JPS648616B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is based on the general formula () [In the formula, A is

[Formula] (wherein, R is a hydrogen atom or a methyl group, Y is a lower alkyl group having 1 to 6 carbon atoms or an unsaturated lower alkyl group,
or - CH ₂ NH ₂ group, or

[Formula] group) or

[Formula] (wherein, X is a lower alkoxy group, n is 1 to 3
4-aminomethylcyclohexanecarboxylic acid derivatives]. To explain A in the general formula () more specifically,

[Formula] R is a hydrogen atom or a methyl group, Y is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,
tert-butyl, n-pentyl, isopentyl, n
- Straight chain or branched chain with 1 to 6 carbon atoms such as hexyl, isohexyl, 4-methyl-3-pentenyl, etc.
a lower alkyl group or an unsaturated lower alkyl group consisting of -CH ² NH ₂ group, or

[Formula] means a group, and

X in [Formula] is methoxy, ethoxy, n-propoxy, isopropoxy, n
- means a lower alkoxy group such as butoxy or isobutoxy. In recent years, trans-4, which has an anti-plasmin effect, has been
- Research on aminomethylcyclohexanecarboxylic acid (tranexamic acid) and its derivatives has been actively conducted, and pharmacological effects such as antiulcer and antitumor effects have been discovered. Furthermore, tranexamic acid has been reported to have anti-complementary action, although the action is weak. Therefore, the present inventors became interested in the anti-complementary action of tranexamic acid, and with the aim of developing even better anti-complement agents, we synthesized a series of new tranexamic acid derivatives and investigated their pharmacological actions. . As a result, the compounds of the present invention have significant anti-complementary effects;
It has been found to be useful as a prophylactic and therapeutic agent for allergic diseases such as nephritis, rheumatism, collagen disease, and autoimmune diseases. Furthermore, the compound of the present invention has anti-plasmin, anti-tumor, anti-ulcer and anti-thrombotic effects and is a useful compound as a pharmaceutical. Next, a method for producing the compound of the present invention will be explained, but this is only an example, and the compound can of course be produced by other chemically similar methods. Production method A method in which a compound represented by the general formula () is reacted with a carboxylic acid represented by the general formula () and a reactive derivative of the carboxylic acid. [In the formula, A has the same meaning as above] To explain the production method in more detail,
The object compound () of the present invention is a reactive derivative of the carboxylic acid represented by the general formula () [for example, acid chloride, acid anhydride, Alkyl esters (methyl esters, ethyl esters, etc.), active esters (methanesulfonate, toluenesulfonate, carbonate esters, etc.) are used in equimolar to slightly excess amounts to water, methanol, ethanol, acetone, ethyl acetate, chloroform, benzene,
In solvents such as toluene, xylene, tetrahydrofuran, dioxane, dimethylformamide, and dimethyl sulfoxide, dehydrating agents such as dicyclohexylcarbodiimide, and deoxidizing agents such as caustic alkali, alkali carbonate, pyridine, triethylamine, and tributylamine, depending on the type of reaction raw materials. The target compound () can be obtained in good yield by reacting in the presence of an agent at room temperature or under reflux. The compound thus obtained can be converted into an inorganic salt (metal salts such as potassium, calcium, sodium, aluminum, etc.) or an organic salt (salts such as glycine, alanine, etc.) as desired. EXAMPLES The present invention will be explained in more detail with reference to Examples below. Example 1 2.0 g of trans-4-n-pentylcyclohexanecarboxylic acid was dissolved in 20 ml of dry tetrahydrofuran, and 1 g of ethyl chlorocarbonate and 1 g of triethylamine were added dropwise to this solution while stirring under ice cooling, followed by stirring for 10 minutes. Next, 0.5N sodium hydroxide aqueous solution
A solution of 1.6 g of trans-4-aminomethylcyclohexanecarboxylic acid dissolved in 20 ml was slowly added dropwise and allowed to react at room temperature for 6 hours. After the reaction is completed, the crystals are made weakly acidic with dilute hydrochloric acid and the precipitated crystals are collected by filtration, and then recrystallized from isopropyl ether, trans-
2.4 g of 4-(trans-4-n-pentylcyclohexylcarbonylaminomethyl)cyclohexanecarboxylic acid was obtained. The melting point, infrared absorption spectrum, mass spectrum, and elemental analysis values of this substance were as follows. Melting point: 207-208℃ Infrared absorption spectrum: νc = 0 1695, 1640cm ^-1 Mass spectrum: M ⁺ 337 Elemental analysis value: C ₂₀ H ₃₅ NO ₃ theoretical value: C: 71.15 H: 10.45 N: 4.15 Actual value :C:71.11 H:10.44 N:4.12 Example 2 A solution of 2.5 g of cis-1-methyl-4-isohexylcyclohexane carbonyl chloride dissolved in 10 ml of acetone was mixed with 1.6 g of trans-4-aminomethylcyclohexanecarboxylic acid at 0.5N. It was added dropwise to a solution of 20 ml of sodium hydroxide aqueous solution and 10 ml of acetone under ice cooling. When the mixture was stirred at room temperature after the dropwise addition, white crystals precipitated, which were collected by filtration and washed successively with water and petroleum ether. The obtained crystals were recrystallized from isopropyl ether to obtain 2.5 g of trans-4-(cis-1-methyl-4-isohexylcyclohexylcarbonylaminomethyl)cyclohexanecarboxylic acid. The melting point, infrared absorption spectrum, mass spectrum, and elemental analysis values of this substance were as follows. Melting point: 160-161℃ Infrared absorption spectrum: re=0 1705, 1620cm ^-1
Mass spectrum: M ⁺ 365 Elemental analysis value: C ₂₂ H ₃₉ NO ₃ Theoretical value: C: 72.21 H: 10.75 N: 3.86 Actual value: C: 72.27 H: 10.71 N: 3.82 Example 3 3,4-dimethoxycinnamic 5.0 g of acid was dissolved in 50 ml of dry tetrahydrofuran, and 2.6 g of ethyl chlorocarbonate and 2.4 g of triethylamine were added dropwise to this solution while stirring under ice cooling, followed by stirring for 30 minutes. Next, a solution of 2.7 g of trans-4-aminomethylcyclohexanecarboxylic acid dissolved in 20 ml of water was added dropwise at room temperature.
The reaction was allowed to proceed for 1.5 hours. After the reaction was completed, the solvent was distilled off under reduced pressure to obtain an oily substance. After washing this oily substance with water, adding a small amount of ethyl acetate to crystallize it and recrystallizing it from ethanol, trans-4-(3,4-
5.8 g of dimethoxycinnamoylaminomethyl)cyclohexanecarboxylic acid was obtained. The melting point, infrared absorption spectrum, mass spectrum, and elemental analysis values of this substance were as follows. Melting point: 186-187℃ Infrared absorption spectrum: νc = 0 1700, 1646 cm ^-1 Mass spectrum: M ⁺ 347 Elemental analysis value: C ₁₉ H ₂₅ NO ₅ theoretical value: C: 65.69 H: 7.25 N: 4.03 Actual value :C:65.62 H:7.20 N:4.09 Examples 4-7 The following compounds were synthesized according to the methods of Examples 1-3. Trans-4-(trans-4-benzyloxycarbonylaminomethylcyclohexylcarbonylaminomethyl)cyclohexanecarboxylic acid Melting point 170-171℃ Trans-4-(trans-4-aminomethylcyclohexylcarbonylaminomethyl)cyclohexanecarboxylic acid Melting point 252 ~254℃ Trans-4-[(4-methyl-3-pentenyl)-3-cyclohexanoylaminomethyl]cyclohexanecarboxylic acid Melting point 159-160℃ Trans-4-(Trans-4-isobutylcyclohexylcarbonylaminomethyl) Cyclohexanecarboxylic acid Melting point 185-186℃

Claims (1)

[Claims] 1. General formula [In the formula, A is [Formula] (wherein, R is a hydrogen atom or a methyl group, Y is a lower alkyl group having 1 to 6 carbon atoms or an unsaturated lower alkyl group,
or -CH ₂ NH ₂ group, or [Formula] group) or [Formula] (wherein, X is a lower alkoxy group, and n is 1 to 3
4-aminomethylcyclohexanecarboxylic acid derivative represented by the formula 4-aminomethylcyclohexanecarboxylic acid derivative.