BE885263A - DERIVATIVES OF CYCLOHEXANE-CARBOXYLIC ACIDS - Google Patents

Description

       

  The present invention relates to new

  
derivatives of cyclohexane-carboxylic acids, their process

  
preparation, as well as a pharmaceutical composition

  
containing it.

  
Tranexamic acid (trans-4-aminomethylcyclohexane-carboxylic acid) is a derivative of cyclohexanecarboxylic acid and is known to exert excellent anti-plasmin effects. We also know that acid esters

  
  <EMI ID = 1.1>

  
  <EMI ID = 2.1>

  
However; it has been reported that 4-guanidinomethylcyclohexane-carboxylic acid has few anti-plasmin effects

  
(ibid.).

  
Now, a variety of derivatives of

  
cyclohexanc and we ended up with the discovery

  
of the present invention.

  
An object of the present invention is to provide

  
new derivatives of cyclohexane-carboxylic acids exerting powerful inhibitory effects on the protease,

  
anti-ulcer effects, anti-histamine effects, anti-inflammatory effects and anti-allergic effects.

  
Another object of the present invention is to

  
provide a process for the preparation of these new derivatives

  
cyclohexane-carboxylic acids.

  
In addition, another object of the present invention

  
is to provide a cyclohexane-carboxylic acid derivative

  
useful as an anti-ulcer agent.

  
These various objects of the invention, as well as

  
others which will appear more clearly below, may

  
be made thanks to the discovery of compounds meeting

  
to formula (I):

  

  <EMI ID = 3.1>


  
in which R represents a vanilyl group, a naphthyl group, a pyri & y group, an α-tocopheryl group,

  
a formula group

  

  <EMI ID = 4.1>


  
in which R2 represents

  
  <EMI ID = 5.1>

  
formyl, a lower alkanoyl group or a phenyl group,

  
  <EMI ID = 6.1>

  
in which R3 represents a hydrogen atom, a lower alkyl group, a phenyl group, a benzyl group, an anisyl group or a lower alkoxy-carbonylmethyl group, while n represents an integer from 0 to 2. It has been found that these derivatives and their pharmaceutically acceptable salts exerted excellent inhibitory effects on the protease, as well as excellent anti-ulcer, anti-histamine, anti-inflammatory and anti-allergic effects.

  
In particular, it has been found that the compounds of formula (II):

  

  <EMI ID = 7.1>


  
in which R3 and n have the same meanings as those defined above, exerted excellent inhibitory effects

  
  <EMI ID = 8.1>

  
preventive and curative effects on various gastric and duodenal ulcers.

  
  <EMI ID = 9.1>

  
  <EMI ID = 10.1>

  
mention a vanilyl group, a naphthyl group, a group

  
  <EMI ID = 11.1>

  

  <EMI ID = 12.1>


  
Among the suitable naphthyl groups are

  
  <EMI ID = 13.1>

  
suitable pyridyl groups, there is the 2-pyridyl group, the 3-pyridyl group or the 4-pyridyl group. From

  
appropriate formula groups

  

  <EMI ID = 14.1>


  
, there is the group

  
phenyl, methoxyphenyl group, ethoxyphenyl group, propoxyphenyl group, formylphenyl group, acetylphenyl group, propanoylphenyl group, butyrylphenyl group, biphenyl group or a group of formula

  

  <EMI ID = 15.1>


  
Among the appropriate groups of

  
formula

  

  <EMI ID = 16.1>


  
there is the hydroxy-

  
carbonylphenyl, the methoxycarbonylphenyl group, the

  
ethoxycarbonylphenyl group, t-butoxycarbonylphenyl group, phenoxycarbonylphenyl group, benzyloxycarbonylphenyl group, anisyloxycarbonylphenyl group,

  
(ethoxycarbonyl) methoxycarbonylphenyl group, hydroxycarbonylmethylphenyl group, methoxycarbonylmethylphenyl group, ethoxycarbonylmethylphenyl group, t-butoxycarbonylmethylphenyl group, phenoxycarbonylmethylphenyl group, benzyloxycarbonyl group

  
hydroxycarbonylethylphenyl group, ethoxycarbonylethylphenyl group, (ethoxycarbonyl) ethoxycarbonylethylphenyl group, phenoxycarbonylethylphenyl group, benzyloxycarbonylethylphenphenyl group, anisyloxycarbonylethylphenphenyl group or the like.

  
  <EMI ID = 17.1>

  
  <EMI ID = 18.1>

  
strongly preferred.

  
Pharmaceutically acceptable salts of the compounds of the present invention are the acid addition salts formed from hydrochloric acid,

  
  <EMI ID = 19.1>

  
hydrobromic, acetic acid, lactic acid, maleic acid, fumaric acid, tartaric acid, <EMI ID = 20.1>

  
According to the present invention, the

  
  <EMI ID = 21.1>

  
dinomethyl-cyclohexane-carboxylic acid or one of its derivatives reactive with a compound of formula (III):

  

  <EMI ID = 22.1>


  
  <EMI ID = 23.1>

  
naphthyl, a pyridyl group, an a-tocopheryl group or

  
a formula group

  

  <EMI ID = 24.1>


  
  <EMI ID = 25.1>

  
a hydrogen atom, a lower alkoxy group, a formyl group, a lower alkanoyl group, a phenyl group

  
  <EMI ID = 26.1>

  
represents a lower alkyl group, a phenyl group, a benzyl group, an anisyl group or a lower alkoxy-carbonylmethyl group, while n represents an integer of 0 to 2 and, if desired, removing the benzyl group, the anisyl group or the lower alkoxycarbonylmethyl group of the product.

  
Among the suitable reactive derivatives of 4-guanidinomethyl-cyclohexane-carboxylic acid are acid halides, for example, acid chloride,

  
acid bromide or the like, as well as mixed anhydrides using ethyl chloroformate, butyl chloroformate or the like. The acid halides are prepared by reacting 4-guanidinomethylcyclohexane-carboxylic acid with halogenating reagents such as thionyl chloride and thionyl bromide; at a temperature between room temperature and the boiling point of the halogenation reagent. The acid halides thus obtained are reacted with the compounds of formula (III) to obtain the compounds of the present invention. This reaction is carried out by stirring at a temperature between room temperature

  
and the boiling point of the solvent for a period of

  
1 to 40 hours. Among the solvents that can be used,

  
there is dimethylformamide, dimethylacetamide, pyridine, dichloromethane, dichlorethane, chloro-

  
  <EMI ID = 27.1>

  
instructed to use an acid scavenger, for example, triethylamine, dimethylaniline or pyridine.

  
When the 4-guanidinomethyl-cyclohexane-carboxylic acid is reacted directly without transformation into <EMI ID = 28.1> reaction, preferably in the presence of a condensing agent, for example, a carbodiimide such as dicyclohexyl-

  
  <EMI ID = 29.1>

  
aminopropyl) carbodiimide, a sulfuric acid / boric acid complex, carbodiimidazole, sulfodiimidazole or

  
a Lewis acid such as phosphorus oxychloride or boron trifluoride. The reaction is carried out with a solvent, for example, toluene, xylene or dimethylformamide,

  
a solvent of the type mentioned above, or mixtures of these solvents, at a temperature between room temperature and the boiling point of the solvent.

  
The compounds of formula (I) are prepared in

  
  <EMI ID = 30.1>

  
  <EMI ID = 31.1>

  
a benzyl group or an anisyl group, in the presence of a catalyst, for example, palladium. These compounds can also be prepared by hydrolyzing the compounds of formula (I) in which R3 represents a butyl group or a lower alkoxy-carbonylmethyl group, in the presence of a catalyst, for example, trifluoroacetic acid or an acid complex hydrochloric / acetic acid.

  
The compounds of formula (IV) can also be prepared:

  

  <EMI ID = 32.1>


  
  <EMI ID = 33.1>

  
those defined above, by reacting the compounds of formula (V):

  

  <EMI ID = 34.1>


  
in which n has the same meaning as that defined above, or one of its reactive derivatives, with a compound of formula (VI):

  

  <EMI ID = 35.1>


  
in which R3 'has the same meaning as that defined above.

  
The reaction is carried out by the same esterification process as that mentioned above. Then,

  
  <EMI ID = 36.1>

  
classic techniques.

  
It is usually far preferable to recover the compounds of the present invention in the form of their acid addition salts as mentioned above.

  
The compounds of formula (I) can contain water of crystallization in equimolar amounts.

  
  <EMI ID = 37.1>

  
  <EMI ID = 38.1>

  
words, the compounds of the present invention exert excellent inhibitory effects on a protease such as trypsin, chymotrypsin, thrombin or urokinase. The compounds of the present invention also exert excellent anti-ulcer effects. Therefore, we can use them

  
for ulcer models such as Shay's ulcers,

  
ulcers due to aggression, ulcers due to indomethacin, Ulcers caused by acetic acid, ulcers due to cysteamine or histamine.

  
These compounds have been found to strongly inhibit the volume of gastric secretion, the acidity of gastric juices and peptic activity. In addition, these effects seem to be very long lasting. Acute and subacute toxicity experiments have confirmed that the compounds

  
of the present invention had a low degree of toxicity. In particular, the compounds of formula (II) exert excellent anti-ulcer effects and seem to be remarkably safe.

  
The compounds of the present invention also exert antihistamine effects, antiinflammatory effects and antiallergic effects (passive cutaneous anaphylaxis test).

  
The compounds of formula (I) exert excellent inhibitory effects on the protease. The inhibitory effects were determined by the following methods:

  
1) Inhibitory effects on trypsin:

  
The inhibitory effects of compounds on trypsin

  
  <EMI ID = 39.1>

  
M. Muramatsu et al. ("The Journal of Biochemistry", volume
58, 214 (1965)). In particular, the inhibitory effects exerted by the compounds on the hydrolysis of the methyl ester of p-tosylarginine by trypsin were examined.
(incubation at 37 [deg.] C for 10 minutes).

  
2) Inhibitory effects on chymotrypsin:
The inhibitory effects exerted by the compounds on chymotrypsin were determined according to the method described by M. Muramatsu ("The Journal of Bioche-

  
  <EMI ID = 40.1>

  
examined the inhibitory effects exerted by the compounds on the hydrolysis of the ethyl ester of N-acetyl-L-tyrosine by chymotrypsin (incubation at 37 [deg.] C for 10 minutes).

  
3) Inhibitory effects on thrombin:

  
The inhibitory effects exerted by the compounds on thrombin were determined according to the method described by M. Murarnatsu et al. ("The Journal of Biochemistry" &#65533; volume 65 (1), 17 (1969)). In particular, the inhibitory effects exerted by the compounds on the hydrolysis of the methyl ester of p-tosylarginine by thrombin were examined.
(incubation at 37 [deg.] C for 10 minutes).

  
4) Inhibitory effects on urokinase:

  
The inhibitory effects exerted by the compounds

  
on urokinase were determined according to the method described by A.J. Joeson et al. ("Throm. Diath. Haemorrh,"

  
21, 259-272 (1969)). In particular, the inhibitory effects exerted by the compounds on the hydrolysis of the methyl ester of N-acetylglycyl-lysine by urokinase were determined (incubation at 37 [deg.] C for 10 minutes).

  
The results obtained are shown in Table 1 below.

  
TABLE 1

PROTEASE INHIBITOR EFFECTS

  

  <EMI ID = 41.1>


  
Compound 1: trans-4-guanidinomethyl-cyclo- hydrochloride

  
2'-benzyloxycarbonylphenyl hexane-carboxylate. Compound 2: trans-4-guanidincmethyl-cyclo- hydrochloride

  
  <EMI ID = 42.1>

  
Compound 3: trans-4-guanidinomethyl-cyclo- hydrochloride

  
phenyl hexane carboxylate.

  
Compound 4: trans-4-guanidinomethyl-cyclo- hydrochloride

  
2'-ethoxyphenyl hexane-carboxylate. Compound 5: trans-4-guanidinomethyl-cyclo- hydrochloride

  
2'-phenoxycarbonylphenyl hexane-carboxylate. Compound 6: trans-4-guanidinomethyl-cyclo- hydrochloride

  
4'-ethoxycarbonylphenyl hexane carboxylate. Compound 7: trans-4-guanidinomethyl-cyclo- hydrochloride

  
3'-pyridyl hexane-carboxylate.

  
  <EMI ID = 43.1>

  
  <EMI ID = 44.1>

  
4 'carboxylate - (2 "-hydroxycarbonylethyl) -

  
  <EMI ID = 45.1>

  
1. Shay's ulcers

  
Male rats of the "Sprague-Dawley" family weighing 160-180 g are deprived of food, but they are allowed free access to water for 20 hours before the experiment.

  
Under ether anesthesia, the abdomen is incised and the pylorus is ligated as described by Shay et al. ("Gastroenterology",

  
  <EMI ID = 46.1>

  
18 hours later, the rats are sacrificed with an ether overdose and the stomach is removed.

  
The stomach is incised along its greatest curvature and

  
we measure with the naked eye the area of each lesion that has occurred

  
in the front of the stomach. The lesion is assessed arbitrarily

  
in 6 degrees as an ulcer index according to the Adami process

  
et al. ("arch, int. Pharmacodyn.", 147, 113-145 (1964)) as follows:

  
0 = no lesion

  
1 = hemorrhagic suffusion

  
  <EMI ID = 47.1>

  
3 = many small ulcers (more than 5) or 1

  
large ulcer

  
4 = many large ulcers

  
5 = perforated ulcer.

  
Test drugs are administered intraperitoneally immediately after ligation of the pylorus.

  
The results obtained are shown in Table 2 below.

  
TABLE 2

SHAY ULCERES

  

  <EMI ID = 48.1>


  
Compound B: atropine sulfate.

  
Compound 1, compound 3, compound 8 and compound A are the same as those defined above.

  
2. Ulcers caused by acetic acid.

  
Male rats of the "SpragueDawley" family weighing approximately 200 g are used. 0.05 ml of acetic acid solution is carefully injected under ether anesthesia

  
  <EMI ID = 49.1>

  
pylorus, then we close the abdomen .. Then we maintain

  
  <EMI ID = 50.1>

  
of each test drug in solution or suspension

  
  <EMI ID = 51.1>

  
daily administration orally for 10 days from the day after the operation.

  
On the eleventh day, the rats are sacrificed under ether anesthesia and the stomachs are removed. The surface area of the ulcer is measured and evaluated in 5 degrees as an ulcer index according to the following procedure:

  

  <EMI ID = 52.1>


  
The results obtained are shown in Table 3 below.

  
TABLE 3

ULCERES CAUSED BY ACETIC ACID

  

  <EMI ID = 53.1>
 

  
Compound 10: trans-4-guanidinomethyl hydrochloride

  
2'-hydroxy- cyclohexane-carboxylate

  
  <EMI ID = 54.1>

  
  <EMI ID = 55.1>

  
compound 9 and compound A are the same as those defined above.

  
3. Duodenal ulcers (caused by cysteamine).

  
For 24 hours before the experiment, we deprive

  
of food for female Sprague-Dawley rats weighing about 200 g. Then, to these rats, 400 mg of cysteamine / kg is administered once subcutaneously.

  
Seven hours later, animals are fed ad libitum. The test drug is administered orally as an aqueous suspension 7 hours after administration of cysteamine, then daily for 4 days. The day after the last administration, the animals are sacrificed under ether anesthesia. The surface area of the ulcers (mm2) is measured and the index is thus established

  
  <EMI ID = 56.1>

  
The results obtained are shown in Table 4.

  
TABLE 4

ULCERES CAUSED BY CYSTEAMINE

  

  <EMI ID = 57.1>


  
Compound 1 is the same as that defined above.

  
4. Influence on gastric secretion.

  
Male rats of the "Sprague-Dawley" family weighing 160-180 g are deprived of food, but they are allowed free access to water for 20 hours before the experiment. Under ether anesthesia, the abdomen is incised and the pylorus is ligated as described by Shay et al.

  
  <EMI ID = 58.1>

  
When the pylorus is ligated, the test drug is administered intraperitoneally. 3; 6 and 12 hours later,

  
the rats are sacrificed and the stomachs are removed. The gastric juice is collected and analyzed to determine the volume. The gastric juice is then subjected to centrifugation at 1,300 g for 10 minutes at room temperature to obtain the supernatant. The total acidity and the peptic activity of the supernatant are determined. The total acidity is determined by titration with 0.01N NaOH. Peptic activity was determined according to the method described by Anson et al. ("J. Gen. Physiol.", 22, 79-89 (1938)). the results are shown in Tables 5-7. Total acidity is indicated by the titration volume (ml), while peptic activity is indicated by the corresponding weight (mg) of crystalline pepsin.

  

  <EMI ID = 59.1>


  

  <EMI ID = 60.1>
 

  

  <EMI ID = 61.1>


  

  <EMI ID = 62.1>


  

  <EMI ID = 63.1>
 

  

  <EMI ID = 64.1>


  

  <EMI ID = 65.1>


  

  <EMI ID = 66.1>
 

  
The toxicity of a specific compound according to the present invention will be described below:

  
1. Acute toxicity.

  
We use normal family mice

  
  <EMI ID = 67.1>

  
Test drugs are administered orally using a gastric tube. The animals are observed for 7 days. The lethal dose is calculated at 50% (value

  
  <EMI ID = 68.1>

  
TABLE 8

  

  <EMI ID = 69.1>


  
Compound 1 is the same as that defined above.

  
2. Subacute toxicity.

  
  <EMI ID = 70.1>

  
weighing approximately 150 g. The dose is administered once a day for 1 month. The dosages are set to 4 values:
40 mg / kg, 130 mg / kg, 400 mg / kg, 1,300 mg / kg of trans-4-guanidinomethyl-cyclohexane-carboxylate hydrochloride 2'benzyloxycarbonylphenyl. The following observations are made:

  
1) Observations of general symptoms, body weight,

  
food intake and water intake.

  
2) Hematological examinations.

  
3) Biochemical examinations of the serum.

  
4) Weight of the organs.

  
5) Histopathological examinations.

  
  <EMI ID = 71.1>

  
die at the maximum dose (1,300 mg / kg), while toxic lesions are not observed at the other doses.

  
  <EMI ID = 72.1>

  
  <EMI ID = 73.1>

  
phenyl trans-4-guanidinomethyl-cyclohexane-phenyl carboxylate completely inhibit contraction of the ileum

  
  <EMI ID = 74.1>

  
ment contraction of the ilelun of a guinea pig, sensitized

  
with egg albumin, when the compound is administered

  
  <EMI ID = 75.1>

  
phenyl trans-4-guanidinomethyl-cyclohexane-carboxylate inhibits the inflammation caused by carrageenan
(rats of the "Wister" family, intraperitoneal route, dose

  
  <EMI ID = 76.1>

  
the compounds of the present invention as antiulcer agents, the compounds corresponding to formula (II) are particularly preferred. These compounds exert

  
both oral and parenteral activities but, of course, the preferred mode of administration is oral administration. Oral administration can be by capsules, tablets,

  
powders or granules. In the dosage form, the active compounds are mixed with at least one diluent

  
inert such as lactose, corn starch and crystalline cellulose; a lubricant such as magnesium stearate, a binding agent such as hydroxypropyl cellulose; a coloring agent; a perfume; a sweetening agent or the like.

  
The dosages of the compounds can be varied

  
of the present invention in various compositions actually used. However, it is necessary that the amount of the compounds is calculated so as to obtain two suitable dosage forms. Any dosage chosen depends on the desired therapeutic effect, the mode of administration and the duration of treatment. This dosage is generally in the range between 50 and about 1,500 mg / day. The present invention is illustrated in more detail by certain specific examples which are given here only by way of illustration and which in no way limit the invention.

Example 1

  
Vitamin E trans-4-guanidinomethyl-cyclohexane-carboxylate hydrochloride:

  
For 3 hours, a suspension of 11.8 g of trans-4-guanidinomethyl-cyclohexane-carboxylic acid hydrochloride, 17.2 g of vitamin E and 12.4 g of dicyclohexylcarbodiimide is stirred at room temperature.

  
in 150 ml of pyridine. After removal of the insoluble matter by filtration, the filtrate is evaporated to dryness and the residual solid is treated with a mixture of

  
  <EMI ID = 77.1>

  
ethyl for one hour. Insoluble matter is removed. The organic slurry is filtered, concentrated by filtration and also ether is added to obtain pale yellow crystals, namely 16.1 g (62.1%) of trans-4-guanidinomethyl-cyclohexanecarboxylate hydrochloride. vitamin E with a melting point of 183-186 [deg.] C.

  
  <EMI ID = 78.1>

  
1740 (C = O).

  

  <EMI ID = 79.1>
 

  
  <EMI ID = 80.1>

  
approximately 50% of hydrolytic activity by thrombin and trypsin.

Example 2

  
Trans-4-guanidinomethyl-cyclohexane hydrochloride

  
  <EMI ID = 81.1>

  
  <EMI ID = 82.1>

  
  <EMI ID = 83.1>

  
trans-4-guanidinomethyl-cyclohexane-carboxylic acid, 8.5 g of benzyl 4-hydroxyphenyl propionate and 7.2 g of dicyclohexyl-carbodiimide in 75 ml of pyridine. After removal of the insoluble matters by filtration, the filtrate is concentrated under reduced pressure. We process the

  
  <EMI ID = 84.1>

  
0.1N and 50 ml of ethyl acetate, then the solid obtained is filtered off. The organic layer is filtered, concentrated and the residual gummy materials are treated with ether, then stirred to obtain white crystals which, after recrystallization from a

  
  <EMI ID = 85.1>

  
1745, 1725 (C = 0).

  

  <EMI ID = 86.1>
 

Example 3

  
  <EMI ID = 87.1>

  
  <EMI ID = 88.1>

  
a suspension of 11.8 g of trans-4-guanidinomethyl-cyclohexane-carboxylic acid hydrochloride, 10.7 g of ethyl 4-hydroxyphenyl propionate and 11.4 g of dicyclohexylcarbodiimide are stirred in 150 ml of pyridine. After removal of the insoluble matter by filtration, the filtrate is evaporated. The residue is treated with 150 ml

  
  <EMI ID = 89.1>

  
by filtration and the filtrate is washed with ether. The aqueous layer is concentrated and the residue is treated with

  
  <EMI ID = 90.1>

  
in a mixture of ethanol and ether, give 17.9 g (86.9%) of trans-4-guanidinomethyl-cyclohexane hydrochloride

  
  <EMI ID = 91.1>

  
melting point of 90-91 [deg.] C.

  
  <EMI ID = 92.1>

  
1725, 1740 (C = O).

  

  <EMI ID = 93.1>

Example 4

  
Phenyl trans-4-guanidinomethyl-cyclohexane hydrochloride hydrochloride:

  
Overnight at room temperature,

  
stirred a suspension of 11.8 g of trans-4-guanidinomethyl-cyclohexane-carboxylic acid hydrochloride, of 5.6 g

  
of phenol and 12.4 g of dicyclohexylcarbodiimide in

  
75 ml of pyridine. After evaporation of the solvent, we treat <EMI ID = 94.1>

  
insoluble matter by filtration and the filtrate is washed with ethyl acetate. Concentrate the aqueous layer

  
at 100 ml, the crystals obtained are filtered and washed

  
with a mixture of isopropyl alcohol and isopropyl ether

  
  <EMI ID = 95.1>

  

  <EMI ID = 96.1>

Example 5

  
Trans-4-guanidinomethyl-cyclohexane-carbo- hydrochloride

  
  <EMI ID = 97.1>

  
Overnight at room temperature, a suspension of 11.8 g of the acid hydrochloride is stirred

  
  <EMI ID = 98.1>

  
  <EMI ID = 99.1>

  
solvent evaporation, the residue is treated with a mixture

  
  <EMI ID = 100.1>

  
of ethyl, the insoluble matters are removed by filtration and the organic layer is separated. After evaporation to dryness, methanol, acetic acid and water are added, then the clear solution obtained is subjected to hydrogenation on 10% palladium on charcoal. After absorption of the theoretical amount of hydrogen, the catalyst is separated by filtration. The filtrate is concentrated to dryness and the crystals formed are recrystallized from a mixture of methanol and acetic acid to obtain 14.3 g

  
  <EMI ID = 101.1>

  

  <EMI ID = 102.1>

Example 6

  
  <EMI ID = 103.1>

  
2'-benzyloxycarbonylphenyl xylate:

  
  <EMI ID = 104.1>

  
a suspension of 10.6 g of the trans-4-guanidinomethyl-cyclohexane-carboxylic acid hydrochloride, 11.4 g of benzyl salicylate and 11.3 g of dicyclohexylcarbodiimide in 100 ml of pyridine are stirred. After removing the insoluble materials, the solvent is evaporated. We treat

  
  <EMI ID = 105.1>

  
crystals are thus obtained which are extracted with methanol. The extract is concentrated and water is added, then the solid obtained is recrystallized from aqueous acetone to obtain 17.9 g (89.2%) of trans-4-guanidino hydrochloride

  
  <EMI ID = 106.1>

  
1730 (c = o).

  
  <EMI ID = 107.1>

  
Calculated: C 61.95 H 6.33; N 9.42

  
  <EMI ID = 108.1>

  
  <EMI ID = 109.1>

  
methanol and ether to obtain white crystals,

  
  <EMI ID = 110.1>

  
melting point of 83 [deg.] C.

  
  <EMI ID = 111.1>

  
2'-hydroxycarbonylphenyl trans-4-guanidinomethyl-cyclohexanecarboxylate hydrochloride:

  
A solution of 8.9 g of 2'-benzyloxycarbonylphenyl trans-4-guanidinomethyl-cyclohexane-carboxylate hydrochloride in 30 ml of acetic acid and 10 ml of methanol is subjected to hydrogenation on 10% palladium on carbon. After absorption of hydrogen (approximately
500 ml), the catalyst is separated by filtration. The filtrate is concentrated to dryness, the crystals are washed with ether and they are recrystallized from a mixture of ethanol and ether to obtain 6.5 g (91.3%) of the title compound a melting point of 166-168 [deg.] C.

  
  <EMI ID = 112.1>

  
Calculated: C 54.01; H 6.23; N 11.81

  
Found: C 53.85; H 6.05; N 11.42.

Example 8

  
2'-ethoxycarbonylphenyl trans-4-guanidinomethyl-cyclohexane-carboxylate hydrochloride:

  
For 15 hours, at room temperature, a suspension of 7.1 g of trans-4-guanidinomethyl-cyclohexane-carboxylic acid hydrochloride, 5.5 g of ethyl salicylate and 7.2 g of dicyclohexylcarbodiimide in 100 ml of pyridine. After removing the

  
  <EMI ID = 113.1>

  
  <EMI ID = 114.1>

  
other insoluble matter is further separated by filtration and the filtrate is washed with ether. After evaporation, the residue is treated with ether and stirred, then the crude product obtained is recrystallized from a mixture of ethanol and

  
  <EMI ID = 115.1>

  
2'-ethoxy- 4-guanidinomethyl-cyclohexane-carboxylate

  
  <EMI ID = 116.1>

  

  <EMI ID = 117.1>

Example 9

  
Trans-4-guanidinomethyl-cyclohexane-carbo- hydrochloride

  
  <EMI ID = 118.1>

  
For 15 hours, at 30 ° C., a suspension of 7.1 g of trans-4-guanidinomethyl acid hydrochloride is stirred.

  
  <EMI ID = 119.1>

  
  <EMI ID = 120.1>

  
  <EMI ID = 121.1>

  
the solution. The residue is treated with a mixture of 100 ml of hydrochloric acid O, IN and 100 ml of ethyl acetate, then the mixture is stirred for 1 hour. Other insoluble matter is filtered and the organic layer is separated. After evaporation to dryness, the residual solid is washed with ether and recrystallized from a mixture of isopropyl alcohol and ether to obtain

  
9.6 g (86.5%) of 2'-methoxy-4'-formylphenyl trans-4-guanidinomethylcyclohexane-carboxylate hydrochloride

  
  <EMI ID = 122.1>

  
  <EMI ID = 123.1>

  
1760 (c = o).

  

  <EMI ID = 124.1>

Example 10

  
2'-Phenoxycarbonylphenyl trans-4-guanidinomethyl-cyclohexanecarboxylate hydrochloride:

  
For 21 hours, at room temperature, a suspension of 27.5 g of trans-4-guanidinomethyl-cyclohexane-carboxylic acid hydrochloride, 25 g of phenyl salicylate and 26.5 g of dicyclohexylcarbodiimide is stirred for 100 hours. ml of dimethylformamide. To this solution, 150 ml of water and 120 ml of concentrated hydrochloric acid are added, then the solid thus precipitated is washed with water. The solid is then treated with methanol and the layer of methanol is evaporated to dryness, then

  
  <EMI ID = 125.1>

  
2'-phenoxycarbonylphenyl trans-4-guanidinomethyl-cyclohexanecarboxylate hydrochloride with a melting point of 157-162 [deg.] C.

  
  <EMI ID = 126.1>

  
  <EMI ID = 127.1>

  
6.8.-8.1 (m, 9H).

  

  <EMI ID = 128.1>
 

Example 11

  
3Lbenzyloxycarbonylphenyl trans-4-guanidinomethyl-cyclohexanecarboxylate hydrochloride:

  
For 22 hours, at room temperature,

  
109.8 g of trans-4-guanidinomethylcyclohexane-carboxylic acid hydrochloride are stirred, 106.3 g of benzyl 3-hydroxybenzoate and 105.7 g of dicyclohexylcarbodiimide in

  
450 ml of pyridine. After evaporation of the pyridine,

  
100 ml of water are added and acidified with acid

  
  <EMI ID = 129.1>

  
a centrifugal separator. The solid obtained is treated with methanol, then the methanol layer is concentrated.

  
By recrystallizing the residue from isopropyl alcohol, 169.5 g (81.6%) of 3'-benzyloxy- trans-4guanidinomethyl-cyclohexane-hydrochloride are obtained.

  
  <EMI ID = 130.1>

  
1725, 1755 (C = 0).

  
  <EMI ID = 131.1>

  

  <EMI ID = 132.1>

Example 12

  
3'-hydroxycarbonyl trans-4-guanidinomethyl-cyclohexanecarboxylate hydrochloride:

  
80 g of 3'-benzyloxycarbonylphenyl trans-4guanidinomethyl-cyclohexane-carboxylate hydrochloride are dissolved in a mixture of 300 ml of methanol and <EMI ID = 133.1>

  
hydrogenation on 10% palladium-on-carbon. After absorption of the theoretical amount of hydrogen, the catalyst is filtered off. The filtrate is concentrated to dryness and the crystals formed are recrystallized from methanol to obtain 56.8 g (89%) of the compound

  
  <EMI ID = 134.1>

  
1700, 1740 (C = 0).

  
  <EMI ID = 135.1>

  

  <EMI ID = 136.1>

Example 13

  
Trans-4-guanidinomethylcyclohexane hydrochloride

  
  <EMI ID = 137.1>

  
For 17 hours, at room temperature, a suspension of 35 d 4 g of the acid hydrochloride is stirred

  
  <EMI ID = 138.1>

  
  <EMI ID = 139.1>

  
carbodiimide in 350 ml of pyridine. After evaporation

  
of pyridine, 300 ml of water are added to the residue and the mixture is acidified with hydrochloric acid. We dissolve the

  
white solid obtained in methanol and the

  
insoluble matter by filtration. We concentrate the

  
methanol layer and the residue is recrystallized from ethanol to obtain 33.7 g (58.5%) of the hydrochloride

  
  <EMI ID = 140.1>

  
ethoxycarbonylphenyl with a melting point of 181-1840C.

  
  <EMI ID = 141.1>

  
  <EMI ID = 142.1>

  

  <EMI ID = 143.1>

Example 14

  
4'-hydroxycarbonylphenyl trans-4-guanidinomethyl-cyclohexanecarboxylate hydrochloride:

  
By adopting the method described in Example 12 and

  
  <EMI ID = 144.1>

  
  <EMI ID = 145.1>

  
phenyl as starting material, 45.8 g (88.3%) of 4'-hydroxycarbonylphenyl trans-4-guanidinomethyl-cyclohexanecarboxylate hydrochloride are obtained.

  
  <EMI ID = 146.1>

  
Infrared absorption spectrum: J max (cm)
1750 (C = 0).

  
Nuclear magnetic resonance spectrum: 6-dimethyl sulfoxide-d6, D20

  

  <EMI ID = 147.1>
 

Example 15

  
3'-methoxycarbonylphenyl trans-4-guanidinomethyl-cyclohexanecarboxylate hydrochloride:

  
Pendaat 24 hours, at room temperature,

  
a suspension of 35.4 g of the trans-4-guanidinomethyl-cyclohexane-carboxylic acid hydrochloride, 22.8 g of methyl 3-hydroxybenzoate and 34 g of dicyclohexyl are stirred

  
  <EMI ID = 148.1>

  
insoluble matter and evaporation of the pyridine, the residue is acidified with concentrated hydrochloric acid and extracted with chloroform. After concentrating the chloroform layer, the residual solid is recrystallized from acetone to obtain 20.9 g (37.7%) of trans-4-guanidinomethyl-cyclohexane hydrochloride.

  
  <EMI ID = 149.1>

  
1705, 1745 (C = 0).

  
  <EMI ID = 150.1>

  

  <EMI ID = 151.1>

Example 16

  
Trans-4-guanidinomethyl-cyclohexanecarboxylate 3'-pyridyl dihydrochloride:

  
A suspension of 47.1 g of trans-4-guanidinomethyl-cyclohexane-carboxylic acid hydrochloride, 19 g of 3-hydroxypyridine and 45.4 g of dicyclohexyl-carbo is stirred for 24 hours at room temperature. -diimide in 400 ml of pyridine. The solid collected is extracted with methanol and the methanol layer is evaporated to dryness. We recrystallize the residue

  
  <EMI ID = 152.1>

  
trans-4-guanidinomethyl-cyclohexane-carboxylate hydrate

  
  <EMI ID = 153.1>

  
1750 (C = 0).

  
Nuclear magnetic resonance spectrum: 6 CD OD

  

  <EMI ID = 154.1>

Example 17

  
Trans-4-guanidinomethyl-cyclohexane hydrochloride

  
  <EMI ID = 155.1>

  
For 24 hours, at room temperature,

  
  <EMI ID = 156.1>

  
trans-4-guanidinomethyl-cyclohexane-carboxylic, 28.8 g of &#65533; -naphthol and 45.4 g of dicyclohexylcarbodiimide

  
in 400 ml of pyridine. After evaporation of the solvent,

  
500 ml of water are added to the residue and the mixture is acidified with hydrochloric acid. The white crystals obtained are dissolved in 500 ml of methanol. After evaporation of the methanol, the residue is recrystallized from methanol

  
  <EMI ID = 157.1>

  
p-naphthyl guanidinomethyl-cyclohexane-carboxylate with a melting point of 195-202 [deg.] C.

  
  <EMI ID = 158.1>

  
sulfoxide-d6

  

  <EMI ID = 159.1>

Example 18

  
Trans-4-guanidinomethyl-cyclohexane hydrochloride

  
  <EMI ID = 160.1>

  
Following the method of Example 17 and using 28.8 g of a-naphthol instead of (3-naphthol as

  
  <EMI ID = 161.1>

  
anaphthyl trans-4-guanidinomethyl-cyclohexane-carboxylate with a melting point of 191-203 [deg.] C,

  
  <EMI ID = 162.1>

  
1745 (C = O).

  
  <EMI ID = 163.1>

  

  <EMI ID = 164.1>

Example 19

  
2'-formylphenyl trans-4-guanidinomethyl-cyclohexanecarboxylate hydrochloride:

  
For 16 hours, at room temperature, a suspension of 94.3 g of the trans-4-guanidinomethyl-cyclohexane-carboxylic acid hydrochloride of 50 g is stirred. <EMI ID = 165.1>

  
pyridine, 200 ml of water are added to the residue and the mixture is acidified with hydrochloric acid. The white solid obtained is filtered and extracted with 500 ml of methanol.

  
The insoluble material is removed by filtration and the filtrate is concentrated. 200 ml of acetone are added to the residue

  
and insoluble matter is removed by filtration. We

  
  <EMI ID = 166.1>

  
2'-formylphenyl carboxylate 4-guanidinomethyl-cyclohexane-carboxylate with a melting point of 135-138 [deg.] C.

  
  <EMI ID = 167.1>

  
1740 (c = o).

  
  <EMI ID = 168.1>

  

  <EMI ID = 169.1>


  
An amount of 0.1 mM of this compound inhibits 56% of hydrolytic activity by urokinase.

Example 20

  
2'-methoxyphenyl trans-4-guanidinomethyl-cyclohexanecarboxylate hydrochloride:

  
For 24 hours, at room temperature,

  
  <EMI ID = 170.1>

  
  <EMI ID = 171.1>

  
  <EMI ID = 172.1>

  
After removing the insoluble matter, the solution is concentrated to dryness. 300 ml of water are added to the residue and the solution is acidified with hydrochloric acid. The crystals obtained are filtered and recrystallized from isopropyl alcohol to obtain

  
  <EMI ID = 173.1>

  
fusion of 141-145 [deg.] C.

  
  <EMI ID = 174.1>

  

  <EMI ID = 175.1>


  
An amount of 0.1 mM of this compound inhibits 50% of the hydrolytic activity by urokinase.

Example 21

  
4'-methoxyphenyl trans-4-guanidinomethyl-cyclohexanecarboxylate hydrochloride:

  
A suspension of 47 g of the acid hydrochloride is stirred for 23 hours at room temperature.

  
  <EMI ID = 176.1>

  
in 200 ml of dimethylformamide. To the reaction mixture, 200 ml of water, 100 g of ice and 200 ml of concentrated hydrochloric acid are added. The crystals obtained are filtered and washed with water, then dissolved in
300 ml of methanol. The insoluble matters are separated by filtration and the filtrate is concentrated to dryness.

  
The residue is crystallized from methanol to obtain
29.2 g (42% 4%) of the point compound

  
  <EMI ID = 177.1>

  

  <EMI ID = 178.1>


  
0.1 mM of this compound inhibits
52% hydrolytic activity by urokinase.

Example 22

  
  <EMI ID = 179.1>

  
  <EMI ID = 180.1>

  
a suspension of 70.7 g of the hydrochloride of trans-4-guanidinomethyl-cyclohexane-carboxylic acid, of 41.5 g, is stirred

  
  <EMI ID = 181.1>

  
in 300 ml of dimethylformamide. To the reaction mixture, 100 ml of water and 350 ml of concentrated hydrochloric acid are added. The crystals obtained are filtered and washed with water, then dissolved in 300 ml of methanol. The insoluble materials are separated by filtration and the filtrate is concentrated to dryness. Dissolve the residue in acetone and treat with ether to obtain 65 g (60.9%) of the dot compound

  
of fusion of 144-148 [deg.] C.

  
  <EMI ID = 182.1>

  
1750 (C = 0).

  
  <EMI ID = 183.1>

  

  <EMI ID = 184.1>

Example 23

  
2'-acetylphenyl trans-4-guanidinomethyl-cyclohexanecarboxylate hydrochloride:

  
For 24 hours, at room temperature,

  
  <EMI ID = 185.1>

  
carbodiimide in 300 ml of pyridine. After removing the insoluble matter, the solution is concentrated to dryness. 200 ml of water are added to the residue and the mixture is acidified with hydrochloric acid, then it is extracted with chloroform. The chloroform layer is concentrated to dryness and the residue is recrystallized from isopropyl alcohol to obtain 22.7 g (43.7%) of the

  
  <EMI ID = 186.1>
  <EMI ID = 187.1>
 
  <EMI ID = 188.1>
 0.05 mM of this compound inhibits

  
50% hydrolytic activity by chymotrypsin.

Example 24

  
4'-acetylphenyl trans-4-guanidinomethyl-cyclohexanecarboxylate hydrochloride:

  
For 24 hours, at room temperature,

  
a suspension of 35.4 g of trans-4-guanidinomethyl-cyclohexane-carboxylic acid hydrochloride, 20.4 g of p-hydroxyacetophenone and 34 g of dicyclohexylcarbodiimide is stirred in 300 ml of pyridine. After elimination of <EMI ID = 189.1> dry. 300 ml of water are added to the residue and the mixture is acidified with hydrochloric acid. The crystals obtained are filtered and recrystallized from ethanol to obtain 42.4 g (80%) of the compound under the heading of a

  
  <EMI ID = 190.1>

  
1750 (C = 0).

  
  <EMI ID = 191.1>

  

  <EMI ID = 192.1>
 

Example 25

  
Trans-4-guanidinomethyl-cyclohexane hydrochloride

  
  <EMI ID = 193.1>

  
For 24 hours, at room temperature,

  
  <EMI ID = 194.1>

  
  <EMI ID = 195.1>

  
300 ml of water are added to the residue and the solution is acidified with hydrochloric acid, then it is extracted with chloroform. The chloroform layer is washed with

  
  <EMI ID = 196.1>

  

  <EMI ID = 197.1>

Example 26

  
4Lphenylphenyl trans-4-guanidinomethyl-cyclohexanecarboxylate hydrochloride:

  
For 24 hours, at room temperature,

  
  <EMI ID = 198.1>

  
trans-4-guanidinomethyl-cyclohexane-carboxylic, 34 g of p-phenylphenol and 44.5 g of dicyclohexylcarbodiimide in 250 ml of dimethylformamide. After removal of the insoluble matter, the solution is evaporated to dryness.

  
300 ml of water are added to the residue and the solution is acidified with hydrochloric acid. We recrystallize the crystals

  
  <EMI ID = 199.1>

  
  <EMI ID = 200.1>

  
  <EMI ID = 201.1>

  
Nuclear magnetic resonance spectrum: CD CD30D

  

  <EMI ID = 202.1>

Example 27

  
4'-phenoxycarbonylphenyl trans-4-guanidinomethyl-cyclohexanecarboxylate hydrochloride:

  
For 30 hours, at room temperature,

  
a suspension of 22 g of the hydrochloride of trans-4-guanidinomethyl-cyclohexane-carboxylic acid, of 20 g, is stirred

  
of phenyl 4-hydroxybenzoate and 22.9 g of dicyclohexylcarbodiimide in 100 ml of pyridine. After evaporation of the pyridine, 300 ml of water are added to the residue and the solution is acidified with hydrochloric acid. The solid obtained is extracted with 500 ml of methanol. After concentrating the extract, the residue is recrystallized from ethanol to obtain 21.5 g (53.5%) of trans-4-guanidinomethyl-cyclohexane-carboxylate hydrochloride of 4 <1> -phenoxy-

  
  <EMI ID = 203.1>

  
Nuclear magnetic resonance spectrum: 0 CD, OD

  

  <EMI ID = 204.1>

Example 28

  
  <EMI ID = 205.1>

  
For 18 hours at room temperature,

  
  <EMI ID = 206.1>

  
  <EMI ID = 207.1>

  
  <EMI ID = 208.1>

  
of dicyclohexylcarbodiimide in 30 ml of pyridine. At this

  
  <EMI ID = 209.1>

  
the solution with hydrochloric acid and stirred

  
  <EMI ID = 210.1>

  
methanol. After evaporation of the methanol, the residue is recrystallized from aqueous methanol to obtain 8.4 g (88.2%) of trans-4-guanidinomethyl-cyclohexane hydrochloride

  
  <EMI ID = 211.1>

  

  <EMI ID = 212.1>
 

Example 29

  
Trans-4-guanidinomethyl-cyclohexane hydrochloride

  
  <EMI ID = 213.1>

  
By adopting the method of Example 12 and using 2.5 g of 3'-anisyloxycarbonylphenyl trans-4-guanidinomethylcyclohexane-carboxylate hydrochloride as starting material, 1.5 g (80.3%) of the compound are obtained. under heading.

Example 30

  
Trans-4-guanidinomethyl-cyclohexanecarboxylate hydrochloride 4'-benzyloxycarbonylphenyl:

  
A suspension of 119.4 g of trans-4-guanidinomethyl-cyclohexane-carboxylic acid hydrochloride, 115.6 g of benzyl 4-hydroxybenzoate and 114.9 g is stirred for 20 hours at room temperature. of dicyclohexylcarbodiimide in 430 ml of dimethylformamide. To this reaction mixture is added 1,500 ml of water and the solution is acidified with 500 ml of hydrochloric acid. The solid obtained is extracted with 500 ml of methanol. After removal of the insoluble matter by filtration, the filtrate is concentrated and the residue is recrystallized from a mixture

  
methanol and water to obtain 148.5 g (65.8%) of trans-4-guanidinomethyl-cyclohexane-carboxylate hydrochloride

  
  <EMI ID = 214.1>

  
  <EMI ID = 215.1>

  
1710, 1750 (c-o).

  
  <EMI ID = 216.1>

  

  <EMI ID = 217.1>
 

  

  <EMI ID = 218.1>

Example 31

  
  <EMI ID = 219.1>

  
4'-benzyloxycarbonylphenyl carboxylate:

  
For 30 hours, at room temperature, a suspension of 2.15 g of 4-hydroxycarbonylphenyl trans-4-guanidinomethyl-cyclohexane-carboxylate is stirred, 0.65 g of benzyl alcohol and

  
  <EMI ID = 220.1>

  
propyl) -carbodiimide in 10 ml of pyridine. To this reaction mixture, 50 ml of water are added and the solution is acidified with hydrochloric acid, then the crystals formed are filtered and they are recrystallized from a mixture of methanol

  
  <EMI ID = 221.1>

Example 32

  
Trans-4-guanidinomethyl-cyclohexanecarboxylate hydrochloride 2 <1> -benzyloxycarbonylphenyl:

  
For 24 hours, at room temperature,

  
  <EMI ID = 222.1>

  
trans-4-guanidinomethyl-cyclohexane-carboxylic, 5.71 g of benzyl salicylate and 5.75 g of hydrochloride

  
  <EMI ID = 223.1>

  
of pyridine. To this reaction mixture is added 50 ml of water and the solution is acidified with hydrochloric acid. The solid obtained is filtered and washed with water, then recrystallized from a mixture of methanol and ether to obtain 9.27 g (83.2%) of the title compound.

Example 33

  
3'-methoxyphenyl trans-4-guanidinomethyl-cyclohexanecarboxylate hydrochloride:

  
For 24 hours, at room temperature,

  
a suspension of 35.4 g of the hydrochloride of trans-4-guanidinomethyl-cyclohexane-carboxylic acid, of 18.6 g, is stirred

  
  <EMI ID = 224.1>

  
in 300 ml of pyridine. After removal of the insoluble matter, the residue is acidified with hydrochloric acid and extracted with chloroform. After concentrating the chloroform layer under reduced pressure, the residue is washed with water. The solid obtained is filtered and recrystallized from ethanol to obtain 28.4 g
(55.4%) of the compound under a melting point of

  
  <EMI ID = 225.1>

  
1740 (C = 0).

  
Nuclear magnetic resonance spectrum: o CD30D

  

  <EMI ID = 226.1>

Example 34

  
4'-formylphenyl trans-4-guanidinomethyl-cyclohexanecarboxylate hydrochloride:

  
For 24 hours at room temperature, a suspension of 35.4 g of the acid hydrochloride is stirred

  
  <EMI ID = 227.1>

  
p-hydroxybenzaldehyde and 34 g of dicyclohexylcarbodiimide in 300 ml of pyridine. After evaporation of the

  
  <EMI ID = 228.1>

  
the solution with hydrochloric acid. The solid obtained is filtered and extracted with methanol. The extract is concentrated to dryness and the residue is recrystallized from methanol to obtain 22.5 g (44.2%) of the compound

  
  <EMI ID = 229.1>

  
  <EMI ID = 230.1>

  
  <EMI ID = 231.1>

  

  <EMI ID = 232.1>

Example 35

  
4'-propionylphenyl trans-4-guanidinomethyl-cyclohexanecarboxylate hydrochloride:

  
For 24 hours at room temperature, a suspension of 35.4 g of the acid hydrochloride is stirred

  
  <EMI ID = 233.1>

  
p-hydroxypropiophenone and 34 g of dicyclohexylcarbodiimide in 30 ml of pyridine. The crystals obtained are filtered and extracted with 500 ml of methanol.

  
The extract is evaporated to dryness and recrystallized

  
  <EMI ID = 234.1>

  
  <EMI ID = 235.1>

  
  <EMI ID = 236.1>

  
1750 (c = o).

  
  <EMI ID = 237.1>

J

  

  <EMI ID = 238.1>

Example 36

  
  <EMI ID = 239.1>

  
4'-diphenyl carboxylate:

  
By adopting the method of Example 26 and using 2.95 g of trans-4- acid methane sulfonate

  
  <EMI ID = 240.1> trans-4-guanidinomethyl-cyclohexane- hydrate

  
  <EMI ID = 241.1>

  
  <EMI ID = 242.1>

Example 37

  
trans-4-guanidinomethyl-cyclohexane- p-toluene sulfonate

  
  <EMI ID = 243.1>

  
By adopting the method of Example 6 and using 3.71 g of trans-4guanidinomethyl-cyclohexane-carboxylic acid p-toluene sulfonate instead of trans-4-guanidinomethyl-cyclohexanecarboxylic acid hydrochloride, 4 , 3 g (73.9%) of the compound under a melting point of 110-114 [deg.] C.

  
  <EMI ID = 244.1>

  
1735, 1760 (C = O).

  
  <EMI ID = 245.1>

  

  <EMI ID = 246.1>

Example 38

  
Trans-4-guanidinomethyl-cyclohexanecarboxylate hydrochloride (3-naphthyl:

  
  <EMI ID = 247.1>

  
suspension of 1.8 g of trans-4guanidinomethyl-cyclohexane-carboxylic acid hydrochloride, 1.44 g of
(3-naphthol, 0.05 g sulfuric acid and 0.03 g

  
boric acid in a mixture of 10 ml of dimethylsulfo-

  
xyde and 50 ml of xylene. The water formed is removed by azeotropic distillation with xylene. After concentration

  
of the reaction mixture, the residue is subjected to chromatography in a column of silica gel with a mixture

  
of chloroform and methanol as eluent to obtain the title compound.

Example 39

  
4'-diphenyl trans-4-guanidinomethyl-cyclohexanecarboxylate hydrochloride:

  
For 2 hours, at a temperature of 80-85 [deg.] C &#65533; a mixture of 23.6 g of the hydrochloride is stirred

  
  <EMI ID = 248.1>

  
  <EMI ID = 249.1>

  
After adding 50 ml of toluene, the mixture is stirred

  
at 80-85 [deg.] C for 2 more hours. The solvent is removed by decantation and water is added. The solution is deposited overnight in a refrigerator and the white crystals formed are recrystallized from methanol

  
  <EMI ID = 250.1>

Example 40

  
Trans-4-guanidinomethyl-cyclohexane hydrochloride

  
  <EMI ID = 251.1>

  
For 1 hour, at a temperature of 60 ° C., a suspension of 1.92 g of the trans hydrochloride is stirred.

  
  <EMI ID = 252.1>

  
xyethyl) -phenyl in 10 ml of thionyl chloride. After evaporation of the excess thionyl chloride, it is dissolved

  
the residue in 15 ml of chloroform. At room temperature, the pale yellow solution obtained is added to a solution of 0.65 g of benzyl alcohol and 0.51 g of triethylamine in 5 ml of chloroform. After shaking

  
at 3S-40 [deg.] C for 5 hours, the solvent is evaporated and the residue is solidified with water to obtain 1.4 g (59.1%) of the title compound.

Example 41

  
Trans-4-guanidinomethyl-cyclohexane hydrochloride

  
  <EMI ID = 253.1>

  
For 10 hours at a temperature of 130-
135 [deg.] C, a suspension of 1.92 g of the hydrochloride is stirred

  
  <EMI ID = 254.1>

  
After evaporation of the excess benzyl alcohol, the residue is recrystallized from a mixture of methanol and ether to obtain 1.2 g (50.6%) of the title compound.

Example 42

  
Trans-4-guanidinomethyl-cyclohexanecarboxylate hydrochloride 3 <1> -methoxycarbonylphenyl:

  
For 30 minutes, a reflux is heated

  
  <EMI ID = 255.1>

  
3'-carboxyphenyl methyl-cyclohexane-carbarboxylate in

  
10 ml of thionyl chloride. After concentrating

  
the reaction mixture, the residue is dissolved in 10 ml

  
of chloroform and to the solution thus formed is added

  
5 ml of methanol while cooling. After stirring for 30 minutes, the solution is deposited overnight in a refrigerator. The crystals formed are filtered and

  
they are washed with a mixture of water and acetone to obtain

  
  <EMI ID = 256.1>

  
  <EMI ID = 257.1>

  
  <EMI ID = 258.1>

  
2'-benzyloxycarbonylphenyl carboxylate to a molecule of water:

  
The 2'-benzyloxycarbonylphenyl trans-4guanidinomethyl-cyclohexane-carboxylate hydrochloride is recrystallized from a mixture of acetone and water (85/15) <EMI ID = 259.1>

  
with a melting point of 96-105 [deg.] C.

  
  <EMI ID = 260.1>

  

  <EMI ID = 261.1>


  
  <EMI ID = 262.1>

  
Calculated: 3.88

  
Found: 3.98.

Example 44

  
Trans-4-guanidinomethyl-cyclohexane hydrochloride

  
  <EMI ID = 263.1>

  
For 24 hours, at room temperature,

  
a solution of 9.4 g of the hydrochloride of trans-4-guanidinomethyl-cyclohexane-carboxylic acid, of 9 g, is stirred

  
9.1 g ethoxycarbonylmethyl p-hydroxybenzoate

  
dicyclohexylcarbodiimide in 50 ml of dimethylformamide,

  
Insoluble matter is removed by filtration and the filtrate is evaporated to dryness. We add water

  
to the residue and the solution is acidified with hydrochloric acid, then extracted with chloroform.

  
The extract is evaporated to dryness. We recrystallize

  
the residue in methanol to obtain 10.6 g (60%) of the

  
  <EMI ID = 264.1>

  
  <EMI ID = 265.1>

  
  <EMI ID = 266.1>

  
  <EMI ID = 267.1>

  

  <EMI ID = 268.1>


  
  <EMI ID = 269.1>

  
  <EMI ID = 270.1>

  
4 .'-diphenyl carboxylate:

  
For 2.5 hours, it is heated to a temperature

  
  <EMI ID = 271.1>

  
trans-4-guanidinomethyl-cyclohexane-carboxylic acid and

  
  <EMI ID = 272.1>

  
After cooling, the reaction mixture is washed with petroleum ether and dissolved in chloroform. The clear solution obtained is added to a solution of

  
0.69 g of p-phenylphenol in 5 ml of pyridine and the mixture is stirred overnight at room temperature. The reaction mixture is evaporated and water is added to the residue. The solution is extracted with chloroform. The extract is concentrated and subjected to chromatography in a column packed with silica gel using a mixture of chloroform and methane? 1 as eluent. Then, the crude product obtained is treated with a mixture of ether,

  
methanol and 6N hydrochloric acid to obtain the title compound.

Example 46

  
4-diphenyl trans-4-guanidinomethyl-cyclohexanecarboxylate hydrochloride:

  
For 2 hours, a mixture of 1 g of trans-4-guanidinomethylcyclohexane-carboxylic acid hydrochloride and 5 ml of thionyl chloride is heated to reflux.

  
After concentration, 10 ml of chloroform are added to the reaction mixture. The solution thus obtained is added

  
to a solution of 0.7 g of p-phenylphenol in 5 ml of pyridine and the mixture is heated at 40-50 [deg.] C for 2 hours. Hydrochloric acid is added to the reaction mixture and the solution obtained is stirred, then purified by chromatography to obtain the title compound.

Example 47

  
Trans-4-guanidinomethyl-cyclohexane hydrochloride

  
  <EMI ID = 273.1>

  
For 40 hours, at room temperature,

  
a suspension of 10.64 g of the hydrochloride of trans-4-guanidinomethyl-cyclohexane-carboxylic acid, of 10.94 g, is stirred

  
  <EMI ID = 274.1>

  
removal of insoluble matter by filtration, the filtrate is concentrated and water is added to the residue.

  
The solution is acidified with hydrochloric acid to obtain precipitates which are collected by filtration

  
and which is extracted with methanol. The extract obtained is evaporated under vacuum until dry. The oily residue is dissolved in a mixture of methanol and acetic acid

  
and it is subjected to hydrogenation on palladium carbon. After absorption of the hydrogen, the catalyst is removed <EMI ID = 275.1>

  
acetone to the residue to obtain crystals. The crystals are collected by filtration and recrystallized from ethanol to give 5.4 g (32.4%) of the title compound with a melting point of 174-176.5 [deg.] C.

  
  <EMI ID = 276.1>

  
  <EMI ID = 277.1>

  
  <EMI ID = 278.1>

  

  <EMI ID = 279.1>

Example 48

  
Trans-4-guanidinomethyl-cyclohexane hydrochloride

  
  <EMI ID = 280.1>

  
At a temperature between -15 and -10 [deg.] C,

  
0.65 g of ethyl chloroformate is added to a suspension of 1.92 g of trans-4-guanidinomethyl hydrochloride

  
  <EMI ID = 281.1>

  
in 3 ml of pyridine and 10 ml of chloroform. After stirring the mixture at the same temperature for one hour, 1.08 g of benzyl alcohol is added to the reaction mixture. The solution obtained is continuously stirred for 30 minutes at a temperature between -15 and
-10 [deg.] C. The reaction mixture is evaporated in vacuo to dryness and water and hydrochloric acid are added to the residue. The solution thus obtained is extracted with chloroform. The solvent is removed from the extract. Water is added to the residue to obtain the title compound.

Example 49

  
Trans-4-guanidinomethyl-cyclohexanecarboxylate hydrochloride 4 <1> -carboxymethylphenyl:

  
1) For 20 hours, at ambient temperature, a solution of 4.7 g of trans-4-guanidinomethyl-cyclohexane-carboxylic acid hydrochloride, 5.5 g of tert-butyl p-hydroxyphenylacetate and 6.2 g of dicyclohexylcarbodiimide in 20 ml of dimethylformamide.

  
The reaction mixture is evaporated in vacuo and chloroform is added to the residue. Insoluble matter is removed by filtration and the filtrate is washed with water. The chloroform layer thus formed is concentrated to obtain 6.9 g (81%) of trans-4-guanidino hydrochloride.

  
  <EMI ID = 282.1>

  
methylphenyl with a melting point of 110-125 [deg.] C.

  
2) For 4 hours, at room temperature, a solution of 3 g of the trans-4guanidinomethyl-cyclohexane-carboxylate hydrochloride of 4'-tert-butoxycarbonylmethylphenyl is stirred in 30 ml of acetic acid and a solution of acetic acid and hydrogen chloride to
15%. The reaction mixture is evaporated in vacuo until dry to obtain the compound under heading.

  
  <EMI ID = 283.1>

  
2'-Benzyloxycarbonylphenyl trans-4-guanidinomethyl-cyclohexanecarboxylate hydrochloride:

  
1) Trans-acid chloride hydrochloride

  
  <EMI ID = 284.1>

  
A suspension of 1.2 g of trans-guanidinomethyl-cyclohexane-carboxylic acid hydrochloride and 15 ml of thionyl chloride is stirred for 3 hours at room temperature. Then we remove the chloride

  
of excess thionyl by distillation under reduced pressure. The residue is washed with ethyl ether

  
anhydrous to obtain 1.2 g of the hydrochloride chloride

  
  <EMI ID = 285.1>

  
as a colorless powder.

  
  <EMI ID = 286.1>

  
BtBX

  
1790 (C = 0).

  
2) 2'-Benzyloxycarbonylphenyl trans-4-guanidinomethylcyclohexane-carboxylate hydrochloride:

  
At a temperature of 0 [deg.] C, a solution of 0.75 g of triethylamine in 2 ml of anhydrous methylene chloride is added to a suspension of 1.2 g of hydrochloride.

  
  <EMI ID = 287.1>

  
carboxylic acid and 1 g of benzyl salicylate in 10 ml

  
of anhydrous methylene chloride, then the mixture obtained is stirred at 0 [deg.] C for 10 hours. After distilling off the solvent, the residue is washed with a saturated sodium hydrogen carbonate solution to remove the tr-ans4-guanidinomethyl-cyclohexane-carboxylic acid which does not have

  
reacted and, to the residue formed, anhydrous sodium sulfate is added. Then extract the mixture with chloride

  
methylene. After distilling off the solvent, the residue is washed with ether to remove the unreacted benzyl salicylate. Isopropyl alcohol is added to the residue, then insoluble matter is removed

  
by filtration. The solvent is removed from the filtrate by distillation and the residue formed is recrystallized from

  
water to obtain 320 mg of 2'-benzyloxycarbonylphenyl trans-4guanidinomethyl-cycloi.exane-carboxylate hydrochloride to a molecule of water in the form of colorless crystals.

Example 51

  
  <EMI ID = 288.1>

  
of water:

  
  <EMI ID = 289.1>

  
guanidinomethyl-cyclohexane-carboxylic and 0.74 g of triethylamine suspended in 20 ml of methylene chloride and to the suspension thus formed, the following is added

  
  <EMI ID = 290.1>

  
30 minutes, 1.66 g of benzyl salicylate are added.

  
The mixture obtained is stirred for 2 hours while cooling with ice and again stirred for 36 hours

  
at room temperature. After distilling off the solvent,

  
the residue is washed with a hydrogen carbonate solution

  
of sodium saturates and it is extracted with methylene chloride. After distillation of the solvent, the

  
residue with ether and purified by thin layer chromatography (n-butanol / acetic acid / water = 4: 1: 1)

  
to obtain 285 mg of 2'-benzyloxycarbonylphenyl trans-4-guanidinomethyl-cyclohexane-carboxylate hydrochloride to one molecule of water.

Example S2

  
Tablets: A 220 mg film-coated tablet contains the following materials:

  

  <EMI ID = 291.1>


  
Compound 1 is the same as that defined above.

  
  <EMI ID = 292.1>

  
following:

  

  <EMI ID = 293.1>


  
Compound 1 is the same as that defined above.

  
  <EMI ID = 294.1>

  
a person skilled in the art will understand that numerous modifications can be made to it without departing from the spirit or the framework as defined by the claims below.


    

Claims (1)

1. Compound corresponding to the formula:  <EMI ID = 295.1>  <EMI ID = 296.1> naphthyl, a pyridyl group or an α-tocopheryl group, or a group of formula  <EMI ID = 297.1> in which R2 represents a hydrogen atom, a lower alkoxy group, a formyl group, a lower alkanoyl group or a phenyl group, or R2 represents a group  <EMI ID = 298.1> hydrogen atom, lower alkyl group, phenyl group, benzyl group, anisyl group or lower alkoxy-carbonyimethyl group and n represents a whole number from 0 to 2, or a pharmaceutically acceptable salt of this compound. 2. Compound corresponding to the formula:  <EMI ID = 299.1>  <EMI ID = 300.1> naphthyl, a pyridyl group or an α-tocopheryl group, or a group of formula  <EMI ID = 301.1> in which  <EMI ID = 302.1> laughing, a formyl group, a lower alkanoyl group  <EMI ID = 303.1>  <EMI ID = 304.1> hydrogen atom, lower alkyl group, phenyl group, benzyl group, anisyl group or lower alkoxy-carbonylmethyl group, while n represents an integer of 0 to 2, or a pharmaceutically acceptable salt of this compound . 3. Compound corresponding to the formula:  <EMI ID = 305.1> lower alkoxy, a formyl group, a lower alkanoyl group, a phenyl group or a group of formula <EMI ID = 306.1> gene, a lower alkyl group, a phenyl group, a benzyl group, an anisyl group or a lower alkoxy-carbonylmethyl group, while n represents a  <EMI ID = 307.1> acceptable of this compound. 4. Compound corresponding to the formula:  <EMI ID = 308.1> in which R represents a hydrogen atom, a lower alkyl group, a phenyl group, a benzyl group, an anisyl group, a lower alkoxy-carbonyl-methyl group, while n represents an integer from 0 to 2, or a pharmaceutically acceptable salt of this compound. 5. 4-guanidinomethyl-cyclohexane-carboxylate vanilyl or a pharmaceutically acceptable salt thereof. 6. Naphthyl 4-guanidinomethyl-cyclohexane-carboxylate or one of its pharmaceutically acceptable salts. 7. Pyridyl 4-guanidinomethyl-cyclohexane-carboxylate or one of its pharmaceutically acceptable salts, 8. The α-tocopheryl 4-guanidinomethyl-cyclohexane-carboxylate ester or a pharmaceutically acceptable salt thereof. 9. Trans-4-guanidinomethylcyclohexane-carboxylate (2'-benzyloxycarbonyl) phenyl hydrochloride. 1% ni. Trans-4-guanidinomethylcyclohexane-carboxylate (2'-benzyloxycarbonyl) phenyl hydrochloride to one molecule of water. 11. process for the preparation of a compound corresponding to the formula:  <EMI ID = 309.1>  <EMI ID = 310.1> naphthyl, a pyridyl group, an a-tocopheryl group or a formula group  <EMI ID = 311.1> in which R2 represents a hydrogen atom, a lower alkoxy group, a formyl group, a lower alkanoyl group or a phenyl group,  <EMI ID = 312.1> in which R3 represents a hydrogen atom, a lower alkyl group, a phenyl group, a benzyl group, an anisyl group or an inner carbonyl methyl group, while n represents an integer of 0 to 2, characterized in that it consists in reacting 4-guanidinomethyl-cyclohexane-carboxylic acid or one of its reactive derivatives with a compound of formula:  <EMI ID = 313.1>  <EMI ID = 314.1> naphthyl, a pyridyl group, an a-tocopheryl group or a formula group  <EMI ID = 315.1>  <EMI ID = 316.1> a hydrogen atom, a lower alkoxy group, a formyl group, a lower alkanoyl group or a phenyl group,  <EMI ID = 317.1> in which R ′ represents a lower alkyl group, a phenyl group, a benzyl group, an anisyl group or a lower alkoxy-carbonylmethyl group, while n represents an integer of 0 to 2. 12. The method of claim 11, characterized in that the benzyl group, the anisyl group, the lower alkoxy-carbonylmethyl group or the t-butyl group is replaced by a hydrogen atom. 13. A method according to any one of claims 11 and 12, characterized in that the compound is subjected to a complementary treatment with a pharmaceutically acceptable acid to form the corresponding salt.  <EMI ID = 318.1> to the formula:  <EMI ID = 319.1>  <EMI ID = 320.1> a phenyl group, a benzyl group, an anisyl group or a lower alkoxy-carbonylmethyl group, while n represents an integer of 0 to 2, characterized in that it consists in reacting a compound of formula:  <EMI ID = 321.1> where n has the same meaning as defined  <EMI ID = 322.1> of formula:  <EMI ID = 323.1>  <EMI ID = 324.1> above. 15. Anti-ulcer agent, characterized in that it comprises a compound corresponding to the formula:  <EMI ID = 325.1> in which R3 represents a hydrogen atom, a lower alkyl group, a phenyl group, a benzyl group, an anisyl group or a lower alkoxy-carbonylmethyl group, while n represents an integer of 0 to 2, or alternatively a pharmaceutically acceptable salt of this compound. 16. Anti-ulcer agent according to claim 15,  <EMI ID = 326.1> (2'-Benzyloxycarbonyl) phenyl guanidinomethyl-cyclohexane-carboxylate. 17. Anti-ulcer agent according to claim 15, characterized in that it is the trans-4guanidinomethyl-cyclohexane-carboxylate hydrochloride of (2'-benzyloxycarbonyl) phenyl to a molecule of water.