JPH0147461B2 - - Google Patents

Description

[Detailed Description of the Invention] The present invention relates to the general formula () [In the formula, R is a hydrogen atom or a lower alkyl group,
X is an oxygen atom or a sulfur atom, A is an alkyl group,
Unsaturated alkyl groups, cycloalkyl groups, aryl groups, benzyl groups and -(CH ₂ ) _o COOR' groups (however,
R' is a lower alkyl group, n is an integer from 1 to 8)
This invention relates to a novel urea derivative represented by:

To explain A in the above general formula () more specifically, the alkyl group is methyl, ethyl,
n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, isopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl groups, etc., unsaturated alkyl groups include allyl group, propargyl group, etc., and cycloalkyl groups include allyl group, propargyl group, etc. A ring composed of _C3 to _C7 carbon atoms, optionally substituted with 1 to 2 lower alkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc., and the aryl group is a phenyl group. or halogen atoms such as fluorine, chlorine, bromine, and iodine, lower alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, and isobutyl groups, lower alkoxy groups such as methoxy and ethoxy, nitro groups, trifluoromethyl Groups are 1 to 3
Aralkyl groups include benzyl or halogen atoms such as fluorine, chlorine, bromine, and iodine, lower alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, and isobutyl, and methoxy and ethoxy groups. Lower alkoxy groups such as
It means a benzyl group substituted with 1 to 3 nitro groups, trifluoromethyl groups, etc.

In recent years, trans-4-
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, it was found that the compound of the present invention has a significant anti-complement effect and is useful as a prophylactic and therapeutic agent for allergic diseases such as nephritis, rheumatism, collagen disease, and autoimmune diseases. It also has anti-plasmin, anti-tumor, anti-ulcer, and anti-thrombotic effects, making it a useful compound as a pharmaceutical.

Next, the 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 an isocyanate and a thioisocyanate derivative represented by the general formula () [In the formula, R, X, and A have the same meanings as above.] To explain the production method in more detail, the target compound () of the present invention is a 4-aminomethylcyclohexanecarbonyl compound represented by the general formula (). Isocyanate or thioisocyanate derivatives represented by the general formula () for acid or ester derivatives (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, isopentyl, n-hexyl, isohexyl, n -heptyl, isoheptyl, allyl, cyclopropylmethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, methylcyclohexyl, phenyl, fluorophenylchlorophenyl, bromphenyl,
Iodophenyl, methoxyphenyl, ethoxyphenyl, methylphenyl, nitrophenyl, trifluoromethylphenyl, benzyl, fluorobenzyl, chlorbenzyl, methoxybenzyl, methylbenzyl, trimethoxybenzyl, nitrobenzyl, acetate ester, propionate ester,
Solvents such as tetrahydrofuran, dioxane, benzene, toluene, xylene, dimethylformamide, pyridine, etc. using equimolar to slightly excessive amounts of isocyanates such as butyric acid ester, valeric acid ester, heptanoic acid ester, pelargonic acid ester, and thioisocyanates) It can be obtained in good yield at room temperature or by heating.

EXAMPLES The present invention will be explained in more detail with reference to Examples below.

Example 1 3.1 g of trans-4-aminomethylcyclohexanecarboxylic acid was added to 50 ml of pyridine at 80-85°C.
heated to. Then cyclohexyl isocyanate
After 2.5 g was slowly added dropwise with stirring, the reaction was allowed to proceed for 4 hours. After distilling off the reaction solution under reduced pressure, ether was added to the residue to collect the precipitated crystals, and recrystallization from methanol yielded colorless prism crystals of N-(trans-4-carboxycyclohexylmethyl)-
5.5 g of N'-cyclohexylurea was obtained.

The melting point, infrared absorption spectrum, mass spectrum, and elemental analysis values of this substance were as follows.

Melting point: 170-172℃ Infrared absorption spectrum; vc=0, 1715cm ^-1 1625cm
^-1 Mass spectrum; M ⁺ 282 Elemental analysis value; C ₁₅ H ₂₆ N ₂ O ₃ theoretical value; C: 63.80 H: 9.28 N: 9.92 Actual value; C: 63.71 H: 9.24 N: 9.86 Example 2 In 50 ml of pyridine Add 3.1g of trans-4-aminomethylcyclohexanecarboxylic acid to 80-85℃
heated to. Next allyl thioisocyanate 2.0
g was slowly added dropwise with stirring, and the mixture was allowed to react for 3 hours. After the reaction solution was distilled off under reduced pressure, the residue was dissolved in ethyl acetate and adsorbed on a column packed with silica gel, developed with ether, and the solvent in the eluate was distilled off to form colorless prism crystals of N-(trans-4-carboxylate). 4.4 g of cyclohexylmethyl)-N'-allylthiourea was obtained.

The melting point, infrared absorption spectrum, mass spectrum, and elemental analysis values of this substance were as follows.

Melting point: 95-97℃ Infrared absorption spectrum; vc = 0 1693 cm ^-1 mass spectrum; M ⁺ 256 Elemental analysis value; C ₁₂ H ₂₀ N ₂ O ₂ S theoretical value; C: 56.22 H: 7.86 N: 10.93 Actual measurement Value; C: 56.26 H: 7.81 N: 10.79 Example 3 3.1 g of trans-4-aminomethylcyclohexanecarboxylic acid was added to 50 ml of pyridine at 80-85°C.
heated to. Then benzylthioisocyanate
After 3.0 g was slowly added dropwise with stirring, the reaction was allowed to proceed for 7 hours. After evaporating the reaction solution under reduced pressure, the residue was dissolved in methanol and adsorbed on a column packed with silica gel, developed with ethyl acetate, and the solvent in the eluate was distilled off to form colorless prism crystals of N-(trans-4
-Carboxycyclohexylmethyl)-N'-benzylthiourea (2.2 g) was obtained.

The melting point, infrared absorption spectrum, mass spectrum, and elemental analysis values of this substance were as follows.

Melting point: 185-187℃ Infrared absorption spectrum: vc=0 1693cm ^-1 Mass spectrum: M ⁺ 306 Elemental analysis value: C ₁₆ H ₂₂ N ₂ O ₂ S Theoretical value: C: 62.72 H: 7.24 N: 9.14 Actual measurement Values; C: 62.66 H: 7.30 N: 9.07 The following compounds were synthesized according to the methods of Examples 1 to 3.

N-(trans-4-carboxycyclohexylmethyl)-N'-ethoxycarbomethylurea Melting point 120-123℃ N-(trans-4-carboxycyclohexylmethyl)-N'-ethylurea Melting point 145-147℃ N-(trans -4-carboxycyclohexylmethyl)-N'-n-butyl urea Melting point 107~109℃ N-(trans-4-carboxycyclohexylmethyl)-N'-O-chlorophenylurea Melting point 198~200℃ N-(trans-4 -carboxycyclohexylmethyl)-N'-cyclohexylthiourea Melting point 168-170°C N-(trans-4-carboxycyclohexylmethyl)-N'-phenylurea Melting point 188-190°C.

Claims (1)

[Claims] 1. General formula [In the formula, R is a hydrogen atom or a lower alkyl group,
X is an oxygen atom or a sulfur atom, A is an alkyl group,
unsaturated alkyl group, cycloalkyl group, aryl group, aralkyl group and -(CH ₂ ) _o COOR' group (wherein R' is a lower alkyl group and n is an integer from 1 to 8)]. Urea derivatives represented.