JPS6353984B2 - - Google Patents

Description

[Detailed description of the invention]

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

A novel cyclohexanecarboxylic acid derivative represented by the formula It is related to. To explain A in the general formula () more specifically, A's

The substituent Y in [Formula] is a hydrogen atom, a halogen atom (e.g., chlorine, bromine, iodine, fluorine, etc.), a lower alkoxy group (e.g., a methoxy group, an ethoxy group, a propoxy group,
butoxy group, etc.), nitro group, amino group, etc. at any position, and pyridyl group means 2-pyridyl group, 3-pyridyl group, 4-pyridyl group, etc.
-Means a pyridyl group. In recent years, trans-4, which has an anti-plasmin effect, has been
-Aminomethylcyclohexanecarboxylic acid (tranexamic acid) and its derivatives have been actively researched, 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 a drug with even better action, we synthesized a series of new tranexamic acid derivatives and investigated their pharmacological actions. Ta. As a result, it was found that the compound of the present invention has a remarkable anti-complement effect and is useful as a prophylactic and therapeutic agent for allergic diseases such as nephritis, rheumatism, collagen disease, and autoimmune diseases. Also anti-plasmin,
It also has antitumor, antiulcer, antithrombotic, and anticholesterol effects, making it a useful compound as a pharmaceutical. The cyclohexanecarboxylic acid derivative represented by the general formula () according to the present invention is produced according to the production method shown below. However, A in the formula has the same meaning as above. However, A in the formula has the same meaning as above. However, in the formula, X means a halogen atom such as a chlorine atom and a bromine atom, or a reactive sulfonic acid residue, and A
has the same meaning as above. To explain each of the above-mentioned production methods in more detail, production method A uses tranexamic acid represented by the general formula () and an aromatic aldehyde represented by the general formula () in an organic solvent that does not participate in the reaction (for example, methanol, ethanol, tetrahydrofuran). , diglyme, etc.), add a reducing agent (e.g., palladium-carbon, etc.) and conduct the reaction at room temperature or under heating at normal pressure or under pressure (0.1 to 10 Kg/cm) to obtain the target compound represented by the general formula (). can be obtained. In production method B, a Schiff base derivative represented by the general formula () is treated in the presence of a reducing agent (e.g., sodium borohydride, potassium borohydride, palladium-carbon, etc.) in an organic solvent that does not participate in the reaction (e.g., water, methanol, ethanol, tetrahydrofuran, acetic acid, etc.) under ice-cooling, room temperature, or heating under normal pressure or increased pressure (0.1 to 10 Kg/cm ² )
By carrying out the reaction, the target compound represented by the general formula () can be obtained. Production method C uses a reactive derivative represented by the general formula () in an organic solvent that does not participate in the reaction (water, tetrahydrofuran, dioxane, benzene, toluene,
By carrying out the reaction under heating in xylene, pyridine, dimethylformamide, hexamethylphosphoric triamide, etc.), the general formula ()
The target compound represented by can be obtained. Production method D involves the production of a nitro compound represented by the general formula () in the presence of a reducing agent (Raney-nickel, platinum oxide, palladium-carbon, etc.) in an organic solvent that does not participate in the reaction (for example, methanol, ethanol, acetic acid, etc.). The amino compound represented by the general formula () can be obtained in good yield by carrying out the reaction at room temperature or under heating and normal pressure or increased pressure. The compound thus obtained can be converted into an inorganic salt (eg, potassium, calcium, sodium, aluminum, hydrochloric acid, etc.) or an organic salt (eg, amino acid salts such as arginine, lysine, dimethylaminoethanol, etc.) as desired. EXAMPLES The present invention will be explained in more detail with reference to Examples below. Example 1 2.45 g of trans-4-benzylideneaminomethylcyclohexanecarboxylic acid in 50 ml of methanol
and 0.76g of sodium borohydride under ice cooling.
was added gradually. Next, the reaction was allowed to proceed at room temperature for 8 hours, the solvent was distilled off under reduced pressure, water was added to the residue, and the residue was made weakly acidic with dilute acetic acid. The precipitated crystals were collected, dried, and then dissolved in ethanol-water (8:2). Recrystallization was performed to obtain 2.2 g of colorless prismatic crystals of trans-4-benzylaminomethylcyclohexanecarboxylic acid. The melting point, infrared absorption spectrum, mass spectrum, and elemental analysis values of this substance were as follows. Melting point 233-235℃ Infrared absorption spectrum νc=o 1640cm ^-1 Mass spectrum M ⁺ 247 Elemental analysis value C ₁₅ H ₂₁ NO ₂ Theoretical value C: 72.84 H: 8.56 N: 5.66 Actual value C: 72.96 H: 8.43 N: 5.82 Example 2 2.8 g of trans-4-(p-chlorobenzylidene)aminomethylcyclohexanecarboxylic acid and 10% palladium-carbon in 150 ml of ethanol.
1.0 g was added to carry out catalytic reduction at 0.5 Kg/cm ² .
When the theoretical amount of hydrogen has been absorbed, the reaction is stopped, the reaction solution is filtered, and the liquid is concentrated under reduced pressure to precipitate crystals, which are removed, dried, and then recrystallized with acetone to form colorless prism crystals. 4-
2.6 g of (p-chlorobenzyl)aminomethylcyclohexanecarboxylic acid was obtained. The melting point, infrared absorption spectrum, mass spectrum, and elemental analysis values of this substance were as follows. Melting point 225-226℃ Infrared absorption spectrum νc=o 1640cm ^-1 Mass spectrum M ⁺ 281 Elemental analysis value C ₁₅ H ₂₀ ClNO ₂ Theoretical value C: 63.71 H: 7.13 N: 4.95 Actual value C: 63.82 H: 7.05 N: 4.88 Example 3 3.14 g of trans-4-aminomethylcyclohexanecarboxylic acid and 2.14 g of -isonicotinaldehyde
g and 2.5 g of 10% palladium-carbon were added to 100 ml of ethanol, and catalytic reduction was carried out under heating at 80 to 100° C. for 4 hours. The reaction solution was filtered, the liquid was concentrated under reduced pressure, the precipitated crystals were collected, and recrystallized from methanol to obtain colorless prismatic crystals of trans-4-
2.5 g of (4'-pyridylmethyl)aminomethylcyclohexanecarboxylic acid was obtained. The melting point, infrared absorption spectrum, mass spectrum, and elemental analysis values of this substance were as follows. Melting point 186-188℃ Infrared absorption spectrum νc=o Mass spectrum M ⁺ 248 Elemental analysis value C ₁₄ H ₂₀ N ₂ O ₂ Theoretical value C: 67.71 H: 8.12 N: 11.28 Actual value C: 67.61 H: 8.04 N: 11.36 Example 4 2.9 g of trans-4-(p-nitrobenzyl)aminomethylcyclohexanecarboxylic acid and 0.3 g of platinum oxide were added to 50 ml of methanol acetic acid (9.5:0.5) and contacted at room temperature at 1 to 2 Kg/ ^cm2. I made a return. The reaction stops when the theoretical amount of hydrogen has been absorbed,
The reaction solution was filtered, the liquid was concentrated under reduced pressure, the precipitated crystals were collected, and further recrystallized from a mixed solvent of acetone-isopropyl ether to give pale yellow prismatic crystals of trans-4-(p-aminobenzyl)aminomethylcyclohexanecarboxylic acid. 2.4g was obtained. The melting point, infrared absorption spectrum, mass spectrum, and elemental analysis values of this substance were as follows. Melting point 208-210℃ Infrared absorption spectrum νc=o Mass spectrum M ⁺ 262 Elemental analysis value C ₁₅ H ₂₂ N ₂ O ₂ Theoretical value C: 68.67 H: 8.45 N: 10.68 Actual value C: 68.76 H: 8.31 N: 10.78 Examples 5-12 The compounds of the present invention shown in the following table were synthesized according to the methods of Examples 1-4.

【table】

Claims (1)

[Claims] 1. General formula [Wherein, A is represented by [Formula] (wherein Y means a hydrogen atom, a halogen atom, a lower alkoxy group, a nitro group, an amino group, or a trifluoromethyl group) or a pyridyl group] Cyclohexanecarboxylic acid derivative.