[0001] In U.S. Patent No. 3,961,056, certain benzyl derivatives of guanidine are described
as having anti- arrhythmic and diuretic uses. However, no benzhydryl derivatives of
guanidine are described.
[0002] This invention relates to benzhydryl guanidine derivatives having the formula
wherein:
R, is a member selected from the group consisting of hydrogen and loweralkyl, preferably
methyl and ethyl;
R2 is a member selected from the group consisting of hydrogen and loweralkyl, preferably
methyl and ethyl;
R3 is a member selected from the group consisting of hydrogen, loweralkyl, preferably
methyl and ethyl, and cycloalkyl, preferably cyclopentyl and cyclohexyl;
taken together may represent a member selected from the group consisting of
and Y and Z are each a member selected from the group consisting of hydrogen, halo,
loweralkyl, preferably methyl, and loweralkyloxy, preferably methoxy and ethoxy.
[0003] The novel benzhydryl guanidine derivatives of Formula (I) as free bases are generally
soluble in many common polar and non-polar organic solvents such as aromatic hydrocarbons,
e.g., benzene or toluene; haloaromatic hydrocarbons, e.g., chlorobenzene or 1,2-dichlorobenzene;
haloaliphatic hydrocarbons, e.g., chloroform, methylene dichloride or 1,2-dichloroethane;
lower alkanols, e.g., methanol, isopropanol or t-butanol; ethers, e.g., diethyl ether
or dioxane; and ketones, e.g., acetone or 2-butanone. They are preferably obtained
and employed in the form of their acid addition salts which are generally white crystalline
solids soluble in water and polar solvents such as the lower alkanols or ketones.
[0004] The non-toxic, therapeutically acceptable acid addition salts of the Formula (I)
compounds are also embraced within the scope of this invention. Suitable acids may
be inorganic acids such as hydrochloric, hydrobromic, hydroiodic, phosphoric and nitric
acids, or organic acids such as acetic, propionic, glycolic, pamoic, pyruvic, malonic,
succinic, maleic, fumaric, malic, tartaric, citric, benzoic, cinnamic, mandelic, methanesulfonic,
ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclohexanesulfamic, salicylic
and p-aminosalicylic acids. The preferred acid addition salts are the hydrohalic addition
salts.
[0005] As used herein, the term "loweralkyl" refers to a straight or branch chained hydrocarbon
radical having from 1 to 5 carbons, such as, for example, methyl, ethyl, propyl, isopropyl,
n-butyl, t-butyl, pentyl or isoamyl; and the term "halo" represents a halogen of atomic
weight less than 127, i.e., chloro, bromo, fluoro and iodo.
[0006] The compounds of Formula (I) are conveniently prepared by reacting a methylthio compound
of Formula (II), wherein R,, Y and Z are as previously defined, in acid addition salt
(HX) form with an appropriate amine of Formula (III), wherein R
2, R
3 and -NR
2R
3 are as previously defined, preferably utilizing a stoichiometric excess of (III),
in a lower alkanol solvent such as isopropanol and t-butanol and generally at reflux
temperatures to yield the benzhydryl guanidine compounds of Formula (I) in acid addition
salt form which are readily transformed into the corresponding base form by conventional
treatment with suitable alkali. Alternatively, the reaction of (II) with (111) may
be performed utilizing approximately equimolar amounts in which case up to an equimolar
amount of a suitable tertiary amine, such as, for example, triethylamine or tripropylamine,
is preferably added in order to enhance the rate of reaction. The foregoing reaction
may be illustrated as follows:
[0007] The precursors of Formula (II) are obtainable by methods reported in the literature.
For example, the compound wherein Y, Z and R, all equal hydrogen may be prepared according
to S. O. Winthrop et a/., J. Am. Chem. Soc., 79, 3496 (1957), which describes the
reaction of benzhydryl amine, preferably as the hydrochloride salt, with ammonium
thiocyanate to yield N-benzhydryl thiourea which is then methylated by standard S-methylation
techniques to yield methyl N-benzhydrylcarbamimidothioate as an acid addition salt.
[0008] Alternatively, the precursors of Formula (II) may be prepared by the following synthetic
sequence. The benzhydrylamines of Formula (IV), which compounds and methods of preparing
same are known in the literature, are transformed into the corresponding benzhydryl
isothiocyanates of Formula (V) according to the method described by J. C. Jochims
et al., Angew. Chem. Internat. Ed., 6 (2), 174 (1967), which method involves the interaction
of (IV) with excess carbon disulfide in the presence of an equimolar amount of dicyclohexylcarbodiimide
(DCC) at initial temperatures preferably below 0°C in anhydrous ether.
[0009] The resultant benzhydryl isothiocyanate (V), which may be isolated from the reaction
mixture and purified by conventional means, is then converted to the corresponding
N-benzhydrylthiourea of Formula (VI) by the reactions of (V) with ammonia or a primary
amine of the formula, R,NH
2, wherein R, is a substituent as previously defined, preferably in an ethereal solvent
such as, for example, diethyl ether, tetrahydrofuran (THF), dioxane or 1,2-dimethoxyethane
at about 0°C to ambient temperature.
[0010] The thus-obtained N-benzhydrylthiourea (VI), which may be isolated from the reaction
mixture and purified by conventional techniques, is then subjected to S-methylation
according to methods reported in the literature for the conversion of thioureas to
S-methyl-pseudothioureas, e.g., see Winthrop et al., loc. cit., which utilize methyl
iodide and methyl chloride as the methylating agent. Other methylating agents which
may be employed include methyl mesylate, methyl tosylate and methyl fluorosulfonate.
The preferred methylating agent is methyl iodide. In general, the S-methylated product
(II) is obtained in the form of an acid addition salt (HX).
[0012] Typical benzhydryl guanidine derivatives of Formula (I) which may be prepared according
to the synthetic procedures described herein by using appropriate precursors are:
N-(4,4'-dichlorobenzhydryl)-4-thiamorpholinecarboximidamide;
N-(4,4'-dichlorobenzhydryl)-N',N'-diethylguanidine;
N-(4-chlorobenzhydryl)-N'-cyclohexyl-N'-methylguanidine;
N-(4-chlorobenzhydryl)-N'-ethyl-N',N"-dimethylguanidine;
N-(4,4'-diethoxybenzhydryl)-N'-ethyl-1-piperidinecarboximidamide;
N-(4,4'-diethoxybenzhydryi)-N'-ethyt-1-pyrroiidinecarboximidamide;
N-(4,4'-dimethoxybenzhydryl)-N'-cyclopentyl-N'-methylguanidine;
N-(4,4'-dimethoxybenzhydryl)-4-morpholinecarboximidamide;
N-(4,4'-dimethoxybenzhydryl)-1-(4-phenylpiperazine) carboximidamide;
N-(4,4'-dibromobenzhydryl)-1-piperidinecarboximidamide;
N-(3-bromobenzhydryl)-4-thiamorpholinecarboximidamide;
N-(3-bromobenzhydryl)-N'-methyl-4-thiamorpholinecarboximidamide;
N-(4-chlorobenzhydryl)-1-(4-methylpiperazine)carboximidamide;
N-(4-chlorobenzhydryl)-N'-cyclohexyl-N'-methylguanidine;
N-(4,4'-diethoxybenzhydryl)-N',N'-diethylguanidine;
N-(4,4'-diethoxybenzhydryl)-1-pyrrolidinecarboximidamide;
N-(4,4'-dimethylbenzhydryl)-4-morpholinecarboximidamide;
N-(4,4'-dimethylbenzhydryl)-N',N'-diethylguanidine;
N-(4-methylbenzhydryl)-N'-cyclohexyl-N'-methylguanidine;
N-(4-methylbenzhydryl)-N'-ethyl-N'-methylguanidine;
N-(4-methoxybenzhydryl)-N'-cyclopentyl-N'-methylguanidine;
N-(4-methoxybenzhydryl)-1-pyrrolidinecarboximidamide; and
N-(4-methoxybenzhydryl)-4-morpholinecarboximidamide.
[0013] In view of their structure, the compounds of Formula (I) are inherently capable of
existing in tautometric forms (I-a) and (I-b):
[0014] Furthermore, when the benzhydryl substituents Y and Z are non-identical or in different
positions on their respective phenyl rings, it is evident that optical isomeric forms
(d- and I-) of the Formula (I) products are possible. For example, by utilizing an
appropriate resolved (d- or I-) benzhydrylamine of Formula (IV) as a precursor in
the synthetic sequence previously described, the final Formula (I) product thus-obtained
will similarly be a d- or I-optical isomer.
[0015] In the following examples, the terms "benzhydryl" and "diphenylmethyl" are equivalent.
Furthermore, the terms "guanidine" and "N-carboximidamide" are utilized as dictated
for purposes of clarity according to the structure of the particular compound of Formula
(I) under consideration.
[0016] The compounds represented by Formula (I) and the acid addition salts thereof are
useful as hypoglycemic agents suitable for lowering blood sugar. This property may
be demonstrated by the rat glucose tolerance test, an extremely sensitive standard
procedure used in the diagnosis of diabetes and hypoglycemic disease states.
[0017] In this test, male Sprague-Dawley rats (Charles River 184-250 grams) are given water
ad libitum and fasted 24 hours prior to the experiment. Two to five rats are used
for each test and control group. Test compounds, 0.5-100 mg/kg., are administered
(s.c., i.p. or orally) suspended in 0.5 or 1.0 milliliter, but preferably the former,
of 0.5-1.0% methylcellulose vehicle. Control animals are given an equal amount of
vehicle. Serial blood samples (0.1 milliliter) are obtained from the tail without
anesthesia prior to and at 30, 60, 90, 120, 150 and 180 minutes after administration
of 0.8 to 1.0 gram of glucose per kilogram of body weight in 1 milliliter of water.
(The glucose is given orally if the test compound has been given parenterally, and
subcutaneously if the test compound has been given orally.) Specimens of blood are
immediately deproteinized with aqueous solutions of Ba(OH)
2 and ZnS0
4 and glucose levels are determined using the glucose oxidase assay described by L.
P. Cawley et al., "Ultra Micro Chemical Analysis of Blood Glucose with Glucose Oxidase",
Amer. J. Clin. Path., 32, 195 (1959). The blood glucose values at each time point
are expressed in terms of milligram percent (mg. glucose/100 ml. of blood). The mean
glucose values of the controls are compared statistically by the Student's t-Test
to the means of the experimental group at each of the corresponding time points. If
the compound lowers the blood glucose significantly at any time at a 95% confidence
limit, the compound is considered to have hypoglycemic activity. The blood glucose
lowering, expressed as percent lowering, is obtained by dividing the difference between
the mean blood glucose values for test and control animals by the mean glucose value
for the control animal.
[0018] For reducing blood glucose, the compounds of Formula (I) may be employed at a dosage
range of about 0.5-100 mg./kg. body weight. It has been found, for example, that administration
of the most preferred compounds, the acid addition salts of N-benzhydryl-1-pyrrolidinecarboximidamide
or N-benzhydryl-4-morpholinecarboximidamide, at 1-10 mg./kg. body weight p.o. provides
a marked lowering of blood sugar in test animals.
[0019] In view of the aforementioned hypoglycemic activity of the Formula (I) compounds
and salts thereof, this invention provides valuable pharmaceutical compositions comprising
the said compounds as the active hypoglycemic ingredient in admixture with a pharmaceutical
carrier.
[0020] To prepare the pharmaceutical compositions of this invention, a benzhydryl guanidine
of Formula (1) or acid addition salt thereof, as the active hypoglycemic ingredient,
is intimately admixed with a pharmaceutical carrier according to conventional pharmaceutical
compounding techniques, which carrier may take a wide variety of forms depending on
the form of preparation desired for administration, e.g., oral or parenteral. In preparing
the compositions in oral dosage form, any of the usual pharmaceutical media may be
employed: Thus, for liquid oral preparations, such as, for example, suspensions, elixirs
and solutions, suitable carriers and additives include water, glycols, oils, alcohols,
flavoring agents, preservatives and coloring agents; for solid oral preparations such
as, for example, powders, capsules and tablets, suitable carriers and additives include
starches, sugars, diluents, granulating agents, lubricants, binders and disintegrating
agents. Because of their ease in administration, tablets and capsules represent the
most advantageous oral dosage unit form, in which case solid pharmaceutical carriers
are obviously employed. If desired, tablets may be sugar coated or enteric coated
by standard techniques. For parenterals, the carrier will usually comprise sterile
water, though other ingredients, for example, for purposes such as aiding solubility
or for preservation, may be included. Injectable suspensions may also be prepared,
in which case appropriate liquid carriers and suspending agents may be employed. The
pharmaceutical compositions herein will contain, per dosage unit, e.g., tablet, capsule,
powder, injection or teaspoonful, from about 10 to about 500 mg. of the active ingredient,
and, preferably, from about 10 to about 250 mg.
[0021] Following are specific examples of compounds of Formula (I) which can be compounded
into pharmaceutical compositions and used within the scope of this invention. These
examples are not intended to be limitations upon the broad scope of the invention
but merely illustrative.
Example I
A. N-Diphenylmethyl-1-pyrrolidinecarboximidamide Hydroiodide:
[0022] To 76.86 g (0.2 mole) of methyl N-(diphenylmethyl)-carbamidothioate hydroiodide in
t-BuOH (120 ml) is added 28.44 g (0.4 mole) of pyrrolidine. The resulting mixture
is heated under reflux on the steam bath for 3-1/2 hours. The reaction mixture is
cooled to room temperature affording crystals of crude HI salt, mp. 200-203°C. Recrystallization
from tert.-BuOH gives pure N-diphenylmethyl-1-pyrrolidinecarboximidamide hydroiodide;
mp. 205-206°C.
B. N-Diphenylmethyl-1-pyrrolidinecarboximidamide Hydrochloride Hemihydrate:
[0023] Conversion of the HI salt of Example IA to the free base in CH
2CI
*2 by treatment with cold 20% NaOH; drying the organic layer over K
ZC0
3, filtration, and solvent removal in vacuo gives the free base.
[0024] Treatment of the free base in moist isopropanol with HCI gas furnishes the crude
hydrochloride hemihydrate. The crystals are recrystallized from i-PrOH to give the
pure salt; N-diphenylmethyl-1-pyrrolidinecarboximidamide hydrochloride hemihydrate;
m.p. 230-233°C.
Example II
N-(Diphenylmethyl)-4-morpholinecarboximidamide:
[0025] 1-(Diphenylmethyl)-2-methyl-2-thiopseudourea hydroiodide (19.2 g, 0.05 mole) in 75
ml tert- butanol is heated at reflux for 24 hours with morpholine (8.7 g, 0.1 mole)
under a slow stream of nitrogen. The effluent gas is passed through sodium hypochlorite
and sodium hydroxide traps to remove the methyl mercaptan formed in the reaction.
The mixture was taken to dryness in vacuo and the residue was treated with 3N sodium
hydroxide. Extraction with methylene chloride, washing the combined extracts with
water, drying over potassium carbonate, filtration and solvent removal under reduced
pressure furnishes an oil which solidifies on standing. Recrystallization several
times from acetone-ether gives N-(diphenylmethyl)-4-morpholinecarboximidamide as a
white solid; mp. 122-124
0C.
Example III
N,N-Diethyl-N'-diphenylmethylguanidine Hydroiodide:
[0026] To a suspension of 9.61 g (0.025 mole) of methyl N-(diphenylmethyl)-carbamimidothioate
hydroiodide in 20 ml of t-BuOH is added 3.66 g (0.05 mole) of diethylamine. The mixture
is heated under reflux for twenty hours (trapping the methyl mercaptan formed in the
reaction with NaOH and NaOCI sol'n). About two additional mls of dimethyl amine is
added and refluxing is resumed for another 4 hours. The resulting white solid is filtered
from the cooled reaction mixture and washed with t-BuOH and ether to yield crude product
mp. 187-189°C. The pure product, N,N-diethyl-N'- diphenylmethylguanidine hydroiodide,
is isolated after one recrystallization from 1:1:1 MeOH/i-PrOH/t-BuOH as a white crystalline
solid, mp. 187-189°C.
Example IV
N-(Diphenylmethyl)-1-piperidinecarboximidamide :Monohydroiodide:
[0027] To a suspension of 9.61 g (0.025 mole) of methyl N-(diphenylmethyl)-carbamimidothioate
hydroiodide in 20 ml of t-BuOH is added 4.26 g (0.05 mole) of piperidine. The mixture
is heated under reflux overnight. The resulting crystals after cooling in ice, are
filtered; mp. 200-213°C. One crystallization from methanol-t-BuOH yields the pure
product, N-(diphenylmethyl)-1-piperidinecarboximidamide monohydroiodide as a white
crystalline solid; mp. 207-210
0C.
Example V
N-(Diphenylmethyl)-1-(4-methylpiperazine)carboximidamide Monohydroiodide Hydrate:
[0028] To 8.84 g (0.023 mole) of methyl N-diphenylmethylcarbamidothioate hydroiodide in
t-BuOH is added 4.71 g (0.047 mole) of N-methylpiperazine. The resultant mixture is
allowed to heat under reflux overnight. The mixture is evaporated to dryness in vacuo
then diluted with i-PrOH to give crystals; mp. 200-204°C. The crystals are recrystallized
from 2-propanol affording pure product, N-(diphenylmethyl)-1-(4-methylpiperazine)carboximidamide
monohydroiodide hydrate; mp. 202-204°C.
Example VI
A. p-Chlorobenzhydryl lsothiocyanate:
[0029] A mixture of 80 ml of carbon disulfide and 39.82 g (0.193 mole) of dicyclohexylcarbodiimide
in 100 ml of anhydrous ether, under dry N
2, is cooled with stirring to -35°C. Then 42.23 g (0.194 mole) of p-chlorobenzhydrylamine
in 500 ml of dry ether is added over about 5 min such that the temperature within
the reaction vessel does not rise above -20°C. The temperature is allowed to rise
slowly over 3 hrs. to ca. 25°C and stirring is continued overnight. Dicyclohexylthiourea
was removed by filtration and the filtrate is taken to dryness in vacuo. The cloudy
oil is treated with 500 ml of pentane which dissolves the product and precipitates
more insoluble impurities. Filtration through filter aid (diatomaceous earth) and
solvent removal in vacuo gives p-chlorobenzhydryl isothiocyanate as an oil; IR (neat)
2140 cm
-1.
B. N-(4-Chlorobenzhydryl)thiourea:
[0030] A solution of 4-chlorobenzhydryl isothiocyanate (5.2 g, 0.02M) in 50 ml of dry ether
at 0°C is treated with NH
3 (anhyd.) for 1/2 hour while maintaining a temperature of 0.2 with stirring. Stirring
is continued an additional 1.5 hours at 9 to 10°C during which time a white solid
appears. The crude thiourea is filtered and washed thoroughly with ether; mp. 173-175°C.
The filtrate is concentrated in vacuo to yield additional product. The combined crops
of N-(4-chlorobenzhydryl)thiourea are used in the next step without further purification.
C. Methyl N-(4-chlorobenzhydrylJcarbamimidothioate Hydroiodide:
[0031] A solution of 5.3 g (0.019 mole) of N-(4-chlorobenzhydryl)thiourea in 25 ml of methanol
is treated with 2.64 g (0.019 mole) of methyl iodide and allowed to stir at room temperature
overnight. The methanol is removed in vacuo to yield the crude pseudothiourea as an
oil. The oily methyl N-(4-chlorobenzhydryl)-carbamimidothioate hydroiodide is used
in the next step without further purification.
D. N-(4-Chlorobenzhydryll-1-pyrrolidinecarboximidamide Hydroiodide:
[0032] A mixture of 7.0 g (0.017 mole) of methyl N-(4-chlorobenzhydryl)carbamimidothioate
hydroiodide and 2.85 g (0.04 mole) of pyrrolidine in 20 ml of t-BuOH is heated at
reflux overnight. The t-BuOH is removed in vacuo and the crude guanidine hydroiodide
is crystallized from methanol-ether. The crude product is recrystallized from methanol-t-butanol
to yield pure N-(4-chlorobenzhydryl)-1-pyrrolidinecarboximidamide hydroiodide; mp.
218-220°C (dec.).
Example VII
N-Cyclopentyl N-methyl-N'-(diphenylmethylJguanidine:
[0033] To a suspension of 9.61 g (0.025 mole) of methyl N-(diphenylmethyl)carbamimidothioate
hydroiodide in 20 ml of t-BuOH is added 3.5 g (0.035 mole) of N-methylcyclopentylamine
and 4 ml of triethylamine. The mixture is then heated under reflux overnight. Upon
cooling, the crude guanidine hydroiodide forms as an oil that does not crystallize
under various conditions. The free base is liberated with 10% NaOH and extracted with
CH
2CI
2. The methylene chloride sol'n is dried (K
2CO
3) and concentrated to dryness in vacuo to yield 8.0 g of an oil. The free base crystallizes
from ether to give N-cyclopentyl-N-methyl-N'-(diphenylmethyl)guanidine; mp. 102-104°C.
Example VIII
N-Diphenylmethyl-4-phenyl-1-piperazinecarboximidamide Monohydroiodide Hemihydrate
[0034] A mixture of 6.38 g (0.017 mole) of N-benzhydryl-S-methyl-pseudothiourea monohydroiodide
and 5.81 g (0.034 mole) of N-phenylpiperazine in t-BuOH is heated under reflux overnight.
About 50 ml of moist 2-propanol is added and the mixture is then allowed to crystallize.
The crude guanidine melts at 119-128'C. Recrystallization from 1:2 MeOH/t-BuOH and
then from 2-pr
qpanol gives pure N-diphenylmethyl-4-phenyl-1-piperazinecarboximidamide monohydroiodide
hemihydrate; mp. (113-117) 208-210°C.
Example IX
A. N-Benzhydryl-N'-methylthiourea:
[0035] A solution of 13.50 g (0.06 mole) of benzhydrylisothiocyanate in ether is saturated
with anhydrous methylamine in an ice bath. The crystals are filtered to yield the
product, N-benzhydryl-N'- methylthiourea; mp. 152-154°C, which is sufficiently pure
for the next step.
B. Methyl N-Diphenylmethyl-N'-methylcarbamimidothioate Hydroiodide:
[0036] A suspension of 14.64 g (0.057 mole) of N-benzyl-N'-methylthiourea in methanol is
treated with 8.09 g (0.057 mole) of methyl iodide and stirred overnight. The solvent
is removed in vacuo and the residue dissolved in t-BuOH and 2-propanol. Cooling and
scratching yields methyl N-diphenylmethyl-N'-methylcarbamimidothioate hydroiodide;
mp. 170-173°C.
C. N-(Diphenylmethyl)-N'-methyl-1-pyrrolidinecarboximidamide Hydroiodide Hydrate:
[0037] A mixture of 20.81 g (0.052 mole) of the compound of Example IX B and 7.4 g (0.104
mole) of pyrrolidine in t-BuOH is heated at reflux overnight. Crystals started forming
after about two hours of heating. The mixture is filtered to yield crude guanidine;
mp. 200-205°C. Recrystallization from t-BuOH yields N-(diphenylmethyl)-N'-methyl-1-pyrrolidinecarboximidamide
hydroiodide hydrate; mp. 211.5-213.5°C.
Example X
A. 4-Methylbenzhydrylisothiocyanate:
[0038] A solution of 20.42 g (0.099 mole) of N,N-dicyclohexylcarbodiimide and 40 ml of carbon
disulfide in 50 ml of dry Et
2O at -40°C under N
2 is treated dropwise with stirring over a 5 min period (so that temperature does not
exceed -30°C) with a solution of 19.7 g (0.1 mole) of 4-methylbenzhydrylamine. The
temperature is allowed to rise slowly over 3 hours to ca. 25°C and stirring is continued
overnight. The insoluble dicyclohexylthiourea formed is filtered off and the filtrate
concentrated in vacuo to an oil. A second crop of the thiourea is obtained via trituration
of the crude isothiocyanate with hexane. 4-methylbenzhydrylisothiocyanate is obtained
as an oil; IR (neat) 2080 cm
-1.The material is of sufficient purity to use in the next step.
B. N-(4-Methylbenzhydryl)thiourea:
[0039] A solution of 22 g (0.092 mole) of 4-methylbenzhydrylisothiocyanate in 250 ml of
dry ether at 0°C is treated with anhydrous NH
3 for 3 hours while stirring. The mixture is stirred an additional 1.5 hours at 0 to
10°C during which time the crude product precipitates as a white solid. Filtration
and washing with Et
20 affords the product; mp. 167-168°C.
C. Methyl N-(4-Methylbenzhydryl)-carbamimidothioate Hydroiodide (and free baseJ:
[0040] A suspension of 16.5 g (0.064 mole) of N-(4-methylbenzhydryl)thiourea in 75 ml of
MeOH is treated with 9.08 g (0.064 mole) of methyl iodide and allowed to stir overnight
at room temperature. The reaction mixture is concentrated in vacuo to yield 26.5 g
(100%) of the crude product, which crystallizes. Recrystallization from t-BuOH affords
pure methyl N-(4-methylbenzhydryl)-carbamimidothioate hydroiodide; mp. 145-147°C.
[0041] The free base of the product is obtained by treatment of the salt with ammonium hydroxide.
Recrystallization of the free base from ether-hexane furnishes pure methyl N-(4-methylbenzhydryl)-carbamimidothioate;
mp. 130-132°C.
D. N-(4-Methylbenzhydryl)-1-pyrrolidinecarboximidamide Hydroiodide:
[0042] A mixture of 13.3 g (0.0334 mole) of methyl N-(4-methylbenzhydryl)carbamimidothioate
hydroiodide and 5.0 g (0.07 mole) of pyrrolidine in 40 ml of t-BuOH is heated under
reflux for 24 hrs. The crude product crystallizes out of the reaction mixture while
refluxing. The mixture is allowed to cool overnight at room temperature and filtered
to yield crude product; mp. 227-230°C. Recrystallization from MeOH/t-BuOH yields the
pure N-(4-methylbenzhydryl)-1-pyrrolidinecarboximidamide hydroiodide; mp. 229-230°C,
as a white solid.
Example XI
[0043] By repeating the amine-to-isothiocyanate procedure of Example VI-A or X-A, except
that an equivalent amount of an appropriate benzhydrylamine is employed, the following
benzhydryl- isothiocyanates of Formula (V) are:
4,4'-dichlorobenzhydrylisothiocyanate;
4,4'-diethoxybenzhydrylisothiocyanate;
4-methoxybenzhydrylisothiocyanate;
4,4'-dimethoxybenzhydrylisothiocyanate;
4,4'-dibromobenzhydrylisothiocyanate;
3-bromobenzhydrylisothiocyanate; and
4,4'-dimethylbenzhydrylisothiocyanate.
Example XII
[0044] The isothiocyanate-to-thiourea procedures of the applicable foregoing examples are
followed using appropriate starting materials to yield the following benzhydrylthioureas
of Formula (VI).
Example XIII
[0045] A solution of an appropriate benzhydrylthiourea of Formula (VI) is S-methylated with
an appropriate methylating agent (as indicated by the resultant HX salt below) to
furnish the following methyl N-benzhydryl-N'-R,-carbamimidothioates of Formula (II)
in the form of an acid addition (HX) salt:
Example XIV
[0046] By heating an appropriate methyl N-benzhydryl-N'-R
1-carbamimidothioate salt of Formula (II) with an appropriate R
2R
3NH amine of Formula (III) in the indicated molar ratios at reflux temperature in either
isopropanol or t-butanol according to the procedures previously described, the following
benzhydryl guanidine derivatives of Formula (I) are obtained in the form of the indicated
acid addition (HX) salt: