JPS6239558A - Alpha-cyanoacrylamide derivative - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I [R<1> is substituted phenyl or ferrocenyl expressed by formula II (both R<2> and R<3> are OH or at least either one of R<2> and R<3> is phenoxy)]. USE:An antimicrobial agent, tyrosine kinase inhibitor, having possibility of being useful as a carcinostatic agent and carcinogenic inhibitor and useful as a synthetic intermediate for many organic compounds. PREPARATION:An aldehyde expressed by the formula R<1>-CHO and alpha- cyanoacetamide are subjected to the Knoevenagel reaction using a basic catalyst, e.g. piperidine or ammonium acetate, to afford the aimed compound expressed by formula I. Alternatively, the aldehyde expressed by the formula R<1>-CHO is condensed with the alpha-cyanoacetamide on the absence or presence of an acid or base catalyst, e.g. sulfuric acid or pyridine, to give the aimed compound expressed by formula I.

Description

Detailed Description of the Invention (Field of Industrial Application) The present invention relates to α-cyanoacrylic acid amide derivatives that have antibacterial and tyrosine kinase inhibitory effects and are useful as intermediates for many organic compounds, and their preparation. The present invention relates to salts of salts and antibacterial agents and tyrosine kinase inhibitors containing the salts as active ingredients.

(Prior Art) The compound according to the present invention is a novel compound that has not been described in any literature and was synthesized for the first time by the present inventors.

(Problems to be Solved by the Invention) The present inventors believe that the novel α-cyanoacrylic acid amide derivative according to the present invention is useful as an intermediate for many organic compounds, and is itself an antibacterial agent and a tyrosine kinase inhibitor. The present invention was completed based on the discovery that the present invention has an effect.

(Means for Solving the Problems and Effects) The novel compound according to the present invention is represented by the following general formula (1).

Both are OH, or at least one of R2 and R8 is a phenoxy group. ] Among the compounds represented by general formula (1) according to the present invention,
A compound having a phenolic hydroxyl group can form a salt with a base, and the salt of the compound according to the present invention includes any salt that can be formed from the compound of the present invention and a base. Specifically, for example, (1) metal salts, especially alkali metals, alkaline earth metals, aluminum salts, (2) ammonium salts, (3) amine salts, especially methylamine, ethylamine, diethylamine, triethylamine, pyrrolidine, piperidine. , morpholine, hexamethyleneimine, aniline, pyridine, etc. When these salts are used as antibacterial agents or tyrosine kinase inhibitors, they should be selected as physiologically acceptable salts.

Representative examples of the compounds according to the present invention are shown in Table 1.

(Left below) Examples of methods for synthesizing the compound represented by general formula (1) of the present invention include the following. For example, a compound represented by (a) general formula (1) (R1 is the same as above) is a compound represented by general formula (1) (R1 is the same as above).
2) Reacting an aldehyde represented by the formula % (2) (R1 is the same as above) with α-cyanoacetamide using a base catalyst can be more easily synthesized. This reaction uses a reaction known as the so-called Knoeffenagel reaction, and bases that can be used as catalysts include ammonia, -
primary or secondary amines or their salts. Specific examples include piperidine, pyrrolidine, ammonium acetate,
Examples include piperidium acetate.

(b) The compound represented by the above general formula (1) is H9
The method of Zimmer et al. (Journal of Organic Chemistry (J, Org, Chem),
24.

28 (1959), Journal of Heterocyclic Chemistry (J, Het. Chem.),
2.

171 (1965)) etc., the above-mentioned general formula (2)
It can be synthesized by condensing an aldehyde represented by the formula with α-cyanoacetamide without a catalyst or with an acid or a base as a catalyst. Examples of acids used as catalysts include protonic acids such as halosulfuric acid and benzenesulfone #p-)luene-nulphonic acid; and Lewis acids such as boron trifluoride. Bases that can be used as catalysts include pyridine, 1,8-azabicyclo(5,
4,0] Organic bases such as undec-7-ene i Organic acids alkali metal salts such as sodium acetate and potassium acetate; Alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; Alkali metal amides such as lithium diisopropylamide ; Alkali metal alcoholades such as sodium methylate and sodium ethylate; Alkali metal hydrides such as sodium hydride and potassium hydride.

(c) The compound represented by the above general formula (1) is the aldehyde represented by the above general formula (2) and the compound represented by the general formula (3).
A compound represented by R400CCH2CN (3) (R4 represents hydrogen or a lower alkyl group) is reacted with the compound represented by R400CCH2CN (3) (R4 represents hydrogen or a lower alkyl group) as described in the previous section (a) or by the Nephenagel reaction as described in the previous section (a).
The compound represented by the general formula (4) (R1 is the same as above) obtained by the condensation reaction in the method described in b) is converted into an amide according to a general synthesis method for obtaining an amide from a carboxylic acid or an ester. It can be synthesized by converting it into

The α-cyanoacrylic acid amide derivative represented by the general formula (1) (wherein R1 is the same as above) and its salt-formable salts according to the present invention are:
Effective as an antibacterial agent and tyrosine kinase inhibitor.

Antibacterial activity was measured by the paper disk method.

That is, a Mueller-Hinton agar plate medium inoculated with 105 microorganisms/xt was prepared, an ethanol solution (10 mM) of the sample was added thereon, an air-dried paper disk was placed, and the culture was incubated at 33°C for 20 hours. The diameter (IIIll) of the formed growth inhibition circle was measured. Table 2 shows the antibacterial activity of representative compounds of the present invention.

Table 2 Tyrosine kinases are known to be involved in the carcinogenic mechanism, suggesting that tyrosine kinase inhibitors may be useful as anticancer or anticancer agents.

The tyrosine kinase inhibitory effect of the compound of the present invention is S
, Cohen et al.'s tyrosine kinase activity measurement method [The.
Journal of Biological Chemistry (J
, Biol, Chem, ), 257.1528 (198
2)) was measured using as a reference.

Human cancer cell-derived established strain A-481 was treated with fetal bovine serum 10% streptomycin (50 μg/Mt) and penicillin G (
50 international units/gl) and kanamycin (50 μg/v
The cells were cultured in Dulbecco's modified Eagle medium (Hinaga Pharmaceutical ■) containing tt) at 37°C and 5% CO2. The obtained cells were treated according to the method of S. Cohen et al. described above to obtain a membrane preparation containing the epidermal growth factor receptor-tyrosine kinase complex (hereinafter abbreviated as membrane preparation). This membrane preparation was used for the following measurements without solubilizing it.

N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid buffer (20mM, pH 7,4), Mn
CMnC12 (1, bovine serum albumin (7,5 pg),
A sample dissolved in dimethyl sulfoxide was added to a membrane preparation (10 μg as protein), and after incubation at 0°C for 5 minutes, epidermal growth factor (hereinafter abbreviated as EGF) was added.
100n! i' was added and incubated for 15 minutes at 0°C. Then [γ−h? J I) 〕AT P
(8000Ci/mmol, 0.1 μCi)
After further incubation for 15 minutes at O'C, 50 μl of the reaction solution was added to Whatman 8MM.
Immediately after soaking into P paper, add 10% trichloroacetic acid.
The reaction was stopped with a 10mM sodium pyrophosphate aqueous solution. P paper was thoroughly washed with solid liquid, then washed with ethanol, dried, and the radioactivity remaining on F paper was measured using a liquid scintillation counter, and this value was designated as A. At the same time, as controls, a reaction without the addition of EGF, a reaction without the addition of the sample, and a reaction without the addition of EGF and the sample were performed, and the same measurements were carried out and labeled as B, C, and D, respectively.

The tyrosine kinase inhibition rate was determined by the following formula.

Table 3 shows the tyrosine kinase inhibitory effects of the compounds according to the present invention. This result shows that the compound according to the present invention strongly inhibits tyrosine kinase.

Table 3: Acute toxicity ICR female mice (body weight 23-26 g) were used, with 6 mice per group. 2. Compounds (1) to (I[) containing 0.2% Tween 80; A suspension of gum arabic in an aqueous solution was orally administered at a rate of 0.11 m//10 g body weight. For two weeks after administration, general symptoms were observed to determine the number of deaths/tested cases, and the lethal dose LD50 (■/?) of 50c4 was estimated. As a result, the compounds (I)~@) of the present invention were 3
No deaths were observed even after administration of 00rn9/kg, and the LD50 of compound (I) (ml) was estimated to be 300 m9//Cf1 or more.

Preparation and Dosage The antibacterial agent or tyrosine kinase inhibitor according to the present invention may be formulated for oral, enteral or parenteral administration. Specific formulations include tablets, capsules, fine granules, syrups, suppositories, ointments, injections, and the like.

Carriers for the formulations of antibacterial agents or tyrosine kinase inhibitors according to the invention include organic or inorganic solid or liquid carriers suitable for oral, enteral or other parenteral administration.
Usually an inert pharmaceutical carrier material is used. Specifically, for example, crystalline cellulose, gelatin, lactose, starch,
Magnesium stearate, talc, vegetable and animal fats and oils, gums, polyalkylene glycols.

The ratio of the antimicrobial agent or tyrosine kinase inhibitor of the invention to the carrier in the formulation can vary between 0.2 and 100%. The antibacterial agent or tyrosine kinase inhibitor according to the present invention may also include other antibacterial agents or tyrosine kinase inhibitor IJ, and other pharmaceuticals that are compatible therewith. In this case, it goes without saying that the antibacterial agent or tyrosine kinase inhibitor of the present invention does not need to be the main ingredient in the preparation.

The antibacterial agent or tyrosine kinase inhibitor according to the present invention is
Generally, doses will be administered that will achieve the desired effect without side effects. The specific value should be determined by a doctor, but in general, it is 10 to 10 times per day for adults.
It will normally be administered at about 201n9 to 51g, preferably about 201n9 to 51. The antibacterial agent or tyrosine kinase inhibitor of the present invention can be administered as a pharmaceutical preparation containing IWi to 5 g, preferably 3 to 1 g, as an active ingredient.

(Example) Next, the present invention will be specifically explained with reference to production examples of the compounds of the present invention, but these Examples are not intended to limit the present invention.

Example 1 Synthesis of Compound I 2.76 g of 2.5-dihydroxybenzaldehyde and α
- 1.85 g of cyanoacetamide in 80 t of ethanol
ttt, piperidine lye was added thereto, and the mixture was heated under reflux for 1.5 hours under a nitrogen atmosphere. After cooling, the precipitated crystals were separated from each other and crystallized from ethanol to obtain 3.0 g of Compound I.

Example 2 Synthesis of compound (1) 15 m/ethanol, 1.98 g of m-phenoxybenzaldehyde, 0.94 g of cyanoacetamide.

0.1 ml of piperidine was added and the mixture was stirred at room temperature for 16 hours. 0.20 g of cyanoacetamide was added, and the mixture was further stirred at room temperature for 5.5 hours. 200 ml of water was poured into the reaction mixture, and the mixture was extracted twice with ethyl acetate (200 yet in total), and the extract was washed twice with brine and dried over anhydrous sodium sulfate. This was concentrated to dryness and recrystallized from methanol.1. i a y objective was obtained.

Example 3 Synthesis of compound (1) Ethanol 15/7 erocene carboxaldehyde 2.14 g, cyanoacetamide 0.84 g.

0.1 t of piperidine was added, and the mixture was heated and stirred at 80°C for 50 minutes. After cooling, water 200mf? was added, and 7 precipitates were taken and washed with water. This was vacuum dried at room temperature to remove moisture, and then recrystallized from chloroform-carbon tetrachloride to obtain the desired product 1.32. ! I got i'.

Claims (5)

[Claims] (1) α-cyanoacrylic acid amide derivatives represented by the following general formula (1) and salts thereof that can be salt-formed. ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (1) [Here, R^1 is a formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (R^2 and R^3 are both OH, or R^2, represents a substituted phenyl group or ferrocenyl group (at least one of R^3 represents a phenoxy group). ] (2) α according to claim 1, wherein R^1 is a substituted phenyl group represented by the formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (R^2 and R^3 both represent OH) -Cyanoacrylic acid amide derivatives and salts thereof. (3) A claim in which R^1 is a substituted phenyl group represented by the formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (at least one of R^1 and R^2 represents a phenoxy group) α-cyanoacrylic acid amide derivative according to item 1. (4) The α-cyanoacrylic acid amide derivative according to claim 1 or 3, which is represented by the formula ▲ Numerical formula, chemical formula, table, etc. ▼. (5) The α-cyanoacrylic acid amide derivative according to claim 1, which is represented by the formula ▲ Numerical formula, chemical formula, table, etc. ▼.