Note: Descriptions are shown in the official language in which they were submitted.
1039308
This invention concerns substituted amidine compounds, processes
for their preparation, and compositions containing the compounds
The compounds of the invention correspond to the formula
N-R'
R-C
\ NHR"
wherein R' and R" each independently represent Cl 3 alkyl, and R represents
. X4
xl ~ or X ~ ~ CH
wherein Xl represents halo, and X2, X3, and X4 each independently represent
- halo, or hydrogen, with the proviso that at least one of X3 and X4 represents
halo, and pharmaceutically acceptable salts thereof.
10 The compounds can be prepared by (A) reacting a nitrile of the
formula R-CN or an amide of the formula R-CONH2, where R is as defined above,
sequentially with a trialkyloxonium fluoroborate and with a Cl 3 monoalkyl-
amine, or (B) reacting a nitrile of the formula R-CN with an alkylamine of
the formula R-NH2 and an ammonium ion of the formula R"-NH3~, wherein R, R',
and R" are as defined above.
The compounds of the invention are generally crystalline solids at
ordinary temperatures, and are variously soluble in conventional solvents -
such as water, alcohols, ether, benzene, or chlorinated hydrocarbons. The
free base compounds are generally less soluble in water than the salts,
,
.
,~
t ~ -1-
, --"
1039;~08
particularly under alkaline conditions, while the
pharmaceutically-acceptable salts are generally
of moderate to good solubility in water and alcohols.
In the present specification and claims,
the term "halo" is employed to designate one of
the halogen moieties chloro or bromo.
For convenience, the compounds can be
referred to generically as "substituted amidines".
When R' and R" are different, the amidine moiety is
subject to tautomerization, e.g.
NR' ~,_ NHR'
--C
~HR" ~ ~R"
and the compound will generally be obtained as a
mixture of the tautomers. Such mixtures of tautomers
are useful as described herein, and for convenience will -
be named by naming only one tautomeric form. Compounds
wherein R' and R" are identical are generally preferrea.
The term "pharmaceutically-acceptable salt" as herein
; 20 employed refers to salts of a substituted amidine which
are substantially non-toxic at dosages consistent with
good pharmacological activity. Such pharmaceutically-
acceptable salts include nontoxic acid addition salts
with inorganic acids such as hydrochloric, hydrobromic,
- 25 sulfuric or phosphoric acid, or with organic acids such
as acetic, succinic, malic, maleic, tartaric or citric
acid, or with organic sulfonic acids such as methane-
sulfonic or p-toluenesulfonic acid.
The substituted amidines of the invention
have been found to be useful for administration to
17,412A-F -2-
` 10393Q8
laboratory animals in the study of drug effects on
the central nervous system, and have been found to
be particularly useful as antidepressants and anti-
anxiety or calmative agents. The compounds wherein
xl and X3 are chloro and x2 and X4 are hydrogen or
chloro have excellent antidepressant activity as well
as calmative activity, and are preferred compounds.
The substituted amidines of the invention
can be prepared by the reaction of the corresponding
sub~tituted phenylacetonitrile or benzonitrile with
a trialkyloxonium fluoroborate to prepare the cor-
responding N-alkyl substituted arylnitrilium fluo-
roborate salt; followed by the reaction of the N-
-alkyl substituted arylnitrilium fluoroborate with
a primary alkylamine. Alternatively, the substituted
; amidines of the invention can be prepared by the
reaction of the corresponding N-alkyl-phenylaceta-
mide or N-alkylbenzamide with a trialkyloxonium fluoro-
borate to prepare the corresponding N-alkyl acetimi-
date salt; followed by the reaction of the N-alkyl --
acetimidate fluoroborate with a primary alkylamine.
.
m ese reactions are preferably carried out
in the presence of an inert organic liquid such as
methylene chloride or nitromethane. -
In the preparation of the fluoroborate salt
intermediates, the reaction proceeds when the nitrile
or N-alkyl amide starting material and the trialkyl-
oxonium fluoroborate are contacted and mixed in the
presence of an anhydrous organic liquid reaction
medium. The mixing is carried out in dry reaction
17,412~-P -3-
1039308
.
vessels under an inert gas blanket. The reaction
proceeds at temperature~ from about 0C to about
boiling under reflux, and is conveniently carried
out at temperatures from 25C to 50C. The exact
proportions of the reactants to be employed can be
varied. However, it is convenient to employ from
l to 3 molar proportions of the trialkyloxonium
fluoroborate reactant for each molar proportion of
nitrile or amide starting material. The reaction
is generally complete within 12 to 72 hours depending --
on temperature employed. The intermediate salt can
be separated by evaporation of the reaction medium,
if desired, or it can be reacted with the primary
alkylamine without separation. Preferably, the flu-
lS oroborate salt intermediate is not separated from
the reaction mixture, but is reacted directly with
a primary alkylamine to prepare a substituted ami-
-~ dine product.
The reaction of the fluoroborate salt in- - -
termediate with the primary alkylamine proceeds when
the reactants are contacted and mixed in the presence
of an inert organic liquid reaction medium, such as
nitromethane or methylene chloride. The reaction
proceeds at temperatures of from -70C to 30C. The
exact proportions of the reactants to be employed
can be varied; however, the reaction consumes the
reactants in equimolar proportions, and use of the
reactants in such proportions or with an excess of
the primary alkylamine reactant is preferred. The
reaction is generally complete in one to 18 hours.
17,412A-P -4-
1039308
.,:
The product can be separated by evaporation under
reduced pressure followed by the addition o aqueous
alkali to neutralize any remaining fluoroborate,
followed by extraction with an organic solvent such
as ethyl acetate. Alternatively, the product can
be isolated directly as the fluoroborate salt by
evaporation of the reaction medium and washing with
water. The product can be purified by conventional
procedures such as washing, recrystallization,
extraction, or treatment on ion exchange resins.
The free base product can also be purified by con-
version to a pharmaceutically-acceptable salt and
purification in the salt form. When the product
is obtained as the fluoroborate salt, it can be
conveniently neutralized to obtain the free base
which can be purified or converted to a pharmaceu-
tically-acceptable salt.
The foregoing procedure includes a number
of disadvantages. It requires a two-step process; -
it requires an expensive and somewhat esoteric start- -
ing material, the trialkyloxonium fluoroborate salt; --
and the reactior. requires anhydrous conditions and
an inert gas blanket.
In addition, the yields of ultimate product
have been found to be undesirably low - on the order
of 30 to 40 per cent. Accordingly, the invention
also provides a novel method for preparing the ami-
dines by a one-step procedure using relatively in-
expensive reactants, which can produce the product
17,~12A-P -5-
, 1039308
in a desirable form in good yields and without requiring an inert g~s to pro-
tect the reactants.
In the new procedure, the substituted acetamidines are produced
; by (A) reacting a nitrile of the formula R-CN or an amide of the formula
R-CONH2, where R is as defined above, sequentially with a trialkyloxonium
fluoroborate and with a Cl 3 monoalkylamine, or (B) reacting a nitrile of
the formula R-CN with an alkylamine of the formula R'-NH2 and ammonium ion
of the formula R"-NH3~ , wherein R, R', and R" are as defined above.
me structure of the amidine portion of the product in the
above formula can also be written as
. .
~ NHR'
-C ~ A
NHR"
.
The reaction proceeds when the reactants are contacted and mixed, at a
temperature in the range from 130C to 180C and under superatmospheric
...
:i pressure. In a convenient procedure, the primary ammonium ion is convenient-
ly supplied by using a primary ammonium salt, the anion of which (A in the
above formula) is not detrimentally reactive with the other reactants.
Suitable anions include inorganic anions, chloride, bromide, iodide, fluoride,
sulfate, carbonate and organic anions such as toluenesulfanate, acetate,
formate, etc., preferably a pharmaceutically-acceptable salt such as the
chloride or bromide.
r~
~039308
The proportions of reactants to be employed
can be varied considerably; however, it is critical
to employ an excess of the alkylamine. When a portion
of alkylamine is employed as a salt, at least one
molar proportion of the salt for each molar proportion
of the nitrile starting material must be used so
as to provide sufficient of the anion to obtain the
product as a salt. In general, good results can
be obtained by using, for each molar proportion of
the nitrile, from one to ten molar proportions of
alkylamine salt; and from 20 to 40 molar proportions
of alkylamine (free base). A lower alkanol and excess
alkylamine can also serve as a reaction medium, and
the maximum proportions to be employed are limited `
by factors such as convenience of separating the
product from the medium and increased reaction time
and energy requirements as the excess of reaction
medium is increased.
In a convenient procedure, 20 to 40 molar -
proportions alkylamine, one to ten molar proportions
of alkylamine salt, and 20 to 100 molar proportions -
of a lower alkanol of 1 to 3 carbon atoms are employed
per molar proportion of the nitrile. The materials
are mixed together in a sealed reactor; such as a
~ 25 bomb, and heated at a temperature of 130 to 180C
- under a pressure of 15 to 30 atmospheres until the
reaction is substantially complete, generally from
12 to 20 hours. Substantially anhydrous conditions
are preferably maintained during this procedure.
The product can be separated by conventional procedures
17,412A-F _7_
. , ~
9308
such as evaporation or distillation to remove excess
medium and low boiling starting materials. It can
be purified by conventional procedures, such as
liquid-liquid extraction, washing, recrystallization
and the like, and can be conveniently converted to
the free base, purified in that form then converted
to a pharmaceutically-acceptable salt for further
purification.
The pharmaceutically-acceptable salts of
the free base substituted amidines can be prepared
by dissolving the free base in a minimal amount of
alcohol, ether, or chloroform and adding an alcohol
solution of an acid such as hydrochloric acid, hy-
drobromic acid, malic acid, maleic acid, p-toluene-
sulfonic acid, or succinic acid until precipitation
of the corresponding salt is complete. The salt
can further be purified by recrystallization or
converted to the free base form.
The free base substituted amidine can be
prepared by hydrolysis of the salt in aqueous base.
m e salt is mixed with a molar equivalent amount of
sodium hydroxide in aqueous solution, excess aqueous
sodium carbonate or the like, after which the free
base can be separated by extraction with an organic
solvent. The solvent can be removed by conventional
methods such as evaporation or distillation. The
product can be purified by conventional procedures
such as washing or recrystallization.
The following examples illustrate the in-
vention.
17,41~A-P -8-
: i03930~
Example 1
21 Grams (0.1 mole) of triethyloxonium
fluoroborate is dissolved in 150 milliliters of
anhydrous methylene chloride and 18.6 grams (0.1
mole) of 3,4-dichlorophenylacetonitrile are added.
All glassware employed has been previously dried -
at 125C and held in a desiccator prior to use.
The addition is carried out under dry nitrogen.
The resulting mixture is heated with stirring for
about 72 hours at a temperature of 35-45C under -~
dry nitrogen. The reaction mixture, containing the ~ -
resulting N-ethyl-3,4-dichlorophenylacetonitrilium
fluoroborate intermediate, is cooled to a temperature
of -70C in a dry ice-acetone bath, and 10 grams
,;,, -; .
(0.22 mole) of dry monoethylamine is added. The
resulting mixture is allowed to warm to room temper-
ature (about 25C) and is held for about 18 hours
at room temperature with stirring. The mixture is
~~ concentrated by evaporation under reduced pressure,
and the residue is taken up in a minimal amount of
water, and made strongly basic by addition of excess
aqueous 20 percent sodium hydroxide solution. The
basic solution is extracted with an approximately
equal volume of ethyl acetate, and the ethyl acetate -
extract is dried over anhydrous magnesium sulfate.
The ethyl acetate solution of the free base 2-(3,4-
-dichlorophenyl)-N,N'-diethylacetamidine is saturated
with dry hydrogen chloride gas, whereupon the product
precipitates in the form of the hydrochloride salt.
The mixture is cooled to about 5C and filtered to
,, .
17,412A-P _g_
~0393~8
.
obtain the hydrochloride salt as a filter cake.
- A second crop of the 2-(3,4-dichlorophenyl)-N,N'-
-diethylacetamidine hydrochloride is obtained by
evaporation of the filtrate, taking the residue up
in acetone, and filtering the acetone mixture. The
combined product is recrystallized from a mixture
of acetone and isopropanol and found to melt at
230-232C. The product is found by elemental ana-
lysis to have carbon and hydrogen contents of 48.79
and 5.85 percent, respectively, as compared to the
theoretical contents of 48.75 and 5.80 percent, re-
,4 spectively. The structure of the named product is
confirmed by infrared spectroscopy and nuclear mag-
netic resonance analysis.
In a similar procedure, the following are
prepared: N,N'-dimethyl-2-(3,4-dibromophenyl)aceta-
- midine hydrochloride, 2-(3-chloro-4-bromo-phenyl)-
-N,N'-diethylacetamidine hydrobromide, and 2-(3,4-
-dibromophenyl)-N,N'dipropylacetamidine hydrobromide.
.
. ~ -10-
,~
: 103931~8
,
Example 2
Using glass vessels dried at 125C. before
; use, N-methyl-2-(4-chlorophenyl)acetamide (18.4 grams;
0.1 mole) is dispersed in a mixture of 150 milliliters
of methylene chloride and triethyloxonium fluoro-
borate (19 grams; 0.1 mole). The reaction mixture
is stirred at room temperature for 72 hours, then
` cooled in an acetone-dry ice bath while monomethyl-
amine (10 grams; 0.33 mole) is added. The mixture
i8 then stirred an additional 18 hours at room tem-
perature. During the foregoing additions and mixing
of reactants, the mixture is maintained under a dry
nitrogen blanket. The reaction mixture is then con-
centrated under vacuum, and the residue is suspended
in water, made strongly alkaline by addition of
cold aqueous 20 percent sodium hydroxide, and extracted
:',
, ,'~ ~,
v ~ ~s ~, --1 1--
. .
~J
39308
with ethyl acetate. The organic phase is separated
and dried over anhydrous sodium sulfate. Excess
dry gaseous hydrogen chloride is introduced into
the mixture, and the resulting mixture is evaporated
under reduced pressure, residual oil is taken up
in methyl ethyl ketone, filtered and the filtrate
evaporated. The product is obtained as a residue
which is recrystallized from isopropanol. The 2-(4-
-chlorophenyl)- N,N'-dimethylacetamidine hydrochloride
is obtained in a yield of 4 grams, corresponding
to a 17.1 percent yield based on the acetamide start-
ing material. The product is found to melt at
242.5-243.5C. ~nfrared and nuclear magnetic re-
sonance analyses also confirm the named structure.
Example 3
1.15 Mole of anhydrous methylamine is
dissolvéd in 100 millilite~s of anhydrous metha-
nol, and 0.05 mole of 2-(4-chlorophenyl)acetoni-
trile and 0.1 mole of methylamine hydrochloride
are added. The resulting mixture is placed in a
300-milliliter bomb and heated for 15 hours at
140C. The pressure in the bomb during this reaction
period is about 300 pounds per square inch gauge,
about 21.4 atmospheres or 16274 millimeters of mer-
cury absolute. The mixture is allowed to return
to room temperature and pressure, then evaporated
to dryness under reduced pressure. The residue is
taken up in a mixture of 100 milliliters of chloroform
and 100 milliliters of cold (0C) aqueous 10 percent
godiurn hydroxide. The organic layer is washed with
., ~ ,
17,412~-~ -12-
~0393~)8
three 100-milliliter portions of aqueous sodium chloride, dried over anhydrous
sodium sulfate and evaporated to dryness in vacuo. The residue is taken up
in a minimal amount of chloroform and an ether solution of hydrogen chloride
is added whereupon, the product precipitates in the form of the hydrochloride
salt. The mixture is filtered to obtain the hydrochloride salt product as a
filter cake, and dried in vacuo at room temperature to obtain the N,N'-
dimethyl-2-(4-chlorophenyl)acetamidine hydrochloride. Recrystallized from
2-propanol, mp 242.5-243.5C.
In a procedure similar to that of Examples 1-4 the following com-
pounds of the invention are prepared: N,N'-Diethyl-2-(4-bromophenyl)acet-
amidine hydrochloride, melting at 173-174C (recrystallized from isopropanol);
N,N'-Diisopropyl-2-(3-bromophenyl)acetamidine hydrochloride; N,N'-Dimethyl-2-
(3,4-dichlorophenyl)acetamidine hydrochloride; N,N'-Di-n-propyl-2-(4-chloro-
phenyl)acetamidine hydrochloride.
In a procedure similar to that of Example 2 the following are
prepared: N,N'-Dimethyl-4-chlorobenzamidine hydrochloride, melting at 285-
286C (recrystallized from isopropanol); N,N'-Diisopropyl-3,4-dibrobenz-
amidine hydrochloride; N,N'-Dimethyl-3,4-dichlorobenzamidine hydrochloride, -
melting at 320 -321C (recrystallized from isopropanol); N,N'-Di-n-propyl-4-
chlorobenzamidine (free base) melting at 97-98C (recrystallized from
; hexane).
~ ~ -13-
, . . .
,, , , ,, ,,, , "
:, 1039308
- 15 The substituted amidines of the invention
have pharmacological activity in alleviating central
nervous system depression and in alleviating symp-
toms of anxiety or nervous agitation. Thus, they
can be administered to mammals by conventional routes
such as orally or by intraperitoneal, intramuscular
or intravenous injection to alleviate central nervous
system depression or anxiety symptoms. A particular
advantage of the compounds is that they exhibit little
or no effect on the cardiovascular system other than
antithrombi~ic activity at dosages consistent with
good central nervous system activity. The compounds
can be formulated with conventional pharmaceutical
excipients to facilitate administration. As with
- most known pharmacologically active compounds, the
substituted amidines vary somewhat in activity, and
" .
~ . . . . . .
-14-
.
.
1039308
the amount of compound to be employed in a given
situation will depend on such factors as the exact
compound or pharmaceutically-acceptable salt employed,
the route of administration, the animal treated, the
formulation employed, etc.
N,N'-Dimethyl-3,4-dichlorobenzamidine
hydrochloride is found to protect mice against central
nervous system depression and ptosis resulting from
intraperitoneal injection of reserpine at a dosage
rate of 2.5 milligrams reserpine, per kilogram of -
body weight. The compound is found to have an in-
traperitoneal ED50 f 9.3 milligrams per kilogram
(mg/kg). Its intraperitoneal acute LD50 is found
to be 60 mg/kg and its oral acute LD50 is found to
- lS be 200 mg/kg. When administered orally, the ED50
is found to be 10.8 mg/kg for the same compound in
the same procedure with mice, and 9.1 mg/kg in a
similar procedure with rats. The compound is also
found to potentiate hyperactivity, fighting and death
resulting from subcutaneous administration of 20
mg/kg of yohimbine hydrochloride to mice aggregated
in small cages. In these operations, the compound
is administered by intraperitoneal injection 30
minute~ before the yohimbine challenge, and is found
to potentiate lethality with an ED50 of 2.4 mg/kg,
indicating potent antidepressant action. In similar
operations, N,N'-dimethyl-4-chlorobenzamidine hydrochloride
''
is found to antagonize reserpine induced ptosis in
mice with an oral ED50 of 6.2 mg/kg, and an oral
- A
. , ,
17,412A-F -~-
,
`- 1039308
LD50 of 200 mg/kg. The test compound N,N'-dipropyl-
-3,4-dibromobenzamidine is found to inhibit reserpine
induced ptosis when administered intraperitoneally
at 30 mg/kg.
In other operations, N,N'-dimethyl-4-chloro-
benzamidine hydrochloride is tested to evaluate its
effect on behavior of mice trained to avoid a mild
electric shock administered through the cage floor
by jumping to an insulated platform. Intraperitoneal
administration of 4, 10, and 21.5 mg/kg of the test
compound is found to have no significant effect
on the learned shock-avoidance behavior.
N,N'-Dimethyl-2-(4-chlorophenyl)acetamidine
hydrochloride is found to protect mice against central
- 15 nervous system depression and ptosis resulting from
; intraperitoneal injection of reserpine at a dosage
rate of 2.5 milligrams reserpine, per kilogram of
body weight. The test compound is found to have
an intraperitoneal ED50 of 2 milligrams per kilogram,
about one thirty-fifth its intraperitoneal acute
LD50 and about one two hundred-fifteenth its oral
acute LD50. When administered orally, the ED50
- is found to be 3 mg/kg for the same compound in the
~` same procedure with mice, and 2 mg/kg in a similar
procedure with rats. The compound is also found
to potentiate hyperactivity, fighting and death -~
resulting from subcutaneous administration of 20 ,
mg/kg of yohimbine hydrochloride to mice aggregated
in small cages. In these operations, the test com-
pound is administered by intraperitoneal injection
,~
~ 6
17,412A-F
1039308
30 minutes before the yohimbine challenge, and is
found to potentiate lethality with an ED50 of 15
mg/kg, indicating potent antidepressant action. N,N'-
-Diethyl-2-(3,4-dichlorophenyl)acetamidine hydro-
chloride is found to antagonize reserpine induced
ptosis in mice with an intraperitoneal ED50 f 3
mg/kg, and an oral ED50 of 7 mg/kg. N,N'-Diethyl-
-2-(4-bromophenyl)acetamidine hydrochloride and N,N'-
-diethyl-2-(3-trifluoromethylphenyl) hydrochloride
are also found to inhibit reserpine induced ptosis.
N,N'-Dimethyl-2-(4-chlorophenyl)acetamidine ~
; hydrochloride is tested to evaluate its effect on --
- behavior of mice trained to avoid a mild electric
shock administered through the cage floor by jumping
to an insulated platform. Intraperitoneal admini-
~ stration of 10, 21.5 and 46 mg/kg of the test compound -;
;; is found to have no significant effect on the learned
shock-avoidance behavior. Calmative or anxiolytic
activity is evaluated in a similar test in which
- 20 two mice are combined in a small glass cage and
subjected to mild electric shock through the cage
floor. In this procedure, untreated mice exhibit
aggression and fighting. N,N'-Dimethyl-2-(4-chloro-
phenyl)acetamidine hydrochloride is found to inhibit
the electroshock-induced aggression with an intra-
peritoneal ED50 of 43 mg/kg, when admînistered 30
; minutes before the test.
,, /,, ~
~ l7
17,412A-P _ ~_
