KR20020000272A - New derivatives of berberrubine and their salts for antibiotics and antifungal agents - Google Patents

Abstract

PURPOSE: Provided are novel berberrubin derivatives and their salts, which have excellent antifungal and antibacterial activities, thus inhibit the growth of fungi. CONSTITUTION: Novel berberrubin derivatives, particularly, 9-O-alkyl berberrubin derivative and 9-O-acyl berberrubin derivative are formula(I) and formula(II) respectively, wherein R is hydrogen or C1-C18 alkyl group, and aromatic hydrocarbon including chained, branched and cyclic saturated hydrocarbon or unsaturated hydrocarbon, and a benzene ring; and X¬- is inorganic acid ion, organic acid ion or halide.

Description

Novel BERBERRUBIN derivatives and salts thereof having antibacterial and antifungal activity {NEW DERIVATIVES OF BERBERRUBINE AND THEIR SALTS FOR ANTIBIOTICS AND ANTIFUNGAL AGENTS}

The present invention relates to novel berberubin derivatives and salts thereof having antibacterial and antifungal activity, and more particularly, 9-Ο-alkyl berberubin derivatives represented by the following general formula (I) and salts thereof and the following general It relates to a 9-?-Acyl berberubin derivative represented by formula (II) and its salts.

(Ⅰ)

(Ⅱ)

R in formulas (I) and (II) is hydrogen or an alkyl group having 1 to 18 carbon atoms and is an aromatic hydrocarbon containing a chain, branched, cyclic saturated hydrocarbon or unsaturated hydrocarbon, or benzene ring; X ⁻ is an inorganic acid ion, organic acid ion or halide.

Coptis chinensis Fr., commonly known as oriental medicine in oriental medicine, is a perennial herb that grows or grows in Korea, China, Japan, and Nepal. Their roots are berberine, coptisine, and jate Alkaloids such as jateorrhizine and palmatine have been used as main ingredients for medicines such as gastrointestinal diseases, hyperemia, arteriosclerosis and mental anxiety. Among these, berberine chloride is not only an animal pathogen such as Bacillus subtilis, Escherichia coli, pneumococcus pneumoniae, Staphylococcus aureus, P. aeruginosa, Seleus, Cholera and Diphtheria, but also Candida and Cryptococcus. It has been reported to exhibit a broad spectrum of antimicrobial spectrum, from plant pathogens such as yeast and fungi. Chi HJ Woo YS, Lee YJ, Kor. J. Pharma. , 22, 45 (1991)]

In addition, it has recently been reported that derivatives of berberine have a significant antimicrobial effect against gram positive bacteria or gram negative bacteria and fungi. Isawa K., Kamigauchi M., Ueki M., Taniguchi M., Eur. J. Med. Chem. , 31, 409 (1996)]

Meanwhile, berberrubine is obtained by pyrolyzing berberine with 9-dimethylberberine. Although many studies have been conducted on berberine and its derivatives, few studies have been conducted on berberubin and its derivatives.

The present invention provides novel antimicrobial actives associated with berberubin, and the novel compounds synthesized in the present invention exhibit better antimicrobial activity than existing berberine derivatives.

In the present invention, 9-O-alkyl and 9-O-Acyl berberubin-like novel compounds were synthesized using the berberubin as a precursor, and these novel compounds were Enterococcus Faecalis and Staphyloco. Staphylococcus aureus, Micrococcus luteus, Staphylococcus epidermis, Bacillus subtilis, Propionibacterium acnes Gram-positive bacteria such as Candida Krusei, Candida Lusitaniea, Candida albicans, Candida tropicalis, Cryptococcus neoformans, Candida Candida parapsilosis, Candida glabrata, Candida utilis, Trichophyton metagroite (Tr) It has bactericidal or bacteriostatic effects against fungi such as ichophytonmetagrophytes) and Saccharomyces cerevisiae.

It is therefore an object of the present invention to provide novel berberubin derivatives and salts thereof which exhibit bactericidal and bacteriostatic effects against Gram-positive bacteria and fungi.

Still another object of the present invention is to provide a method for synthesizing the berberuvin derivative from berberine, which is a starting material, via berberubin.

Berberubin derivatives and their salts for achieving the above object are represented by the following formula (1) and (2).

R in Formula 1 and Formula 2 is hydrogen or an alkyl group having 1 to 18 carbon atoms and is an aromatic hydrocarbon including chain, branched, cyclic saturated hydrocarbon or unsaturated hydrocarbon, and benzene ring; X ⁻ is an inorganic acid ion, organic acid ion or halide.

Berberubin derivatives and salt compounds thereof according to the present invention represented by the formula (1) for achieving the above object, the berberubin compound represented by the formula (4) by thermal decomposition of the berberine salt compound represented by the formula (3) 1 mole of this berberubin compound is prepared by reacting 1-3 moles of an electrophilic alkyl substituent (RX) with an organic solvent.

In addition, the berberubin derivative of the present invention represented by the formula (2) and a salt compound thereof are obtained by heat decomposition of the berberine salt compound represented by the formula (3) to obtain a berberubin compound represented by the formula (4), 1 mole of rubin compound was converted to an electrophilic acyl substituent ( ) To 1 to 2 moles with an organic solvent.

Hereinafter, the present invention will be described in detail.

Pyrolysis of the berberine salt represented by the formula (3) which is a starting material for preparing the novel compounds represented by the formula (1) and the formula (2) according to the present invention to obtain a berberubin compound represented by the formula (4). At this time, the berberine salt was pyrolyzed at high temperature (190 ° C.) and reduced pressure (10 mmHg) to obtain a berberubin compound, which is represented by the following Scheme 1.

1 mole of berberubin obtained in the reaction was refluxed with 1-3 moles of electrophilic alkyl substituent (RX) in an organic solvent to obtain a 9-?-Alkyl berberubin derivative represented by Chemical Formula 1 and a salt compound thereof. . This process is represented by the following scheme 2.

R is hydrogen or an alkyl group having 1 to 18 carbon atoms and is an aromatic hydrocarbon containing chain, branched, cyclic saturated hydrocarbon or unsaturated hydrocarbon, benzene ring; X ⁻ is an inorganic acid ion, organic acid ion or halide.

Preferably, X ⁻ is a hydroxy ion, nitrate ion, sulfate ion, acetate ion, phosphate ion, tartaric acid ion, succinate ion, lactic acid ion, citric acid ion, fumaric acid ion, maleic acid ion, glycolic acid ion, formic acid ion, dried Acid ions, benzoic acid ions, methanesulfonic acid ions, benzenesulfonic acid ions, aspartic acid ions, salicylic acid ions, glycerate ions, ascorbic acid ions, fluorides, chlorides, bromides or iodides.

Among the compounds represented by the formula (1) obtained by the above reaction, in particular R is a C ₆ ~C ₁₁ and X ^- is I ^-, and the compound R is C ₆ ~C ₁₁ and X ^- is Cl ^- compound of the antibacterial and antifungal activity It is preferable at the point of view.

In addition, pyrolysis of the berberine salt represented by the formula (3) as described above to obtain a berberrubin compound represented by the formula (4), 1 mole of the berberrubin is an electrophilic acyl substituent ( ) A room temperature is reacted with 1 to 2 moles of an organic solvent to obtain a 9-?-Acyl berberubin derivative represented by Chemical Formula 2 and a salt compound thereof. This process is represented by the following scheme 3.

R is hydrogen or an alkyl group having 1 to 18 carbon atoms and is an aromatic hydrocarbon containing chain, branched, cyclic saturated hydrocarbon or unsaturated hydrocarbon, benzene ring; X ⁻ is an inorganic acid ion, organic acid ion or halide.

Preferably, X ⁻ is a hydroxy ion, nitrate ion, sulfate ion, acetate ion, phosphate ion, tartaric acid ion, succinate ion, lactic acid ion, citric acid ion, fumaric acid ion, maleic acid ion, glycolic acid ion, formic acid ion, dried Acid ions, benzoic acid ions, methanesulfonic acid ions, benzenesulfonic acid ions, aspartic acid ions, salicylic acid ions, glycerate ions, ascorbic acid ions, fluorides, chlorides, bromides or iodides.

Among the compounds represented by Formula 2, compounds in which R is C ₈ , C ₁₀ , C ₁₂ and X ^- is Cl ^- are preferred in terms of antibacterial and antifungal activity.

The novel compounds represented by Formula 1 and Formula 2 are Enterococcus Faecalis, Staphylococcus aureus, Micrococcus luteus, Staphylococcus epi Gram-positive bacteria such as Staphylococcus epidermis, Bacillus subtilis, Propionibacterium acnes, Candida Krusei, Candida Lusitaniea, Candida al-Kandi (Candida albicans), Candida tropicalis, Cryptococcus neoformans, Candida parapsilosis, Candida glabrata, Candida utilis, Against fungi such as Trichophyton metagrophytes and Saccharomyces cerevisiae W represents the antibacterial and antifungal activity in vitro.

In vitro test results for the antimicrobial activity, R is C ₆ ~C ₁₁ and X ^- is I ^- a compound of formula with R 1 C ₆ ~C ₁₁ and X ^- is Cl ^- in the compounds are listed in the above formula (1) The antimicrobial activity of the most Gram-positive bacteria, i.e., most of the experimental strains, was in the range of 0.125 ~ 16㎍ / ㎖. In addition, the compound of formula (2) wherein R is C ₈ , C ₁₀ , C ₁₂ and X ⁻ is Cl ⁻ showed antimicrobial activity against most experimental strains in the concentration range of 1 to 64 µg / ml. In addition, other compounds of the formulas (1) and (2) used in the experiments generally exhibited selective antimicrobial activity against specific experimental strains at 0.5 to 1 µg / ml or more.

In vitro test results for antifungal activity showed that compounds of Formula 1 wherein R is C ₆ -C ₁₁ and X ^- is I ^- in the above listed fungi, i.e. in the range of 1-16 µg / ml for all experimental strains. It showed antifungal activity, and the compounds of the formula (1) in which R is C ₆ -C ₁₁ and X ^- is Cl ^- showed better antifungal activity in the concentration range of 0.5-8 µg / ml which was better for all experimental strains. In addition, the compounds of the formula (2) wherein R is C ₈ , C ₁₀ , C ₁₂ and X ⁻ is Cl ⁻ showed antifungal activity against most experimental strains in the concentration range of 2 to 64 µg / ml. In addition, the other compounds of the formulas (1) and (2) used in the experiments generally showed selective antifungal activity against specific experimental strains at 1 to 2 µg / ml or more.

The compounds represented by Chemical Formulas 1 and 2 may be prepared in various forms by adding a pharmaceutically acceptable excipient or adjuvant by a conventional pharmaceutical method or including a carrier. Examples of possible formulations include oral formulations such as tablets, capsules, syrups; Injections; Suppositories; External preparations such as ointments, creams, lotions, and external preparations. Formulated agents can be administered by oral administration, by injection, by mucosal administration, or by topical topical administration to the skin.The effective dosage is within the range of antimicrobial and antifungal activity and the type and amount of the excipient or carrier, and administration. It can be changed according to the path.

Hereinafter, the present invention will be described in more detail with reference to Examples. However, the scope of the present invention is not limited by the following examples, and those of ordinary skill in the art to which the present invention pertains should be within the equivalent scope of the technical concept of the present invention and the claims to be described below. Of course, various modifications and variations are possible. In the following examples, the compound number refers to the compound numbers of the following Tables 1-3.

Example 1

Synthesis of 9-Ο-ethyl Berberubin Iodide (Compound No. 1)

3 g of berberubin and 1 ml of ethyl iodide were added to 100 ml of dimethyl formamide (DMF) and vigorously refluxed at 120 ° C. for 5 hours. The reaction solution was concentrated under reduced pressure, diluted with diethylether, and the remaining solids were filtered. The filtered solids were washed with diethyl ether, and silica gel was used as a filler, and chloroform and methanol were 9: 1. 2.73 g of 9-Ο-ethyl berberubin iodide was obtained by liquid chromatography using the mixed organic solvent as an eluent.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ: 9.81 (s, 1H), 8.92 (s, 1H), 8.21 (d, 1H), 7.99 (d, 1H), 7.80 (s, 1H), 7.09 ( s, 1H), 6.18 (s, 1H), 4.95 (t, 2H), 4.28 (t, 2H), 4.06 (s, 3H), 3.22 (t, 2H), 1.41 (t, 3H)

Example 2

Synthesis of 9-Ο-propyl Berberubin Iodide (Compound No. 2)

Except for using 1.2 ml of propyl iodide instead of 1 ml of ethyl iodide in Example 1, 2.94 g of 9-Ο-propyl berberubin iodide was obtained in the same manner.

¹ H NMR (300MHz, DMSO-d ₆ ) δ: 9.78 (s, 1H), 8.92 (d, 1H), 8.21 (d, 1H), 7.80 (s, 1H), 6.18 (s, 2H), 4.95 ( t, 2H), 4.06 (s, 3H), 3.22 (t, 2H), 1.85 (m, 2H), 1.05 (t, 3H)

Example 3

Synthesis of 9-Ο-butyl Berberubin Iodide (Compound No. 3)

Except for using 1.3 ml of butyl iodide instead of 1 ml of ethyl iodide in Example 1, 2.84 g of 9-Ο-butyl berberubin iodide was obtained in the same manner.

¹ H NMR (300MHz, DMSO-d ₆ ) δ: 9.77 (s, 1H), 8.91 (s, 1H), 8.21 (d, 1H), 7.98 (d, 1H), 7.80 (s, 1H), 7.08 ( s, 1H), 6.19 (s, 2H), 4.94 (t, 2H), 4.27 (t, 2H), 4.04 (s, 3H), 3.22 (t, 2H), 1.84 (m, 2H), 1.32 (m , 2H), 1.05 (t, 3H)

Example 4

Synthesis of 9-Ο-pentyl Berberubin Iodide (Compound No. 4)

Except for using 1 ml of ethyl iodide 1.5 ml pentyl iodide in Example 1 was carried out in the same manner to obtain 3.16 g of 9- O-pentyl berberubin iodide.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ: 9.74 (s, 1H), 8.92 (s, 1H), 8.20 (d, 1H), 7.98 (d, 1H), 7.79 (s, 1H), 7.09 ( s, 1H), 6.18 (s, 2H), 4.94 (t, 2H), 4.28 (t, 2H), 4.05 (s, 3H), 3.21 (t, 2H), 1.85 (m, 2H), 1.45 to 1.30 (m, 4H), 0.97 (t, 3H)

Example 5

Synthesis of 9-Ο-hexyl Berberubin Iodide (Compound No. 5)

Except for using 1.7 ml of hexyl iodide instead of 1 ml of ethyl iodide in Example 1, 3.21 g of 9-Ο-hexyl berberrubin iodide was obtained in the same manner.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ: 9.75 (s, 1H), 8.93 (s, 1H), 8.21 (d, 1H), 7.98 (d, 1H), 7.79 (s, 1H), 7.09 ( s, 1H), 6.18 (s, 2H), 4.95 (t, 2H), 4.29 (t, 2H), 4.05 (s, 3H), 3.22 (t, 2H), 1.86 (m, 2H), 1.45 to 1.30 (m, 6 H), 0.97 (t, 3 H)

Example 6

Synthesis of 9-Ο-heptyl Berberubin Iodide (Compound No. 6)

Except for using 1 ml of ethyl iodide 1.9 ml of heptyl iodide in Example 1 was carried out in the same manner to obtain 3.16 g of 9- o-heptyl berberubin iodide.

¹ H NMR (300MHz, DMSO-d ₆ ) δ: 9.73 (s, 1H), 8.91 (s, 1H), 8.21 (d, 1H), 7.99 (d, 1H), 7.79 (s, 1H), 7.10 ( s, 1H), 6.21 (s, 2H), 4.93 (t, 2H), 4.26 (t, 2H), 4.02 (s, 3H), 3.21 (t, 2H), 1.86 (m, 2H), 1.45 to 1.30 (m, 8 H), 0.97 (t, 3 H)

Example 7

Synthesis of 9-Ο-octyl berberubin iodide (Compound No. 7)

Except for using 1 ml of ethyl iodide instead of 2.1 ml of octyl iodide in Example 1, 3.19 g of 9-O-octyl berberubin iodide was obtained in the same manner.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ: 9.74 (s, 1H), 8.92 (s, 1H), 8.20 (d, 1H), 7.98 (d, 1H), 7.79 (s, 1H), 7.09 ( s, 1H), 6.18 (s, 2H), 4.94 (t, 2H), 4.28 (t, 2H), 4.05 (s, 3H), 3.21 (t, 2H), 1.85 (m, 2H), 1.46-1.30 (m, 10 H), 0.97 (t, 3 H)

Example 8

Synthesis of 9-Ο-nonyl berberuvin iodide (Compound No. 8)

Except for using 1 ml of ethyl iodide instead of 2.5 ml of nonyl iodide in Example 1 was carried out in the same manner to obtain 3.42 g of 9- O-nonyl berberubin iodide.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ: 9.72 (s, 1H), 8.91 (s, 1H), 8.18 (d, 1H), 7.97 (d, 1H), 7.79 (s, 1H), 7.09 ( s, 1H), 6.19 (s, 2H), 4.96 (t, 2H), 4.28 (t, 2H), 4.07 (s, 3H), 3.23 (t, 2H), 1.85 (m, 2H), 1.44 to 1.27 (m, 12 H), 0.97 (t, 3 H)

Example 9

Synthesis of 9-Ο-decyl Berberubin Iodide (Compound No. 9)

Except for using 1 ml of ethyl iodide 1.5 ml instead of 1 ml of ethyl iodide in the same manner as in the same method to obtain 3.83 g of 9- O-decyl berberubin iodide.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ: 9.74 (s, 1H), 8.92 (s, 1H), 8.19 (d, 1H), 7.98 (d, 1H), 7.79 (s, 1H), 7.09 ( s, 1H), 6.17 (s, 2H), 4.94 (t, 2H), 4.28 (t, 2H), 4.05 (s, 3H), 3.21 (t, 2H), 1.87 (m, 2H), 1.47 to 1.25 (m, 14H), 0.85 (t, 3H)

Example 10

Synthesis of 9-Ο-Undecyl Berberubin Iodide (Compound No. 10)

In Example 1, except that 3.0 ml of undecyl iodide was used instead of 1 ml of ethyl iodide, the same procedure was followed to obtain 3.85 g of 9-Ο-undecyl berberrubin iodide.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ: 9.80 (s, 1H), 8.89 (s, 1H), 8.20 (d, 1H), 7.96 (d, 1H), 7.78 (s, 1H), 7.01 ( s, 1H), 6.16 (s, 2H), 4.92 (t, 2H), 4.26 (t, 2H), 4.02 (s, 3H), 3.19 (t, 2H), 1.81 (m, 2H), 1.48-1.23 (m, 16H), 0.82 (t, 3H)

Example 11

Synthesis of 9-Ο-dodecyl Berberubin Iodide (Compound No. 11)

In Example 1, except that 3.5 ml of dodecyl iodide was used instead of 1 ml of ethyl iodide, 3.95 g of 9-Ο-dodecyl berberrubin iodide was obtained in the same manner.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ: 9.74 (s, 1H), 8.93 (s, 1H), 8.21 (d, 1H), 7.98 (d, 1H), 7.80 (s, 1H), 7.01 ( s, 1H), 6.18 (s, 2H), 4.94 (t, 2H), 4.27 (t, 2H), 4.05 (s, 3H), 3.21 (t, 2H), 1.87 (m, 2H), 1.47 to 1.21 (m, 18 H), 0.82 (t, 3 H)

Example 12

Synthesis of 9-Ο-hexadecyl Berberubin Iodide (Compound No. 12)

The same procedure was followed as in Example 1 except that 4.0 ml of hexadecyl iodide was used instead of 1 ml of ethyl iodide to obtain 4.27 g of 9-Ο-hexadecyl berberrubin iodide.

¹ H NMR (300MHz, DMSO-d ₆ ) δ: 9.75 (s, 1H), 8.93 (s, 1H), 8.19 (d, 1H), 7.97 (d, 1H), 7.82 (s, 1H), 7.00 ( s, 1H), 6.19 (s, 2H), 4.96 (t, 2H), 4.25 (t, 2H), 4.02 (s, 3H), 3.23 (t, 2H), 1.89 (m, 2H), 1.49-1.20 (m, 26H), 0.82 (t, 3H)

Example 13

Synthesis of 9-Ο-octadecyl Berberubin Iodide (Compound No. 13)

In Example 1, except that 1.5 ml of octadecyl iodide was used instead of 1 ml of ethyl iodide, 4.21 g of 9-O-octadecyl berberrubin iodide was obtained in the same manner.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ: 9.74 (s, 1H), 8.93 (s, 1H), 8.21 (d, 1H), 7.98 (d, 1H), 7.80 (s, 1H), 7.01 ( s, 1H), 6.18 (s, 2H), 4.94 (t, 2H), 4.27 (t, 2H), 4.05 (s, 3H), 3.21 (t, 2H), 1.87 (m, 2H), 1.48-1.19 (m, 30H), 0.82 (t, 3H)

Example 14

Synthesis of 9-Ο-ethyl berberuvin chloride (Compound No. 14)

After dissolving 2 g of 9- O-ethyl berberubin iodide synthesized in Example 1 in methanol and then adding silver chloride (AgCl), the solid material produced by filtration was removed. The remaining solution was concentrated to give 1.5 g of 9-Ο-ethyl berberuvin chloride.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ: 9.78 (s, 1H), 8.91 (s, 1H), 8.21 (d, 1H), 7.98 (d, 1H), 7.80 (s, 1H), 7.09 ( s, 1H), 6.18 (s, 2H), 4.95 (t, 2H), 4.28 (t, 2H), 4.06 (s, 3H), 3.22 (t, 2H), 1.42 (t, 3H)

Example 15

Synthesis of 9-Ο-propyl berberuvin chloride (Compound No. 15)

1.42 g of 9-Ο-propyl berberuvin chloride in the same manner as in Example 14, except that 9-Ο-propyl berberuvin iodide was used instead of 9-Ο-ethyl berberuvin iodide. Got.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ: 9.78 (s, 1H), 8.91 (s, 1H), 8.21 (d, 1H), 7.97 (d, 1H), 7.79 (s, 1H), 7.09 ( s, 1H), 6.18 (s, 2H), 4.95 (t, 2H), 4.25 (t, 2H), 4.05 (s, 3H), 3.22 (t, 2H), 1.85 (m, 2H), 1.05 (t , 3H)

Example 16

Synthesis of 9-Ο-butyl Berberubin Iodide (Compound No. 16)

1.42 g of 9-Ο-butyl berberuvin chloride was carried out in the same manner as Example 14, except that 9-Ο-butyl berberuvin iodide was used instead of 9-Ο-ethyl berberuvin iodide. Got.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ: 9.78 (s, 1H), 8.91 (s, 1H), 8.21 (d, 1H), 7.97 (d, 1H), 7.79 (s, 1H), 7.09 ( s, 1H), 6.18 (s, 2H), 4.95 (t, 2H), 4.25 (t, 2H), 4.05 (s, 3H), 3.22 (t, 2H), 1.86 (m, 2H), 1.39 (m , 2H), 1.05 (t, 3H)

Example 17

Synthesis of 9-Ο-pentyl berberuvin chloride (Compound No. 17)

1.34 g of 9-Ο-propyl berberuvin chloride was carried out in the same manner as in Example 14, except that 9-Ο-pentyl berberuvin iodide was used instead of 9-Ο-ethyl berberuvin iodide. Got.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ: 9.74 (s, 1H), 8.92 (s, 1H), 8.19 (d, 1H), 7.98 (d, 1H), 7.80 (s, 1H), 7.09 ( s, 1H), 6.17 (s, 2H), 4.94 (t, 2H), 4.28 (t, 2H), 4.05 (s, 3H), 3.21 (t, 2H), 1.85 (m, 2H), 1.45 to 1.30 (m, 4H), 0.96 (t, 3H)

Example 18

Synthesis of 9-Ο-hexyl Berberubin Chloride (Compound No. 18)

1.34 g of 9-Ο-hexyl berberuvin chloride in the same manner as in Example 14, except that 9-Ο-hexyl berberuvin iodide was used instead of 9-Ο-ethyl berberuvin iodide. Got.

¹ H NMR (300MHz, DMSO-d ₆ ) δ: 9.74 (s, 1H), 8.93 (s, 1H), 8.18 (d, 1H), 8.01 (d, 1H), 7.80 (s, 1H), 7.09 ( s, 1H), 6.18 (s, 2H), 4.94 (t, 2H), 4.28 (t, 2H), 4.05 (s, 3H), 3.23 (t, 2H), 1.85 (m, 2H), 1.45 to 1.29 (m, 6H), 0.99 (t, 3H)

Example 19

Synthesis of 9-Ο-heptyl berberuvin chloride (Compound No. 19)

1.31 g of 9-Ο-heptyl berberuvin chloride in the same manner as in Example 14, except that 9-Ο-heptyl berberubin iodide was used instead of 9-Ο-ethyl berberuvin iodide. Got.

¹ H NMR (300MHz, DMSO-d ₆ ) δ: 9.76 (s, 1H), 8.92 (s, 1H), 8.19 (d, 1H), 7.98 (d, 1H), 7.80 (s, 1H), 7.09 ( s, 1H), 6.17 (s, 2H), 4.94 (t, 2H), 4.28 (t, 2H), 4.05 (s, 3H), 3.21 (t, 2H), 1.85 (m, 2H), 1.37-1.24 (m, 4H), 0.96 (t, 3H)

Example 20

Synthesis of 9-Ο-octyl berberuvin chloride (Compound No. 20)

1.35 g of 9-Ο-octyl berberuvin chloride in the same manner as in Example 14, except that 9-Ο-octyl berberuvin iodide was used instead of 9-Ο-ethyl berberuvin iodide. Got.

¹ H NMR (300MHz, DMSO-d ₆ ) δ: 9.74 (s, 1H), 8.92 (s, 1H), 8.19 (d, 1H), 7.98 (d, 1H), 7.80 (s, 1H), 7.11 ( s, 1H), 6.15 (s, 2H), 4.96 (t, 2H), 4.28 (t, 2H), 4.11 (s, 3H), 3.21 (t, 2H), 1.84 (m, 2H), 1.41-1.28 (m, 4H), 0.96 (t, 3H)

Example 21

Synthesis of 9-Οnonyl berberuvin chloride (Compound No. 21)

Except for using 9-Ο-nonyl berberuvin iodide instead of 9-Ο-ethyl berberuvin iodide in Example 14, 1.34 g of 9-Ο-nonyl berberuvin chloride Got.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ: 9.74 (s, 1H), 8.92 (s, 1H), 8.19 (d, 1H), 7.98 (d, 1H), 7.80 (s, 1H), 7.09 ( s, 1H), 6.17 (s, 2H), 4.94 (t, 2H), 4.28 (t, 2H), 4.05 (s, 3H), 3.21 (t, 2H), 1.85 (m, 2H), 1.47 to 1.27 (m, 12 H), 0.96 (t, 3 H)

Example 22

Synthesis of 9-Ο-decyl Berberubin Chloride (Compound No. 22)

1.72 g of 9-Ο-decyl berberrubin chloride was carried out in the same manner as in Example 14, except that 9-Ο-decyl berberuvin iodide was used instead of 9-Ο-ethyl berberuvin iodide. Got.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ: 9.74 (s, 1H), 8.92 (s, 1H), 8.18 (d, 1H), 7.98 (d, 1H), 7.80 (s, 1H), 7.09 ( s, 1H), 6.17 (s, 2H), 4.94 (t, 2H), 4.28 (t, 2H), 4.05 (s, 3H), 3.21 (t, 2H), 1.86 (m, 2H), 1.47 to 1.24 (m, 14H), 0.86 (t, 3H)

Example 23

Synthesis of 9-Ο-Undecyl Berberubin Chloride (Compound No. 23)

Except for using 9-Ο-undecyl berberrubin iodide instead of 9-Ο-ethyl berberuvin iodide in Example 14 was carried out in the same manner 9-Ο-undecyl berberrubin chloride 1.38 g was obtained.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ: 9.72 (s, 1H), 8.93 (s, 1H), 8.21 (d, 1H), 7.98 (d, 1H), 7.82 (s, 1H), 7.02 ( s, 1H), 6.14 (s, 2H), 4.94 (t, 2H), 4.26 (t, 2H), 4.06 (s, 3H), 3.21 (t, 2H), 1.88 (m, 2H), 1.48-1.20 (m, 4H), 0.85 (t, 3H)

Example 24

Synthesis of 9-Ο-dodecyl Berberubin Chloride (Compound No. 24)

Except for using 9-Ο-dodecyl berberuvin iodide instead of 9-Ο-ethyl berberubin iodide in Example 14 was carried out in the same manner 9-Ο-dodecyl berberubin chloride 1.45 g was obtained.

¹ H NMR (300MHz, DMSO-d ₆ ) δ: 9.74 (s, 1H), 8.93 (s, 1H), 8.20 (d, 1H), 7.98 (d, 1H), 7.80 (s, 1H), 7.01 ( s, 1H), 6.18 (s, 2H), 4.94 (t, 2H), 4.26 (t, 2H), 4.06 (s, 3H), 3.21 (t, 2H), 1.87 (m, 2H), 1.41-1.18 (m, 18 H), 0.85 (t, 3 H)

Example 25

Synthesis of 9-Ο-hexadecyl Berberubin Chloride (Compound No. 25)

9-Ο-hexadecyl berberrubin chloride was carried out in the same manner as Example 14 except that 9-Ο-hexadecyl berberrubin iodide was used instead of 9-Ο-ethyl berberuvin iodide. 1.43 g was obtained.

¹ H NMR (300MHz, DMSO-d ₆ ) δ: 9.77 (s, 1H), 8.92 (s, 1H), 8.20 (d, 1H), 7.98 (d, 1H), 7.80 (s, 1H), 7.01 ( s, 1H), 6.19 (s, 2H), 4.92 (t, 2H), 4.25 (t, 2H), 4.02 (s, 3H), 3.20 (t, 2H), 1.83 (m, 2H), 1.49 to 1.23 (m, 26H), 0.85 (t, 3H)

Example 26

Synthesis of 9-Ο-octadecyl Berberubin Chloride (Compound No. 26)

9-Ο-octadecyl berberuvin chloride was carried out in the same manner as Example 14 except that 9-Ο-octadecyl berberuvin iodide was used instead of 9-Ο-ethyl berberuvin iodide. 1.45 g was obtained.

¹ H NMR (300MHz, DMSO-d ₆ ) δ: 9.74 (s, 1H), 8.93 (s, 1H), 8.20 (d, 1H), 7.98 (d, 1H), 7.80 (s, 1H), 7.01 ( s, 1H), 6.18 (s, 2H), 4.94 (t, 2H), 4.26 (t, 2H), 4.06 (s, 3H), 3.21 (t, 2H), 1.87 (m, 2H), 1.48-1.19 (m, 30H), 0.85 (t, 3H)

Example 27

Synthesis of 9-Ο-acetyl berberuvin chloride (Compound No. 27)

After dissolving 1.5 g of berberubin in 100 ml of acetonitrile, 0.4 ml of acetyl chloride was added at room temperature and reacted for 1 hour. The reaction solution was concentrated under reduced pressure, diluted with diethyl ether, filtered, and the resulting solid was purified by liquid chromatography using silica gel as a filler and an organic solvent in which chloroform and methanol were mixed with 4: 1 as an eluent. 1.38 g of O-acetyl berberuvin chloride were obtained.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ: 10.05 (s, 1H), 9.05 (s, 1H), 8.29 (d, 1H), 7.80 (s, 1H), 7.09 (s, 1H), 6.18 ( s, 2H), 4.98 (t, 2H), 4.05 (s, 3H), 3.23 (t, 2H), 2.55 (s, 3H)

Example 28

Synthesis of 9-Ο-propionyl berberuvin chloride (Compound No. 28)

Except for using 0.45 ml of propionyl chloride instead of 0.4 ml of acetyl chloride in Example 27, 1.41 g of 9-Ο-propionyl berberuvin chloride was obtained in the same manner.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ: 10.01 (s, 1H), 9.06 (s, 1H), 8.28 (d, 1H), 8.23 (d, 1H), 7.80 (s, 1H), 7.07 ( s, 1H), 6.18 (s, 2H), 4.97 (t, 2H), 4.06 (s, 3H), 3.23 (t, 2H), 2.87 (t, 2H), 1.16 (t, 3H)

Example 29

Synthesis of 9-Ο-butyryl Berberubin Chloride (Compound No. 29)

Except for using 0.4 mL of butyryl chloride instead of 0.4 mL of acetyl chloride in Example 27, 1.43 g of 9-Ο-butyryl berberubin chloride was obtained in the same manner.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ: 9.99 (s, 1H), 9.05 (s, 1H), 8.28 (d, 1H), 8.23 (d, 1H), 7.79 (s, 1H), 7.07 ( s, 1H), 6.17 (s, 2H), 4.97 (t, 2H), 4.05 (s, 3H), 3.23 (t, 2H), 2.87 (t, 2H), 1.52 (m, 2H), 1.01 (t , 3H)

Example 30

Synthesis of 9-Ο-Valeryl Berberubin Chloride (Compound No. 30)

Except for using 0.45 ml of valeryl chloride instead of 0.4 ml of acetyl chloride in Example 27, 1.44 g of 9-Ο-valeryl berberrubin chloride was obtained in the same manner.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ: 9.98 (s, 1H), 9.08 (s, 1H), 8.29 (d, 1H), 8.24 (d, 1H), 7.81 (s, 1H), 7.09 ( s, 1H), 6.18 (s, 2H), 4.95 (t, 2H), 4.02 (s, 3H), 3.22 (t, 2H), 2.90 (t, 2H), 1.73 (m, 2H), 1.45 (m , 2H), 0.99 (t, 3H)

Example 31

Synthesis of 9-Ο-hexanoyl berberuvin chloride (Compound No. 31)

Except for using 0.4 mL of hexanoyl chloride instead of 0.4 mL of acetyl chloride in Example 27 was carried out in the same manner to obtain 1.51 g of 9- o-hexanoyl berberubin chloride.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ: 9.98 (s, 1H), 9.08 (s, 1H), 8.28 (d, 1H), 8.20 (d, 1H), 7.81 (s, 1H), 7.10 ( s, 1H), 6.18 (s, 2H), 4.94 (t, 2H), 4.03 (s, 3H), 3.22 (t, 2H), 2.86 (t, 2H), 1.75 (m, 2H), 1.42 (m , 2H), 1.13 (m, 2H), 0.98 (t, 3H)

Example 32

Synthesis of 9-Ο-octanoyl berberuvin chloride (Compound No. 32)

Except for using 0.45 octanoyl chloride 0.65 mL instead of 0.4 mL of acetyl chloride in the same manner to obtain 1.50 g of 9-O-octanoyl berberuvin chloride.

¹ H NMR (300MHz, DMSO-d ₆ ) δ: 9.93 (s, 1H), 9.05 (s, 1H), 8.28 (d, 1H), 8.21 (d, 1H), 7.81 (s, 1H), 7.10 ( s, 1H), 6.18 (s, 2H), 4.94 (t, 2H), 4.03 (s, 3H), 3.23 (t, 2H), 2.85 (t, 2H), 1.76 (m, 2H), 1.42-1.15 (m, 8H), 0.98 (t, 3H)

Example 33

Synthesis of 9-Ο-decanoyl Berberubin Chloride (Compound No. 33)

In Example 27, except that 0.7 ml of decanoyl chloride was used instead of 0.4 ml of acetyl chloride, the same procedure was followed to obtain 1.56 g of 9-Ο-decanoyl berberrubin chloride.

¹ H NMR (300MHz, DMSO-d ₆ ) δ: 9.87 (s, 1H), 9.03 (s, 1H), 8.29 (d, 1H), 8.19 (d, 1H), 7.81 (s, 1H), 7.10 ( s, 1H), 6.18 (s, 2H), 4.93 (t, 2H), 4.02 (s, 3H), 3.22 (t, 2H), 2.85 (t, 2H), 1.74 (m, 2H), 1.42-1.23 (m, 12H), 0.89 (t, 3H)

Example 34

Synthesis of 9-Ο-lauroyl berberuvin chloride (Compound No. 34)

In Example 27, except that 0.8 ml of lauroyl chloride was used instead of 0.4 ml of acetyl chloride, the same procedure was followed to obtain 1.59 g of 9-Ο-lauroyl berberrubin chloride.

¹ H NMR (300MHz, DMSO-d ₆ ) δ: 9.92 (s, 1H), 9.03 (s, 1H), 8.29 (d, 1H), 8.22 (d, 1H), 7.82 (s, 1H), 7.10 ( s, 1H), 6.18 (s, 2H), 4.94 (t, 2H), 4.03 (s, 3H), 3.23 (t, 2H), 2.86 (t, 2H), 1.74 (m, 2H), 1.42 to 1.22 (m, 16H), 0.88 (t, 3H)

Example 35

Synthesis of 9-Ο-myristoyl berberuvin chloride (Compound No. 35)

Except for using 0.9 ml of myristoyl chloride instead of 0.4 ml of acetyl chloride in Example 27 to give 1.55 g of 9- o-myristoyl berberubin chloride.

¹ H NMR (300MHz, DMSO-d ₆ ) δ: 9.91 (s, 1H), 9.06 (s, 1H), 8.23 (d, 1H), 8.23 (d, 1H), 7.82 (s, 1H), 7.10 ( s, 1H), 6.18 (s, 2H), 4.94 (t, 2H), 4.03 (s, 3H), 3.23 (t, 2H), 2.86 (t, 2H), 1.74 (m, 2H), 1.45 to 1.21 (m, 20H), 0.87 (t, 3H)

Example 36

Synthesis of 9-Ο-palmitoyl berberuvin chloride (Compound No. 36)

1.54 g of 9-Ο-palmitoyl berberubin chloride was obtained in the same manner as in Example 27, except that 1 ml of palmitoyl chloride was used instead of 0.4 ml of acetyl chloride.

¹ H NMR (300MHz, DMSO-d ₆ ) δ: 9.85 (s, 1H), 9.02 (s, 1H), 8.28 (d, 1H), 8.20 (d, 1H), 7.81 (s, 1H), 7.10 ( s, 1H), 6.18 (s, 2H), 4.91 (t, 2H), 4.02 (s, 3H), 3.22 (t, 2H), 2.85 (t, 2H), 1.74 (m, 2H), 1.45 to 1.21 (m, 24H), 0.85 (t, 3H)

Example 37

Synthesis of 9-Ο-benzoyl berberuvin chloride (Compound No. 37)

Except for using 0.7 ml of benzoyl chloride instead of 0.4 ml of acetyl chloride in Example 27, 1.41 g of 9-Ο-benzoyl berberubin chloride was obtained in the same manner.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ: 10.01 (s, 1H), 9.07 (s, 1H), 8.35 (d, 1H), 8.32 (s, 1H), 8.23 (d, 1H), 7.82 ( s, 1H), 7.65 (t, 3H), 7.11 (s, 1H), 6.21 (s, 2H), 4.92 (t, 2H), 4.02 (s, 3H), 3.21 (t, 2H)

Example 38

Synthesis of 9-Ο-3,4,5-trimethoxy benzoyl berberuvin chloride (Compound No. 38)

9-Ο-3,4,5-trimethoxy benzoyl berberubin was carried out in the same manner as Example 27, except that 1 g of 3,4,5-trimethoxy benzoyl chloride was used instead of 0.4 ml of acetyl chloride. 1.53 g of chloride were obtained.

¹ H NMR (300MHz, DMSO-d ₆ ) δ: 9.96 (s, 1H), 9.07 (s, 1H), 8.36 (d, 1H), 8.26 (s, 1H), 7.83 (s, 1H), 7.53 ( s, 1H), 7.23 (s, 1H), 6.19 (s, 2H), 4.93 (t, 2H), 4.04 (s, 3H), 3.91 (t, 2H), 3.82 (s, 3H), 3.73 (s , 3H), 3.20 (t, 2H)

Example 39

Synthesis of Berberubin (Compound No. 39)

The mixture obtained by heating 5 g of berberine chloride (compound No. 41) at 190 DEG C and 10 mmHg for 30 minutes was subjected to liquid chromatography using silica gel as a filler and an organic solvent in which chloroform and methanol were 4: 1 as an eluent. 3.53 g of berberubin was obtained.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ: 9.09 (s, 1H), 8.02 (s, 1H), 7.62 (s, 1H), 7.25 (d, 1H), 6.95 (s, 1H), 6.41 ( d, 1H), 6.09 (s, 2H), 4.48 (t, 2H), 3.75 (s, 3H), 3.05 (t, 2H)

Example 40

Synthesis of Berberubin Hydrochloride (Compound No. 40)

3 g of berberubin was dissolved in 100 ml of boiling water and 5 ml of 35% hydrochloric acid was added. The solution was cooled at room temperature and then recrystallized at 4 ° C. The crystals were filtered and dried to yield 2.54 g of berberubin hydrochloride.

¹ H NMR (300MHz, DMSO-d ₆ ) δ: 9.89 (s, 1H), 8.83 (s, 1H), 7.78 (s, 1H), 7.70 (d, 1H), 7.06 (s, 1H), 6.16 ( s, 2H), 4.88 (t, 2H), 4.03 (s, 3H), 3.17 (t, 2H)

The compounds prepared in Examples 1 to 40 are summarized in Tables 1 to 3 below.

Berberubin derivative compound (Compound Nos. 1 to 13: Compound number R General formula One Ethyl (C ₂ H _5- ) 2 Profile (C ₃ H _7- ) 3 Butyl (C ₄ H _9- ) 4 Pentyl (C ₅ H _11- ) 5 Hexyl (C ₆ H _13- ) 6 Heptyl (C ₇ H _15- ) 7 Octyl (C ₈ H _17- ) 8 Nonyl (C ₉ H _19- ) 9 Decyl (C ₁₀ H _21- ) 10 Undecyl (C ₁₁ H _23- ) 11 Dodecyl (C ₁₂ H _25- ) 12 Hexadecyl (C ₁₃ H _27- ) 13 Octadecyl (C ₁₄ H _29- )

Berberubin derivative compound (Compound Nos. 14 to 26: Formula 1) Compound number R General formula 14 Ethyl (C ₂ H _5- ) 15 Profile (C ₃ H _7- ) 16 Butyl (C ₄ H _9- ) 17 Pentyl (C ₅ H _11- ) 18 Hexyl (C ₆ H _13- ) 19 Heptyl (C ₇ H _15- ) 20 Octyl (C ₈ H _17- ) 21 Nonyl (C ₉ H _19- ) 22 Decyl (C ₁₀ H _21- ) 23 Undecyl (C ₁₁ H _23- ) 24 Dodecyl (C ₁₂ H _25- ) 25 Hexadecyl (C ₁₃ H _27- ) 26 Octadecyl (C ₁₄ H _29- )

Berberubin derivative compound (Compound Nos. 27 to 38: Formula 2) Compound number R General formula 27 Acetyl (CH ₃ CO-) 28 Propionyl (C ₂ H ₅ CO-) 29 Butyryl (C ₃ H ₇ CO-) 30 Baleryl (C ₄ H ₉ CO-) 31 Hexanoyl (C ₅ H ₁₁ CO-) 32 Octanoyl (C ₇ H ₁₅ CO-) 33 Decanoyl (C ₉ H ₁₉ CO-) 34 Lauroyl (C ₁₁ H ₂₃ CO-) 35 Myristoil (C ₁₃ H ₂₇ CO-) 36 Palmitoyl (C ₁₅ H ₃₁ CO-) 37 Benzoyl (C ₆ H ₅ CO-) 38 3,4,5-trimethoxybenzoyl

Compound number Chemical formula 39 40 41

Example 41

Antimicrobial Effect Against Gram-positive Bacteria

Staphylococcus aureus (Staphylococcus aureus), Staphylococcus epidermis, Bacillus subtilis, which are compounds 1 to 41 and the comparative drug kanamycin (compound number 42) synthesized in the above examples. Microbial growth inhibitory concentration (MIC) values for Bacillus subtilis, Micrococcus Luteus, Enterococcus Faecalis, and Propionibacterium acnes were measured and measured. The results are shown in the following Tables 4a to 4c.

The strains were incubated at 37 ° C. for 24 hours using Nutrient Agar (DIFCO) and Muuer Hinton Broth (DIFCO), and the synthesized compounds were dissolved in DMSO to concentrate the stock solution. Was prepared poorly.

5 μl of each compound was dispensed into 96 well plates at each concentration, followed by addition of 95 μl of medium and 100 μl of each strain of 10 ⁶ CFU / ml prepared by incubation. The concentration of the solution containing the compound was prepared to decrease by 0.5-fold from 128 μg / ml to 0.125 μg / ml. The 96 well plate thus prepared was incubated at 37 ° C. for 24 hours to determine the concentration at which the bacteria were not fully grown as a MIC value. Decided.

MIC values for Gram-positive bacteria of compounds CompoundTestorganism MIC (μg / ml) One 2 3 4 5 6 7 8 9 10 11 12 13 14 Enterococcusfaecalis ATCC 29212 128 128 64 64 16 8 4 4 8 16 64 > 128 > 128 128 Staphylococcusaureus ATCC 25923 128 64 32 32 8 4 4 4 8 64 128 > 128 128 128 Staphylococcusarueus ATCC 6538 128 128 64 32 16 4 4 4 4 16 64 > 128 > 128 128 S. aureus IFO12732 128 128 64 32 8 4 4 4 4 16 64 > 128 > 128 128 MicrococcusluteusATCC 10240 2 2 One 0.5 0.5 0.125 0.125 0.125 0.25 0.25 0.5 4 16 4 MicrococcusluteusATCC 9341 4 4 2 2 One One 0.5 0.5 0.5 One One 8 8 8 Propionibacteriumacnes 128 64 32 16 8 4 2 2 4 16 64 128 128 128 StaphylococcusepidermidisATCC 0155 128 64 16 8 4 2 One One 2 One One 64 128 64 Staphylococcusepidermidis ATCC 12228 128 128 16 5 5 2 2 One One 2 2 64 128 64 Bacillus subtilis ATCC 6633 128 128 64 32 8 8 4 4 16 32 64 128 > 128 128 B.subtilisIAM 1609 128 128 64 32 8 8 4 4 16 16 64 128 > 128 128

CompoundTestorganism MIC (μg / ml) 15 16 17 18 19 20 21 22 23 24 25 26 27 28 Enterococcusfaecalis ATCC 29212 128 64 64 8 8 2 2 2 8 64 128 > 128 > 128 > 128 Staphylococcusaureus ATCC 25923 64 32 32 8 4 2 2 2 8 128 > 128 > 128 > 128 > 128 Staphylococcusarueus ATCC 6538 128 64 32 8 4 4 2 2 4 64 128 > 128 > 128 > 128 S. aureus IFO12732 64 32 16 8 8 2 2 2 4 64 128 > 128 > 128 > 128 MicrococcusluteusATCC 10240 8 4 One 0.5 0.125 0.125 0.125 0.125 0.5 0.5 4 32 64 64 MicrococcusluteusATCC 9341 4 4 2 One 0.5 0.5 0.5 0.5 One One 8 64 > 128 > 128 Propionibacteriumacnes 64 32 8 4 4 One One One 4 16 64 128 > 128 > 128 StaphylococcusepidermidisATCC 0155 64 8 8 2 2 One 0.5 0.5 One One 64 128 > 128 > 128 Staphylococcusepidermidis ATCC 12228 32 8 4 2 One 0.5 0.5 0.5 One One 64 128 > 128 > 128 Bacillus subtilis ATCC 6633 64 32 32 8 4 2 2 2 8 64 > 128 > 128 > 128 > 128 B.subtilisIAM 1609 64 116 16 8 4 2 2 2 8 32 128 > 128 > 128 > 128

CompoundTestorganism MIC (μg / ml) 29 30 31 32 33 34 35 36 37 38 39 40 41 42 Enterococcusfaecalis ATCC 29212 > 128 > 128 128 32 128 > 128 > 128 > 128 > 128 > 128 > 128 > 128 128 4 Staphylococcusaureus ATCC 25923 > 128 > 128 128 4 128 > 128 > 128 > 128 > 128 > 128 > 128 > 128 128 8 Staphylococcusarueus ATCC 6538 > 128 > 128 128 64 128 128 > 128 > 128 > 128 > 128 > 128 > 128 > 128 4 S. aureus IFO12732 > 128 > 128 128 64 128 128 > 128 > 128 > 128 > 128 > 128 > 128 > 128 14 MicrococcusluteusATCC 10240 64 16 64 64 4 One 2 4 64 16 64 32 2 2 MicrococcusluteusATCC 9341 64 64 64 32 8 4 4 8 64 64 64 32 8 2 Propionibacteriumacnes > 128 > 128 > 128 64 128 128 > 128 > 128 > 128 > 128 > 128 > 128 > 128 2 StaphylococcusepidermidisATCC 0155 > 128 > 128 > 128 64 4 8 32 > 128 > 128 > 128 > 128 > 128 > 128 0.5 Staphylococcusepidermidis ATCC 12228 > 128 > 128 > 128 64 8 16 64 > 128 > 128 > 128 > 128 > 128 > 128 0.5 Bacillus subtilis ATCC 6633 > 128 > 128 > 128 > 128 8 128 > 128 > 128 > 128 > 128 > 128 > 128 > 128 2 B.subtilisIAM 1609 > 128 > 128 > 128 > 128 32 128 > 128 > 128 > 128 > 128 > 128 > 128 > 128 4

Compounds 5-10 and 18-23 of the above compounds showed better growth inhibitory effect than kanamycin (42), which is a 9-alkyl-berberubin derivative hydrochloride compound. Compound 26 showed excellent growth inhibitory effect on Gram-positive bacteria.

Example 42

Antifungal effect

Candida Krusei, Candida Lusitaniea, Candida albicans, targeting Compounds 1 to 41 and the comparative drug Ampotericin B (Compound No. 42) synthesized in the above examples. (Candida albicans), Candida tropicalis, Cryptococcus neoformans, Candida parapsilosis, Candida glabrata, Candida utilis, Microbial growth inhibitory concentration (MIC) values for Trichophyton metagrophytes and Saccharomyces cerevisiae were measured and the results are shown in Tables 5a to 5c below.

The strains were cultivated using Sabourad Dextrose medium (DIFCO), Candida Krusei, Candida Lusitaniea, Candida albicans, Candida tropicalis ( Candida tropicalis) was incubated for 48 hours and Cryptococcus neoformans for 72 hours at 28-30 ° C.

All compounds were dissolved in DMSO to prepare stock solutions by concentration. Compounds used in the experiment were dispensed 5μL into 96 well plate for each concentration, and then added 95μL of medium and 100μL of each strain solution of 10 ⁴ CFU / ㎖ prepared by incubation. The concentration of the solution containing the compound was prepared to decrease by 0.5-fold from 128 μg / ml to 0.125 μg / ml. The 96 well plate thus prepared was incubated at 28 to 30 ° C. during the incubation time to determine the concentration at which the bacteria were not fully grown as the MIC value, and the medium was based on the absorbance at 650 nm by a microplate reader (Emax Microplate reader). The turbidity of was determined.

MIC value for fungi of compounds

CompoundTestorganism MIC (μg / ml) One 2 3 4 5 6 7 8 9 10 11 12 13 14 Candida kruseiATCC 6258 64 32 32 32 16 4 One One One 4 32 64 64 64 Candida kruseiIFO 1162 64 64 16 16 8 2 One One One 2 16 64 64 64 Candida kruseiIFO 0584 64 32 16 8 2 One One One One 2 16 64 64 64 Candida kruseiIFO 1664 64 64 32 32 8 4 2 2 2 8 64 64 > 128 64 C. lusitaniaeATCC 42720 64 32 16 16 8 2 One One One 2 16 64 > 128 > 128 C. albicansATCC 10231 128 32 16 8 4 2 One One One 2 16 64 64 > 128 C. albicansATCC 11651 128 128 64 32 16 4 4 2 2 4 16 64 128 > 128 C. albicansATCC 28838 64 16 8 2 2 One One One 4 8 16 64 > 128 C.albicansATCC 90028 128 128 64 32 16 4 4 2 2 4 16 64 128 > 128 C. albicansATCC 90029 128 64 64 16 16 2 One One One 4 64 64 128 > 128 C. albicansIFO 1385 128 64 16 8 8 2 One One 2 4 8 64 64 > 128 C.albicansIAM 4905 128 64 16 8 4 2 One One 2 4 16 64 128 > 128 C.parapsilosisATCC 90018 128 64 32 16 8 2 One One 2 4 16 64 128 > 128 C.glabrataATCC 90030 128 64 32 8 8 4 2 2 4 8 16 64 128 128 C.glabrataIFO 0622 128 64 32 16 8 2 One One 2 4 8 64 128 64

C.utilisIFO 0619 128 64 16 16 8 2 2 One One 4 32 64 > 128 > 128 Sacchromycescerevisiae IFO 0209 128 64 16 8 4 2 One One One 4 16 128 > 128 > 128 C. tropicalisATCC 13803 64 32 16 8 4 2 One One One 4 16 64 > 128 > 128 C. tropicalisIFO 0587 64 32 16 16 4 4 2 2 2 4 16 64 128 64 C. tropicalisIFO 10241 64 32 16 16 8 4 2 2 2 8 32 128 > 128 128 CryptococusneoformansATCC 2344 16 16 16 16 8 2 One 2 One 4 16 16 16 16 CryptococusneoformansATCC 36556 64 32 16 8 4 2 One One One 4 16 64 64 64 CryptococusneoformansATCC 90112 32 16 8 4 4 2 2 2 2 8 8 16 32 64 CrytococusneoformansATCC 90113 32 16 16 4 4 2 One One One 4 16 64 64 32 TrichophytonmetagrophytesATCC 9533 128 128 16 8 8 4 4 2 2 8 16 128 128 > 128

CompoundTestorganism MIC (μg / ml) 15 16 17 18 19 20 21 22 23 24 25 26 27 28 Candida kruseiATCC 6258 64 32 16 4 One 0.5 0.5 0.5 2. 4 64 64 > 128 > 128 Candida kruseiIFO 1162 32 32 32 8 One 0.5 0.5 0.5 2 8 64 64 > 128 > 128 Candida kruseiIFO 0584 32 16 16 4 One 0.5 0.5 0.5 2 8 64 64 > 128 > 128 Candida kruseiIFO 1664 32 32 32 8 4 One One One 4 16 64 > 128 > 128 > 128 C. lusitaniaeATCC 42720 32 16 16 4 2 One One One 4 16 64 > 128 > 128 > 128 C. albicansATCC 10231 64 64 64 8 4 2 One One 4 16 64 > 128 > 128 > 128 C. albicansATCC 11651 64 64 64 8 4 2 One One 4 16 64 > 128 > 128 > 128 C. albicansATCC 28838 64 32 16 4 One 0.5 0.5 0.5 4 16 64 > 128 > 128 > 128

C.albicansATCC 90028 64 32 16 2 One 0.5 0.5 One 4 16 32 > 128 > 128 > 128 C. albicansATCC 90029 64 32 16 2 One 0.5 0.5 0.5 8 16 32 > 128 > 128 > 128 C. albicansIFO 1385 64 32 16 4 One 0.5 0.5 0.5 4 16 32 64 > 128 > 128 C.albicansIAM 4905 64 32 16 4 2 One One One 4 16 64 > 128 > 128 > 128 C. parapsilosisATCC 90018 64 32 16 4 2 0.5 0.5 One 8 32 64 > 128 > 128 > 128 C.glabrataATCC 90030 32 16 8 8 2 One One 2 8 32 64 > 128 > 128 > 128 C.glabrataIFO 0622 64 32 16 4 2 One One One 8 32 64 64 > 128 > 128 C.utilisIFO 0619 64 32 16 8 One One 0.5 0.5 2 16 32 64 > 128 > 128 Sacchromycescerevisiae IFO 0209 64 32 16 4 2 One 0.5 0.5 2 16 128 > 128 > 128 > 128 C. tropicalisATCC 13803 32 16 8 4 2 One 0.5 0.5 4 16 128 128 > 128 > 128 C. tropicalisIFO 0587 32 16 8 4 2 One One One 4 16 64 128 > 128 > 128 C. tropicalisIFO 10241 32 16 16 4 2 One One 2 8 16 32 > 128 > 128 > 128 CryptococusneoformansATCC 2344 32 16 16 One One 0.5 0.5 One 4 8 32 64 128 128 CryptococusneoformansATCC 36556 64 32 16 4 2 One 0.5 One 4 16 32 64 > 128 > 128 CryptococusneoformaATCC 90112 32 16 8 2 One 0.5 0.5 0.5 2 8 16 64 > 128 > 128 CrytococusneoformaATCC 90113 32 16 8 2 One 0.5 0.5 0.5 2 4 16 64 > 128 > 128 TrichophytonmetagrophytesATCC 9533 64 64 32 8 2 One One One 8 16 32 64 > 128 > 128

CompoundTestorganism MIC (μg / ml) 29 30 31 32 33 34 35 36 37 38 39 40 41 42 Candida kruseiATCC 6258 > 128 > 128 64 16 8 16 32 128 > 128 > 128 > 128 > 128 64 0.5 Candida kruseiIFO 1162 > 128 > 128 128 16 4 16 32 128 > 128 > 128 > 128 > 128 64 0.5 Candida kruseiIFO 0584 > 128 > 128 64 16 4 16 64 128 > 128 > 128 > 128 > 128 64 0.5 Candida kruseiIFO 1664 > 128 > 128 128 32 8 64 > 128 > 128 > 128 > 128 > 128 > 128 32 0.5 C. lusitaniaeATCC 42720 > 128 > 128 128 16 2 > 128 > 128 > 128 > 128 128 > 128 > 128 > 128 0.5 C. albicansATCC 10231 > 128 > 128 128 32 2 4 > 128 > 128 > 128 > 128 > 128 > 128 128 0.125 C. albicansATCC 11651 > 128 > 128 128 8 4 64 128 128 > 128 > 128 > 128 > 128 128 0.125 C. albicansATCC 28838 > 128 > 128 128 16 8 64 128 128 > 128 > 128 > 128 > 128 128 0.5 C.albicansATCC 90028 > 128 > 128 64 16 8 64 128 128 > 128 > 128 > 128 > 128 > 128 0.5 C. albicansATCC 90029 > 128 > 128 64 8 4 64 128 128 > 128 > 128 > 128 > 128 > 128 0.5 C. albicansIFO 1385 > 128 > 128 64 8 4 64 128 128 > 128 > 128 > 128 > 128 > 128 0.5 C.albicansIAM 4905 > 128 > 128 64 4 2 64 128 128 > 128 > 128 > 128 > 128 > 128 0.5 C. parapsilosisATCC 90018 > 128 > 128 64 8 2 64 128 128 > 128 > 128 > 128 > 128 > 128 One C.glabrataATCC 90030 > 128 > 128 64 4 2 64 64 128 > 128 > 128 > 128 > 128 128 One C.glabrataIFO 0622 > 128 > 128 64 8 4 64 64 64 128 > 128 > 128 > 128 128 One C.utilisIFO 0619 > 128 > 128 64 4 2 32 64 64 128 > 128 > 128 > 128 64 0.5 Sacchromycescerevisiae IFO 0209 > 128 > 128 64 4 2 32 64 64 128 > 128 > 128 > 128 64 0.5 C. tropicalisATCC 13803 > 128 > 128 64 4 2 64 128 128 > 128 > 128 > 128 > 128 64 0.25 C. tropicalisIFO 0587 > 128 > 128 128 8 4 64 64 64 128 > 128 > 128 > 128 32 0.25 C. tropicalisIFO 10241 > 128 > 128 128 32 4 4 > 128 > 128 > 128 64 > 128 > 128 16 0.25 CryptococusneoformansATCC 2344 128 128 128 16 2 2 4 64 > 128 32 > 128 128 8 0.125

CryptococusneoformaATCC 36556 > 128 > 128 32 16 2 8 32 64 64 64 > 128 > 128 32 0.125 CryptococusneoformaATCC 90112 > 128 > 128 32 8 2 8 32 64 64 128 > 128 > 128 32 0.125 CrytococusneoformaATCC 90113 > 128 > 128 64 4 2 8 32 64 64 64 > 128 > 128 32 0.125 TrichophytonmetagrophytesATCC 9533 > 128 > 128 64 16 8 32 32 64 128 128 > 128 > 128 64 0.5

Among the compounds, compounds 9 to 10-alkyl berberubin derivatives, compounds 5 to 10 and 18 to 23, showed potent anti-fungal growth inhibitory effect similar to that of amphotericin B. -Among the salt compounds of acyl berberubin derivatives, compounds 32, 33, and 34 showed excellent growth inhibitory effect on fungi.

As can be seen from the above examples, the present invention provides novel antibacterial and antifungal active substances, berberubin derivatives and salts thereof, and these novel compounds exhibit better antimicrobial activity than conventional berberine derivatives.

Claims (12)

9- O-alkyl berberubin salt derivative represented by the following general formula (I). (Ⅰ) Wherein R is hydrogen or an alkyl group having 1 to 18 carbon atoms and is an aromatic hydrocarbon containing chain, branched, cyclic saturated hydrocarbon or unsaturated hydrocarbon, benzene ring; X ⁻ is an inorganic acid ion, organic acid ion or halide. The method of claim 1, X ⁻ represents hydroxy ion, nitrate ion, sulfate ion, acetate ion, phosphate ion, tartaric acid ion, succinate ion, lactic acid ion, citric acid ion, fumaric acid ion, maleic acid ion, glycolic acid ion, formic acid ion, dried acid ion, 9- characterized in that it is selected from the group consisting of benzoic acid ions, methanesulfonic acid ions, benzenesulfonic acid ions, aspartic acid ions, salicylic acid ions, glyceric acid ions, ascorbic acid ions, fluoride, chloride, bromide and iodide O-alkyl berberuine salt derivatives. The method of claim 1, In which R is C ₆ -C ₁₁ ; X ^- is I ^- or Cl ^- 9-Ο- alkyl suberic chopping Rubin salt derivatives, characterized in that. The 9-Ο-acyl berberubin salt derivative represented by the following general formula (II). (Ⅱ) Wherein R is hydrogen or an alkyl group having 1 to 18 carbon atoms and is an aromatic hydrocarbon containing chain, branched, cyclic saturated hydrocarbon or unsaturated hydrocarbon, benzene ring; X ⁻ is an inorganic acid ion, organic acid ion or halide. The method of claim 4, wherein X ⁻ represents hydroxy ion, nitrate ion, sulfate ion, acetate ion, phosphate ion, tartaric acid ion, succinate ion, lactic acid ion, citric acid ion, fumaric acid ion, maleic acid ion, glycolic acid ion, formic acid ion, dried acid ion, 9- characterized in that it is selected from the group consisting of benzoic acid ion, methanesulfonic acid ion, benzenesulfonic acid ion, aspartic acid ion, salicylic acid ion, glycerate ion, ascorbic acid ion, fluoride, chloride, bromide and iodide O-acyl berberubin salt derivatives. The method of claim 4, wherein In which R is C ₈ , C ₁₀ , C ₁₂ ; X ^- is Cl ^- 9-Ο- acyl suberic chopping Rubin salt derivatives, characterized in that. Thermally decomposing the berberine salt compound represented by the following general formula (III) to obtain a berberuvin compound represented by the general formula (IV); 1 mole of the berberubin compound thus obtained is reacted with 1 to 3 moles of the electrophilic alkyl substituent (RX) in an organic solvent to obtain a 9-?-Alkyl berberubin salt derivative represented by the general formula (I). Manufacturing method. (Ⅲ) (Ⅳ) (Ⅰ) Wherein R is hydrogen or an alkyl group having 1 to 18 carbon atoms and is an aromatic hydrocarbon containing chain, branched, cyclic saturated hydrocarbon or unsaturated hydrocarbon, benzene ring; X ⁻ is an inorganic acid ion, organic acid ion or halide. Thermally decomposing the berberine salt compound represented by the following general formula (III) to obtain a berberuvin compound represented by the general formula (IV); 1 mole of the berberubin compound thus obtained was converted to an electrophilic acyl substituent ( A method for producing a 9-Ο-acyl berberuvin salt derivative represented by formula (II) characterized by reacting in an amount of 1 to 2 mol with an organic solvent. (Ⅲ) (Ⅳ) (Ⅱ) Wherein R is hydrogen or an alkyl group having 1 to 18 carbon atoms and is an aromatic hydrocarbon containing chain, branched, cyclic saturated hydrocarbon or unsaturated hydrocarbon, benzene ring; X ⁻ is an inorganic acid ion, organic acid ion or halide. A pharmaceutical agent formulated according to a conventional pharmaceutical method comprising the 9-Ο-alkyl berberubin salt derivative compound of claim 1 as an antibacterial and antifungal active ingredient, and additionally including a pharmaceutically acceptable excipient, adjuvant or carrier. Pharmaceutical preparations. The method of claim 9, The pharmaceutical preparations include tablets, capsules, syrups for oral administration; Injections; Suppositories; Pharmaceutical formulation, characterized in that it has a formulation of any one of ointment, cream, lotion, external preparation for external application. A pharmaceutical preparation comprising the 9-acyl berberubin salt derivative compound of claim 4 as an antimicrobial and antifungal active ingredient and additionally included a pharmaceutically acceptable excipient, adjuvant or carrier, Pharmaceutical preparations. The method of claim 11, The pharmaceutical preparations include tablets, capsules, syrups for oral administration; Injections; Suppositories; Pharmaceutical formulation, characterized in that it has a formulation of any one of ointment, cream, lotion, external preparation for external application.