JPH0791260B2 - Guanidine derivative and its salt - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial field of application] The present invention provides compounds of formula (I) [Wherein Z ₁ and Z ₂ are independently = CH- or = N-
R ₁ is a hydrogen atom or a formula —Q—R ₅ (wherein Q represents a single bond or an alkylene group, and R ₅ represents a cyclic alkyl group which may be substituted with a lower alkyl group). A group, an alkoxycarbonyl group, a carboxyl group, a hydroxyalkyl group or an alkyl group, R ₂ means a hydrogen atom, an alkoxycarbonyl group or a carboxyl group, and R ₂ together with R ₁ forms an alkylene group. Also, R ₃ and R ₄ are each independently a hydrogen atom, a halogen atom, an alkyl group,
Alkoxy group, carboxyl group, cyano group or formula (In the formula, R ₆ and R ₇ each independently represent a hydrogen atom or an alkyl group.). However, R ₁
And R ₂ is a hydrogen atom, Z is ═CH—, and R ₃ and R ₄ are hydrogen atoms. ] The compound and its salt shown by these.

The compound of formula (I) has a strong anticoagulant effect and is useful as a medicine.

[Prior Art] Heparin and warfarin are known as conventional anticoagulants. Moreover, arginine derivatives and amidine derivatives are known as compounds having an anticoagulant effect.

[Problems to be Solved by the Invention] The present inventors have completed the present invention as a result of extensive studies on novel compounds having an anticoagulant effect.

The present invention relates to compounds of formula (I) and salts thereof.

Examples of the alkyl group in the formula (I) include methyl, ethyl, propyl, isopropyl, butyl, tertiary butyl,
Examples thereof include linear or branched ones such as pentyl, hexyl, heptyl and decyl. Examples of the alkoxy group include linear or branched ones such as methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, decyloxy and the like. As the alkylene group, methylene, ethylene, propylene, butylene,
Examples thereof include linear or branched ones such as pentylene, hexylene and heptylene. Examples of the cyclic alkyl group include cyclopropyl, cyclobutyl, cyclopentyl,
Cyclohexyl, cycloheptyl, etc. can be mentioned.

As the salt of the compound of formula (I), when R ₁ , R ₂ , R ₃ or R _{4 of} formula (I) is a carboxyl group, those carboxyl groups and alkali metals such as sodium, potassium, calcium or alkaline earth Salts with metals and ammonia, amines such as ethanolamine, and guanidine with hydrochloric acid,
Examples thereof include acid addition salts with inorganic acids such as acetic acid and organic acids.

The compound of formula (I) has tautomers as shown below in its guanidine moiety, and these tautomers are also included in the scope of the compound of the present invention.

Further, some of the compounds of formula (I) have optical isomers, and these optical isomers are also included in the scope of the compound of the present invention.

The compounds of formula (I) can be prepared by various methods,
Typical examples are shown below.

(In the formula, R ₁ , R ₂ , R ₃ , R ₄ , Z ₁ and Z ₂ are the same as above.) The dihydrochloride of the compound of the formula (II) is reacted with cyanamide in an organic solvent such as ethanol. Thereby, the compound of formula (I) can be produced. The reaction is usually about 70 to about 14
It is carried out at a temperature of 0 ° C. for about 5 to about 72 hours.

(In the formula, R ₁₁ represents a hydrogen atom, —Q—R ₅ , a hydroxyalkyl group, a carboxyl group or an alkyl group, and R ₂₁ represents a hydrogen atom or a carboxyl group, and R ₂₁ together with R ₁₁ represents an alkylene group. A group may be formed, and R ₃₁ and R ₄₁ are each a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, a carboxyl group or And Z ₁ , Z ₂ , Q, R ₅ and R ₇ are the same as defined above. The compound of formula (Ia) can be produced by reacting the compound of formula (III) with hydrochloric acid in the presence of dilute hydrochloric acid, a mineral acid with dilute sulfuric acid, or an alcohol solvent such as ethanol. The reaction is usually performed at a temperature of about 70 to about 150 ° C. for about 3 to about 72 hours.

In the formula (I), the compound in which R ₁ or R ₂ is a carboxyl group can also be prepared by reacting the compound of the formula (I) in which R ₁ or R ₂ is an alkoxycarbonyl group with a mineral acid such as dilute hydrochloric acid. It can be manufactured. Also, in formula (I)
The compound in which R ₃ or R ₄ is a carboxyl group can be produced by treating the compound of the formula (I) in which R ₃ or R ₄ is a cyano group with a mineral acid in the same manner as above. The reaction is usually performed at a temperature of about 80 to about 150 ° C. for about 1 to about 18 hours.

Next, a method for producing the raw material compounds of the formulas (II) and (III) will be described.

(In the formula, R ₁ , R ₂ , R ₃ , and R ₄ are the same as above.) The compound of the formula (IV) is reacted with fuming nitric acid in a protic solvent such as acetic acid. It can be a compound. By catalytic reduction of this in a protic solvent such as ethanol or in a mixed solvent thereof with a non-polar solvent such as dimethylformamide and ethyl acetate using a catalyst such as platinum, palladium carbon or Raney nickel under atmospheric pressure or several atmospheres. Compounds of formula (IIa) can be prepared.

(In the formula, R ₁ , R ₂ , R ₃ , R ₄ and Z ₁ are the same as above.) The compound of the formula (VI) can be prepared by a known method (tetrahedron 21 vol.
P.53 1965) by reacting according to formula (VII)
Can be a compound of The compound of formula (IIb) can be produced by reacting this with sodium hypobromite and then catalytically reducing it in a protic solvent such as ethanol.

(In the formula, R ₁ , R ₂ , R ₃ , R ₄ , Z ₁ and Z ₂ are the same as above.) A compound of formula (IIc) is produced by reacting a compound of formula (VIII) in the same manner as above. can do.

Further, the compound of the formula (II) in which R ₁ is a hydroquinoalkyl group can also be produced as follows.

(In the formula, R ₁₂ represents an alkoxycarbonyl group or an alkoxycarbonylalkyl group, R ₁₃ represents a hydroxyalkyl group, and R ₂ , R ₃ , R ₄ , Z ₁ and Z ₂ are the same as above.) A compound of formula (IIe) can be prepared by reacting a compound of IIc) with lithium aluminum hydride in a non-polar solvent such as tetrahydrofuran.

By reacting the compound of formula (II) produced as described above with N-benzoylcyanamide in a nonpolar solvent such as dimethylformamide, a compound of formula (III) can be obtained.

The starting compounds of the above formulas (IV), (VI) and (VIII) can be produced from known compounds by combining various known methods.

[Effect of the Invention] The compound of formula (I) of the present invention has a novel skeleton completely different from conventional anticoagulants, and is a useful compound as a drug. The anticoagulant effect of the compound of the present invention will be specifically shown below.

Anticoagulant action Plasma was separated from human blood by a centrifuge. To 100 μl of the plasma, add 100 μl of the sample Tris buffer,
Pre-incubated for 3 minutes at ° C. To this, 100 μ of a 0.02 molar solution of calcium chloride was added, and the coagulation time was measured using Klotech (manufactured by Sanko Junyaku Co., Ltd.). Sample concentration (CT ₂₎ that doubles control clotting time
Is abbreviated) and used as an index of anticoagulant action.

The anticoagulant activity of representative compounds is shown in Table 1.

As is clear from Table 1, the compounds of the present invention showed a strong anticoagulant action.

Hereinafter, the present invention will be further described with reference to examples, but the present invention is not limited thereto.

Example 1 4,4 '-[(Cyclohexyl) methylene] bis (phenylguanidine) dihydrochloride (1) 4,4'-[(Cyclohexyl) methylene] bis (nitrobenzene) In a mixed acid of fuming nitric acid 9 ml and acetic acid 4 ml. , (Cyclohexyl)
A solution of 2.3 g of (diphenyl) methane in 5 ml of acetic acid was added dropwise at 0-5 ° C. After stirring at the same temperature for 1 hour, the reaction solution was poured into ice water. The precipitate was extracted with benzene. The extract was washed successively with saturated aqueous sodium hydrogen carbonate and water and dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was triturated with ether and recrystallized from methylene chloride-petroleum ether to give the title compound (1.6 g). Melting point 173-175 [deg.] C.

(2) 4,4 ′-[(cyclohexyl) methylene] dianiline dihydrochloride 1.8 g of the compound prepared in (1), 10% palladium on carbon 0.3 g,
A mixture of 2 ml of N, N-dimethylformamide and 50 ml of ethanol was shaken under hydrogen-atmosphere at room temperature for 4 hours. After removing the catalyst by filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in 30 ml of ethanol. 2 ml of concentrated hydrochloric acid was added to the solution, and the solution was concentrated under reduced pressure.
The precipitated crystals were collected by filtration, washed with ether and dried to give the title compound (2.4 g). Decomposition point 240-245 ℃ (3) 4,4'-
[(Cyclohexyl) methylene] bis (phenylguanidine) dihydrochloride (2) A mixture of the compound (1.8 g) prepared in (2), cyanamide (0.63 g), and ethanol (10 ml) in a sealed tube in an argon atmosphere at a bath temperature.
Heated at 125 ° C. for 15 hours. The reaction solution was concentrated under reduced pressure, and water was added to the residue. After washing the aqueous solution with ether, 10%
An aqueous sodium hydroxide solution was added to adjust the pH to 11 or higher.
The precipitated gum-like substance was collected, washed with water and chloroform, and then dissolved in a mixed solvent of ethanol-dilute hydrochloric acid. The solution was concentrated under reduced pressure, and the precipitated crystals were collected by filtration to give the title compound (1.2 g).
Got Melting point 211-213 ° C Table 3 shows the physical property data of this compound.

The compounds of Example 2 and Example 3 were produced in the same manner as in Example 1. See Tables 2 and 3 below. Example 4 Bis (4-guanidinophenyl) acetic acid dihydrochloride (1) Methyl bis [4- (3-benzoylguanidino) phenyl] acetate Bis (prepared in the same manner as in Example 1 Methyl 4-aminophenyl) acetate 1.1 g, N-benzoyl cyanamide 1.5 g
A 10 ml solution of N, N-dimethylformamide of was heated and stirred at 90-110 ° C for 4 hours. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over Glauber's salt, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (1.6 g). ¹ H-NMR (DMSO-d ₆ ) δppm: 3.7 (3H, s) 5.18 (1H, s) 7.25-7.7 (14H, m) 8.0-8.2 (4H, m) 7.8-8.6 (4H, br) 8.9- 9.6 (2H, br).

(2) Bis (4-guanidinophenyl) acetic acid dihydrochloride 10.9 ml of 6N hydrochloric acid suspension containing 0.96 g of the compound prepared in (1)
The mixture was heated under reflux for 3 hours. After cooling, the reaction solution was washed with ether and concentrated under reduced pressure. The precipitate is collected by filtration, washed with tertiary butanol and ether in that order, and dried to give the title compound (0.58 g)
Got Decomposition point 239-240 ° C. Table 3 shows the physical property data of this compound.

Example 5 2,2-Bis (4-guanidinophenyl) ethanol (1) 2,2-Bis (4-aminophenyl) ethanol Example 1 was added to a suspension of 0.48 g of lithium aluminum hydride in 10 ml of anhydrous tetrahydrofuran. A solution of 1.3 g of methyl bis (4-aminophenyl) acetate prepared by the same method in 10 ml of anhydrous tetrahydrofuran was added dropwise at 10 ° C or lower. The mixture was heated under reflux for 3 hours, cooled on ice, then 0.5 ml of water, 1
0.5 ml of a 5% aqueous sodium hydroxide solution and 1.5 ml of water were sequentially added. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and then recrystallized from ethanol to obtain 0.6 g of the title compound. Melting point 138-1
39.5 ° C.

(2) 2,2-Bis (4-guanidinophenyl) ethanol In the same manner as in Example 4, the title compound was produced from the compound produced in (1). Table 3 shows the physical property data of this compound.
Shown in.

Example 6 Ethyl 2,2-bis (4-guanidinophenyl) -3-cyclohexylpropionate dihydrochloride (1) Ethyl 3-cyclohexyl-2,2-diphenylpropionate Ethyl diphenylacetate 15 g anhydrous N, N-dimethyl To the formamide solution, 50% oily sodium hydride was added little by little at 5 ° C or lower. After stirring for 40 minutes at the same temperature, 16 g of cyclohexylmethyl iodide anhydrous N, N-dimethylformamide
A 12 ml solution was added dropwise. After stirring at 10 ° C or lower for 15 hours, an aqueous solution of ammonium chloride was added to the reaction solution, and the mixture was extracted with benzene.
The extract was washed with water, dried over Glauber's salt, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (17 g) as an oil. ¹ H-NMR (CDCl ₃ ) δppm: 0.6-1.6 (11H, m) 1.1 (3H, t) 2.25 (2H, m) 4.06 (2H, q) 7.1-7.5 (10H, m) (2) 2,2 -Bis (4-guanidinophenyl) -3-cyclohexylpropionate ethyl dihydrochloride In the same manner as in Example 1, the title compound was produced from the compound produced in (1). Table 3 shows the physical property data of this compound.
Shown in.

Example 7 2,2-Bis (4-guanidinophenyl) -3-cyclohexylpropionate hydrochloride A 10% hydrochloric acid solution of 1 g of the compound of Example 6 was heated under reflux for 30 hours. After the reaction solution was concentrated under reduced pressure, the residue was dissolved in ethanol and treated with activated carbon. The treatment liquid is dried under reduced pressure to give the title compound.
0.8g was obtained. Table 3 shows the physical property data of this compound.

Example 8 3,4 ′-[(Cyclohexyl) methylene] bis (phenylguanidine) dihydrochloride (1) Cyclohexyl 3-nitrophenyl ketone In the same manner as in (1) of Example 1, the title compound was converted from cyclohexyl phenyl ketone. Was manufactured. Melting point 60-62
° C.

(2) (Cyclohexyl) (3-nitrophenyl) methanol To a solution of 1 g of the compound prepared in (1) in 10 ml of ethanol, 0.07 g of sodium borohydride was added little by little under ice cooling. After stirring at room temperature for 30 minutes, ethanol was distilled off under reduced pressure.
The residue was dissolved in methylene chloride. The solution was washed with water, dried over sodium sulfate, and concentrated under reduced pressure to give the title compound (1 g) as a yellow oil. ¹ H-NMR (CDCl ₃ ) δppm: 0.8-2.0 (11H, m) 2.91 (1H, br) 4.49 (1H, d) 7.3-7.7,7.95-8.2 (4H, m) (3) 1-[(cyclohexyl ) (Phenyl) methyl]
-3-Nitrobenzene (2) In a benzene 30 ml solution of the compound 6.2 g, 10
At -15 ° C, 4.3 g of anhydrous aluminum chloride was added little by little.
After stirring for 40 minutes at the same temperature, 3.7 g of anhydrous aluminum chloride
Was added. After stirring at 15-20 ° C for 30 minutes, the mixture was poured into ice water and extracted with benzene. The extract was washed with water, dried over Glauber's salt, and concentrated under reduced pressure to obtain 7.4 g of the title compound as a yellow oil. ¹ H-NMR (CDCl ₃ ) δppm: 0.6-1.9 (10H, m) 1.9-2.4 (1H, m) 3.58 (1H, d) 7.1-7.65 (7H, m) 7.92 (1H, d) 8.12 (1H, t) (4) 3,4 '-[(Cyclohexyl) methylene] bis (phenylguanidine) dihydrochloride In the same manner as in Example 1, the title compound was prepared from the compound prepared in (3). Table 3 shows the physical property data of this compound.

Example 9 4-[(Cyclohexyl) (4-guanidinophenyl)
Methyl] -2-methoxyphenylguanidine dihydrochloride (1) 3-[(cyclohexyl) (phenyl) methyl]
Phenol In the same manner as in (2) of Example 1, 3-[(cyclohexyl) (phenyl) methyl] aniline was produced from the compound of (8) in Example 8. 1 g of this compound acetic acid
10ml solution at -5 ° C, 1g sodium nitrite, 10ml concentrated sulfuric acid
Dropped into the solution. After adding 10 ml of acetic acid and stirring at the same temperature for 1.5 hours, the reaction solution was added dropwise to a solution of 0.6 g of urea in 50 ml of water at 0 ° C. After stirring at the same temperature for 1 hour, the reaction solution was added dropwise to 50 ml of hot water at 80 ° C while maintaining the temperature. After stirring at the same temperature for 1 hour, the precipitated oily substance was extracted with ether. The extract was washed with water, dried, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (0.5 g) as an oil. ¹ H-NMR (CDCl ₃ ) δppm: 0.6-2.1 (11H, m) 3.35 (1H, d) 6.45 (1H, d) 6.7 (1H, s) 6.85 (1H, d) 7.0,7.13 (6H, m) (2) 1-[(cyclohexyl) (phenyl) methyl]
-3-Methoxybenzene (1) In a solution of 0.36 g of the compound prepared in (8) in 8 ml of ethanol,
5 ml of 1N aqueous sodium hydroxide solution and dimethylsulfate 0.3
ml was added alternately at room temperature. The reaction solution was heated under reflux for 3 hours, water was added, and the mixture was extracted with benzene. The extract was washed with water, dried over sodium sulfate, and evaporated under reduced pressure to give the title compound (0.3 g) as an oil. ¹ H-NMR (CDCl ₃ ) δppm: 0.6-2.1 (11H, m) 3.4 (1H, d) 3.66 (3H, s) 6.57 (1H, dd) 6.7-7.2 (8H, m) (3) 1- [ (Cyclohexyl) (4-nitrophenyl) methyl] -3-methoxy-4-nitrobenzene (2) To a solution of 2.3 g of the compound in 10 ml of acetic anhydride, 70
A mixed solution of 2 ml of% nitric acid and 5 ml of acetic anhydride was added dropwise at -10 ° C. After stirring at the same temperature for 30 minutes, the mixture was stirred at room temperature overnight. Hereinafter, Example 1
The post-treatment was carried out in the same manner as in (1) above to obtain 1.2 g of the title compound as an oil. ¹ H-NMR (CDCl ₃ ) δppm: 0.8-1.7 (10H, m) 2-2.4 (1H, m) 3.73 (1H, d) 3.95 (3H, s) 6.98 (1H, d,) 7.01 (1H, s ) 7.45 (2H, d) 7.75 (1H, d) 8.07 (2H, d) (4) 4-[(cyclohexyl) (4-aminophenyl) methyl] -2-methoxyaniline dihydrochloride (3) To a solution of 0.9 g of the compound in 6 ml of acetic acid, a solution of 3.3 g of stannous chloride in 6 ml of concentrated hydrochloric acid was added dropwise at room temperature. 70-80 ° C
After stirring for 4 hours, the mixture was poured into ice water, a sodium hydroxide aqueous solution was added to adjust the pH to 11 or higher, and the mixture was extracted with benzene. The extract was washed with water, dried over Glauber's salt, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and then treated with methanol-hydrochloric acid to obtain 0.76 g of the title compound. Decomposition point 1
80 (start of coloring) -195 ° C.

(5) 4-[(cyclohexyl) (4-guanidinophenyl) methyl] -2-methoxyphenylguanidine dihydrochloride In the same manner as in (3) of Example 1, the title compound was prepared from the compound prepared in (4). Manufactured. Table 3 shows the physical property data of this compound.

Example 10 2- [3-Cyclohexyl-1- (4-guanidinophenyl) propyl] -5-guanidinobenzoic acid dihydrochloride (1) 2- (2-bromophenyl) -2-phenylacetaldehyde methoxymethyltriphenylphosphonium Chloride 11g
In 50 ml of anhydrous ether under a nitrogen stream at 0 ° C.
18 ml of a 1.8 mol hexane solution of butyl lithium was added dropwise. After stirring for 1 hour at the same temperature, 2-bromobenzophenone
A solution of 5.5 g of 50 ml of anhydrous ether was added dropwise into the mixture. After stirring at the same temperature for 3 hours, water was added. The ether layer was separated, washed with water, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, 1-bromo-2-[(2-methoxy-1-phenyl) ethenyl].
5.2 g of benzene was obtained. This was dissolved in 200 ml of ether. 50 ml of 70% perchloric acid was added dropwise to the solution under ice cooling. The mixture was stirred at room temperature for 3 hours, poured into ice water and extracted with benzene. The extract was washed with water, dried over Glauber's salt, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (3.4 g) as an oil. ¹ H-NMR (CDCl ₃ ) δppm: 5.36 (1H, s) 7.2 (8H, br) 7.5 (1H, br) 9.82 (1H, s) (2) 1-bromo-2- (3-cyclohexyl-1-) (Phenyl-2-propen-1-yl) benzene In an argon atmosphere, 1.4 ml of a 1.6 mol hexane solution of butyllithium was added to a suspension of 1 g of cyclohexylmethyltriphenylphosphonium bromide in 4 ml of anhydrous ether, and the mixture was stirred at room temperature for 2 hours. A solution of 0.3 g of the compound prepared in (1) in 2 ml of anhydrous ether was added to this mixture, and the mixture was stirred at room temperature for 2 hours and then left overnight. Water was added to the reaction solution, which was extracted with ether. After washing the extract with water and drying with Glauber's salt,
It was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (0.1 g) as an oil. ¹ H-NMR (CDCl ₃ ) δppm: 1.12,1.6 (10H, br) 2.4 (1H, br) 5.0-5.7 (3H, m) 7.0 (8H, br) 7.45 (1H, d) (3) 2- ( 3-cyclohexyl-1-phenyl-2-
A mixture of 5.5 g of the compound prepared from (propen-1-yl) benzonitonyl (2), 1.4 g of cuprous cyanide and 25 ml of dimethylformamide was heated under reflux for 8 hours under a nitrogen atmosphere. Ice water was added to the mixture, and the mixture was extracted with benzene. The extract was washed with water, dried over Glauber's salt, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (3.7 g) as an oil. ¹ H-NMR (CDCl ₃ ) δppm: 1.2,1.6 (10H, br) 2.5 (1H, br) 5.05-5.7 (3H, m) 7.18 (7H, br) 7.38 (1H, d) 7.53 (1H, d) (4) 2- (3-Cyclohexyl-1-phenylpropyl) benzonitrile 3.6 g of the compound prepared in (3), 0.4 g of 10% palladium carbon,
A mixture of 30 ml of methanol was shaken under 3 atm of hydrogen at room temperature for 7 hours. After removing the catalyst by filtration, the filtrate was concentrated under reduced pressure to give the title compound (2.9 g) as an oil. ¹ H-NMR (CDCl ₃ ) δppm: 1.2,1.6 (13H, br) 2.1 (2H, br) 4.32 (1H, t) 7.2 (9H, br) (5) 2- [3-cyclohexyl-1- (4 -Guanidinophenyl) propyl] -5-guanidinobenzonitrile dihydrochloride In the same manner as in Example 1, the title compound was produced from the compound produced in (4). Melting point 155-160 [deg.] C.

(6) 2- [3-Cyclohexyl-1- (4-guanidinophenyl) propyl] -5-guanidinobenzoic acid dihydrochloride A solution of 1.2 g of the compound prepared in (5) in concentrated hydrochloric acid (25 ml) was charged in a sealed tube at 120 The mixture was heated with stirring at 0 ° C overnight. The reaction mixture was concentrated under reduced pressure, the residue was purified by high performance liquid chromatography (column: Microbonder pack C ₁₈ ) and then powdered with ether to give the title compound (0.5 g). Table 3 shows the physical property data of this compound.

Example 11 2- [3-Cyclohexyl-1- (4-guanidinophenyl) propyl] -N, N-dimethyl-5-guanidinobenzamide dihydrochloride (1) 2- [3-Cyclohexyl-1- (4-nitro (Phenyl) propyl] -5-nitrobenzoic acid The compound prepared in Example 10 (4) was converted to Example 1 (1).
2- [3-cyclohexyl-1- (4
-Nitrophenyl) propyl) -5-nitrobenzonitrile was prepared. A solution of 8.4 g of this compound in 100 ml of acetic acid was added to a 60 ml solution of 80% sulfuric acid, and the mixture was heated with stirring at 120 ° C. for 2 hours. After cooling with ice, 10 ml of a 3 molar aqueous sodium nitrite solution was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was poured into ice water and extracted with chloroform. The extract was washed with water, dried over Glauber's salt and evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (4.5 g) as an amorphous substance. ¹ H-NMR (CDCl ₃ ) δppm: 1.1-2.1 (15H, m) 5.3 (1H, t) 7.4 (2H, d) 7.53 (1H, d) 8.06 (2H, d) 8.26 (1H, dd) 8.76 ( 1H, d) (2) 2- [3-Cyclohexyl-1- (4-nitrophenyl) propyl] -N, N-dimethyl-5-nitrobenzamide A mixture of 4.4 g of the compound prepared in (1) and 10 ml of thionyl chloride. Was heated to reflux for 1 hour. The reaction solution was dried under reduced pressure, and 5 ml of dioxane was added to the residue. To the solution was added 10 ml of 50% aqueous dimethylamine solution, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was extracted with chloroform. The extract was washed successively with water, diluted hydrochloric acid and water, dried over sodium sulfate and dried under reduced pressure to give 3.6 g of the title compound as an oil. ¹ H-NMR (CDCl ₃ ) δppm: 1.1-2.1 (15H, m) 3.07 (3H, s) 3.69 (3H, s) 4.4 (1H, br) 7.3-7.8 (3H, m) 8.0-8.3 (4H, m) (3) 2- [3-Cyclohexyl-1- (4-guanidinophenyl) propyl] -N, N-dimethyl-5-guanidinobenzamide dihydrochloride Prepared in (2) in the same manner as in Example 1. The title compound was prepared from the above compound. Table 3 shows the physical property data of this compound.

Example 12 2-[(Cyclohexyl) (4-guanidinophenyl)
Methyl] -5-guanidinopyridine dihydrochloride (1) 6-[(cyclohexyl) (phenyl) methyl-
1,2-Dihydro-2-oxo-3-pyridinecarbonitrile 50% Oily sodium hydride 23.5 g In a suspension of 300 ml of anhydrous benzene, at 5-15 ° C, 1-cyclohexyl-1-phenyl-2-propanone 96 g And a mixture of ethyl formate 54g 1
It took time and was dripped. After stirring at the same temperature for 2 hours, the mixture was left overnight. 200 ml of water was added to the reaction solution, and the aqueous layer was separated. The organic layer was extracted 3 times with 100 ml of water. Combine the water layers,
After washing 3 times with ether, 38 g of cyanoacetamide,
65 g of N, N-diisopropylethylamine and 9 ml of acetic acid were added at room temperature. The low-boiling substance (fraction up to boiling point 98 ° C.) in the mixture was distilled off, and the mixture was heated under reflux for 4 hours. After cooling, acetic acid was added to the reaction solution to adjust the pH to 4, and the mixture was extracted with chloroform.
The extract was washed with water, dried over Glauber's salt, and concentrated under reduced pressure. The residue was purified by column chromatography and recrystallized from chloroform-ether to give the title compound (17 g). Melting point 244-24
6 ° C.

(2) 2-chloro-6-[(cyclohexyl) (phenyl) methyl] -3-pyridinecarbonitrile A mixture of 1.1 g of the compound prepared in (1), 1 g of phosphorus pentachloride, 0.25 ml of phosphorus oxychloride and 5 ml of chlorobenzene was added. The mixture was heated under reflux for 5 hours. After cooling, it was poured into ice water, sodium bicarbonate powder was added to adjust the pH to 9, and the mixture was extracted with chloroform. The extract was washed with water, dried over Glauber's salt, and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound (0.9 g) as an oil. ¹ H-NMR (CDCl ₃ ) δppm: 0.6-1.9 (10H, m) 2.1-2.6 (1H, m) 3.67 (1H, d) 7.1-7.4 (6H, m) 7.8 (1H, d) (3) 2 -Chloro-6-[(cyclohexyl) (phenyl) methyl] -3-pyridinecarboxamide (2) was added to a solution of 0.9 g of the compound prepared in (2) in 6 ml of methanol,
A mixed solution of 0% sodium hydroxide 0.7 ml and 35% hydrogen peroxide water 0.8 ml was added dropwise at room temperature. After stirring at the same temperature for 1 hour, water was added and the mixture was extracted with chloroform. The extract was washed with water, dried over sodium sulfate and concentrated under reduced pressure to give the title compound as an amorphous substance. ¹ H-NMR (CDCl ₃ ) δppm: 0.7-1.8 (10H, m) 2.1-2.5 (1H, m) 3.66 (1H, d) 6.67 (2H, br) 7.15-7.5 (6H, m) 8.02 (1H, d) (4) 6-[(Cyclohexyl) (4-nitrophenyl) methyl] -3-pyridinecarbonamide In the same manner as in (2) of Example 1, the compound produced in (3) was catalytically reduced, 6-[(Cyclohexyl) (phenyl) methyl] -3-pyridinecarbonamide was obtained. Then, this compound was treated in the same manner as in (1) of Example 1 to obtain the title compound. ¹ H-NMR (CDCl ₃ ) δppm: 0.6-1.9 (10H, m) 2.1-2.6 (1H, m) 3.8 (1H, d) 6.4 (2H, br) 7.28 (1H, d) 7.61 (2H, d) 8.03 (1H, dd) 8.12 (2H, d) 9.01 (1H, d) (5) 3-amino-6-[(cyclohexyl) (4-nitrophenyl) methyl] pyridine In 72 ml of 2N aqueous sodium hydroxide solution, Bromine 2g-5
Dropwise at ° C. 3.2 g of the compound prepared in (4) after dissolution of bromine
A 16 ml solution of dioxane in was added dropwise at the same temperature. 30 at 0 ° C
Min, 10 ° C. for 30 minutes, 30 ° C. for 30 minutes, and 70 ° C. for 2 hours.
The reaction solution was concentrated under reduced pressure, pH was adjusted to 7 with acetic acid and then with potassium carbonate, and extracted with chloroform. The extract was washed with water, dried over Glauber's salt, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound.
1 g was obtained as an amorphous. ¹ H-NMR (CDCl ₃ ) δppm: 0.6-1.9 (10H, m) 2.1-2.6 (1H, m) 3.3-3.9 (2H, br) 3.65 (2H, d) 6.89 (1H, dd) 7.0 (1H, dd) 7.60 (2H, d.) 8.08 (1H, s) 8.13 (2H, d) (6) 2-[(cyclohexyl) (4-guanidinophenyl) methyl] -5-guanidinopyridine dihydrochloride Example 4 and The title compound was prepared from the compound prepared in (5) in the same manner. Table 3 shows the physical property data of this compound.

Continuation of the front page (51) Int.Cl. ⁶ Identification code Office reference number FI Technical display location A61K 31/235 9454-4C 31/275 9454-4C 31/44 ACB

Claims (1)

[Claims] 1. A formula [Wherein Z ₁ and Z ₂ are independently = CH- or = N-
R ₁ is a hydrogen atom or a formula —Q—R ₅ (wherein Q represents a single bond or an alkylene group, and R ₅ represents a cyclic alkyl group which may be substituted with a lower alkyl group). A group, an alkoxycarbonyl group, a carboxyl group, a hydroxyalkyl group or an alkyl group, R ₂ means a hydrogen atom, an alkoxycarbonyl group or a carboxyl group, and R ₂ together with R ₁ forms an alkylene group. Also, R ₃ and R ₄ are each independently a hydrogen atom, a halogen atom, an alkyl group,
Alkoxy group, carboxyl group, cyano group or formula (In the formula, R ₆ and R ₇ each independently represent a hydrogen atom or an alkyl group.). However, R ₁
And R ₂ is a hydrogen atom, Z is ═CH—, and R ₃ and R ₄ are hydrogen atoms. ] The compound and its salt shown by these.