KR840001423B1 - Process for the preparation of cyclohexane carborylic acid - Google Patents

Abstract

Title compds. (I; R1=vanillyl, naphthyl, pyridil, α-to-copheryl), used as antiulcers, were prepd. by the reaction of 4-guanidinomethylohexane carboxylic acid or its reactive derivs. and III. In an example, a suspension of 11.8g (E)-4-guanidinomethylcyclohexane carboxylic acid hydrochloride, 17.2g vitamin E and 12.4g dicyclohexylcarboimide in 150ml pyridine was stirred at room temp for 30min. The reactant was distilled and dried, treated with 0.1N 200ml and 100ml ethylacetate for 1 hr. vitamin E (E)-4-guanidinomethylcyclo-hexanecarboxylate hydrochloride(16.1g) was obtained. (m.p. 183-186oC)

Description

Method for preparing cyclohexane carboxylic acid derivative

The present invention relates to a process for the preparation of novel cyclohexane carboxylic acid derivatives of the following general formula (I) which are useful as anti-ulcer agents.

In the above formula,

의 그룹을 나타내고, 여기에서 R₂는 수소원자, 저급알콕시, 포르밀, 저급알카노일, 페닐 또는 일반식-(CH₂)_nCOOR₃(여기서는 R₃는 수소원자, 저급알킬, 페닐, 벤질, 아니실 또는 저급알콕시카보닐 메틸그룹을 나타내며, n은 0 내지 2의 정수를 나타낸다)의 그룹을 나타낸다.R ₁ is vanylyl, naphthyl, pyridyl, α-tocopheryl, or a general formula

Wherein R ₂ represents a hydrogen atom, lower alkoxy, formyl, lower alkanoyl, phenyl or a general formula- (CH ₂ ) _n COOR ₃ , where R ₃ represents a hydrogen atom, lower alkyl, phenyl, benzyl, Anylyl or lower alkoxycarbonyl methyl group, n represents an integer of 0 to 2).

Tranexamic acid (trans-4-amino methylcyclohexane carboxylic acid) is a cyclohexane carboxylic acid derivative and is known to have an excellent antiplasmin effect. Esters of transexamic acid are also known to have good antiplasmin effects.

〔Reference. A. okano et al., J. Med. Chem., Vol. 15, No. 3,247 (1972).] However, 4-guanidinomethylcyclohexane carboxylic acid has been reported to show little antiplasmin effect (see above).

As a result of studying various cyclohexane derivatives, the present invention has been reached.

It is an object of the present invention to provide a novel cyclohexane carboxylic acid derivative and a method for producing the same, which show a strong inhibitory effect, anti-ulcer effect, anti-histamine effect, anti-inflammatory effect and anti-allergic effect on proteases.

The present invention also provides cyclohexane carboxylic acid derivatives useful as antiulcers.

These derivatives and their pharmaceutically harmless salts have been found to have excellent inhibitory, antiulcer and antihistamine, anti-inflammatory and anti-allergic effects on proteases. In particular, the compounds of the following general formula (II) have been found to have excellent gastric secretion inhibitory effect, preventive and therapeutic effects against various gastric and duodenal ulcers.

[Wherein R ₃ and n are as defined above.]

의 그룹일 수 있다. 적당한 나프틸 그룹에는 α-나프틸 또는 β-나프틸 그룹이 포함된다. 적당한 피리딜 그룹에는 2-피리딜, 3-피리딜 또는 4-피리딜 그룹이 포함된다. 적당한 일반식

의 그룹으로는 페닐, 메톡시페닐, 에톡시페닐, 프로폭시페닐, 포르밀페닐, 아세틸페닐, 프로파노일페닐, 부티릴페닐, 비페닐 또는 일반식

그룹이 있다. 적당한 일반식

그룹에는 하이드록시카보닐페닐, 메톡시카보닐페닐, 에톡시카보닐페닐, t-부톡시카보닐페닐, 페녹시카보닐페닐, 벤질옥시카보닐페닐, 아니실옥시카보닐페닐, (에톡시카보닐)메툭시카보닐페닐, 하이드록시카보닐메틸페닐, 메톡시카보닐메틸페닐, 에톡시카보닐메틸페닐, t-부톡시카보닐메틸페닐, 페녹시카보닐메틸페닐, 벤질옥시카보닐메틸페닐, 하이드록시카보닐에틸페닐, 엑톡시카보닐에틸페닐, (에톡시카보닐)에툭시카보닐에틸페닐, 페눅시카보닐에틸페닐, 벤질옥시카보닐에틸페닐, 또는 아니실옥시카보닐에틸페닐 등이 포함된다.The ester residue R ₁ of the compound of formula (I) according to the present invention is vanylyl, naphthyl pyridyl, α-tocopheryl, or a general formula

It may be a group of. Suitable naphthyl groups include α-naphthyl or β-naphthyl groups. Suitable pyridyl groups include 2-pyridyl, 3-pyridyl or 4-pyridyl groups. Suitable general formula

Groups of phenyl, methoxyphenyl, ethoxyphenyl, propoxyphenyl, formylphenyl, acetylphenyl, propanoylphenyl, butyrylphenyl, biphenyl or general formula

There is a group. Suitable general formula

The group includes hydroxycarbonylphenyl, methoxycarbonylphenyl, ethoxycarbonylphenyl, t-butoxycarbonylphenyl, phenoxycarbonylphenyl, benzyloxycarbonylphenyl, anyloxyoxycarbonylphenyl, (ethoxy Carbonyl) methoxycarbonylphenyl, hydroxycarbonylmethylphenyl, methoxycarbonylmethylphenyl, ethoxycarbonylmethylphenyl, t-butoxycarbonylmethylphenyl, phenoxycarbonylmethylphenyl, benzyloxycarbonylmethylphenyl, hydroxycarbon Nylethylphenyl, ethoxycarbonylethylphenyl, (ethoxycarbonyl) ethoxycarbonylethylphenyl, phenoxycarbonylethylphenyl, benzyloxycarbonylethylphenyl, or anyloxycarbonylethylphenyl and the like .

The compound of formula (I) may be cis- or trans-isomer.

Pharmaceutically nontoxic salts of the compounds of the present invention are acid addition salts produced from hydrochloric acid, sulfur, phosphoric acid, hydrobromic acid, acetic acid, lactic acid, maleic acid, fumaric acid, tartaric acid, citric acid, methanesulfonic acid, or P-toluenesulfonic acid. to be.

According to the invention, the compound of formula (I), except where R ₃ represents a hydrogen atom, reacts 4-guanidinomethylcyclohexane carboxylic acid or a reactive derivative thereof with a compound of formula (III) and optionally Produced by removing benzyl, anylyl or lower alkoxycarbonylmethyl groups from the product.

In the above formula

의 그룹을 나타내며, 여기에서 R₂′는 수소원자 또는 저급알콕시, 포르밀, 저급알카노일, 페닐 또는 일반식-(CH₂)_nCOOR₃′(여기에서 R₃′은 저급알킬, 페닐, 벤질, 아니실 또는 저급알콕시카보닐메틸그룹을 나타내며, n은 0 내지 2의 정수를 나타낸다)의 그룹을 타나낸다.R ₁ ′ is vanylyl, naphthyl, pyridyl, α-tocopheryl, or general formula

Where R ₂ ′ is a hydrogen atom or lower alkoxy, formyl, lower alkanoyl, phenyl or general formula- (CH ₂ ) _n COOR ₃ ′ where R ₃ ′ is lower alkyl, phenyl, benzyl Or an acyl or lower alkoxycarbonylmethyl group, n represents an integer of 0 to 2).

Suitable reactive derivatives of 4-guanidinomethyl cyclohexane carboxylic acid are acid anhydrides (e.g. acid chloride, acid bromide and the like) and mixed anhydrides using ethyl chloroformate or butylchloroformate and the like. Acid halides are produced by reacting 4-guanidinomethylcyclohexane carboxylic acid with halogenating agents such as thionyl chloride and thionyl bromide at room temperature to the boiling point of the halogenating agent. The acid halide thus obtained is reacted with a compound of general (III) to give a compound of the present invention. This reaction is carried out by stirring for 1 to 40 hours at room temperature to the boiling point of the solvent. Suitable solvents that may be used include dimethylformamide, dimethylacetamide, pyridine, thymelomethane, dichloroethane, glofoform, acetonitrile and the like. For example, acid binders such as triethylamine, dimethylaniline, pyridine and the like are sometimes used.

When directly reacting 4-guanidino methyl cyclohexane carboxylic acid without converting it to its reactive intermediate, the reaction is carried out with a condensing agent such as dicyclohexylcarbodiimide or 1-ethyl-3- (3′-dimethylaminopropyl) Carbodiimides such as carbodiimide hydrochloride; Sulfuric acid-boric acid; Carbodiimidazole; Sulfodiimidazole; Preference is given to performing in the presence of Lewis acids such as phosphorus oxychloride or boron trifluoride.

Compounds of general formula (I) in which R ₃ represents a hydrogen atom are produced by hydrogenation of a compound of general formula (I) in which R ₃ represents a benzyl or anylyl group in the presence of a catalyst such as palladium. These compounds may also be produced by hydrolyzing compounds of formula (I) in which R ₃ represents butyl or lower alkoxycarbonyl methyl groups in the presence of a catalyst such as trifluoro acetic acid or hydrochloric acid-acetic acid.

The resulting compound of formula (I) is then separated by conventional methods.

Usually, it is best to recover the compounds of the present invention in the form of acid addition salts as described above.

Compounds of formula (I) according to the invention have good pharmaceutical activity. That is, the compound of the present invention exhibits excellent inhibitory activity against proteases such as trypsin, chymotrypsin, thrombin or urokinase. The compounds of the present invention also exhibit good antiulcer effect. Thus, they can be used to prevent or treat ulcers, such as shay ulcers, tonic ulcers, indomethacin ulcers, acetic acid-induced ulcers, cysteamine ulcers or histamine ulcers in rats.

The compounds of the present invention have been shown to strongly inhibit gastric secretion, acidity of gastric juice and digestion. Moreover, these effects last considerably longer. The compound of the present invention was confirmed to have low toxicity as a result of acute and subacute toxicity. In particular, the compounds of the general formula (II) show good antiulcer effect, and the stability of the compounds is notable.

The compounds of the present invention also exhibit antihistamine, anti-inflammatory and anti-allergic effects (passive cutaneous anaphylaxis test in the skin).

Compounds of general formula (I) have excellent inhibitory effects on proteases. The inhibitory effect is demonstrated by the following method.

1) Inhibitory effect on trypsin

Inhibitory effect of the compounds of the present invention on trypsin is M. a. Method described by Muramatsu et al. M. Muramatsu et al., The Journal of Biochemistry, Vol. 58,214 (1965). In particular, the inhibitory effect of the compounds of the present invention on the hydrolysis of P-tosyl arginine methyl ester by trypsin is tested. (Incubated for 10 minutes at 37 ℃)

2) inhibitory effect on chymotrypsin

Inhibitory effect of the compounds of the present invention on chymotrypsin is M. a. Proven according to the method described by Muramatsu. The. Journal of Biochemistry, Volume 62 (4), 408 (1967)]. In particular, the inhibitory effect of the compounds of the present invention on the hydrolysis of N-acetyl-L-santyrosine ethyl ester by chymotrypsin is tested (incubation at 37 ° C. for 10 minutes).

3) inhibitory effect on thrombin

Inhibitory effect of the compounds of the present invention on thrombin is M. a. It is determined according to the method described by Muramitsu et al. The Journal of Biochemeistry, Volume 65 (1), 17 (1969)]. In particular, the inhibitory effect of the compounds of the present invention on the hydrolysis of P-tosyl arginine methyl ester by thrombin is tested (incubated for 10 minutes at 37 ° C).

4) Inhibitory Effect on Eurokinase

Inhibitory effect of the compounds of the present invention on urokinase is A. a. second. Proven according to the method described by Johnson et al. A.J. Joeson et al., Throm. Diath Haemorrh. 21, 259-272 (1969)]. In particular, the inhibitory effect of the compounds of the present invention on the hydrolysis of N-acetylglycilysin methyl ester by urokinase is tested. (Incubation at 37 ° C. for 10 minutes).

The results obtained are shown in Table 1 below.

TABLE 1

Compound 1: 2′-benzyloxycarbonylphenyl trans-4-guanidinomethylcyclohexanecarboxylate hydrochloride

Compound 2: 2'-methoxy-4'-formylphenyl trans-4-guanidinomethylcyclohexanecarboxylate hydrochloride

Compound 3: Phenyl Trans-4-gunidinomethylcyclohexane-carboxylate hydrochloride

Compound 4: 2'-ethoxyphenyl trans-4-guanidinomethyl-cyclohexanecarboxylate hydrochloride

Compound 5: 2'-phenoxycarbonylphenyl trans-4-guanidino-methylcyclohexanecarboxylate hydrochloride

Compound 6: 4′-ethoxycarbonylphenyl trans-4-guanidino-methylcyclohexanecarboxylate hydrochloride

Compound 7: 3′-pyridyl trans-4-guanidino methylcyclohexane carboxylate hydrochloride

Compound 8: 4 ′-(2 ″ -ethoxycarbonylethyl) phenyl trans-4-guanidinomethyl cyclohexane carboxylate hydrochloride

Compound 9: 2'-ethoxycarbonylphenyl trans-4-guanidino-methylcyclohexane carboxylate hydrochloride

Compound A: 4 ′-(2 ″ -hydroxycarbonylethyl) phenyl trans-4-amino methylcyclohexanecarboxylate hydrochloride

(See J. Med. Chem., Vol. 15, No. 3, 247 (1972)).

1. Shade ulcers

Sprague-Dolithic males weighing 160-180 g are not fed while freely drinking water for 20 hours prior to the experiment. Anesthesia with ether, incised abdomen and as described by Shae et al. Shay et al., Gastroenterology 5, 43 (1945)].

After 18 hours, the rats are sacrificed with excess ether to remove the stomach. The stomach is incised along a larger bend and the surface area of each lesion tissue during visual displacement is visually measured. Methods [cf. such as tatami lesions] Adami et al., Arch. int. Pharmacodyn 147,113-145 (1964)], and the ulceration index is determined as follows.

0 = no lesion tissue.

1 = hemorrhagic suffusion

2 = 1 to 5 small ulcers (3 mm or less)

3 = multiple ulcers (greater than 5) or one remarkable ulcer

4 = multiple ulcers of remarkable size

5 = perforated ulcer

The test drug is administered intraperitoneally immediately after pyloric binding. The obtained results are shown in Table 2.

TABLE 2

Compound B: Atropine Sulfate

Compound 1, compound 3, compound 8 and compound A are as described above.

2. Acetic Acid Ulcers

Use spray-Dolithic males weighing approximately 200 g. Under ether anesthesia, a 10% acetic acid solution (0.5 ml) is carefully injected between the serous membrane and the muscles near the pyloric glands and the abdomen is sealed. Animals are then kept under conditions and 1 ml / 100 g of each test drug dissolved or suspended in 0.5% carboxymethyl cellulose is administered orally daily for 10 days from the day following surgery. On day 11, mice are sacrificed under ether anesthesia and the stomach is removed. The ulcer area is measured and divided into 5 grades as the ulcer index according to the following method.

The results obtained are shown in Table 3.

TABLE 3

Compound 10: 2′-hydroxycarbonylphenyl trans-4-guanidino-methyl-cyclohexane carboxylate hydrochloride

Compound 1, Compound 2, Compound 8, Compound 9 and Compound A are as described above.

3. Duodenal ulcers (cysteamine-induced)

Approximately 200 grams of spray-dolly species are starved for 24 hours prior to the experiment. Rats receive a single subcutaneous injection of 400 mg / kg of cysteamine. After 7 hours, food is freely supplied. Seven hours after the administration of cysteamine, the test drug is administered orally in an aqueous suspension for 4 days daily. The animals are sacrificed under ether anesthesia the morning after the last dose. The ulcer area (m㎡) is measured and described by the ulcer index. The obtained results are shown in Table 4.

TABLE 4

Compound 1 is the same as described above.

4. Effect on gastric secretion

Inspray-Dolithic males weighing between 160 and 180 g are allowed to feed freely with water for 20 hours prior to the experiment. Dissecting the abdomen under ether anesthesia. Gastroenterology 5,43 (1945)]. The test drug is administered intraperitoneally immediately after ligation. Mice are sacrificed after 3, 6 and 12 hours to remove the stomach. Collect gastric juice for volume analysis. The gastric juice is centrifuged at 1,300 g for 10 minutes at room temperature to obtain a supernatant. The total acidity and digestive activity of the supernatant are measured. Titrate with 0.01 N NaOH to determine total acidity. Method described by Anson et al. J. Gen. Physiol, 22, 79-89 (1938)]. The results are shown in Tables 5-7. Total acidity is expressed in titration volume (ml) and digestive activity is expressed in weight (mg) corresponding to crystalline pepsin.

TABLE 5

TABLE 6

Compounds 1, B and C are as described above.

TABLE 7

Compounds 1, B and C are as described above.

The toxicity of representative compounds in the compounds of the invention is described below.

Acute Toxicity

Normal ICR species mice (male. 25-27 g, female. 22-24 g) are used. The test compound is administered orally using gastric sonde. Test animals are observed for 7 days. The LD ₅₀ value is calculated by the probit method (CI Bliss). The obtained results are shown in Table 8.

TABLE 8

Compound 1 is the same as described above.

2. Subacute Toxicity

Use spray-Dolioma rats weighing approximately 150 g. The dose is administered once a month. 2′-benzyloxycarbonylphenyl trans-4-guanidinomethyl cyclohexane carboxylate hydrochloride is administered in four doses of 40 mg / kg, 130 mg / kg, 400 mg / kg, 1300 mg / kg.

Observe the following:

1) Observation of general symptoms, weight, food intake and water intake

2) hematological examination

3) Serum-Biochemical Test

4) long-term weight

5) Histopathological examination

As a result, 4 mice died at the highest dose (1300 mg / kg), but no toxic lesion tissue was observed at other doses.

Certain compounds of formula (I) exhibit an antihistamine effect. For example, 1 to 5 μg of phenyltrans-4-guanidinomethylcyclohexane carboxylate hydrochloride completely inhibits ileal contraction of guineapic caused by ^10-6 g / ml of histamine dihydrochloride. 50 μg of phenyltrans-4-gunidinomethyl cyclohexane carboxylate hydrochloride completely inhibits ileal contraction of guineapic sensitized with egg albumin when the compound is given with 250 μg / ml egg albumin as the antigen. Moreover, phenyl trans-4-guanidinomethyl-cyclohexane carboxylate inhibits carrageenan-induced inflammation (Woster species rat, intraperitoneal administration, ED ₅₀ is about 200 mg / kg). When the compound of the present invention is used as an antiulcer agent, the compound of the general formula (II) is particularly preferable. These compounds show both oral and parenteral activity, but of course oral administration is more preferred. For oral administration, there are capsules, tablets, powders, or granules. In dosage forms, the active compound is mixed with at least one of lactose, corn starch, inert diluents such as crystalline cellulose, lubricants such as magnesium stearate, binders such as hydroxy propylcellulose, colorants, fragrances, and sweeteners.

The dosages of the compounds of the present invention in the various compositions utilized substantially may vary. However, the compound needs a dose sufficient to reach two suitable dosage forms. The dose selected depends on the desired therapeutic effect, route of administration and duration of treatment. Such doses are generally in the range of 50 to 1500 mg per day. The invention is described in more detail with reference to the following specific examples which are provided for purposes of illustration only and are not intended to limit the invention.

Example 1

Vitamin E trans-4-guanidino methylcyclohexane carboxylate hydrochloride.

A suspension of trans-4-guanidinomethyl cyclohexanecarboxylic acid hydrochloride (11.8 g), vitamin E (17.2 g) and dicyclohexylcarbodiimide (12.4 g) in pyridine (150 mL) is stirred at room temperature for 30 minutes. . After filtration to remove insoluble matters, the filtrate was evaporated to dryness and the residual solid was treated with a mixture of 0.1 N hydrochloric acid (200 mL) and ethyl acetate (mL) for 1 hour. Remove insoluble matters. The organic layer is filtered, then concentrated by filtration and ether is added to give vitamin E trans-4-guanidino methylcyclohexanecarboxylate hydrochloride (16.1 g, 62.1 g) as light yellow crystals having a melting point of 183 to 186 ° C.

IR: ν _max (cm ^-1 ) 1740 (C = 0)

Elemental analysis. C ₃₈ H ₆₅ N ₃ O ₃ HCl

Calculation. C 70.39 H 10.26 N 6.48

Actual measurement. C 70.62 H 10.45 N 6.29

0.1 mmol of this compound inhibits about 50% of the hydrolytic activity by thrombin and trypsin.

Example 2

4 ′-(2 ″ -benzyloxycarbonylethyl) phenyl trans-4-guanidino methylcyclohexane carboxylate hydrochloride.

Trans-4-guanidino-methylcyclohexane carboxylate hydrochloride (7.1 g), benzyl 4-hydroxyphenylpropionate (8.5 g) and dicyclohexyl carbodiimide (7.2 g) in pyridine (75 mL) ) Suspension is stirred at 25 ° C. for 15 hours. After filtration removes insoluble matters, the filtrate is concentrated under reduced pressure. The residue is treated with a mixture of 0.1 N hydrochloric acid (100 mL) and ethyl acetate (50 mL) and the resulting solid is filtered off. The organic layer was filtered and concentrated, and the remaining rubbery material was treated with ether, stirred, and recrystallized from methanol-ether. The white crystal 4 ′-(2 ″ -benzyloxycarbonyl-ethyl) phenyl having a melting point of 77 to 80 ° C. Trans-4-guanidinomethyl cyclohexane carboxylate hydrochloride (13.1 g, 92.1%) is obtained.

IR: ν _max (cm ^-1 ) 1745,1725 (C = 0)

Elemental analysis. C ₂₅ H ₃₁ N ₃ O ₄ HCl

Calculation. C 63.55 H 6.08 N 8.86

Actual measurement. C 62.98 H 6.65 N 9.04

Example 3

4 ′-(2 ″ -ethoxycarbonylethyl) phenyl trans-4-guanidino-methyl cyclohexane carboxylate hardchloride.

Trans-4-guanidinomethyl cyclohexane carboxylic acid hydrochloride (11.8 g) in pyridine (150 mL). A suspension of ethyl 4-hydroxyphenylpropionate (10.7 g) and dicyclohexylcarbodiimide (11.4 g) is stirred at 25 ° C. for 15 hours. The filtrate is evaporated after the insoluble matter is removed by filtration. The residue is treated with 1N hydrochloric acid (150 mL), then the resulting solid is filtered off and the filtrate is washed with ether. When the aqueous layer is pesticide and the residue is treated with ether and recrystallized from ethanol ether, 4 '-(2 ″ -ethoxycarbonylethyl) phenyl trans-4-guanidinomethylcyclohexane carboxylate hard has a melting point of 90 to 91 ° C. Rhochloride (17.9 g, 86.9%) is obtained as white crystals.

IR: ν _max (cm ^-1 ) 1725,1740 (C = 0)

Elemental analysis. C ₂₀ H ₂₉ N ₃ O ₄ HCl

Calculation. C 58.32 H 7.34 N 10.24

Actual measurement. C 57.98 H 7.10 N 10.13

Example 4

Phenyl-trans-4-guanidino-methylcyclohexane carboxylate hydrochloride.

A suspension of trans-4-guanidino-methyl cyclohexane carboxylic acid hydrochloride (11.8 g), phenol (5.6 g) and dicyclohexyl carbodiimide (12.4 g) in pyridine (75 mL) is stirred overnight at room temperature. After evaporation of the solvent, the residue was treated with 0.1 N hydrochloric acid (200 mL), the insoluble material was filtered off and the filtrate was washed with ethyl acetate. The aqueous layer was concentrated to 100 mL, and the resulting crystals were filtered and washed with isopropyl alcohol / isopropyl ether to give phenyl trans-4-guanidino methyl cyclohexane carboxylate hardchloride (12.5 g) having a melting point of 150 to 153 占 폚. , 80.2%). Recrystallization of this compound from methanol yields phenyl trans-4-guanidino-methylcyclohexane carboxylate hydrochloride of white crystals having a melting point of 159.5 to 161.5 ° C.

IR: ν _max (cm ^-1 ) 1750 (C = 0), 1620 to 1680 (C = N)

Elemental analysis. C ₁₅ H ₂₁ N ₃ O ₂ HCl

Calculation. C 57.78 H 7.11 N 13.48

Actual measurement. C 57.49 H 7.25 N 13.27

Example 5

4 ′-(2 ″ -carboxyethyl) phenyl trans-4-guanidinomethyl-cyclohexanecarboxylate hydrochloride.

Of trans-4-guanidino-methylcyclohexane carboxylic acid hydrochloride (11.8 g), benzyl 4-hydroxyphenylpropionate (15.4 g) and dicyclohexylcarbodiimide (14.4 g) in pyridine (80 mL) The suspension is stirred overnight at room temperature. After evaporation of the solvent the residue is treated with a mixture of 0.1N hydrochloric acid (200 mL) and ethyl acetate (100 mL), the insoluble material is filtered off and the organic layer is separated. After evaporation to dryness, methanol, acetic acid and water are added and the resulting clear solution is hydrogenated on 10% Pd / C. Once the theoretical amount of hydrogen is absorbed, the stalk is filtered off. The filtrate is concentrated to dryness and the crystals obtained are recrystallized from methanol / acetic acid to give the title compound (14.3 g, 74.5%) with a melting point of 295 to 296 ° C.

IR: ν _max (cm ^-1 ) 1750 (C = 0), 1706 (C = 0), 1630-1680 (C = N)

Elemental analysis. C ₁₈ H ₂₅ N ₃ O ₄ HCl

Calculation. C 56.32 H 6.83 N 10.95

Actual measurement. C 55.98 H 6.51 N 10.72

Example 6

2'-benzyloxycarbonylphenyl trans-4-guanidinomethylcyclohexanecarboxylate hydrochloride.

A suspension of trans-4-guanidino-methylcyclohexane carboxylic acid hydrochloride (10.6 g), benzylsalicylate (11.4 g) and dicyclohexyl carbodiimide (11.3 g) in pyridine (100 mL) Stir at 40 ° C. for 15 hours. The solvent is evaporated after removing the insoluble material. After treating the residue with 0.1 N hydrochloric acid (200 mL), the resulting crystals are obtained, which are extracted with methanol. The extract was concentrated and water was added, and the resulting solid was recrystallized from aqueous acetone to give 2'-benzyloxycarbonylphenyl trans-4-guanidinomethyl cyclohexane carboxylate hydrochloride having a melting point of 70 to 72.5 ° C (17.9). g, 89.2%) is obtained.

IR: ν _max (cm ^-1 ) 1730 (C = 0)

Elemental analysis. C ₂₃ H ₂₇ N ₃ O ₄ HCl

Calculation. C 61.95 H 6.33 N 9.42

Actual measurement. C 61.38 H 6.38 N 9.19

The obtained product is recrystallized from methanol / ether to give 2′-benzyloxycarbonyl phenyltrans-4-guanidinomethylcyclohexanecarboxylate hydrochloride of white crystals having a dew point of 83 ° C.

Example 7

2'-hydroxycarbonylphenyl trans-4-guanidinomethylcyclohexanecarboxylate hydrochloride.

A solution of 2'-benzyloxycarbonylphenyl trans-4-guanidinomethyl cyclohexane carboxylate hydrochloride (8.9 g) in acetic acid (30 mL) and methanol (10 mL) is hydrogenated over 10% Pd / C. After absorbing hydrogen (about 500 mL) the catalyst is filtered off. The filtrate was concentrated to dryness and the crystals washed with ether to recrystallize from ethanol / ether to give the title compound (6.5 g, 91.3%) with a melting point of 166 to 168 ° C.

IR: ν _max (cm ^-1 ) 1750, 1690 (C = 0)

Elemental analysis. C ₁₆ H ₂₁ N ₃ O ₄ HCl

Calculation. C 54.01 H 6.23 N 11.81

Actual measurement. C 53.85 H 6.05 N 11.42

Example 8

2'-ethoxycarbonylphenyl trans-4-guanidinomethylcyclohexanecarboxylate hydrochloride.

A suspension of trans-4-guanidinomethyl cyclohexanecarboxylic acid hydrochloride (7.1 g), ethyl salicylate (5.5 g) and dicyclo hexylcarbodiimide (7.2 g) in pyridine (100 mL) was stirred for 15 hours at room temperature. Stir while. After the insoluble matter is removed by filtration, the solution is concentrated. The residue is treated with 0.1 N hydrochloric acid (100 mL), after which the insoluble material is further filtered off and the filtrate is washed with ether. After evaporation, the residue was treated with ether, stirred and the resulting crude product was recrystallized from ethanol / ether to give 2'-ethoxycarbonylphenyl trans-4-guanidinomethyl cyclohexane with a melting point of 110 to 111 ° C. Obtained carboxylate hydrochloride (8.4 g, 72.9%).

IR: ν _max (cm ^-1 ) 1740 (C = 0)

Elemental analysis. _{C 17 H 25 N 3 O 4} · HCl

Calculation. C 56.32 H 6.83 N 10.95

Actual measurement. C 55.97 H 6.72 N 10.54

Example 9

2'-methoxy-4'-propylphenyltrans-4-guanidinomethylcyclohexane carboxylate hydrochloride.

A suspension of trans-4-guanidinomethyl cyclohexane carboxylate hydrochloride (7.1 g), vanillin (5.0 g) and dicyclohexyl carbodiimide (7.2 g) in pyridine (100 mL) was stirred at 30 DEG C for 15 hours. Stir. The solution is concentrated after removing the insoluble matter. The residue was treated with a mixture of 0.1N hydrochloric acid (100 mL) and ethyl acetate (100 mL) and stirred for 1 hour. The insolubles are further filtered off and the organic layer is separated. After evaporation to dryness, the remaining solids were washed with ether and recrystallized from isopropyl alcohol / ether to melt 2'-methoxy-4'-formylphenyl trans-4-guanidinomethyl cyclohexane carboxylate with melting point 110-111 ° C. Hydrochloride (9.6 g, 86.5%) is obtained.

IR: ν _max (cm ^-1 ) 1760 (C = 0)

Elemental analysis. _{C 17 H 23 N 3 O 4} · HCl

Calculation. C 55.21 H 6.54 N 11.36

Actual measurement. C 54.74 H 6.66 N 11.22

Example 10

2'-phenoxycarbonylphenyl trans-4-guanidino methylcyclohexane carboxylate hydrochloride.

A suspension of trans-4-guanidinomethyl cyclohexane carboxylic acid hydrochloride (27.5 g), phenylsalicylate (25.0 g) and dicyclohexyl carbodiimide (26.5 g) in dimethylformamide (100 mL) was prepared at room temperature. Stir for 21 hours. Water (150 mL) and concentrated hydrochloric acid (120 mL) are added to this solution, and the precipitated solid is washed with water. The solids were treated with methanol and the methanol layer was evaporated to dryness to solidify with ether, and the 2'-phenoxycarbonylphenyl trans-4-guanidinomethyl cyclohexanecarboxylate hydrochloride having a melting point of 157 to 162 ° C (34.1 g, 67.5%) is obtained.

IR: ν _max (cm ^-1 ) 1740, 1750 (C = 0)

NMR: δCD ₃ OD 0.7-3.1 (m, 12H) 6.8-8.1 (m, 9H)

Elemental analysis. C ₂₂ H ₂₅ N ₃ O ₄ HCl

Calculation. C 61.18 H 6.07 N 9.73

Actual measurement. C 61.08 H 5.95 N 9.79

Example 11

3'-benzyloxycarbonylphenyl trans-4-guanidinomethyl cyclohexane carboxylate hydrochloride.

Trans-4-guanidino-methylcyclohexane carboxylic acid hydrochloride (109.8 g), benzyl 3-hydroxybenzoate (106.3 g) and dicyclohexyl carbodiimide (105.7 g) in pyridine (450 mL) at room temperature Stir for 22 hours. Pyridine is evaporated and then water (100 mL) is added and acidified with hydrochloric acid.

The resulting slurry is centrifuged. The solid obtained is treated with methanol and the methanol layer is concentrated. The residue is recrystallized from isopropyl alcohol to give 3'-benzyloxycarbonylphenyl trans-4-guanidinomethyl cyclohexane carboxylate hydrochloride (169.5 g, 81.6%) having a melting point of 75 to 80 ° C.

IR: ν _max (cm ^-1 ) 1725, 1755 (C = 0)

NMR: δCD ₃ OD

0.8-3.2 (m, 12H)

5.3 (S, 2H)

6.9-8.0 (m, 9H)

Elemental analysis. C ₂₃ H ₂₇ N ₃ O ₄ HCl

Calculation. C 61.95 H 6.33 N 9.42

Actual measurement. C 61.37 H 6.18 N 9.58

Example 12

3'-hydroxycarbonylphenyl trans-4-guanidinomethylcyclohexane carboxylate hydrochloride.

3′-benzyloxycarbonylphenyl trans-4-guanidino methylcyclohexanecarboxylate hydrochloride (80 g) is dissolved in a mixture of methanol (300 mL) and acetic acid (300 mL) and the solution is 10% pd / C Hydrogenize in phase. Once the theoretical amount of hydrogen is absorbed, the crystals are filtered off. The filtrate is concentrated to dryness and the crystals obtained are recrystallized from methanol to give the title compound (56.8 g, 89.0%) having a melting point of 197 to 200 ° C.

IR: ν _max (cm ^-1 ) 1700, 1740 (C = 0)

NMR: δCD ₃ OD

0.8-3.2 (m, 12H)

7.8-8.0 (m, 4H)

Elemental analysis. C ₁₆ H ₂₁ N ₃ O ₄ HCl

Calculation. C 54.01 H 6.23 N 11.81

Actual measurement. C 53.96 H 6.21 N 11.89

Example 13

4'-ethoxycarbonylphenyl trans-4-guanidinomethyl cyclohexanecarboxylate hydrochloride.

A suspension of trans-4-guanidinomethyl cyclohexanecarboxylic acid hydrochloride (35.4 g), ethyl 4-hydroxybenzoate (25 g) and dicyclohexylcarbodiimide (34.0 g) in pyridine (350 mL) was stirred at room temperature. Stir for 17 hours. After evaporation of pyridine water (300 mL) is added to the residue and the mixture is acidified with hydrochloric acid. The resulting white solid is dissolved in methanol and the insolubles are filtered off. The methanol layer was concentrated and the residue was recrystallized from ethanol to give 4′-ethoxycarbonylphenyl trans-4-guanidino methylcyclohexane carboxylate hydrochloride (33.7 g, 58.5%) with a melting point of 181 to 184 ° C. Get

IR: ν _max (cm ^-1 ) 1715, 1755 (C = 0)

NMR: δCD ₃ OD

0.6-3.1 (m, t, 15H)

4.3 (q, 2H)

7.1,8.0 (d, d, 4H)

Elemental analysis. C ₁₈ H ₂₅ N ₃ O ₄ HCl

Calculation. C 56.32 H 6.83 N 10.95

Actual measurement. C 56.21 H 6.79 N 11.03

Example 14

4'-hydroxycarbonylphenyl trans-4-guanidino methylcyclohexanecarboxylate hydrochloride.

According to the method of example 12, 4′-hydroxycarbonylphenyl trans-4 using 4′-benzyloxycarbonylphenyl trans-4-guanidino methylcyclohexane carboxylate hydrochloride (65 g) as starting material Obtain guanidinomethyl cyclohexane carboxylate hydrochloride (45.8 g, 88.3%).

Melting point. 225.5 to 228.0 ° C

IR: ν _max (cm ^-1 ) 1750 (C = 0)

NMR: δDMSO-d ₆ , D ₂ O

0.8-3.2 (m, 12H)

7.2,8.0 (d, d, 4H)

Elemental analysis. C ₁₆ H ₂₁ N ₃ O ₄ HCl

Calculation. C 54.01 H 6.23 N 11.81

Actual measurement. C 53.89 H 6.21 N 11.97

Example 15

3'-methoxycarbonylphenyl trans-4-guanidino methylcyclohexanecarboxylate hydrochloride.

A suspension of trans-4-guanidinomethyl cyclohexane carboxylic acid hydrochloride (35.4 g), methyl 3-hydroxybenzoate (22.8 g) and dicyclohexylcarbodiimide (34.0 g) in pyridine (300 mL) was cooled to room temperature. Stir for 24 hours. The insolubles are removed, the pyridine is evaporated and the residue is acidified with concentrated hydrochloric acid and extracted with chloroform. The chloroform layer was concentrated and the remaining solid was recrystallized from acetone to give 3'-methoxycanylphenyl trans-4-guanidinomethylcyclohexanecarboxylate hydrochloride (20.9 g, 37.7%) having a melting point of 138 to 147 ° C. Get

IR: ν _max (cm ^-1 ) 1705, 1745 (C = 0)

NMR: δCD ₃ OD

0.8-3.2 (m, 12H)

3.9 (s, 3H)

7.0-8.1 (m, 12H)

Elemental analysis. _{C 17 H 23 N 3 O 4} · HCl

Calculation. C 55.21 H 6.51 N 11.36

Actual measurement. C 54.93 H 6.48 N 11.43

Example 16

3'-pyridyl trans-4-guanidinomethylcyclohexanecarboxylate hydrochloride.

A suspension of trans-4-guanidinomethyl cyclohexane carboxylic acid hydrochloride (47.1 g), 3-hydroxypyridine (19.0 g) and dicyclo hexylcarbodiimide (45.4 g) in pyridine (400 mL) was added at room temperature Stir for time. The collected solid is extracted with methanol and the methanol layer is evaporated to dryness. The residue is recrystallized from methanol to give 3'-pyridyl trans-4-guanidinomethyl cyclohexane carboxylate hydrochloride (36.1 g, 57.7%) having a melting point of 180 to 185 ° C.

IR: ν _max (cm ^-1 ) 1750 (C = 0)

NMR: δCD ₃ OD

0.7-3.1 (m, 12H)

7.6-8.6 (m, 3H)

Elemental analysis. C ₁₄ H ₂₀ N ₄ O 2 · 2HCl

Calculation. C 48.15 H 6.35 N 16.04

Actual measurement. C 47.98 H 6.24 N 16.31

Example 17

β-naphthyl trans-4-guanidino methyl cyclohexane carboxylate hydrochloride.

A suspension of trans-4-guanidinomethyl cyclohexane carboxylic acid hydrochloride (47.1 g), β-naphthol (28.8 g) and dicyclohexyl carbodiimide (45.4 g) in pyridine (400 mL) was stirred at room temperature for 24 hours. Stir. After evaporation of the solvent, water (500 mL) is added to the residue and the mixture is acidified with hydrochloric acid. The resulting white crystals are dissolved in methanol (500 mL). The methanol is evaporated and the residue is recrystallized from methanol to give β-naphthyl trans-4-guanidino methylcyclohexane carboxylate hydrochloride (49.1 g, 67.8%) having a melting point of 195 to 202 ° C.

IR: ν _max (cm ^-1 ) 1750 (C = 0)

NMR: δDMSO-d ₆

0.8-3.1 (m, 12H)

6.9-8.2 (m, 7H)

Elemental analysis. C ₁₉ H ₂₃ N ₃ O ₂ HCl

Calculation. C 63.06 H 6.68 N 11.61

Actual measurement. C 62.52 H 6.59 N 11.89

Example 18

α-naphthyl trans-4-guanidinomethyl cyclohexane carboxylate hydrochloride.

α-naphthyl trans-4-guanidino methylcyclohexane carboxylate hydrochloride having a melting point of 191 to 203 ° C. according to the method of Example 17 using α-naphthol (28.8 g) instead of β-naphthol as a starting material 36.9 g, 51.0%).

IR: ν _max (cm ^-1 ) 1745 (C = 0)

NMR: δCD ₃ OD

0.9-3.0 (m, 12H)

7.2-8.1 (m, 7H)

Elemental analysis. C ₁₉ H ₂₃ N ₃ O ₂ HCl

Calculation. C 63.06 H 6.68 N 11.61

Actual measurement. C 62.71 H 6.62 N 11.83

Example 19

2'-formylphenyl trans-4-guanidino methyl cyclohexane carboxylate hydrochloride.

A suspension of trans-4-guanidino methyl cyclohexane carboxylic acid hydrochloride (94.3 g), salicylic aldehyde (50 g) and dicyclo hexylcarbodiimide (90.8 g) in pyridine (600 mL) was stirred for 16 h at room temperature do. After evaporation of the pyridine water (200 mL) is added to the residue and the mixture is acidified with hydrochloric acid. The resulting white solid is filtered and extracted with methanol (500 mL). Insoluble material is filtered off and the filtrate is concentrated. Acetone (200 mL) is added to the residue and the insoluble material is filtered off. Concentrate the filtrate. The residue is crystallized from water to give 2'-formylphenyl trans-4-guanidino methyl cyclohexane carboxylate hydrochloride (53.2 g, 39.1%) having a melting point of 135 to 138 ° C.

IR: ν _max (cm ^-1 ) 1740 (C = 0)

NMR: δCD ₃ OD

0.8-3.2 (m, 12H)

5.4 (s, 1H)

6.8 (m, 4H)

Elemental analysis. C ₁₆ H ₂₁ N ₃ O ₃ HCl

Calculation. C 56.55 H 6.53 N 12.37

Actual measurement. C 55.98 H 6.31 N 12.63

0.1 mmol of this compound inhibits 56% of hydrolytic activity by urokinase.

Example 20

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

A suspension of trans-4-guanidino methylcyclohexane carboxylic acid hydrochloride (47.1 g), 0-methoxyphenol (24.8 g) and dicyclo hexylcarbodiimide (45.4 g) is stirred at room temperature for 24 hours. The solution is concentrated to dryness after removing the insoluble material. Water (300 mL) is added to the residue and the solution is acidified with hydrochloric acid. The resulting crystals are filtered and recrystallized from isopropyl alcohol to give the title compound (57.5 g, 84.1%) having a melting point of 141 to 145 ° C.

IR: ν _max (cm ^-1 ) 1760 (C = 0)

NMR: δCD ₃ OD

0.7-3.0 (m, 12H)

3.8 (s, 3H)

6.8-7.3 (m, 4H)

Elemental analysis. C ₁₆ H ₂₆ N ₃ O ₃ HCl

Calculation. C 56.22 H 7.08 N 12.29

Actual measurement. C 56.18 H 7.01 N 12.31

Example 21

4'-methoxyphenyltrans-4-guanidino methylcyclohexanecarboxylate hydrochloride.

A suspension of trans-4-guanidinomethylcyclohexane carboxylic acid hydrochloride (47 g), P-methoxyphenol (25 g) and dicyclo hexylcarbodiimide (45 g) in dimethylformamide (200 mL) was 23 hours at room temperature. Stir while. Water (200 mL), ice (100 g) and concentrated hydrochloric acid (200 mL) are added to the reaction mixture. The resulting crystals are filtered off, washed with water and dissolved in methanol (300 mL). The insoluble material is filtered off and the filtrate is concentrated to dryness. The residue is crystallized from methanol to give the title compound (29.2 g, 42.4%) having a melting point of 203 to 205 ° C.

IR: ν _max (cm ^-1 ) 1745 (C = 0)

NMR: δCD ₃ OD

0.7-3.1 (m, 12H)

3.8 (s, 3H)

7.0 (s, 4H)

Elemental analysis. C ₁₆ H ₂₃ N ₃ O ₂ HCl

Calculation. C 56.22 H 7.08 N 12.29

Actual measurement. C 56.19 H 7.01 N 12.35

Example 22

2'-ethoxyphenyl trans-4-guanidino methylcyclohexane carboxylate hydrochloride.

A suspension of trans-4-guanidino methylcyclohexanecarboxylic acid hydrochloride (70.7 g), 0-ethoxyphenol (41.5 g) and dicyclo hexylcarbodiimide (68.1 g) in dimethylformamide (300 mL) was cooled to room temperature. Stir for 24 hours. To the reaction mixture was added water (100 mL) and concentrated hydrochloric acid (350 mL). The resulting crystals are filtered off, washed with water and dissolved in methanol (300 mL). Insoluble material is filtered off and the filtrate is evaporated to dryness. The residue is taken up in acetone and treated with ether to give the title compound (65.0 g, 60.9%) with a melting point of 144-148 ° C.

IR: ν _max (cm ^-1 ) 1750 (C = 0)

NMR: δCD ₃ OD

0.7-3.0 (m, t, 15H)

4.0 (1, 2H)

6.7-7.2 (m, 4H)

Elemental analysis. C ₁₇ H ₂₅ N ₃ O ₃ HCl

Calculation. C 56.38 H 7.36 N 11.81

Actual measurement. C 56.94 H 7.01 N 12.11

Example 23

2'-acetylphenyltrans-4-guanidino methylcyclohexane carboxylate hydrochloride.

A suspension of trans-4-guanidinomethylcyclohexane hydrochloride (34.7 g), 0-hydroxyacetophenone (20.0 g) and dicyclo hexylcarbodiimide (33.3 g) in pyridine (300 mL) was added at room temperature. Stir for time. After removing the insoluble material, the solution is evaporated to dryness. Water (200 mL) is added to the residue, the mixture is acidified with hydrochloric acid and extracted with chloroform. The chloroform layer is evaporated to dryness and the residue is recrystallized from isopropyl alcohol to give the title compound (22.7 g, 43.7%) with a melting point of 159-166 ° C.

IR: ν _max (cm ^-1 ) 1750 (C = 0)

NMR: δCD ₃ OD

0.8-3.1 (m, s, 15H)

6.9-8.0 (m, 4H)

Elemental analysis. C ₁₇ H ₂₃ N ₃ O ₃ HCl

Calculation. C 57.70 H 6.84 N 11.88

Actual measurement. C 57.47 H 6.78 N 12.03

Example 24

4'-acetylphenyl trans-4-guanidino methylcyclohexane carboxylate hydrochloride.

A suspension of trans-4-guanidinomethyl cyclohexanecarboxylic acid hydrochloride (35.4 g), P-hydroxyacetophenone (20.4 g) and dicyclohexylcarbodiimide (34.0 g) in pyridine (300 mL) was stirred at room temperature. Stir for 24 hours. After removing the insoluble material, the solution is evaporated to dryness. Water (300 mL) is added to the residue and the mixture is acidified with hydrochloric acid. The resulting crystals are filtered and recrystallized from ethanol to give the title compound (42.4 g, 80%) with a melting point of 175 to 180 ° C.

IR: ν _max (cm ^-1 ) 1750 (C = 0)

NMR: δCD ₃ OD

0.7-3.1 (m, s, 15H)

7.2, 8.0 (d, d, 4H)

Elemental analysis. C ₁₇ H ₂₃ N ₃ O ₃ HCl

Calculation. C 57.70 H 6.84 N 11.88

Actual measurement. C 57.63 H 6.81 N 11.92

Example 25

2'-diphenyl trans-4-guanidinomethyl cyclohexane carboxylate hydrochloride.

A suspension of trans-4-guanidinomethyl cyclohexane carboxylic acid hydrochloride (35.4 g), 0-phenylphenol (25.5 g) and dicyclohexylcarbodiimide (34.0 g) in pyridine (300 mL) was stirred for 24 hours at room temperature. Stir while. The solution is evaporated to dryness. Water (300 mL) was added to the residue, the solution was acidified with hydrochloric acid and extracted with chloroform. The chloroform layer is washed with water and evaporated to afford the title compound (55.5 g, 94.6%) with a melting point of 78 to 85 ° C.

IR: ν _max (cm ^-1 ) 1750 (C = 0)

NMR: δCD ₃ OD

0.7-3.0 (m, 12H)

6.8-7.5 (m, 9H)

Elemental analysis. C ₂₁ H ₂₅ N ₃ O ₂ HCl

Calculation. C 65.02 H 6.76 N 10.83

Actual measurement. C 64.69 H 6.49 N 11.04

Example 26

4'-diphenyltrans-4-guanidinomethyl cyclohexane carboxylate hydrochloride.

A suspension of trans-4-guanidino methylcyclohexanecarboxylic acid hydrochloride (47.1 g), P-phenylphenol (34.0 g) and dicyclohexylcarbodiimide (44.5 g) in dimethylformamide (250 mL) was prepared at room temperature. Stir for 24 hours. After removing the insoluble material, the solution is evaporated to dryness. Water (300 mL) is added to the residue and the solution is acidified with hydrochloric acid. The resulting crystals are recrystallized from methanol to give the title compound (47.9 g, 61.7%) having a melting point of 185 to 196 ° C.

IR: ν _max (cm ^-1 ) 1750 (C = 0)

NMR: δCD ₃ OD

0.8-3.1 (m, 12H)

6.9-7.8 (m, 9H)

Elemental analysis. C ₂₁ H ₂₅ N ₃ O ₃ HCl

Calculation. C 65.02 H 6.76 N 10.83

Actual measurement. C 64.94 H 6.57 N 11.03

Example 27

4'-phenoxycarbonylphenyl trans-4-guanidino methylcyclohexane carboxylate hydrochloride.

A suspension of trans-4-guanidinomethyl cyclohexanecarboxylic acid hydrochloride (22.0 g), phenyl-4-hydroxybenzoate (20.0 g) and dicyclohexylcarbodiimide (22.9 g) in pyridine (100 mL) Stir at room temperature for 30 hours. After evaporating pyridine, water (300 mL) is added to the residue and acidified with hydrochloric acid. The resulting solid is extracted with methanol (500 mL). The extract was concentrated and the residue was recrystallized from ethanol to give 4'-phenoxycarbonylphenyl trans-4-guanidinomethyl cyclohexanecarboxylate hydrochloride (21.5 g, 53.5%) having a melting point of 166 to 170 ° C. Get

IR: ν _max (cm ^-1 ) 1740, 1745 (C = 0)

NMR: δCD ₃ OD

0.7-3.1 (m, 12H)

7.0-8.3 (m, 9H)

Elemental analysis. C ₂₂ H ₂₅ N ₃ O ₄ HCl

Calculation. C 61.18 H 6.07 N 9.73

Actual measurement. C 61.09 H 6.12 N 9.78

Example 28

3'-hydroxycarbonylphenyl trans-4-guanidinomethyl cyclohexane carboxylate hydrochloride.

Title compound (1.5 g, 80.3%) according to the method of Example 12 using 3'-anisyloxy carbonylphenyl trans-4-guanidino methyl cyclohexanecarboxylate hydrochloride (2.5 g) as starting material To obtain.

Example 29

4′-benzyloxycarbonylphenyl trans-4-guanidino methyl cyclohexanecarboxylate hydrochloride.

Of trans-4-guanidinomethyl cyclohexane carboxylic acid hydrochloride (119.4 g), benzyl-4-hydroxybenzoate (115.6 g) and dicyclohexylcarbodiimide (114.9 g) in dimethylformamide (430 mL) The suspension is stirred at room temperature for 20 hours. Water (1500 mL) is added to the reaction mixture and the solution is acidified with hydrochloric acid (500 mL). The resulting solid is extracted with methanol (500 mL). After removal of the insoluble material by filtration, the filtrate was concentrated and the residue was recrystallized from methanol / water to 4'-benzyloxycarbonylphenyl trans-4-guanidino methylcyclohexanecarboxylate with a melting point of 134-138 ° C. Hydrochloride (148.5 g, 65.8%) is obtained.

IR: ν _max (cm ^-1 ) 1710, 1750 (C = 0)

NMR: δCD ₃ OD

0.8-3.2 (m, 12H)

5.35 (s, 2H)

7.2, 8.1 (d, d, 4H)

7.4 (s, 5 H)

Elemental analysis. C ₂₃ H ₂₇ N ₃ O ₄ HCl

Calculation. C 61.95 H 6.33 N 9.42

Actual measurement. C 61.47 H 6.18 N 9.53

Example 30

2'-benzyloxycarbonylphenyl trans-4-guanidinomethyl cyclohexane carboxylate hydrochloride.

Trans-4-guanidinomethyl cyclohexane carboxylic acid hydrochloride (5.89 g), benzylsalicylate (5.71 g) and 1-ethyl-3- (3'-dimethylaminopropyl) carbodiimide in pyridine (25 mL) The suspension of hydrochloride (5.75 g) is stirred at rt for 24 h. Water (50 mL) is added to the reaction mixture to acidify the solution with hydrochloric acid. The resulting solid is filtered, washed with water and recrystallized from methanol / ether to give the title compound (9.27 g, 83.2%).

Example 31

3'-methoxyphenyl trans-4-guanidinomethyl cyclohexane carboxylate hydrochloride.

A suspension of trans-4-guanidinomethyl cyclohexanecarboxylic acid hydrochloride (35.4 g), m-methoxyphenol (18.6 g) and dicyclo hexylcarbodiimide (34.0 g) in pyridine (300 mL) was added at room temperature. Stir for time. After removing the insoluble matter, the residue is acidified with hydrochloric acid and extracted with chloroform. The chloroform layer is concentrated under reduced pressure and the residue is washed with water. The resulting solid is filtered and recrystallized from ethanol to give the title compound (28.4 g, 55.4%) having a melting point of 125.5 to 131.5 ° C.

IR: ν _max (cm ^-1 ) 1740 (c = 0)

NMR: δCD ₃ OD

1.0-3.1 (m, 12H)

3.8 (s, 3H)

6.6-7.45 (m, 4H)

Example 32

4′-formylphenyl trans-4-guanidino methyl cyclohexane carboxylate hydrochloride.

A suspension of trans-4-guanidinomethyl cyclohexane carboxylic acid hydrochloride (35.4 g), p-hydroxybenzaldehyde (18.3 g) and dicyclohexylcarbodiimide (34.0 g) in pyridine (300 mL) was stirred at room temperature. Stir for 24 hours. After evaporating pyridine, water (100 mL) is added to the residue and the solution is acidified with hydrochloric acid. The resulting solid is filtered and extracted with methanol. The extract is evaporated to dryness and the residue is recrystallized from methanol to give the title compound (22.5 g, 44.2%) with a melting point of 157.5 to 163.5 ° C.

IR: ν _max (cm ^-1 ) 1750 (C = 0)

NMR: δCD ₃ OD

0.9-3.1 (m, 12H)

7.25-7.95 (d, d, 4H)

Example 33

4′-propionylphenyl trans-4-guanidinomethyl cyclohexane carboxylate hydrochloride.

A suspension of trans-4-guanidinomethyl cyclohexane carboxylic acid hydrochloride (35.4 g), p-hydroxypropiophenone (22.5 g) and dicyclohexylcarbodiimide (34.0 g) in pyridine (300 mL) was cooled to room temperature. Stir for 24 hours. The resulting crystals were filtered and extracted with methanol (500 mL). The extract is evaporated to dryness and the residue is recrystallized from methanol to give the title compound (39.6 g, 71.8%) with a melting point of 179 to 185 ° C.

IR: ν _max (cm ^-1 ) 1750 (C = 0)

NMR: δCD ₃ OD

0.9-3.0 (m, 17H)

7.1-7.95 (d, d, 4H)

Example 34

4'-diphenyl trans-4-guanidinomethyl cyclohexane carboxylate methanesulfonate.

By the method of Example 26, using the trans-4-guanidinomethyl cyclohexane carboxylic acid methanesulfonate (2.95 g) in place of the trans-4-guanidino methyl cyclohexanecarboxylic acid hydrochloride, the title compound (3.2 g, 71.4%).

Melting point. 207 to 210 ° C

Example 35

2'-benzyloxycarbonylphenyl trans-4-guanidinomethyl cyclohexanecarboxylate p-toluenesulfonate.

By the method of Example 6, using a trans-4-guanidinomethyl cyclohexane carboxylic acid p-toluene sulfonate (3.71 g) instead of trans-4-guanidino methylcyclohexanecarboxylic acid hydrochloride, the melting point is 110 to The title compound (4.3 g, 73.9%) is obtained at 114 ° C.

IR: ν _max (cm ^-1 ) 1735, 1760 (C = 0)

NMR: δCD ₃ OD

0.7-3.0 (m, s, 15H)

5.3 (s, 2H)

7.0-8.1 (m, 13H)

Example 36

β-naphthyl trans-4-guanidino methyl cyclohexane carboxylate hydrochloride.

Trans-4-guanidino methyl cyclohexane carboxylic acid hydrochloride (1.8 g), β-naphthol (1.44 g), sulfuric acid (0.05 g) and boric acid in a mixture of dimethyl sulfoxide (10 mL) and xylene (50 mL) (0.03 g) of the suspension is heated under reflux conditions for 20 hours. The resulting water is removed by azeotropic distillation with xylene. The reaction mixture was concentrated and the residue was chromatographed through silica gel column with chloroform / methanol as eluent to afford the title compound.

Example 37

4'-diphenyl trans-4-guanidinomethyl cyclohexane carboxylate hydrochloride.

A mixture of trans-4-guanidino methylcyclohexane carboxylic acid hydrochloride (23.6 g), 4-hydroxybiphenyl (17.0 g) and phosphorus oxychloride (7.7 g) is stirred at 80-85 ° C. for 2 hours. . Toluene (50 mL) is added and the mixture is further stirred at 80 to 85 ° C for 2 hours. The solvent is decanted off and water is added. The solution is stored in the refrigerator overnight and the resulting white crystals are recrystallized from methanol to give the title compound (12.8 g, 61.3%).

Example 38

2'-benzyloxycarbonylphenyl trans-4-guanidinomethyl cyclohexane carboxylate hydrochloride monohydrate.

2′-benzyloxycarbonylphenyl trans-4-gunidino methylcyclohexanecarboxylate hydrochloride was recrystallized from acetone / water (85/15) and dried at 40 ° C. to give the title compound having a melting point of 96-105 ° C. Get

NMR: δ pyridine-d

1.0-3.4 (m, 12H) 5.4 (s, 2H)

5.25 (s, 2H) 7.3-9.1 (m, 14H)

Elemental analysis. _{C 23 H 27 N 3 O 4} · HClH 2 O

Calculation. C 59.54 H 6.52 N 7.64

Actual measurement. C 59.61 H 6.57 N 7.67

Water determination (Karl Fischer method)

Calculation. 3.88

Actual measurement. 3.98

Example 39

4'-ethoxycarbonylmethyl carbonylphenyl trans-4-guanidinomethyl cyclohexane carboxylate hydrochloride.

Trans-4-guanidinomethylcyclohexanecarboxylic acid hydrochloride (9.4 g), ethoxycarbonylmethyl-p-hydroxybenzoate (9.0 g) and dicyclohexyl carbodiimide in dimethylformamide (50 mL) 9.1 g) of the solution is stirred at room temperature for 24 hours. Insoluble material is removed by filtration and the filtrate is evaporated to dryness. Water is added to the residue, the solution is acidified with hydrochloric acid and extracted with chloroform. The extract is evaporated to dryness. The residue is recrystallized from methanol to give the title compound (10.6 g, 60%).

Melting point. 140 to 145 ° C

IR: ν _max (cm ^-1 ) 1735, 1745, 1760 (C = 0)

NMR: δCD ₃ OD

0.9-3.1 (m, t, 15H) 4.9 (s, 2H)

4.25 (q, 2H) 7.25, 8.1 (d, d, 4H)

Example 40

4'-diphenyl trans-4-guanidinomethyl cyclohexane carboxylate hydrochloride.

A solution of trans-4-guanidinomethyl cyclohexane carboxylic acid methanesulfonate (1.0 g) and dimethylformamide (0.5 mL) in thionylchloride (5 mL) is heated at 55-60 ° C. for 2.5 h. After cooling the reaction mixture is washed with petroleum ether and dissolved in chloroform. The resulting clear solution is added to a solution of p-phenyl-phenol (0.69 g) in pyridine (5 mL) and the mixture is stirred at rt overnight. The reaction mixture is evaporated and water is added to the residue. The solution is extracted with chloroform. The extract is concentrated and chromatographed on a column packed with silica gel using chloroform / methanol as eluent. The resulting crude product is treated with ether / methanol / 6N hydrochloric acid to give the title compound.

Example 41

4'-diphenyltrans-4-guanidino methylcyclohexane carboxylate hydrochloride.

A mixture of trans-4-guanidinomethyl cyclohexane carboxylic acid hydrochloride (1.0 g) and thionylchloride (5 mL) was refluxed for 2 hours. After concentration, chloroform (10 mL) is added to the reaction mixture. The solution thus obtained was added to a solution of p-phenylphenol (0.7 g) in pyridine (5 mL) and heated at 40 to 45 ° C. for 2 hours. Hydrochloric acid is added to the reaction mixture, and the resulting solution is stirred and purified by chromatography to obtain the title compound.

Example 42

4'-carboxymethylphenyl trans-4-guanidinomethyl cyclohexanecarboxylate hydrochloride.

Suspension of trans-4-guanidinomethyl cyclohexanecarboxylic acid hydrochloride (10.64 g), benzyl p-hydroxy phenylacetate (10.94 g) and dicyclohexylcarbosilic imide (11.18 g) in pyridine (40 mL) Stir at room temperature for 40 hours. After filtering off the insolubles, the filtrate is concentrated and water is added to the residue. The solution is acidified with hydrochloric acid to give a precipitate, which is collected by filtration and extracted with methanol. The extract obtained is evaporated to dryness in vacuo. The oily residue is dissolved in methanol / acetic acid and hydrogenated over pd-C. After absorbing hydrogen, the catalyst is filtered off and the filtrate is concentrated. Acetone is added to the residue to give a crystal. The crystals are collected by filtration and recrystallized from ethanol to give the title compound (5.4 g, 32.4%).

IR: ν _max (cm ^-1 ) 1720, 1750 (C = 0)

NMR: δCD ₃ OD

0.9-3.1 (m, 12H)

3.6 (3, 2H)

6.95-7.4 (m, 4H)

Example 43

4'-carboxymethylphenyl trans-4-guanidinomethyl cyclohexane carboxylate hydrochloride.

1) trans-4-guanidino methylcyclohexane carboxylic acid hydrochloride (4.7 g), tert-butyl p-hydroxyphenyl acetate (5.5 g) and dicyclohexyl carbodiimide (20 g) in dimethylformamide (20 mL) 8.2 g) is stirred at room temperature for 20 hours. The reaction mixture is evaporated in vacuo and chloroform is added to the residue. Insoluble material is filtered off and the filtrate is washed with water. The chloroform layer thus obtained is concentrated to give 4'-tert-butoxycarbonyl methylphenyl trans-4-guanidinomethyl cyclohexane carboxylate hydrochloride (6.9 g, 81.0%).

Melting point. 110 to 125 ℃

2) a solution of 4′-tert-butoxycarbonyl methylphenyl trans-4-guanidinomethyl cyclohexane carboxylate hydrochloride (3.0 g) and 15% hydrogen chloride-acetic acid solution in acetic acid (30 mL) at room temperature Stir for time. The reaction mixture is evaporated to dryness in vacuo to afford the title compound.

Example 44

2'-benzyloxycarbonylphenyl trans-4-guanidinomethyl cyclohexanecarboxylate hydrochloride.

1) trans-4-guanidinomethyl cyclohexanecarboxylic acid chloride hydrochloride.

A suspension of trans-4-guanidinomethyl cyclohexane carboxylic acid hydrochloride (1.2 g) and thionyl chloride (15 mL) is stirred at room temperature for 3 hours. Excess thionyl chloride is then distilled off under reduced pressure. The residue was washed with anhydrous ethyl ether to give trans-4-guanidinomethyl cyclohexane carboxylic acid chloride hydrochloride (1.2 g) as a colorless powder.

2) 2'-benzyloxycarbonylphenyl trans-4-guanidinomethyl cyclohexane carboxylate hydrochloride.

A solution of triethylamine (0.75 g) in methylene chloride (2 mL) was transferred to trans-4-guanidinomethyl cyclohexane carboxylic acid hydrochloride (1.2 g) and benzyl salicylate in methylene chloride (10 mL). To 1 g) of suspension is added at 0 ° C. and the resulting mixture is stirred at 0 ° C. for 10 hours. After distilling off the solvent, the residue is washed with saturated sodium hydrogen carbonate solution and the unreacted trans-4-guanidino methylcyclohexane carboxylic acid is removed and anhydrous sodium sulfate is added to the resulting residue. The mixture is then extracted with methylene chloride. After distilling off the solvent, the residue is washed with ether to remove unreacted benzyl salicylate. Isopropyl alcohol is added to the residue and the insolubles are removed by filtration. The solvent was removed from the filtrate by distillation and the resulting residue was recrystallized from water to give 2'-benzyloxycarbonylphenyl trans-4-guanidinomethyl cyclohexane carboxylate hydrochloride monohydrate (320 mg) as colorless crystals. Get as.

Example 45

2'-benzyloxycarbonyl phenyltrans-4-guanidinomethyl cyclohexane carboxylate hydrochloride monohydrate.

Trans-4-guanidinomethyl cyclohexane carboxylic acid hydrochloride (1.72 g) and triethylamine (0.74 g) are suspended in methylene chloride (20 mL), and then isobutyloxycarbonyl chloride in suspension at -5 ° C. (1 g) is added. After stirring at −5 ° C. for 30 minutes, benzyl salicylate (1.66 g) is added to the resulting mixture. The resulting mixture is stirred under ice cooling for 2 hours and further stirred at room temperature for 36 hours. After distilling off the solvent, the current was washed with saturated sodium hydrogen carbonate solution and extracted with methylene chloride. After distilling off the solvent, the residue was washed with ether and purified by thin layer chromatography (n-butanol: acetic acid: water = 4: 1: 1) to obtain 2'-benzyloxycarbonyl phenyltrans-4-guanidinomethyl Cyclohexane carboxylate hydrochloride monohydrate (285 mg) is obtained.

Example 46

Tablets: They contain the following substances in 220 mg of film coated tablets.

Compound 1 is as described above.

Granules. They contain the following substances in 1000 mg of granules.

Compound 1 is as described above.

Although the present invention has been fully described, it will be apparent to those skilled in the art that other modifications and variations can be made without departing from the spirit or scope of the invention.

Claims (1)

A method of preparing a compound of formula (I), characterized by reacting 4-guanidino methylcyclohexane carboxylic acid or a reactive derivative thereof with a compound of formula (III).

R ₁ is vanylyl, naphthyl, pyridyl, α-tocopheryl, or a general formula

Wherein R ₂ represents a hydrogen atom, lower alkoxy, formyl, lower alkanoyl, phenyl or a general formula- (CH ₂ ) _n COOR ₃ , where R ₃ represents a hydrogen atom, lower alkyl, phenyl, benzyl, Anylyl or lower alkoxy carbonylmethyl group, n represents an integer of 0 to 2); R ₁ ′ is vanylyl, naphthyl, pyridyl, α-tocopheryl, or a general formula

Where R ₂ ′ is a hydrogen atom, lower alkoxy, formyl, lower alkanoyl, phenyl or a general formula- (CH ₂ ) _n COOR ₃ ′ where R ₃ ′ is lower alkyl, phenyl, benzyl , Anisil or lower alkoxy carbonylmethyl group, n represents an integer of 0 to 2).