
phenylguanidine hydrochloride in 10% sodium hydroxide solution
and extracting with ether. The ether is dried and evaporated
to dryness to obtain 2,6-dichlorophenylguanidine.
When the above procedures are followed using the
amines of Table I, below, then the corresponding product of
Table II, below, is prepared.
- 11 -
TABLE I ~O~L9U~ TABLE II
o-chloroaniline o-chlorophenylguanidine
m-chloroaniline m-chlorophenylguanidine
p-chloroaniline p-chlorophenylguanidine
2,3-dichloroaniline 2,3-dichlorophenylguanidine
2,4-dichloroaniline 2,4-dichlorophenylguanidine
3,4-dichloroaniline 3,4-dichlorophenylguanidine
3,5-dichloroaniline 3,5-dichlorophenylguanidine
p-bromoaniline p-bromophenylguanidine
10 2-chloro-4-bromoaniline 2-chloro-4-bromophenylguanidine
p-fluoroaniline p-fluorophenylguanidine
2,4-difluoroaniline 2,4-difluorophenylguanidine
2,5-difluoroaniline 2,5-difluorophenylguanidine
2,6-difluoroaniline 2,6-difluorophenylguanidine `
p-nitroaniline p-nitrophenylguanidine
2-methyl-4-chloroaniline 2-methyl-4-chlorophenylguanidine
2-methyl-4-bromoaniline 2-methyl-4-bromophenylguanidine
2-methyl-4-iodoaniline 2-methyl-4-iodophenylguanidine
2-bromo-4-methylaniline 2-bromo-4-methylphenylguanidine
20 2-methyl-6-chloroaniline 2-methyl-6-chlorophenylguanidine
2,6-dimethylaniline 2,6-dimethylphenylguanidine
2-trifluoromethyl-4-fluoro- 2-trifluoromethyl-4-fluorophenyl-
aniline guanidine
2-methoxy-4-chloroaniline 2-methoxy-4-chlorophenylguanidine
2,4-dimethoxyaniline 2,4-dimethoxyphenylguanidine
2-methoxy-6-methylaniline 2-methoxy-6-methylphenylguanidine
2-ethyl-6-methylaniline 2-ethyl-4-nitrophenylguanidine
2-ethyl-4-bromoaniline 2-ethyl-4-bromophenylguanidine
3-chloro-4-fluoroaniline 2,4-dichloro-6-fluorophenyl-
guanidine
2-chloro-6-fluoroaniline 2-chloro-4-bromo-6-fluorophenyl-
guanidine
2,3,4,5,6-pentafluoroaniline 2,3,4,5,6-pentafluorophenyl-
guanidine
2,4,6-trimethylaniline 2,4,6-trimethylphenylguanidine
- 12 -
- .
~34 1L~
EXAMPLE 2
1-(2,6-Dichlorophenylamidino)-3-(t-butyl)urea
To a mixture of 10 9. (0.05 mole) of 2,6-dichloro-
; phenylguanidine and 10 ml xylene is added 5 9. of t-butyliso-
cyanate (O.OS mole) and the mixture is refluxed for 2 hours.
The reaction product is cooled, triturated with heptane and
filtered. Recrystallization from 1:1 isopropyl/water results
in 1-(2,6-dichlorophenylamidino)-3-(t-butyl)urea.
When the above procedure is followed using the
guanidines of Table II, Example 1, then the products prepared
are shown in Table III below.
TABLE III
l-(o-chlorophenylamidino)-3-(t-butyl)urea
l-(m-chlorophenylamidino)-3-(t-butyl)urea
l-(p-chlorophenylamidino)-3-(t-butyl)urea
1-(2,3-dichlorophenylamidino)-3-(t-butyl)urea
1-(2,4-dichlorophenylamidino)-3-(t-butyl)urea
1-(3,4-dichlorophenylamidino)-3-(t-butyl)urea
1-(3,5-dichlorophenylamidino)-3-(t-butyl)urea
1-(p-bromophenylamidino)-3-(t-butyl)urea
1-(2-chloro-4-bromophenylamidino)-3-(t-butyl)urea
l-(p-fluorophenylamidino)-3-(t-butyl)urea
1-(2,4-dimethoxyphenylamidino)-3-(t-butyl)urea
1-(2-methoxy-6-methylphenylamidino)-3-(t-butyl)urea
1-(2,4-difluorophenylamidino)-3-(t-butyl)urea
1-(2,5-difluorophenylamidino)-3-(t-butyl)urea
1-(2,6-difluorophenylamidino)-3-(t-butyl)urea
l-(p-nitrophenylamidino)-3-(t-butyl)urea
1-(2-methyl-4-chlorophenylamidino)-3-(t-butyl)urea
1-(2-methyl-4-bromophenylamidino)-3-(t-butyl)urea
'- . '' :
lU~G~
1-(2-methyl-4-iodophenylamidino)-3-(t-butyl)urea
1-(2-bromo-4-methylphenylamidino)-3-(t-butyl)urea
1-(2-methyl-6-chlorophenylamidino)-3-(t-butyl)urea
1-(2,6-dimethylphenylamidino)-3-(t-butyl)urea
1-(2-trifluoromethyl-4-fluorophenylamidino)-3-
(t-butyl)urea
1-(2-methoxy-4-chlorophenylamidino)-3-(t-butyl)urea
1-(2-ethyl-6-methylphenylamidino)-3-(t-butyl)urea
1-(3-chloro-4-fluorophenylamidino)-3-(t-butyl)urea
1-(2-chloro-6-fluorophenylamidino)-3-(t-butyl)urea
1-(2,3,4,5,6-pentafluorophenylamidino)-3-(t-butyl(urea
1-(2,4,6-trimethylphenylamidino)-3-(t-butyl)urea.
EXAMPLE 3
(2,6-Dichlbrophenylamidino)urea hydrochloride
A mixture of 32.1 9. (0.106 moles) of 1-(2,6-
dichlorophenylamidino)-3-(t-butyl)urea and 200 ml of conc.
hydrochloric acid is refluxed for 1/2 hour. The reaction
mixture is cooled, filtered and washed with 10 ml of 1:1
HCl/H20 and dried. The product is then recrystallized from
ethanol-ether to obtain (2,6-dichlorophenylamidino)urea hydro-
- chloride, m.p. 212-213C.
In a similar manner other desired salts may be
prepared using the appropriate acid.
':
The free base is prepared according to Example 1.
EXAMPLES 4 to 36
By proceeding with the compounds of Tables I, II and
I I I and following the procedures of Examples 1, 2 and 3, the
following compounds corresponding to the following formula:
- 14 -
- - . . . -
.
1()'~1~0~
i~ N H O
R4~ NH-C-NH-~-NH2
R5 R6
are obtained and identified in Table IV.
~ . .
.
TABLE IY
Ex R2 R3R4 R5 R6 Mel ti ng Poi nt i n C .
_ BASEHydroch 1 ori de N i trate
4 Cl ~59-160
Cl 171-173
6 Cl 182-183
7 Cl Cl 194-195
8 Cl Cl 184-185
9 Cl Cl 187
Cl Cl 197-198
11 Cl Cl 198-199
12 Br 177-179
13 Cl Br 188.5-189 .
14 F 188-189 198-199
F F 205
16 F F 212 ..
17 CF3 173-174 194
18 N02 215
19 CH3 Cl 190-190.5
CH3 Br 178-180
21 Br CH3 205-206
22 CH3 Cl 205-206
23 CH3 CH3 203-204
24 CF3 F164-165
C2H5 Br152-153
26 CH3 I 189.5-190.5
27 CF3 F 164-165
28 C2H5 CH3 192-195
29 CH3 CH30 160
CH30 Cl 197
31 CH30 CH3 167
.. . .
: ~ - . . . .
.. .
10`~1~0~
TABLE IY (Cont'd)
Ex. R2R3 R4 R5 R6 -~ ~ lelting Point ir C. -
_ __ BASE Hydroch 1 ori de Ni trate
3 2 F F 200
33 Cl F 208
34 F F F F F 206 -207
3 5 C 1 F 1 9 9 - 20 0
36 CH3 CH3 CH3 118
-- 1 7
' . I
