and the salts thereof, and 9-0-acyl berberrubine derivatives represented by the following Formula (II):

and the slats thereof, wherein R is hydrogen, or chain-type, branch-type or ring-type saturated or unsaturated hydrocarbons or aromatic hydrocarbons having benzene ring, as alkyl groups having 1 to 18 of carbon atom; and X-is organic or inorganic acid ions, or halides.

BACKGROUND ART Coptis Chinensis Fr generally known as a'Coptis Chinensis'in herb medicines is a perennial herb, which is grown wild or cultivated in Korea, China, Japan, Nepal, etc., and the root thereof essentially includes alkaloids, such as Berberine, Coptisine, Jateorrhizine, Palmatine. This has been used as a medicine for treating the diseases such as gastrointestinal disorder, hyperemia, arteriosclerosis, anxiety, and so forth. It was reported in Chi H. J. Woo Y. S. , Lee Y. J. , Kor J. Pharma., 22,45 (1991) that Berberine Chloride exhibits a wide antibacterial spectrum for the vegetable pathogenic bacteria, such as Candida, Cryptococcus, yeast, fungi, as well as the animal pathogenic bacteria, such as

Bacillus subtilis, Escherichia coli, pneumonia bacillus, yellow staphylococcus, pyogenic Streptococcus, Celleus bacillus, comma bacillus, Corynebacterium diphtheriae, and so forth.

In recent years, it was reported in Isawa K., Kamigauchi M. , Ueki M. , Taniguchi <BR> <BR> <BR> M. , Eur J. Med. Chem., 31,409 (1996) that derivatives of berberrubine have the significant antibacterial and antifungal effect against Gram-positive bacteria or Gram-negative bacteria and fungi, respectively.

On the one hand, berberrubine is produced by pyrolyzing berberine into 9-dimethyl berberine. As above, although many studies regarding berberine and the derivatives thereof have been proceeded, those regarding berberrubine and the derivatives thereof were scarce.

DISCLOSURE OF INVENTION The present invention provides novel antibacterial active materials related with berberrubine. The novel compounds synthesized in the invention exhibit superior antibacterial activities to those of the existing berberine derivatives.

In the present invention, novel compounds similar to 9-O-alkyl-and 9-O-acyl berberrubine were synthesized from the aforesaid berberrubine. These compounds exhibit a sterilizing or bacteriostatic effect against Gram-positive bacteria, such as Enterococcus Faecalis, Staphylococcus Aureus, Micrococcus Luteus, Staphylococcus Epidermis, Bacillus Subtilis, Propionibacterium Acnes, etc. , and fungi, such as Candida Krusei, Candida Lusitaniea, Candida Albicans, Candida Tropicalis, Cryptococcus Neoformans, Candida Parapsilosis, Candida Glabrata, Candida Utilis, Trichophyton Metagrophytes, Saccharonayees Cerevisiae, and so forth.

Therefore, an object of the present invention is to provide novel berberrubine derivatives and the salts thereof exhibiting a sterilizing or bacteriostatic effect against Gram-positive bacteria and fungi.

Another object of the invention is to provide a method for synthesizing berberrubine derivatives via berberrubine from berberine as a starting material.

The berberrubine derivatives and the salts thereof to achieve the aforesaid objects are represented by the Formula (I) or (II).

where R is hydrogen, or chain-type, branch-type or ring-type saturated or unsaturated hydrocarbons or aromatic hydrocarbons having benzene ring, as alkyl groups having 1 to 18 of carbon atom; and X-is organic or inorganic acid ions, or halides.

In order to achieve the aforesaid objects, the berberrubine derivatives and the salts thereof represented by the Formula (I) are prepared by pyrolyzing berberine salt compounds of Formula (III) into berberrubine compounds of Formula (IV) and reacting 1 mole of the berberrubine compounds with 1-3 mole of electrophilic alkyl substituents (R-X) in an organic solvent.

In addition, the berberrubine derivatives and the salts thereof represented by the Formula (II) in the invention are prepared by pyrolyzing berberine salt compounds of Formula (III) into berberrubine compounds of Formula (IV), and reacting 1 mole of the berberrubine compounds with 1-2 mole of electrophilic acyl substituents organic solvent.

BEST MODES FOR CARRYING OUT THE INVENTION The invention will be described in further detail hereinafter.

The berberrubine compounds of Formula (IV) are obtained by pyrolyzing berberine salts of Formula (III), which are the starting materials for preparing the novel compounds represented by Formula (I) and Formula (II) according to the present invention.

In this case, the berberrubine compounds are obtained by pyrolyzing the berberine salts at high temperature (190°C) under reduced pressure (10 mmHg), as shown in the following Reaction Formula (I) : Reaction Formula (I)

1 mole of berberrubine obtained by the reaction shown in Reaction Formula (I) is reacted with 1 to 3 moles of electrophilic alkyl substituents (R-X) in an organic solvent under reflux to give 9-0-alkyl berberrubine derivatives and the salts thereof represented by Formula (I). This process is represented by the following Reaction Formula (II).

Reaction Formula (II)

where R is hydrogen, or chain-type, branch-type or ring-type saturated or unsaturated hydrocarbons or aromatic hydrocarbons having benzene ring, as alkyl groups having 1 to 18 of carbon atom; and X-is organic or inorganic acid ions, or halides.

Preferably, said X is one selected from the group consisting of hydroxy ion, nitric acid ion, sulfuric acid ion, acetic acid ion, phosphoric acid ion, tartaric acid ion, succinic acid ion, lactic acid ion, citric acid ion, fumaric acid ion, maleic acid ion, glycollic acid ion, formic acid ion, malic acid ion, benzoic acid ion, methanesulfonic acid ion, benzenesulfonic acid ion, asparaginic acid ion, salicylic acid ion, glyceric acid ion,

ascorbic acid ion, fluoride, chloride, bromide and iodide.

Among the compounds represented by Formula (I) obtained from the above reaction, in particular, the compounds wherein R is C6-C11 and X-is I-, and the compounds wherein R is C6~Cll and X-is Cl-are preferable in view of antibacterial and antifungal activities.

Furthermore, 9-0-acyl berberrubine derivatives and the salts thereof represented by the Formula (II) are obtained by pyrolyzing berberine salts of Formula (III) into berberrubine compounds of Formula (IV), and then reacting 1 mole of the berberrubine compounds with 1-2 mole of electrophilic acyl substituents in an organic solvent at room temperature. This process is represented by the following Reaction Formula (III): Reaction Formula (III where R is hydrogen, or chain-type, branch-type or ring-type saturated or unsaturated hydrocarbons or aromatic hydrocarbons having benzene ring, as alkyl groups having 1 to 18 of carbon atom; and X is organic or inorganic acid ions, or halides.

Preferably, said X-is one selected from the group consisting of hydroxy ion, nitric acid ion, sulfuric acid ion, acetic acid ion, phosphoric acid ion, tartaric acid ion, succinic acid ion, lactic acid ion, citric acid ion, fumaric acid ion, maleic acid ion, glycollic acid ion, formic acid ion, malic acid ion, benzoic acid ion, methanesulfonic acid ion, benzenesulfonic acid ion, asparaginic acid ion, salicylic acid ion, glyceric acid ion, ascorbic acid ion, fluoride, chloride, bromide and iodide.

Among the compounds represented by Formula (II), in particular, the compounds wherein R is Cs, CIO, and Cl2 and X is C1-are preferable in view of antibacterial and antifungal activities.

The novel compounds represented by Formula (I) and Formula (II) exhibit in vitro antibacterial and antifungal activities against Gram-positive bacteria, such as Enterococcus Faecalis, Staphylococcus Aureus, Micrococcus Luteus, Staphylococcus Epidermis, Bacillus Subtilis, Propionibacterium Acnes, etc. , and fungi, such as Candida Krusei, Candida Lusitaniea, Candida Albicans, Candida Tropicalis, Cryptococcus Neoformans, Candida Parapsilosis, Candida Glabrata, Candida Utilis, Trichoplayton Metagophytes, Saccharomyces Cerevisiae, and so forth.

As the result of in vitro experiment for the antibacterial activity, the compounds of Formula (I) wherein R is C6-Cn and X'is I', and the compounds of Formula (I) wherein R is C6~Cll and X-is Cl-exhibit antibacterial activity against the most aforesaid Gram- positive bacteria, i. e. the most experimental strains, in the concentration range of 0. 125-16 /19/m. Furthermore, the compounds of Formula (II) wherein R is C8, Clo, and C12 and X is Cl-exhibit antibacterial activity against the most experimental strains in the concentration range of 1#64 µg/m#. In addition, the other compounds of Formula (I) and (II) used in the experiment generally exhibit antibacterial activity against the certain strains in the concentration range of at least 0. 5#1 µg/m#.

As the result of in vitro experiment for the antifungal activity, the compounds of Formula (I) wherein R is C6~Cll and X- is I- exhibit antifungal activity against the most aforesaid fungi, i. e. the most experimental strains, in the concentration range of 1#16 µg/ mQ, and the compounds of Formula (I) wherein R is C6~Col and X- is Cl- exhibit antifungal activity against all of the experimental stains in the more excellent concentration range of 0. 5#8 µg/m#. Furthermore, the compounds of Formula (II) wherein R is C8, Clo, and Cl2 and X- is Cl- exhibit antifungal activity against the most experimental strains in the concentration range of 2-64/Mg/m. In addition, the other compounds of Formula (I) and (II) used in the experiment generally exhibit antifungal activity selectively against the certain strains in the concentration range of at least 1#2 µg/m#.

The compounds represented by Formula (I) and (II) are not limited to but may be prepared in various formulations by adding any pharmaceutically acceptable excipient or adjuvant, or by incorporating any pharmaceutically acceptable carrier using a conventional pharmaceutical method. An example of the possible formulations includes tablets, capsules, and syrups for oral administration; injections; suppositories; and ointments, creams, lotions and liquids for external application. The medical preparations formulated as above are administrated using the methods, such as, oral administration, injection administration, mucous administration and external local application including cutaneous application. The effective dose varies with the kind and amount of excipient or carrier,

route of administration, etc. , in the range exhibiting antibacterial and antifungal acitivty.

The present invention is further illustrated by the following examples, but such examples are not intended to limit the invention in any way. Of course, it is to be understood by the skilled person having an ordinary knowledge in the art that the subject matter of the invention can include all alternatives, modifications and equivalents within the spirit and scope of the attached claims. Compound No. in the following examples means those of the following Tables 1 to 3.

EXMAPLES EXAMPLE 1 Synthesis of 9-O-ethyl berberrubine iodide (Compound No. 1) 3 g of berberrubine and 1 W of ethyl iodide were added to 100 W of dimethyl formamide (DMF) and the mixture was severely reacted at 120° C for 5 hours under reflux. The resulting reaction liquid was concentrated under reduced pressure, diluted with diethyl ether, and then the remained solid ingredients were filtered off. The filtered solid ingredients were washed with diethyl ether to give 2.73 g of 9-O-ethyl berberrubine iodide by using liquid chromatography with the filler being silica gel and the eluent being the organic solvent mixed with chloroform and methanol in the ratio of 9: 1.

'H NMR (300MHz, DMSO-d6) S : 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 9-0-propyl berberrubine iodide (Compound No. 2) 2.94 g of 9-0-propyl berberrubine iodide was obtained by carrying out the same method described in Example 1, except that 1 W of ethyl iodide was replaced with 1.2 t of propyl iodide.

'H NMR (300MHz, DMSO-d6) 8 : 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-O-butyl berberrubine iodide (Compound No. 3)

2.84 g of 9-O-butyl berberrubine iodide was obtained by carrying out the same method described in Example 1, except that 1 of ethyl iodide was replaced with 1.3 me of butyl iodide.

'H NMR (300MHz, DMSO-d6) 6 : 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-O-pentyl berberrubine iodide (Compound No. 4) 3.16 g of 9-0-pentyl berberrubine iodide was obtained by carrying out the same method described in Example 1, except that 1 m# of ethyl iodide was replaced with 1.5 Tze of pentyl iodide.

'H NMR (300MHz, DMSO-d6) 8 : 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#1. 30 (m, 4H), 0.97 (t, 3H) EXAMPLE 5 Synthesis of 9-O-hexyl berberrubine iodide (Compound No. 5) 3.21 g of 9-O-hexyl berberrubine iodide was obtained by carrying out the same method described in Example 1, except that 1 W of ethyl iodide was replaced with 1.7 m# of hexyl iodide.

'H NMR (300MHz, DMSO-d6) 6 : 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#1. 30 (m, 6H), 0.97 (t, 3H) EXAMPLE 6 Synthesis of 9-O-heptYl berberrubine iodide (Compound No. 6) 3.16 g of 9-O-heptyl berberrubine iodide was obtained by carrying out the same method described in Example 1, except that 1 lE of ethyl iodide was replaced with 1.9 W of heptyl iodide.

'H NMR (300MHz, DMSO-d6) 5 : 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. 45-1. 30 (m, 8H), 0.97 (t, 3H) EXAMPLE 7 Synthesis of 9-O-octyl berberrubine iodide (Compound No. 7) 3.19 g of 9-O-octyl berberrubine iodide was obtained by carrying out the same method described in Example 1, except that 1 me of ethyl iodide was replaced with 2.1 m# of octyl iodide.

'H NMR (300MHz, DMSO-d6) 5 : 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, 10H), 0.97 (t, 3H) EXAMPLE 8 Synthesis of 9-O-nonyl berberrubine iodide (Compound No. 8 ! 3.42 g of 9-O-nonyl berberrubine iodide was obtained by carrying out the same method described in Example 1, except that 1 IllQ of ethyl iodide was replaced with 2.5 mE of nonyl iodide.

'H NMR (300MHz, DMSO-d6) 6 : 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#1. 27 (m, 12H), 0.97 (t, 3H) EXAMPLE 9 Synthesis of 9-O-decyl berberrubine iodide (Compound No. 9) 3.83 g of 9-O-decyl berberrubine iodide was obtained by carrying out the same method described in Example 1, except that 1 of ethyl iodide was replaced with 1.5 of decyl iodide.

'H NMR (300MHz, DMSO-d6) 8 : 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. 47-1. 25 (m, 14H), 0.85 (t, 3H) EXAMPLE 10 Synthesis of 9-O-undecyl berberrubine iodide (Compound No. 10)

3. 85 g of 9-O-undecyl berberrubine iodide was obtained by carrying out the same method described in Example 1, except that 1 rri of ethyl iodide was replaced with 3.0 of undecyl iodide.

'H NMR (300MHz, DMSO-d6) 5 : 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-O-dodecyl berberrubine iodide (Compound No. 11) 3.95 g of 9-O-dodecyl berbenubine iodide was obtained by carrying out the same method described in Example 1, except that 1 irlQ of ethyl iodide was replaced with 3.5 rTlQ of dodecyl iodide.

'H NMR (300MHz, DMSO-d6) 8 : 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#1. 21 (m, 18H), 0.82 (t, 3H) EXAMPLE 12 Synthesis of 9-O-hexadecyl berberrubine iodide (Compound No. 12) 4.27 g of 9-0-hexadecyl berberrubine iodide was obtained by carrying out the same method described in Example 1, except that 1 W of ethyl iodide was replaced with 4.0 mi of hexadecyl iodide.

'H NMR (300MHz, DMSO-d6) 8 : 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 9-0-octadecyl berberrubine iodide (Compound No. 13) 4.21 g of 9-0-octadecyl berberrubine iodide was obtained by carrying out the same method described in Example 1, except that 1 W of ethyl iodide was replaced with 1.5 W of octadecyl iodide.

'H NMR (300MHz, DMSO-d6) 8 : 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-O-ethyl berberrubine chloride (Compound No. 14) After 2 g of 9-O-ethyl berberrubine iodide synthesized in Example 1 was dissolved in methanol, AgCl was added thereto and the resulting solid material was filtered off. The remained solution was concentrated to give 1.5 g of 9-O-ethyl berberrubine chloride.

'H NMR (300MHz, DMSO-d6) 8 : 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-O-propyl berberrubine chloride (Compound No. 15) 1.42 g of 9-O-propyl berberrubine chloride was obtained by carrying out the same method described in Example 14, except that 9-O-ethyl berberrubine iodide was replaced with 9-O-propyl berberrubine iodide.

'H NMR (300MHz, DMSO-d6) 8 : 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-O-butyl berberrubine chloride (Compound No. 16) 1.42 g of 9-O-butyl berberrubine chloride was obtained by carrying out the same method described in Example 14, except that 9-O-ethyl berberrubine iodide was replaced with 9-O-butyl berberrubine iodide.

'H NMR (300MHz, DMSO-d6) 8 : 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-O-pentyl berberrubine chloride (Compound No. 17) 1.34 g of 9-O-pentyl berberrubine chloride was obtained by carrying out the same method described in Example 14, except that 9-O-ethyl berberrubine iodide was replaced with 9-0-pentyl berberrubine iodide.

'H NMR (300MHz, DMSO-d6) 6 : 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#1. 30 (m, 4H), 0.96 (t, 3H) EXAMPLE 18 Synthesis of 9-O-hexyl berberrubine chloride (Compound No. 18) 1.34 g of 9-O-hexyl berberrubine chloride was obtained by carrying out the same method described in Example 14, except that 9-O-ethyl berbenubine iodide was replaced with 9-O-hexyl berberrubine iodide.

'H NMR (300MHz, DMSO-d6) 8 : 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. 45-1. 29 (m, 6H), 0.99 (t, 3H) EXAMPLE 19 Synthesis of 9-O-heptyl berberrubine chloride (Compound No. 19) 1.31 g of 9-O-heptyl berberrubine chloride was obtained by carrying out the same method described in Example 14, except that 9-O-ethyl berberrubine iodide was replaced with 9-0-heptyl berberrubine iodide.

'H NMR (300MHz, DMSO-d6) 8 : 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-O-octyl berberrubine chloride (Compound No. 20) 1.35 g of 9-0-octyl berberrubine chloride was obtained by carrying out the same method described in Example 14, except that 9-O-ethyl berberrubine iodide was replaced with 9-0-octyl berberrubine iodide.

'H NMR (300MHz, DMSO-d6) 6 : 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-O-nonyl berberrubine chloride (Compound No. 21) 1.34 g of 9-O-nonyl berberrubine chloride was obtained by carrying out the same method described in Example 14, except that 9-O-ethyl berberrubine iodide was replaced with 9-O-nonyl berberrubine iodide.

'H NMR (300MHz, DMSO-d6) 8 : 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#1. 27 (m, 12H), 0.96 (t, 3H) EXAMPLE 22 Synthesis of 9-O-decyl berberrubine chloride (Compound No. 22) 1.72 g of 9-O-decyl berbenubine chloride was obtained by carrying out the same method described in Example 14, except that 9-O-ethyl berberrubine iodide was replaced with 9-O-decyl berberrubine iodide.

'H NMR (300MHz, DMSO-d6) 6 : 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. 47-1. 24 (m, 14H), 0. 86 (t, 3H) EXAMPLE 23 Synthesis of 9-O-undecyl berberrubine chloride (Compound No. 23) 1.38 g of 9-O-undecyl berberrubine chloride was obtained by carrying out the same method described in Example 14, except that 9-O-ethyl berberrubine iodide was replaced with 9-0-undecyl berberrubine iodide.

1H NMR(300MHz, DMSO-d6) 5 : 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-O-dodecyl berberrubine chloride (Compound No. 24) 1.45 g of 9-0-dodecyl berberrubine chloride was obtained by carrying out the same method described in Example 14, except that 9-O-ethyl berberrubine iodide was replaced with 9-O-dodecyl berberrubine iodide.

'H NMR (300MHz, DMSO-d6) 5 : 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, 18H), 0. 85 (t, 3H) EXAMPLE 25 Synthesis of 9-O-hexadecyl berberrubine chloride (Compound No. 25) 1.43 g of 9-O-hexadecyl berberrubine chloride was obtained by carrying out the same method described in Example 14, except that 9-O-ethyl berberrubine iodide was replaced with 9-0-hexadecyl berberrubine iodide. lH NMR (300MHz, DMSO-d6) 6 : 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#1. 23 (m, 26H), 0.85 (t, 3H) EXAMPLE 26 Synthesis of 9-O-octadecyl berberrubine chloride (Compound No. 26) 1.45 g of 9-0-octadecyl berberrubine chloride was obtained by carrying out the same method described in Example 14, except that 9-O-ethyl berberrubine iodide was replaced with 9-0-octadecyl berberrubine iodide.

'H NMR (300MHz, DMSO-d6) 8 : 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 9-0-acetyl berberrubine chloride (Compound No. 27)

After 1.5 g of berberrubine was dissolved in 100 m of acetonitril, 0.4 W of acetyl chloride was added to the mixture, and then it was reacted for 1 hour. After the reacted liquid was concentrated under reduced pressure, it was diluted with diethyl ether and filtered off, and then the resulting solid material was liquid-chromatographed utilizing the filler being silica gel and the eluent being the organic solvent mixed with chloroform and methanol in the ratio of 4: 1 to give 1. 38 g of 9-O-acetyl berbenubine chloride.

'H NMR (300MHz, DMSO-d6) 6 : 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-propionyl berberrubine chloride (Compound No. 28) 1.41 g of 9-O-propionyl berberrubine chloride was obtained by carrying out the same method described in Example 27, except that 0.4 W of acetyl chloride was replaced with 0.45 n-X of propionyl chloride.

'H NMR (300MHz, DMSO-d6) 8 : 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-O-butyryl berberrubine chloride (Compound No. 29) 1.43 g of 9-0-butyryl berberrubine chloride was obtained by carrying out the same method described in Example 27, except that 0.4 of acetyl chloride was replaced with 0.5 mQ of butyryl chloride. lH NMR (300MHz, DMSO-d6) 8 : 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-O-valeryl berberrubine chloride (Compound No. 30) 1.44 g of 9-O-valeryl berberrubine chloride was obtained by carrying out the same method described in Example 27, except that 0.4 mE of acetyl chloride was replaced with

0.55 mE of valeryl chloride. lH NMR (300MHz, DMSO-d6) 8 : 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-O-hexanoyl berberrubine chloride (Compound No. 31) 1.51 g of 9-O-hexanoyl berbenubine chloride was obtained by carrying out the same method described in Example 27, except that 0.4 mQ of acetyl chloride was replaced with 0.6 mE of hexanoyl chloride. lH NMR (300MHz, DMSO-d6) 6 : 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-O-octanoyl berberrubine chloride (Compound No. 32) 1.50 g of 9-0-octanoyl berberrubine chloride was obtained by carrying out the same method described in Example 27, except that 0.4 W of acetyl chloride was replaced with 0.65 W of octanoyl chloride.

'H NMR (300MHz, DMSO-d6) 6 : 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 9-0-decanoyl berberrubine chloride (Compound No. 33) 1.56 g of 9-O-decanoyl berberrubine chloride was obtained by carrying out the same method described in Example 27, except that 0.4 ! of acetyl chloride was replaced with 0.7 of decanoyl chloride. lHNMR (300MHz, DMSO-d6) b : 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-O-lauroyl berberrubine chloride (Compound No. 34) 1.59 g of 9-O-lauroyl berberrubine chloride was obtained by carrying out the same method described in Example 27, except that 0.4 ! of acetyl chloride was replaced with 0.8 mE of lauroyl chloride.

1H NMR(300MHz, DMSO-d6) 8 : 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#1. 22 (m, 16H), 0. 88 (t, 3H) EXAMPLE 35 Synthesis of (9-myristoyl berberrubine chloride (Compound No. 35) 1.55 g of 9-0-myristoyl berberrubine chloride was obtained by carrying out the same method described in Example 27, except that 0.4 W of acetyl chloride was replaced with 0.9 W of myristoyl chloride.

1H NMR(300MHz, DMSO-d6) 6 : 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#1.21 (m, 20H), 0.87 (t, 3H) EXAMPLE 36 Synthesis of 9-O-palmitoyl berberrubine chloride (Compound No. 36) 1.54 g of 9-0-palmitoyl berberrubine chloride was obtained by carrying out the same method described in Example 27, except that 0.4 W of acetyl chloride was replaced with 1 m# of palmitoyl chloride.

1H NMR (300MHz, DMSO-d6) 8 : 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#1. 21 (m, 24H), 0.85 (t, 3H) EXAMPLE 37 Synthesis of 9-O-benzoyl berberrubine chloride (Compound No. 37) 1.41 g of 9-O-benzoyl berberrubine chloride was obtained by carrying out the

same method described in Example 27, except that 0.4 IllQ of acetyl chloride was replaced with 0.7 of benzoyl chloride.

1H NMR(300MHz, DMSO-d6) 8 : 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-O-3,4,5-trimethoxy benzoyl berberrubine chloride (Compound No.

38 ! 1.53 g of 9-0-3, 4,5-trimethoxy benzoyl berberrubine chloride was obtained by carrying out the same method described in Example 27, except that 0.4 mQ of acetyl chloride was replaced with 1 g of 3, 4,5-trimethoxy benzoyl chloride. lH NMR (300MHz, DMSO-d6) 8 : 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 berberrubine (Compound No. 39) 5 g of berberine chloride (Compound No. 41) was heated at 190°C and 10 mmHg for 30 minutes to give 3.53 g of berberrubine by using liquid chromatography with the filler being silica gel and the eluent being the organic solvent mixed with chloroform and methanol in the ratio of 4: 1.

1H NMR(300MHz, DMSO-d6) 6 : 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 berberrubine hydrochloride (Compound No. 40) 3 g of berberrubine was dissolved in 100 W of boiling water and 5 m# of 35% hydrochloric acid was added thereto. The liquid was cooled at normal temperature and was recrystallized at 4° C. The crystal was filtered off and dried to give 2.54 g of berberrubine hydrochloride. lH NMR (300MHz, DMSO-d6) 6 : 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 mentioned in Examples 1 to 40 were summarized in the following Tables 1 to 3.

Table la Berberrubine derivative compounds (Compound Nos. 1 to 13: Formula (I)) Compound No R General Formula 1 ethyl (C2H5-) O 2 propyl (C3H7-) + 3 butyl (C4H9-) O W 4 pentyl (CsHll-) l l OR o z </ 5 hexyl (C6H13') 6 heptyl (C7Hl5-) OMe 7 octyl (C8H17-) 8 nonyl (CgHlg-) 9 decyl (CloH2l-) 10 undecyl (CllH23-) 11 dodecyl (Cl2H2s-) 12 hexadecyl (C13H27-) 13 octadecyl (C14H29-) Table lb Berberrubine derivative compounds (Compound Nos. 14 to 26: Formula(I)) Compound No R General Formula Compound No 14 ethyl (C2H5-) 0 15 propyl (c3H7-) < O 16 butyl (C4H9-) 0 17 pentyl (CsHII-) OR 18 hexyl (C6H13') 19 heptyl (C7Hos-) \+ OMe 20 octyl (CgHl7-) 21 nonyl (CgHlg-) 22 decyl (C, oH21-) 23 undecyl (CllH23-)

24 dodecyl (C12H25-) 25 hexadecyl (C13H27-) 26 octadecyl (C14H29-) Table 2 Berberrubine derivative compounds (Compound Nos. 27 to 38 : Formula (II)) Compound No R General Formula 27 acetyl (CH3CO-) O/< i 28 propionyl (C2HsCO-) < | + 29 butyryl (C3HC0-) O v valeryl (C4H9CO-) OR 31 hexanoyl (CSH11C0-) 32 octanoYI (C7Hl5CO-) OMe 33 decanoyl (CgHlgCO-) 34 lauroyl (C l IH23CO-) 35 myristoyl (Cl3H27CO-) 36 palmitoyl (Cl5H31CO-) 37 benzoyl (C6H5CO-) 38 3, 4, 5-trimethoxy benzoyl

Table 3 Compound No Chemical Formula H T ! cri /N 39 4 oye o I o N ci 4o IOR orme o C i o , 41 1 1 OMe / TOME

EXAMPLE 41 Antibacterial effect against Gram-positive bacteria The compounds (Compound Nos. 1 to 41) synthesized in the above Examples along with kanamycin (Compound No. 42) were examined for the microorganism growth inhibition concentration (MIC) of Staphylococcus aureus, Staphylococcus Epidermis, Bacillus subtilis, Micrococcus Luteus, Enterococcus Faecalis, Propionibacterium acnes.

The results were shown in the following Tables 4a to 4c.

The aforesaid strains were incubated at 37° C for 24 hours using Nutrient Agar (DIFCO) and Mueuer Hinton Broth (DIFCO), and then the synthesized compounds were dissolved in DMSO to prepare stocks classified by the concentrations thereof.

After all the compounds were divided into 96-well titer plates in the amount of 5 AQ/well according to their concentrations, 95 su of medium was added thereto, and 106 CFU/Tze of each strains solution already prepared by incubation were divided into the well in the amount of 1000/well. The concentration of the solution containing the compounds was controlled to decrease from 128 µg/m# to 0. 125 µg/m# at a half-fold per

well. The 96-well titer plates thus prepared were incubated at 37° C for 24 hours, and then the MIC of the test compound was defined as the lowest concentration at which there was no visible growth. Furthermore, the optical density was determined on the basis of the absorbance at 650 nm with a Microplate reader (Emax Miroplate reader).

Table 4a MIC of the compounds against Gram-positive bacteria Compound MIC (g/m) Test Test 1 2 3 4 5 6 7 8 9 10 11 12 13 14 organism Enterococcus faecalis 128 128 64 64 16 8 4 4 8 16 64 >128 >128 128 ATCC 29212 Staphylococcus aureus 128 64 32 32 8 4 4 4 8 64 128 >128 128 128 ATCC 25923 Staphylococcus arueus 128 128 64 32 16 4 4 4 4 16 64 >128>128 128 ATCC 6538 S. aureus 128 128 64 32 8 4 4 4 4 16 64 >128 >128 128 IFO 12732 Micrococcus 0.1 0.1 0.1 luteus 2 2 1 0.5 0.5 0. 25 0.25 0.5 4 16 4 25 25 25 ATCC 10240 Micrococcus luteus 4 4 2 2 1 1 0.5 0.5 0.5 1 1 8 8 8 ATCC 9341 Propionibacteri um 128 64 32 16 8 4 2 2 4 16 64 128 128 128 acnes Staphylococcus epidermidis 128 64 16 8 4 2 1 1 2 1 1 64 128 64 ATCC 0155 Staphylococcus epidermidis 128 128 16 5 5 2 2 1 1 2 2 64 128 64 ATCC 12228 Bacillus subtilis 128 128 64 32 8 8 4 4 16 32 64 128 >128 128 ATCC 6633 B. subtilis 128 128 64 32 8 8 4 4 16 16 64 128 >128 128 IAM 1609 Table 4b Compound MIC (µg/m#) Test 15 16 17 18 19 20 21 22 23 24 25 26 27 28 organism Enterococcus 12 64 64 8 8 2 2 2 8 64 128>128>128>128 faecalis 8 ATCC 29212 Staphylococcus 64 32 32 8 4 2 2 2 8 128 >12 >128 >128 >128 aureus 8 ATCC 25923 Staphylococcus 12 64 32 8 4 4 2 2 4 64 128>128>128>128 arueus 8 ATCC 6538 S. aureus 64 32 16 8 8 2 2 2 4 64 128 >128 >128 >128 IF012732 Micrococcus 8 4 1 0.5 0.1 0.1 0.1 0.1 0.5 0.5 4 32 64 64 luteus 25 25 25 25 ATCC 10240 Micrococcus 4 4 2 1 0.5 0.5 0.5 0.5 1 1 8 64 >128>128 luteus ATCC 9341 Propionibacterium 64 32 8 4 4 1 1 1 4 16 64 128 >128 >128 acnes Staphylococcus 64 8 8 2 2 1 0.5 0.5 1 1 64 128 >128 >128 epidermidis ATCC 0155 Staphylococcus 32 8 4 2 1 0.5 0.5 0.5 1 1 64 128 >128 >128 epidermidis ATCC 12228 Bacillus 64 32 32 8 4 2 2 2 8 64 >12 >128 >128 >128 subtilis 8 ATCC 6633 B. subtilis 64 116 16 8 4 2 2 2 8 32 128>128>128>128 IAM 1609 Table 4c Compound MIC (ILglw) Test 29 30 31 32 33 34 35 36 37 38 39 40 41 42 organism Enterococcus >12 >12 128 32 128 >12 >12 >12 >12 >12 >12 >12 128 4 faecalis 8 8 8 8 8 8 8 8 8 ATCC 29212 Staphylococcus >12 >12 128 4 128 >12 >12 >12 >12 >12 >12 >12 128 8 aureus 8 8 8 8 8 8 8 8 8 ATCC 25923 Staphylococcus >12 >12 128 64 128 128 >12 >12 >12 >12 >12 >12 >12 4 arueus 8 8 8 8 8 8 8 8 8 ATCC 6538 S. aureus >12 >12 128 64 128 128 >12 >12 >12 >12 >12 >12 >12 14 IF012732 8 8 8 8 8 8 8 8 8 Micrococcus 64 16 64 64 4 1 2 4 64 16 64 32 2 2 luteus ATCC 10240 Micrococcus 64 64 64 32 8 4 4 8 64 64 64 32 8 2 luteus ATCC 9341 Propionibacterium >12 >12 >12 64 128 128 >12 >12 >12 >12 >12 >12 >12 2 acnes 8 8 8 8 8 8 8 8 8 8 Staphylococcus >12 >12 >12 64 4 8 32 >12 >12 >12 >12 >12 >12 0. epidermidis 8 8 8 8 8 8 8 8 8 5 ATCC 0155 Staphylococcus >12 >12 >12 64 8 16 64 >12 >12 >12 >12 >12 >12 0. epidermidis 8 8 8 8 8 8 8 8 8 5 ATCC 12228 Bacillus >12 >12 >12 >12 8 128 >12 >12 >12 >12 >12 >12 >12 2 subtilis 8 8 8 8 8888888 ATCC 6633 B. subtilis >12 >12 >12 >12 32 128 >12 >12 >12 >12 >12 >12 >12 4 IAM 1609 8 8 8 8 8888888

The compounds (Nos. 5 to 10 and 18 to 23) exhibited the higher growth inhibition effect in comparison to those of kanamycin (Compound No. 42) as a compared medicine.

Also, the compounds (Nos. 1 to 26) as the chlorides of 9-O-alkyl berberrubine derivatives entirely exhibited a superior growth inhibition effect against Gram-positive bacteria used.

EXAMPLE 42 Antifungi effect The compounds (Compound Nos. 1 to 41) synthesized in the above Examples along with Amphotericin B (Compound No. 42) were examined for the microorganism growth inhibition concentration (MIC) of Candida Krusei, Candida Lusitaniea, Candida albicans, Candida tropicalis, Cryptococcus neoformans, Candida parapsilosis, Candida glabrata, Candida utilis, Trichophyton metagrophytes, Saccharomyces cerevisiae. The results were shown in the following Tables 5a to 5c.

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

Thereafter, all the compounds were dissolved in DMSO to prepare stocks classified by the concentrations thereof. The compounds used in this experiment were divided into 96-well titer plates in the amount of 5 cQ/well according to their concentrations, 95 AQ of medium was added thereto, and 104 CFU/m# of each strains solution already prepared by incubation were divided into the well in the amount of 100µ# /well. The concentration of the solution containing the compounds was controlled to decreased from 128 1'91W to 0. 125 µg/m# at a half-fold per well. The 96-well titer plates thus prepared were incubated at 28~30° C for the same hours as above, and then the MIC of the test compound was defined as the lowest concentration at which there was no visible growth. Furthermore, the optical density was determined on the basis of the absorbance at 650 nm with a Microplate reader (Emax Miroplate reader).

Table 5a MIC of the compounds against fungi Compound MIC (/, Ig/w) Test 1 2 3 4 5 6 7 8 9 10 11 12 13 14 organism Cand 64 32 32 32 16 4 1 1 1 4 32 64 64 64 ida krusei ATCC 6258 Candida krusei 64 64 16 16 8 2 1 1 1 2 16 64 64 64 IFO 1162 Candida krusei 64 32 16 8 2 1 1 1 1 2 16 64 64 64 IFO 0584 Candida krusei 64 64 32 32 8 4 2 2 2 8 64 64 >128 64 IFO 1664 C. lusitaniae 64 32 16 16 8 2 1 1 1 2 16 64 >128 >128 ATCC 42720 C. albicans 128 32 16 8 4 2 1 1 1 2 16 64 64 >128 ATCC 10231 C. albicans 128 128 64 32 16 4 4 2 2 4 16 64 128 >128 ATCC 11651 C. albicans 64 16 8 2 2 1 1 1 4 8 16 64 >128 ATCC 28838 C. albicans 128 128 64 32 16 4 4 2 2 4 16 64 128 >128 ATCC 90028 C. albicans 128 64 64 16 16 2 1 1 1 4 64 64 128 >128 ATCC 90029 C. albicans 128 64 16 8 8 2 1 1 2 4 8 64 64 >128 IFO 1385 C. albicans 128 64 16 8 4 2 1 1 2 4 16 64 128 >128 IAM 4905 C. parapsilosis 128 64 32 16 8 2 1 1 2 4 16 64 128 >128 ATCC 90018 C. glabrata 128 64 32 8 8 4 2 2 4 8 16 64 128 128 ATCC 90030 C. glabrata 128 64 32 16 8 2 1 1 2 4 8 64 128 64 IFO 0622 C. utilis 128 64 16 16 8 2 2 1 1 4 32 64 >128 >128 IFO 0619 Sacchromyces 128 64 16 8 4 2 1 1 1 4 16 128 >128 >128 cerevisiae IFO 0209 C. tropicalis 64 32 16 8 4 2 1 1 1 4 16 64 >128 >128 ATCC 13803 C. tropicalis 64 32 16 16 4 4 2 2 2 4 16 64 128 64 IFO 0587 C. tropicalis 64 32 16 16 8 4 2 2 2 8 32 128>128 128 IFO 10241 Cryptococus 16 16 16 16 8 2 1 2 1 4 16 16 16 16 neoformans ATCC 2344 Cryptococus 64 32 16 8 4 2 1 1 1 4 16 64 64 64 neoformans ATCC 36556 Cryptococus 32 16 8 4 4 2 2 2 2 8 8 16 32 64 neoformans ATCC 90112 Crytococus 32 16 16 4 4 2 1 1 1 4 16 64 64 32 neoformans ATCC 90113 Trichophyton 128 128 16 8 8 4 4 2 2 8 16 128 128 >128 metagrophytes ATCC 9533 Table 5b Compound MIC (Ag/mQ) Test 15 16 17 18 19 20 21 22 23 24 25 26 27 28 organism Candida krusei 64 32 16 4 1 0.5 0.5 0.5 2.4 64 64 >128 >128 ATCC 6258 Candida krusei 32 32 32 8 1 0.5 0.5 0.5 2 8 64 64 >128 >128 IFO 1162 Candida krusei 32 16 16 4 1 0.5 0.5 0.5 2 8 64 64 >128 >128 IFO 0584 Candida krusei 32 32 32 8 4 1 1 1 4 16 64 >128>128>128 IFO 1664 C. lusitaniae 32 16 16 4 2 1 1 1 4 16 64 >128 >128 >128 ATCC 42720 C. albicans 64 64 64 8 4 2 1 1 4 16 64 >128 >128 >128 ATCC 10231 C. albicans 64 64 64 8 4 2 1 1 4 16 64 >128 >128 >128 ATCC 11651 C. albicans 64 32 16 4 1 0.5 0.5 0.5 4 16 64 >128>128>128 ATCC 28838 C. albicans 64 32 16 2 1 0.5 0.5 1 4 16 32 >128 >128 >128 ATCC 90028 C. albicans 64 32 16 2 1 0.5 0.5 0.5 8 16 32 >128 >128 >128 ATCC 90029 C. albicans 64 32 16 4 1 0.5 0.5 0.5 4 16 32 64 >128 >128 IFO 1385 C. albicans 64 32 16 4 2 1 1 1 4 16 64 >128>128>128 IAM 4905 C. parapsilosis 64 32 16 4 2 0.5 0.5 1 8 32 64 >128 >128 >128 ATCC 90018 C. glabrata 32 16 8 8 2 1 1 2 8 32 64 >128>128>128 ATCC 90030 C. glabrata 64 32 16 4 2 1 1 1 8 32 64 64 >128 >128 IFO 0622 C. utilis 64 32 16 8 1 1 0.5 0.5 2 16 32 64 >128 >128 IFO 0619 Sacchromyces 64 32 16 4 2 1 0.5 0.5 2 16 128 >128>128>128 cerevisiae IFO 0209 C. tropicalis 32 16 8 4 2 1 0.5 0.5 4 16 128 128 >128 >128 ATCC 13803 C. tropicalis 32 16 8 4 2 1 1 1 4 16 64 128 >128 >128 IFO 0587 C. tropicalis 32 16 16 4 2 1 1 2 8 16 32 >128>128>128 IFO 10241 Cryptococus 32 16 16 1 1 0.5 0.5 1 4 8 32 64 128 128 neoformans ATCC 2344 Cryptococus 64 32 16 4 2 1 0.5 1 4 16 32 64 >128>128 neoformans ATCC 36556 Cryptococus 32 16 8 2 1 0.5 0.5 0.5 2 8 16 64 >128 >128 neoforma ATCC 90112 Crytococus 32 16 8 2 1 0. 5 0.5 0.5 2 4 16 64 >128 >128 neoforma ATCC 90113 Trichophyton 64 64 32 8 2 1 1 1 8 16 32 64 >128 >128 metagrophytes ATCC 9533 Table 5c Compound MIC (g/m) Test 29 30 31 32 33 34 35 36 37 38 39 40 41 42 organism Candida krusei >12 >128 64 16 8 16 32 128 >12 >12 >12 >12 64 0.5 ATCC 6258 8 8 8 8 8 Candida krusei >12 >128 128 16 4 16 32 128 >12 >12 >12 >12 64 0.5 IFO 1162 8 8 8 8 8 Candida lcrusei >12 >128 64 16 4 16 64 128 >12 >12 >12 >12 64 0.5 IFO 0584 8 8 8 8 8 Candida krusei >12 >128 128 32 8 64 >128 >12 >12 >12 >12 >12 32 0.5 IFO 1664 8 8 8 8 8 8 C. lusitaniae >12 >128 128 16 2 >128 >128 >12 >12 128 >12 >12 >12 0.5 ATCC 42720 8 8 8 8 8 8 C. albicans >12 >128 128 32 2 4 >128 >12 >12 >12 >12 >12 128 0.1 ATCC 10231 8 8 8 8 8 8 25 C. albicans >12 >128 128 8 4 64 128 128 >12 >12 >12 >12 128 0.1 ATCC 11651 8 8 8 8 8 25 C. albicans >12 >128 128 16 8 64 128 128 >12 >12 >12 >12 128 0.5 ATCC 28838 8 8 8 8 8 C. albicans >12 >128 64 16 8 64 128 128 >12 >12 >12 >12 >12 0.5 ATCC 90028 8 8 8 8 8 8 C. albicans >12 >128 64 8 4 64 128 128 >12 >12 >12 >12 >12 0. 5 ATCC 90029 8 8 8 8 8 8 C. albicans >12 >128 64 8 4 64 128 128 >12 >12 >12 >12 >12 0.5 IFO 1385 8 8 8 8 8 8 C. albicans >12 >128 64 4 2 64 128 128 >12 >12 >12 >12 >12 0.5 IAM 4905 8 8 8 8 8 8 C. parapsilosis >12 >128 64 8 2 64 128 128 >12 >12 >12 >12 >12 1 ATCC 90018 8 8 8 8 8 8 C. glabrata >12 >128 64 4 2 64 64 128 >12 >12 >12 >12 128 1 ATCC 90030 8 8 8 8 8 C. glabrata >12 >128 64 8 4 64 64 64 128 >12 >12 >12 128 1 IFO 0622 8 8 8 8 C. utilis >12 >128 64 4 2 32 64 64 128 >12 >12 >12 64 0.5 IFO 0619 8 8 8 8 Sacchromyces >12 >128 64 4 2 32 64 64 128 >12 >12 >12 64 0.5 cerevisiae 8 8 8 8 IFO 0209 C. tropicalis >12 >128 64 4 2 64 128 128 >12 >12 >12 >12 64 0.2 ATCC 13803 8 8 8 8 8 5 C. tropicalis >12 >128 128 8 4 64 64 64 128 >12 >12 >12 32 0.2 IFO 0587 8 8 8 8 5 C. tropicalis >12 >128 128 32 4 4 >128 >12 >12 64 >12 >12 16 0.2 IFO 10241 8 8 8 8 8 5 Cryptococus 128 128 128 16 2 2 4 64 >12 32 >12 128 8 0. 1 neofonnans 8 8 25 ATCC 2344 Cryptococus >12 >128 32 16 2 8 32 64 64 64 >12 >12 32 0.1 neoforma 8 8 8 25 ATCC 36556 Cryptococus >12 >128 32 8 2 8 32 64 64 128 >12 >12 32 0.1 neoforma 8 8 8 25 ATCC 90112 Crytococus >12 >128 64 4 2 8 32 64 64 64 >12 >12 32 0.1 neoforma 8 8 8 25 ATCC 90113 Trichophyton >12 >128 64 16 8 32 32 64 128 128 >12 >12 64 0.5 metagrophytes 8 8 8 ATCC 9533

The compounds Nos. 5 to 10 and 18 to 23 among the above compounds exhibited the similar inhibition effect to Amphotericin B, which is a strong antifungal medicine as compared. Also, the compounds Nos. 32,33 and 34 among the chlorides of 9-0-acyl berberrubine derivatives entirely exhibited a superior growth inhibition effect against the fungi used.

INDUSTRIAL APPLICABILITY As known from the above Examples, the present invention provides berberrubine derivatives and the salts thereof as a novel antibacterial and antifungal active material, and the antibacterial activity of these novel compounds is superior to that of existent berberine derivatives.

While the present invention has been described in detail and with reference to specific embodiments and examples, it will become apparent to one skilled in the art that various changes and modifications can be made without departing from the spirit and scope thereof on the basis of the time that the present application was filed.