4-(1-imidazolylmethyl)cinnamic acid hydrochloride monohydrate and pharmaceutical compositions

4-(1-Imidazolylmethyl)cinnamic acid hydrochloride monohydrate of the formula: ##STR1## and pharmaceutical compositions containing such compound. The imidazole derivative above has a strong and specific inhibitory effect on thromboxane synthetase from human or bovine platelet microsomes, and is useful as a therapeutical agent for inflammation, hypertension, thrombus, cerebral apoplexy, and asthma.

BACKGROUND OF THE INVENTION 
1. Field of the Invention 
The present invention relates to novel imidazole derivative. More 
particularly, the present invention relates to 
4-(1-imidazolylmethyl)cinnamic acid hydrochloride monohydrate of the 
formula (I): 
##STR2## 
and to pharmaceutical compositions containing such compound. 
2. Description of the Prior Art 
It has been reported that 4-(1-imidazolylmethyl)cinnamic acid and its 
pharmaceutically acceptable salt possess a strong and specific inhibitory 
action for biosynthesis of thromboxane A.sub.2 and are useful for the 
treatment of diseases caused by thromboxane A.sub.2 such as inflammation, 
hypertension, thrombus, cerebral apoplexy, and asthma [U.S. Pat. No. 
4,226,878]. However the former compound, i.e. free compound, is 
amphosteric and is hard to be isolated and purified. The latter compound, 
i.e. salt compound, has highly hygroscopic property and the water 
contained in said compound varies depending upon moisture in atmosphere in 
which said compound is allowed to stand. Accordingly, a net weight of said 
compound tends to vary due to its hygroscopic property by absorbing 
moisture from atmosphere and taking into consideration that a 
pharmaceutical composition has always to contain an active agent at a 
prescribed ratio so as to achieve the expected effects and safety, said 
compound is not necessarily desirable for preparing pharmaceutical 
compositions. 
From an extensive research and experimentation, we found that such problem 
was absolutely solved by using the compound of the formula (I) above. That 
is, the compound of the formula (I) is non-hygroscopic and has a constant 
net weight without being affected by moisture contained in atmosphere. 
SUMMARY OF THE INVENTION 
Accordingly, an object of this invention is to provide a compound which 
exhibits a strong and specific inhibitory effect on thromboxane synthetase 
and which is therapeutically useful. 
Another object of this invention is to provide 
4-(1-imidazolylmethyl)cinnamic acid hydrochloride monohydrate having 
non-hygroscopic property. 
Yet another object of this invention is to provide pharmaceutical 
compositions comprising 4-(1-imidazolylmethyl)cinnamic acid hydrochloride 
monohydrate of the formula (I). 
A further object of this invention is to provide methods for the treatment 
of diseases such as inflammation, hypertension, thrombus, cerebral 
apoplexy, and asthma using 4-(1-imidazolylmethyl)cinnamic acid 
hydrochloride monohydrate of the formula (I). 
Other objects, features and advantages of this invention will become more 
apparent from the following description of the invention.

DETAILED DESCRIPTION OF THE INVENTION 
The present invention provides 4-(1-imidazolylmethyl)cinnamic acid 
hydrochloride monohydrate of the formula (I): 
##STR3## 
and the pharmaceutical compositions containing such compound. 
Specifically, the present invention relates to 
4-(1-imidazolylmethyl)cinnamic acid hydrochloride monohydrate having no 
inexpedient property in the preparation of pharmaceutical composition, 
such as hygroscopic property of 4-(1-imidazolylmethyl)cinnamic acid salt 
and having a strong and specific inhibitory effect on biosynthesis of 
thromboxane A.sub.2 in mammalia including human. 
That is, 4-(1-imidazolylmethyl)cinnamic acid hydrochloride monohydrate of 
the formula (I) has no hygroscopic property and is stable below about 
50.degree. C. under high or low humidity condition. Accordingly this 
compound has always a constant net weight without being affected by 
moisture contained in atmosphere and using 4-(1-imidazolylmethyl)cinnamic 
acid hydrochloride monohydrate, pharmaceutical compositions can easily be 
prepared and the obtained pharmaceutical compositions can be of high 
quality. Furthermore, 4-(1-imidazolylmethyl)cinnamic acid hydrochloride 
monohydrate possesses a specific and strong inhibitory effect 
substantially equal to 4-(1-imidazolylmethyl)cinnamic acid and its salt on 
biosynthesis of thromboxane A.sub.2. 
The term "aqueous organic solvent" as used in this invention means an 
organic solvent wherein water content is more than 5% (V/V%). 
4-(1-Imidazolylmethyl)cinnamic acid hydrochloride monohydrate of the 
formula (I) of this invention can easily be prepared by recrystallizing 
4-(1-imidazolylmethyl)cinnamic acid hydrochloride from an adequate 
recrystallization solvent. 
In this process, water and aqueous organic solvents can be employed as a 
recrystallization solvent. Examples of aqueous organic solvents include 
aqueous methanol, aqueous ethanol, aqueous propanol, aqueous acetone, 
aqueous methylethylketone, aqueous dioxane, etc. Preferred 
recrystallzation solvents are aqueous ethanol and aqueous acetone. Most 
preferred recrystallization solvent is aqueous acetone. 
In case of employing an aqueous organic solvent as a recrystallization 
solvent, yields of the objective compound are affected by water content in 
recrystallization organic solvent. Preferred water content lies in the 
range of 10 to 30% (V/V%). Most preferred water content lies in the range 
of 10 to 25% (V/V%). 
4-(1-Imidazolylmethyl)cinnamic acid hydrochloride used as a starting 
material is well known and can be prepared according to the method 
disclosed in U.S. Pat. No. 4,226,878. That is, said compound can be 
prepared by reacting sodium salt of imidazole with ethyl 
p-bromomethylcinnamate in acetonitrile and by hydrolyzing the reaction 
product with sodium hydroxide and then treating the resulting product with 
hydrochloric acid. 
The above recrystallization is carried out preferably by the following 
procedure. 
4-(1-Imidazolylmethyl)cinnamic acid hydrochloride is dissolved by heating 
in an adequate amount of 50% (V/V%) aqueous acetone and filtrated and the 
filtrate is diluted with acetone in an amount sufficient to make an 
aqueous solution of acetone having water content of about 10-30% (V/V%), 
preferably about 17% (V/V%). The mixture is allowed to stand at room 
temperature for an adequate period of time. The precipitates are collected 
and dried under reduced pressure at room temperature to obtain 
4-(1-imidazolylmethyl)cinnamic acid hydrochloride monohydrate. 
The LD.sub.50 value of this compound is in oral administration to a rat is 
6000 mg/kg or more. 
The compounds can be administered in various forms according to the 
purposed therapy. Typical dosage forms which can be used are tablets, 
pills, powders, liquid preparations, suspensions, emulsions, granules, 
capsules, suppositories and injectable preparations. 
In molding the pharmaceutical composition into a tablet form, a wide 
variety of conventional carriers known in this art can be used. Examples 
of suitable carriers are excipients such as glucose, lactose, starch, 
cacao butter, hardened vegetable oils, kaolin and talc, binders such as 
gum arabic powder, tragacanth powder, and ethanol, and disintegrants such 
as laminaria and agar. The tablets, if desired, can be coated to make 
sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, 
film-coated tablets, or tablets coated with two or more layers. 
When the pharmaceutical composition is formulated into an injectable 
preparation, the resulting solution and suspension are preferably 
sterilized, and are isotonic with respect to the blood. In formulating the 
pharmaceutical composition into the form of a solution or suspension, any 
types of diluents customarily used in the art can be used. Examples of 
suitable diluents are water, ethyl alcohol, propylene glycol, 
polyoxyethylene sorbitol, and sorbitan esters. Sodium chloride, glucose or 
glycerol may be incorporated into a therapeutic agent in an amount 
sufficient to prepare an isotonic solution. The therapeutic agent may 
further contain ordinary dissolving aids, buffers, pain-alleviating 
agents, and preservatives, and optionally, coloring agents, perfumes, 
flavors, sweeteners and other drugs. 
The dosage of the compound of this invention can be about 1 mg to 1,000 
mg/body by oral administration, or about 0.1 mg to 100 mg/body by 
parenteral administration per day for adult human in multiple doses 
depending upon the disease which is being treated. 
This invention is further illustrated in more detail by way of the 
following examples wherein the melting point of the product obtained are 
uncorrected. Unless otherwise indicated, all parts, percents, ratios and 
the like are by weight. 
REFERENCE EXAMPLE 1 
To a suspension of 0.96 g of 50% sodium hydride in 50 ml of dry 
acetonitrile was added 1.3 g of imidazole at room temperature, and then 
the mixture was stirred for 30 min. A solution of 5.38 g of ethyl 
p-bromomethylcinnamate in 20 ml of dry acetonitrile was added to the 
mixture at room temperature for 10 min, and then the mixture was stirred 
at the same temperature for 1 hr. After concentration under reduced 
pressure, the residue was dissolved in 100 ml of benzene and washed with 
water and dried. The solvent was evaporated and the residual oil was 
chromatographed on silica gel using chloroform, and the resulting crystals 
were recrystallized from diethyl ether to give 3.4 g of ethyl 
4-(1-imidazolylmethyl)cinnamate. This compound was added to 30 ml of 80% 
aqueous ethanol containing 0.8 g of sodium hydroxide and the mixture was 
stirred for 4 hr at room temperature. After concentration and reduced 
pressure, 25 ml of water was added to the residue and the mixture was 
washed with diethyl ether. The mixture was adjusted to pH 1 to 2 by an 
addition of concentrated hydrochloric acid and the acidic solution was 
concentrated under reduced pressure. To the residue, 30 ml of 
2-methyl-2-propanol was added and the mixture was evaporated again, and 
the residue was dissolved in 80 ml of ethanol and the insoluble materials 
were filtered off. The filtrate was evaporated to obtain 3.4 g of crude 
4-(1-imidazolylmethyl)cinnamic acid hydrochloride. 
EXAMPLE 1 
In 35 ml of water, 10 g of 4-(1-imidazolylmethyl)cinnamic acid 
hydrochloride was dissolved by heating and the solution was allowed to 
stand overnight at room temperature. The resulting precipitates were 
collected by filtration and dried at room temperature under reduced 
pressure to obtain 6 g of 4-(1-imidazolylmethyl)cinnamic acid 
hydrochloride monohydrate. 
melting point: 227.degree.-228.degree. C. 
IR-absorption spectrum (KBr): .nu.OH: 3270 cm.sup.-1 ; .nu.CO: 1705, 1685 
cm.sup.-1 ; .nu.C.dbd.C: 1635 cm.sup.-1. 
NMR spectrum (DMSO-d.sub.6); .delta.: 5.61(s,2H), 6.58(d,1H), 
7.4-8.0(m,7H), 9.50(m,1H). 
______________________________________ 
Elemental analysis as C.sub.13 H.sub.15 N.sub.2 O.sub.3 Cl 
C % H % N % 
______________________________________ 
Calcd. 55.22 5.35 9.91 
Found 55.01 5.28 9.83 
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EXAMPLE 2 
In 60 ml of aqueous solution of acetone having water content of 25% (V/V%), 
10 g of 4-(1-imidazolylmethyl)cinnamic acid hydrochloride was dissolved by 
heating and then the solution was allowed to stand overnight at room 
temperature. The resulting precipitates were collected by filtration and 
dried at room temperature for 3 hr under reduced pressure to obtain 7.0 g 
of 4-(1-imidazolylmethyl)cinnamic acid hydrochloride monohydrate. This 
product had the same IR-absorption spectrum and NMR spectrum as those of 
the product of EXAMPLE 1. 
EXAMPLE 3 
In 30 ml of 50% (V/V%) aqueous acetone 10 g of 
4-(1-imidazolylmethyl)cinnamic acid hydrochloride was dissolved by heating 
and the solution was filtrated and then 60 ml of acetone was added to the 
filtrate. The mixture was allowed to stand overnight at room temperature. 
The resulting precipites were collected by filtration and dried at room 
temperature for 3 hr under reduced pressure to obtain 8.5 g of 
4-(1-imidazolylmethyl)cinnamic acid hydrochloride monohydrate. This 
product had the same IR-absorption spectrum and NMR spectrum as those of 
the product of EXAMPLE 1. 
FORMULATION EXAMPLE 1 
4-(1-Imidazolylmethyl)cinnamic acid hydrochloride monohydrate, lactose, 
carboxymethylcellulose calcium, crystalline cellulose and calcium stearate 
were blended at a ratio of 100:48:10:40:2, respectively, and the mixture 
was compressed into tablets of 200 mg in weight. 
Each tablet contains the following ingredients: 
4-(1-imidazolylmethyl)cinnamic acid hydrochloride monohydrate: 100 mg 
lactose: 48 mg 
carboxymethylcellulose calcium: 10 mg 
crystalline cellulose: 40 mg 
calcium stearate: 2 mg. 
FORMULATION EXAMPLE 2 
4-(1-Imidazolylmethyl)cinnamic acid hydrochloride monohydrate, lactose and 
talc were blended at a ratio of 100:895:5, respectively, and the mixture 
was sieved to get particles of not more than 350.mu. for the preparation 
of powder. 
The proportion of the ingredients in one gram of the powder is as follows: 
4-(1-imidazolylmethyl)cinnamic acid hydrochloride monohydrate: 100 mg 
lactose: 895 mg 
talc: 5 mg. 
FORMULATION EXAMPLE 3 
4-(1-Imidazolylmethyl)cinnamic acid hydrochloride monohydrate, lactose, 
D-mannitol, hydroxypropylcellulose and talc were blended at a ratio of 
100:675:200:20:5, respectively, and the mixture was granulated. 
The proportion of the ingredients in one gram of the granule is as follows: 
4-(1-imidazolylmethyl)cinnamic acid hydrochloride monohydrate: 100 mg 
lactose: 675 mg 
D-mannitol: 200 mg 
hydroxypropylcellulose: 20 mg 
talc: 5 mg. 
FORMULATION EXAMPLE 4 
4-(1-Imidazolylmethyl)cinnamic acid hydrochloride monohydrate, crystalline 
cellulose, carboxymethylcellulose calcium, hydroxypropylcellulose, calcium 
stearate and talc were blended at a ratio of 100:40:15:2:3:10, 
respectively, and the mixture was charged into hard capsules containing 
170 mg of all ingredients. 
Each capsule contains the following ingredients: 
4-(1-imidazolylmethyl)cinnamic acid hydrochloride monohydrate: 100 mg 
carboxymethylcellulose calcium: 15 mg 
crystalline cellulose: 40 mg 
hydroxypropylcellulose: 2 mg 
calcium stearate: 3 mg 
talc: 10 mg. 
FORMULATION EXAMPLE 5 
50 g of 4-(1-imidazolylmethyl)cinnamic acid hydrochloride monohydrate, 17 g 
of sodium hydroxide, 80 g of aminoacetic acid and 5 g of citric acid were 
dissolved in 5 l of distilled water for injections and the solution was 
filled into amples by 5 ml each. After filled up with nitrogen gas, the 
amples were sealed by fusion and sterilized by heating. 
Each ample contains the following ingredients: 
4-(1-imidazolylmethyl)cinnamic acid hydrochloride monohydrate: 50 mg 
sodium hydroxide: 17 mg 
aminoacetic acid: 80 mg 
citric acid: 5 mg 
distilled water: 5 ml. 
EXAMPLE 4 
Inhibition of Cerebral Infarction Caused by Arachidonic Acid 
The right external carotid artery of a male rabbit weighing about 2 kg was 
ligated, a cannula was inserted in the reverse direction, and arachidonic 
acid was infused into the right internal carotid artery at a rate of 1 
mg/animal/min. for 25 minutes, without blocking the blood flow. 
4-(1-Imidazolylmethyl)cinnamic acid hydrochloride monohydrate and 
acetylsalicylic acid as an active control were orally administered 
respectively, 90 minutes before arachidonic acid infusion. 
On the next day, the animal was sacrificed with pentobarbital (i.v.), the 
brain was taken out and macroscopically examined for infarction sites. 
______________________________________ 
COMPOUND 
##STR4## 
______________________________________ 
control 
##STR5## 
4-(1-imidazolylmethyl)cinnamic acid hydrochloride monohydrate 
##STR6## 
acetylsalicylic acid 
##STR7## 
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