JPS6239564A - Alpha-benzylidene-gamma-butyrolactone or gamma-butyrolactam derivative - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I [Ar is formula II (R<3> and R<4> are 1-4C alkyl) or formula III; X is -(CH2)2- or formula IV; Y is O or NH] and a salt of the compound capable of forming the salt. EXAMPLE:A compound expressed by formula V. USE:A medicine, antimicrobial agent and tyrosinase inhibitor or an intermediate for many organic compounds, having los toxicity, effective for Gram-positive bacteria and yeasts, suggesting the possibility of being useful as a carcinostatic agent or carcinogenic inhibitor and administered in 10mg-10g, preferably 20 mg-5g/adult/day dose. PREPARATION:For example, a benzaldehyde expressed by the formula Ar-CHO and ylide expressed by formula VII (Ary is aryl) are subjected to the Wittig reaction to afford the aimed compound expressed by formula I.

Description

Detailed Description of the Invention (Industrial Application Field) The present invention is directed to the use of α-benzylidene-γ-butyrolactone, which has antibacterial and tyrosine kinase inhibitory effects and is useful as an intermediate for many organic compounds. The present invention relates to γ-butyrolactam derivatives, salts thereof, and antibacterial agents and tyrosine kinase inhibitors containing these 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 have discovered a novel α-benzylidene-γ according to the present invention.
-butyrolactone-straddling γ-butyrolactam derivative,
The present invention was completed based on the discovery that it is useful as an intermediate for many organic compounds, and that it itself has antibacterial and tyrosine kinase inhibitory effects.

(Means and effects for solving the problems) The novel compound according to the present invention is represented by the following general formula (1).
These are benzylidene-γ-butyrolactone or γ-butyrolactam derivatives and salts of salts thereof.

C4 alkyl group) or a substituted phenyl group, and X represents -(CH2)2- or NH. ] 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 salts with alkali metals, alkaline earth metals, and aluminum, (2) ammonium salts, and (3) amine salts, especially methylamine, ethylamine, diethylamine, triethylamine, pyrrolidine, and piperidine. , morpholine, hexamethyleneimine, aniline, pyridine, etc. When using these salts as antibacterial agents or tyrosine kinase inhibitors, physiologically acceptable salts should be selected.

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

Decreasing Margin) Methods for synthesizing the compound represented by the general formula (1) of the present invention include the following. For example, the compound represented by (a) general formula (1) (Ar, X, and Y are all the same as above) can be prepared by the method of
Helvetica Chimica Acta (Helv, Chim
.

Acta), 40, 1242 (1957))
, G., A. & Wie et al. (Journal of Medicinal Chemistry - (J, Med
, Chem, )17. 840 (1974))
, H. Wamhoff et al.'s method (synthesis
931 (1976)), benzaldehyde represented by the general formula (2) (Ar is the same as above) and the general formula (3) (where Ary is an aryl group, It can be synthesized by reacting with a ylide represented by (Y is the same as above). This synthesis method uses the so-called Witzteich reaction, but the ylide to be reacted with the above general formula (2) may be one derived from trialkylphosphine or triarylarsine, in addition to the compound represented by the above general formula (3). Yrids can also be used in the same way.

(b) The compound represented by the above general formula (1) is Hl
The method of Zimmer et al. (Journal of Organic Chemistry (J, 0rCi, Chem, )
24, 28 (1959); Journal of Heterocyclic Chemistry (J, Het, Che
m, ) 2 , 171 (1965)) etc., formula (4) % formula % (4) Same as above, R5 is a C1-C8 alkyl group, benzyl group, C0R6 (R6 is hydrogen or C1-C3 Benzaldehydes represented by formula (5) (X is the same as above, Z is an oxygen atom or NH.

It can be synthesized by condensing a compound represented by NH(COR7) (representing R7 hydrogen or an alkyl group of I/iC1 to C4) without a catalyst or with an acid or base as a catalyst. can.

Examples of the acid used as a catalyst include protonic acids such as sulfuric acid, benzenesulfonic acid and p-toluenesulfonic acid, and luinic acids such as boron tribromide. Bases that can be used as catalysts include organic bases such as monoethanolamine, pyridine, and 1,8-azabicyclo[5,4,0)undec-7-ene; alkali metal hydroxides such as sodium acetate and potassium hydroxide. ; Alkali metal amides such as lithium diisopropylamide; alkali metal alcoholades such as sodium ethylate and sodium ethylate; alkali metal hydrides such as sodium hydride and potassium hydride. If the alkyl group, benzyl group, acyl group or trialkylsilyl group of R5 remains in the reaction product without a catalyst or due to the catalyst used, the target product can be obtained by eliminating these R5. I can do it.

When R5 is an alkyl group, the elimination method for R5 is a cleavage method using an acid such as aluminum halide such as aluminum chloride, boron tribromide, hydrogen halide such as hydrogen bromide, or other methods. There is an ether cleavage method. Further, when R5 is a benzyl group, it can be removed by a catalytic reduction method using a noble metal catalyst such as palladium carbon in addition to the above-mentioned ether cleavage method. When R5 is an acyl group, it can be eliminated by hydrolysis using a base such as an alkali metal hydroxide such as sodium hydroxide or an alkaline earth metal hydroxide such as barium hydroxide. can. When R5 is a trialkylsilyl group, it can be removed with water, methanol, acid, fluorine ions, or the like.

In addition, when reacting using N-acyl lactam, if the acyl group remains in the product, it can be removed by hydrolysis using a base such as an alkali metal hydroxide such as sodium hydroxide. You can get what you want.

(c) A compound represented by general formula (6) (Ar and Y are the same as above) is a compound represented by general formula (7) (Y is the same as above) and benzaldehyde represented by general formula (2) above. It is synthesized by reacting with a compound using a base catalyst. This reaction uses a reaction known as the so-called Knoeffenagel reaction, and examples of bases that can be used as catalysts include ammonia, -class or secondary amines, or salts thereof. Specific examples of bases and their salts that can be used include:
Examples include piperidine, pyrrolidine, ammonium acetate, and piperidinium acetate.

The compound represented by (x, y are the same as above) is obtained by reacting 2,5-dihydroxybenzaldehyde with the ylide represented by the above-mentioned general formula (3) using the Witzteich reaction as described in the previous section (a). A compound represented by the general formula (9), or a compound represented by the general formula α0(R8,R9
is a C1-C3 alkyl group, benzyl group, C0RIO (
Rto represents hydrogen or an acyl group represented by a C1-C3 alkyl group) or a trialkylsilyl group) and benzaldehydes represented by the above general formula (5
) and the compound represented by the above-mentioned general formula (9) obtained by reacting and eliminating R8 and R9 using the method described in the previous section (b), or 2.5-
[General formula 0] obtained by reacting dihydroxybenzaldehyde and the compound represented by the above-mentioned general formula (7) using the Nephenagel reaction as described in the previous section (c)]
) (Y is the same as above) Compounds represented by the above general formula (9), Q
It can be obtained by reacting the compound represented by l) with phenyl isocyanate in the absence of a catalyst or in the presence of an acid or base catalyst. Examples of acids used as catalysts include fluoro acids such as hydrochloric acid, and Lewis acids such as boron trifluoride and aluminum chloride. Examples of bases that can be used as catalysts include organic bases such as pyridine and triethylamine;
Examples include alkali metal carboxylic acid salts such as sodium acetate.

The α-benzylidene-γ-butyrolactone or γ-butyrolactam derivative represented by the general formula (1) according to the present invention (Ar, It is effective as a drug.

The antibacterial activity of compound (1) was measured by the paper disc method.

That is, a Mueller-Hinton Agar plate medium inoculated with 10 Σ cells/ml of each microorganism was prepared, an ethanol solution (10 mM) of compound (1) was added thereon, an air-dried paper disk was placed, and the culture was incubated at 33'C for 20 hours. Then, the diameter of the growth-inhibiting particles formed was measured. The results showed an inhibitory effect of 14 mm against Bacillus subtilis PCI 219, 15 mm against Staphylococcus aureus, and 12 mm against Candida fistulae, indicating that the compounds of the present invention are useful against Durum-positive bacteria and yeast. I found out something.

Tyrosine kinase is known to be involved in the carcinogenic mechanism, and it has been suggested 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, Co
Tyrosine kinase activity measurement method by Hen et al. [The Journal of Fist Biological Chemistry (J, Bi
ol, Chem, ).

257.1523 (1982)) as a reference.

Human cancer cell-derived established strain A-481 was treated with fetal bovine serum 10% streptomycin (50 μg/waste/), penicillin G (
50 international units/at+') and kanamycin (50 μ9
The cells were cultured in Dulbecco's modified Eagle's medium (Tamizu Seiyaku ■) containing 37°C and 5% 002. The obtained cells were treated according to the method of S. Cohen et al. described above to obtain a membrane preparation containing an 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-hydroxyethylpiperazino-N'-2-ethanesulfonic acid buffer (20mM, pH 7.4).

MnCl2 (1mM), bovine serum albumin (7,5t
tg).

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.
100 ng was added and incubated at 0°C for 15 minutes. Next [γ-? 22P, )ATP(3000
Ci/mmol, 0.1 pci) and final 7
After further incubation at 0°C for 15 minutes, 50 μl of the reaction solution was impregnated onto Watfu 3MMF paper, and the reaction was immediately stopped with a 10% trichloroacetic acid-10 mM sodium pyrophosphate aqueous solution. The door paper was thoroughly washed with solid liquid, then washed with ethanol, dried, and the radioactivity remaining on the door 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 2 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 2 Acute toxicity ICR female mice (body weight 23 to 26 g) were used, with 6 mice per group. Compounds (1) to (I [[) were suspended in a 2.5% aqueous gum arabic solution containing 0.2 Chitween 80 at O,t*//10. ! It was administered orally at a proportion of i' body weight. Observe general symptoms for two weeks after administration to determine the number of deaths/tested cases and determine the 50% lethal dose L D50 Cm9/
9) was estimated. As a result, compounds (1) of the present invention ~
For (I[), no fatal cases were observed even after administration of 1000 m97kg, and for compounds (1) to (ID glue, D5.
9/kg or more (!) It was estimated that the toxicity was low.

Preparation and Dosage The antibacterial agent or tyrosine quinade inhibitor according to the present invention may be formulated for oral, enteral or parenteral administration. Specific formulations include tablets, capsules, fine granules, syrups, herbal medicines, ointments, injections, and the like. The carrier for the antibacterial agent or tyrosine kinase inhibitor formulation according to the invention may be an organic or inorganic solid or liquid, normally inert pharmaceutical carrier suitable for oral, enteral or other parenteral administration. material is used. Specifically, for example, crystalline cellulose, gelatin, lactose, starch, magnesium stearate, talc,
These include vegetable and animal fats and oils, gums, and polyalkylene glycols.

The ratio of the antibacterial agent or tyrosine kinase inhibitor of the invention to the carrier in the formulation can vary between 0.2 and 100%. The antimicrobial agent or tyrosine kinase inhibitor according to the present invention may also include compatible antimicrobial agents or tyrosine kinase inhibitors and other pharmaceutical agents. 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.

Antimicrobial agents or tyrosine kinase inhibitors according to the invention are generally administered at dosages that achieve the desired effect without side effects. The specific value should be determined by a doctor's judgment, but in general, it is 10 to 10 g per day for adults.
, preferably in about 20 m9 to 5 g. In addition, the antibacterial agent or tyrosine kinase inhibitor of the present invention has an active ingredient content of 9 to 5 g per ml, preferably 3 to 5 g per ml.
It can be administered as a pharmaceutical preparation in units of rn9-1 g.

(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 To 1.801 g of hydrogenated tll rum oil (content 60%) was added 15 gt of dry tetrahydrofuran (TE(F)) under nitrogen.
was added and suspended, and to this suspension, 5.859 g of 4-tert-butyldimethylsilyloxy-3,5-dimethylthiomethylbenzaldehyde and 1.91 g of 1-7 cetyl-2-pyrrolidone were dissolved in 5 tttl of dry THFL. was added while stirring on a water bath, the temperature was slowly raised to room temperature, and the mixture was allowed to react for 4 hours. After the reaction was completed, 5 ml of methanol was added to the cooled reaction solution, and the mixture was poured with 80 ml of cold water.
I poured it into t.

This was adjusted to pE (2) with 6N&f and acid, and extracted 4 times with 30tttl of chloroform. The extract was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. Ethyl acetate was added to the residue, and crystallization was performed to obtain the desired product. 1.18g of Compound I was obtained.

Example 2 Synthesis of compound (1) 3.64 g of 5-dimethylthiomethyl-4-hydroxybenzaldehyde and 2.0 OS of oxindole were dissolved in 80 g of ethanol, and 0.2 g of ethanolamine was dissolved.
tttt was added, and the mixture was heated under reflux for 16 hours while stirring.

After cooling to room temperature, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography using silica gel as a carrier and chloroform as an eluent.

Both fractions containing the target substance were collected, the solvent was distilled off, and ethyl acetate was added to the residue to perform crystallization to obtain the target compound H.
Obtained 04g.

Example 3 Synthesis of Compound I 1.99.9 g of α-(2,5-dihydroxybenzylidene)-γ-butyrolactone was suspended in 100 ml of dioxane, 5 drops of pyridine was added, and 3.32 g of phenyl isocyanate was suspended in dioxane. A solution dissolved in 30 ytt was added and heated under reflux for 7 hours. After cooling, water was added to the reaction mixture, followed by extraction with ether. After distilling off the ether, the residue was crystallized from tethanol to give compound (1) at 1.35
I got g.

Patent applicant Makoto Asano, agent of Kanebuchi Chemical Industry Co., Ltd. - Procedural amendment (
Dan Showa l/March 2y

Claims (9)

[Claims] (1) Salts of α-benzylidene-γ-butyrolactone or γ-butyrolactam represented by the following general formula (1) and salts thereof. ▲There are mathematical formulas, chemical formulas, tables, etc.▼(1) [In the formula, Ar is ▲There are mathematical formulas, chemical formulas, tables, etc.▼(R
^3, R^4 represents an alkyl group of C_1 to C_4) or ▲
There are mathematical formulas, chemical formulas, tables, etc. Represents a substituted phenyl group shown by ▼, where X is -(CH_2)_2
- or ▲There are mathematical formulas, chemical formulas, tables, etc.▼, and Y represents an oxygen atom or NH. ] (2) Ar is ▲There are mathematical formulas, chemical formulas, tables, etc.▼(R^
3, R^4 is a substituted phenyl group represented by (same as above)
Salts of γ-butyrolactone or γ-butyrolactam derivatives and salts thereof. (3) Claim 1 in which Ar is a substituted phenyl group represented by ▲There are mathematical formulas, chemical formulas, tables, etc.▼
The α-benzylidene-γ-butyrolactone or γ-butyrolactam derivative described in 2. (4) α-benzylidene-γ-butyrolactone or γ-butyrolactam according to claim 1, wherein X is represented by -(CH_2)_2- or Derivatives and their salt-formable salts. (5) The α-benzylidene-γ-butyrolactone derivative and its salt-formable salts according to claim 1, wherein Y is an oxygen atom. (6) The α-benzylidene-γ-butyrolactam derivative and its salt-formable salts according to claim 1, wherein Y is NH. (7) The α-benzylidene-γ-butyrolactam derivative and its salt according to claim 1, 2, 4, or 6, represented by the formula ▲ Numerical formula, chemical formula, table, etc. ▼. (8) The α-benzylidene-γ-butyrolactam derivative and its salt according to claim 1, 2, 4, or 6, represented by the formula ▲ Numerical formula, chemical formula, table, etc. ▼. (9) The α-benzylidene-γ-butyrolactone derivative according to claim 1, 3, 4, or 5, represented by the formula ▲ Numerical formula, chemical formula, table, etc. ▼.