KR100876857B1 - 7-fluoro-3-aminosteroid derivatives or pharmaceutically acceptable salts thereof, preparation method thereof and a pharmaceutical composition for antimicrobial activities containing the same as an active ingredient - Google Patents

Abstract

The present invention relates to a 7-fluoro-3-aminosteroid derivative, a preparation method thereof and an antimicrobial pharmaceutical composition containing the same as an active ingredient, and a 7-fluoro-3-aminosteroid derivative according to the present invention or a pharmaceutical thereof In general, the acceptable salts exhibit higher reaction yields than conventional methods, can perform the reaction at room temperature, and are stable and antimicrobial activity equivalent to or higher than the activity of conventional squalane derivatives against Gram-positive bacteria and Gram-negative bacteria. Since it can be usefully used in various antibacterial agents.

Description

 7-fluoro-3-aminosteroid derivatives or pharmaceutically acceptable salts thereof, preparation method thereof, and antimicrobial pharmaceutical composition containing the same as an active ingredient method particular and a pharmaceutical composition for antimicrobial activities containing the same as an active ingredient}

The present invention relates to a 7-fluoro-3-aminosteroid derivative or a pharmaceutically acceptable salt thereof, a preparation method thereof and an antimicrobial pharmaceutical composition containing the same as an active ingredient.

Introduction of fluorine to organic molecules enhanced the activity of the organic molecules. This can be seen from the many examples of fluorine that have a significant impact on pharmacology and agricultural material chemistry over the past two decades [HJ Bohm, D. Banner, S. Bendels, M. Kansy, B. Kuhn, K. Muller, OS]. Ulrike, M. Stahl, Fluorine in medicinal chemistry. Chem BioChem. 2004 , 5 , 637-643 .; M. Shimizu, T. Hiyama, Modern Synthetic methods for fluorine-substituted target molecules. Angew . Chem . Int . Ed . 2005 , 44 , 214-231]. As such, many examples are cited in the literature in which substitution of hydroxy groups with fluorine in linear, cyclic and heterocycle compounds increases the activity. However, the substitution of hydroxy groups in steroid rings with fluorine groups remains a challenge to be solved with elimination reactions, by-products and low yields.

The steroid skeleton has a large and rigid planar structure, and thus the structure required for molecular recognition is formed only by the steroid skeleton. In addition, the highly hydrophobic portion of the steroid backbone provides high solubility in organic solvents and the functional groups substituted on its inner surface can interact with various substrates through appropriate functional group transformations. Furthermore, functional groups introduced to steroids have the advantage of being able to easily control stereochemistry since stereochemistry is already determined [F. Diedrich, P. Walliman, T. Marti, Chem . Rev. (1997) , 97 , 1567. Therefore, steroid compounds in which functional groups capable of hydrogen bonding, such as amine, carbamate, urea, and the like, are introduced, have high ion selectivity and are used as starting points for the development of new drugs.

Conventionally, as a steroid compound into which a functional group capable of hydrogen bonding is introduced, squalane of the following chemical formula (squalamine) is frequently used.

Squalamine is extracted from the stomach tissues of sharks and is known to have a broad antimicrobial activity against gram-negative bacteria, gram-positive bacteria and fungi and the ability to inhibit yeast growth [SL Wherli, KS Moore, H. Roder, S. Durell, M. Zasloff, Steroids (1993) , 58 , 370; R. Stone, Science (1993) , 259 , 1125].

The molecular mechanism of the biological action of squalane is currently unknown, but it plays an important role as a sodium / hydrogen ion channel (NHE) inhibitor in addition to antibiotics, arrhythmia, myocardial infarction, angina, anemia, diabetes, cancer, and prostate Studies on the treatment and prevention of hypertrophy and the like have been made, and effects as arteriosclerosis, brain tumors and antiviral agents have also been found (International Patent Publication No. 96/40728).

In addition, squalane inhibits vascular endothelin growth factor (VEGF) and thus prevents neovascularization of tumors. This proved to be an excellent effect on the blood vessels of the chorionic membrane of hatching eggs and significantly reduced retinal neovascularization.

Furthermore, squalane along with cisplatin inhibits angiogenesis and growth of human ovarian cancer cells [D. Li, JI Williams, RJ Pietras, Squalamine and cisplatin block angiogenesis and growth of human ovarian cancer cells with or without HER-2 gene overexpression. Oncogene 2002 , 21 , 2805-2814. This interferes with cell membrane migration and inhibits Na-H ⁺ exchange. It has been proposed by Savage et al., Which can act as a cationic surface area amphiphilic material that can destroy bacterial membranes, eventually disrupting cell structure and ultimately causing cell death [PB Savage, C. Li, U. Taotafa, B. Ding, Q. Guan, Antibacterial properties of cationic steroid antibiotics. FEMS Microbiol . Lett . 2002 , 217 , 1-7].

Although many methodologies have been applied to replace hydroxy groups with fluorine in steroids, fluorination of steroids generally results in low yields and is not easy to perform in the laboratory.

For example, the androgen receptor was synthesized by reductive debromination after fluorination of 1,3-dibromo-5,5-dimethylhydantoin with HF-pyridine via bromine ions, which resulted in 54% of the reaction. Yields were shown [YS Choe, PJ Lidstrom, DY Chi, TA Bonasera, MJ Welch, JA Katzenellenbogen, Synthesis of 11β- [ ¹⁸ F] fluoro-5α-dihydrotestosterone and 11β- [ ¹⁸ F] fluoro-19-nor-5α -dihydrotestosterone: preparation via halofluorination-reduction, receptor binding and tissue distribution. J. Med . Chem . 1995 , 38 , 816-825].

Makosza et al. Fluorinated alkyl halides through the formation of potassium difluorotriphenylstannate using KF-Ph ₃ SnF / sulfolan [Makosza, M .; Bujok, R. A new type of phase-transfer via continuous transfer of fluoride anions to the organic phase in the form of potassium difluorotriphenylstannate. Tetrahedron Lett . 2004 , 45 , 1385 ~ 1386], these methods showed low yields.

Diethylaminosulfur trifluoride (DAST) is a very effective and selective nucleophilic fluorinating agent, which is an easy to use and commercially available reagent.

As a specific example of the method fluorinated using the DAST reagent, Lardy et al. (3) -acetoxy-7α- and 7β-hydroxyandrosti-5-en-17-one from pentane to DAST were used. Allyl alcohol was fluorinated to synthesize 7-fluorine derivative in 64% yield. However, the prepared fluorosteroids were decomposed at 5 to 10 ° C. when mixed with chloroform, and stability was affected by heat and acid [P. Marwah, JB Thoden, DR Powell, HA Lardy, Steroidal allylic fluorination using diethylaminosulfur trifluoride: a convenient method for the synthesis of 3β-acetoxy-7α- and 7β-fluoroandrost-5-en-17-one. Steroids , 1996 , 61 , 453-460]. Epimerization was observed high in polar solutions such as dichloromethane and low in nonpolar solvents such as n-pentane.

Selinsky et al. Used hyodeoxycholic acid from n-pentane-dichloromethane to DAST to fluorine C-6 of saturated sterol derivatives, resulting in 6-fluorinated steroids. Was obtained in 28% yield. This is a stepwise synthesis of 7α- and 7β-fluorosterol aldehydes from stigmasterol derivative fluorination, yielding an unseparated mixture of 7-fluorosteroids in 88% yield. Chromatographic separation was performed after fluorination, and the resulting mixture was reduced by lithium in liquid ammonia. Subsequently, the side chain was decomposed by ozone decomposition to produce 24% of 7α-isomer and 14% of 7β-isomer [J. Xia, Y. Chen, KM Liberatore, BS Selinsky, The application of diethylaminosulfur trifluoride in the synthesis of fluorinated sterols and bile acids. Tetrahedron Lett . 2003 , 44 , 9295-9297. However, these methods are carried out under a polar solvent and the reaction temperature is low, such as -40 ℃, low yield, and the separation of the product has a complex disadvantage of several steps. In addition, the purification and stability of the resulting compounds still remain a major problem.

Thus, the present inventors, while synthesizing a novel 7-fluoro-3-aminosteroid derivative, while improving the overall reaction yield and can be carried out at room temperature, while studying a stable and high antimicrobial activity, A new method using DAST was developed to synthesize 7-fluoro-3-aminosteroid derivatives and completed the present invention.

It is an object of the present invention to provide a 7-fluoro-3-aminosteroid derivative or a pharmaceutically acceptable salt thereof.

Another object of the present invention is to provide a method for preparing the 7-fluoro-3-aminosteroid derivative.

Still another object of the present invention is to provide a pharmaceutical composition for antimicrobial containing the 7-fluoro-3-aminosteroid derivative and a pharmaceutically acceptable salt thereof as an active ingredient.

In order to achieve the above object, the present invention provides a 7-fluoro-3-aminosteroid derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof.

The present invention also provides a method for preparing a 7-fluoro-3-aminosteroid derivative represented by the following formula (1).

In the above formula

R ¹ is H or Boc,

R ² is H or SO ₃ H.

Preferred compounds among the derivatives of the general formula (1) of the present invention are specifically as follows.

1) 3α-N- [t-butyl N (3- [4-aminobutyl])-1,3-diaminopropyl dicarbamate] -7α-fluoro-22-hydroxy-23,24-bisnor -5α-colan

2) 3β-N- [t-butyl N (3- [4-aminobutyl])-1,3-diaminopropyl dicarbamate] -7α-fluoro-22-hydroxy-23,24-bisnor -5α-colan

3) 3α-N- [t-butyl N (3- [4-aminobutyl])-1,3-diaminopropyl dicarbamate] -7β-fluoro-22-hydroxy-23,24-bisnor -5α-colan

4) 3β-N- [t-butyl N (3- [4-aminobutyl])-1,3-diaminopropyl dicarbamate] -7β-fluoro-22-hydroxy-23,24-bisnor -5α-colan

5) 3α-N- [t-butyl N (3- [4-aminobutyl])-1,3-diaminopropyl dicarbamate] -7α-fluoro-22-sulfate-23,24-bisnor- 5α-colan

6) 3β-N- [t-butyl N (3- [4-aminobutyl])-1,3-diaminopropyl dicarbamate] -7α-fluoro-22-sulfate-23,24-bisnor- 5α-colan

7) 3α-N- [t-butyl N (3- [4-aminobutyl])-1,3-diaminopropyl dicarbamate] -7 β-fluoro-22-sulfate-23,24-bisnor -5α-colan

8) 3β-N- [t-butyl N (3- [4-aminobutyl])-1,3-diaminopropyl dicarbamate] -7β-fluoro-22-sulfate-23,24-bisnor- 5α-colan.

The derivative represented by Formula 1 of the present invention may be used in the form of a pharmaceutically acceptable salt, and such salts may include acid addition salts formed by pharmaceutically acceptable free acids or metal salts formed by bases. There is this. The free acid may be an inorganic acid and an organic acid, and the inorganic acid may be hydrochloric acid, sulfuric acid, bromic acid, sulfurous acid or phosphoric acid, and the organic acid may be citric acid, acetic acid, maleic acid, fumaric acid, gluconic acid, methanesulfonic acid, or the like. Can be used. The metal salts include alkali metal salts or alkaline earth metal salts, and sodium, potassium or calcium salts are useful.

In addition, the present invention, as shown in Scheme 1,

Preparing a 7β-OH compound of Formula 3 by reducing a double bond of a compound of Formula 2, which is a starting material (step 1);

Preparing a compound of Chemical Formula 4 by fluorinating the compound of Chemical Formula 3 prepared in Step 1 (Step 2); And

It provides a method for producing a 7-fluoro-3-aminosteroid derivative comprising the step (step 3) of preparing a compound of Formula 1 by reducing amination reaction of the compound of Formula 4 prepared in step 2.

Wherein R ¹ And R ² is as defined in Formula 1).

Hereinafter, the manufacturing method according to the present invention will be described in detail step by step.

Step 1: 7β- OH  Preparation of the compound

Step 1 according to the present invention is a step of preparing a 7β-OH compound of Chemical Formula 3 by reducing a double bond present between carbons 5 and 6 of Chemical Formula 2 as starting materials.

The starting compound of Formula 2 can be obtained from commercially available 23,24-bisnorcola-4-en-3-one (bisnor alcohol) by allylic oxidation according to the literature method [HS Kim , BS Choi, KC Kwon, SO Lee, HJ Kwak, CH Lee, Synthesis and antimicrobial activity of squalamine analogue. Bioorg. Med . Chem . 2000 , 8 , 2059-2065. Specifically, bisnor alcohol is refluxed in benzene with ethylene glycol / p- TSA (p-Toluene Sulfonic Acid) and treated with t-butyldimethylsilyl chloride-DMAP in dichloromethane, followed by ruthenium chloride and 70% t- It can be obtained by allyl oxidation using butylhydroperoxide. The yield is about 70%.

The prepared compound of Formula 2 may reduce the double bond of the ketone group at the C-5 position by dissolving in a metal-reducing agent solution. At this time, it is preferable to use lithium, sodium, calcium, and the like, more preferably of lithium, and as a reducing agent solution, liquid ammonia (NH ₃ ), ethanol (CH ₃ CH ₂ OH), dichloro It is preferable to use methane (dichloromethane) and the like, and more preferably to use liquid ammonia.

By step 1, 7β-OH can be obtained in a yield of about 94%, the reaction time can be shortened compared to other reduction methods, and further, the production of unwanted isomers of 7α-OH can be reduced.

Another method for reducing the C-5 position of the compound of Formula 2 is a palladium catalyzed hydrogen reaction in an ethyl acetate solvent. However, the compound obtained by refluxing 7-keto compound with reduced C-5 position to LiAlH ₄ in dry THF (tetrahydrofuran) is unstable when mixed with chloroform in the next step of fluorination, and decomposes rapidly at room temperature. There is.

Step 2: Fluorination ( fluorination ) reaction

Step 2 according to the present invention is a step of preparing a compound of formula 4 substituted with a fluorine group by reacting the 7β-OH group of the compound of formula 3 prepared in step 1 with a fluorinating agent in a suitable solvent.

The fluorinating agent according to the present invention may use DAST, KF / Ph ₃ SnF / sulfolane, KF / 18C6 / ion liquid (ionoc liq.), Etc., but it is preferable to use DAST. In this case, the amount of fluorinating agent to be used is preferably 1 to 2 equivalents. If the amount of fluorinating agent is less than 1 equivalent, there is a problem that the reaction is not completed. It is not economical.

The reaction can be carried out at room temperature, yields of at least about 80%, stereochemistry results in a 7α-fluorine compound: 7β-fluorine compound in a ratio of about 4: 3.

Step 3: Reducible Amination  reaction

Step 3 according to the present invention is a 7-fluoro-3-aminosteroid of formula 1 by carrying out a reductive amination reaction of the 7α-fluorine compound of formula 4 prepared in step 2 with an appropriate reducing agent and an amine compound Preparing a derivative.

Reducing agents according to the present invention include sodium cyanoborohydride (NaBH ₃ CN), sodium 2-ethylhexanoic borohydride (NaB (OEh) ₃ H), sodium acetoxyborohydride (NaB (OAc) ₃ H), and the like, with the amine compound may be used, such as t- butoxycarbonyl, Nils buffer pyrimidine (Boc- spermidine), spermine, butylamine

In this case, the amount of the reducing agent used is preferably 1 to 3 equivalents, and the amount of the amine compound is preferably 25 to 35 equivalents. If the amount of the reducing agent is less than 1 equivalent, the reaction may not be completed or the reaction time may be long. If the amount of the amine compound is less than 25 equivalent, the hydroxy compound may be generated as a side reactant or the reaction time may be long. have. On the other hand, when the amount of the reducing agent and the amine compound exceeds 3 equivalents and 35 equivalents, respectively, the yield is not improved even if the amount of the reducing agent and the amine compound used is increased.

The yield of the reaction is about 93%.

Additionally, the step 3 according to the present invention may further include protecting an amino group to prevent further reaction due to the polarity of the amino compound itself produced by the reductive amination reaction.

Additionally, the preparation method according to the present invention may further comprise the step of reacting a compound subjected to reductive amination by step 3 with sulfur trioxide in a pyridine solvent to introduce a -SO ₃ H group to R ² of Formula 1 .

In addition, the preparation method according to the invention may further comprise the step of treating with dichloromethane with thionyl chloride and methanol at room temperature to form a salt and recrystallization from acetone.

By this step it can be seen that the overall yield of the synthesis of the 7-fluoro-3-aminosteroid derivatives according to the invention is about 78%, which is much higher than the yield of the conventional process.

Furthermore, the present invention provides a pharmaceutical composition containing a 7-fluoro-3-aminosteroid derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

7-fluoro-3-aminosteroid derivatives or pharmaceutically acceptable salts according to the present invention using the agar dilution method using Muller-Hinton medium, the results of antimicrobial activity against Gram-positive bacteria and Gram-negative bacteria, Compared to the activity of conventional non-fluorinated squalane derivatives, the antimicrobial activity was found to be equal or greater (see Table 1). Therefore, the 7-fluoro-3-aminosteroid derivative or pharmaceutically acceptable salt according to the present invention can be usefully used in various antibacterial agents.

The pharmaceutical composition may be a variety of oral or parenteral formulations, and when formulated, it is prepared using diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents, surfactants, etc. which are commonly used. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, and such solid preparations include at least one excipient such as starch, calcium carbonate, sucrose ( Sucrose) or lactose (Lactose), gelatin, etc. are mixed and prepared. In addition to simple excipients, lubricants such as magnesium styrate talc are also used. Liquid preparations for oral administration include suspensions, liquid solutions, emulsions, and syrups, and various excipients such as wetting agents, sweeteners, fragrances, and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin, may be included. have. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories. As the non-aqueous solvent and the suspension solvent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like can be used. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerogelatin and the like can be used.

The dosage for the pharmaceutical composition according to the present invention may vary depending on the age, weight, sex, dosage form, health condition and degree of disease of the patient, and generally 0.001 based on an adult patient weighing 70 kg. It is -10 mg / day, and may be dividedly administered once a day to several times at regular intervals according to the judgment of a doctor or a pharmacist.

As described above, the 7-fluoro-3-aminosteroid derivative or pharmaceutically acceptable salt thereof according to the present invention shows a higher reaction yield than the conventional methods, can perform the reaction at room temperature, and is stable. In the antimicrobial activity test, Gram-positive bacteria and Gram-negative bacteria can be usefully used in various antimicrobial agents because they appear more than or equal to the activity of conventional squalamin derivatives.

Hereinafter, the present invention will be described in detail by Examples and Experimental Examples. However, the following examples are merely to illustrate the present invention, but the content of the present invention is not limited by the following examples.

< Production Example  1> Preparation of Starting Material

HJ Bohm, D, Banner, S. Bendels, M. Kansy, B. Kuhn, K. Muller, OS Ulrike, M. Stahl, Fluorine in medicinal chemistry. Chem Bio Chem . 2004 , 5 , 637 ~ 643 to prepare 3-dioxolane-22-t-butyldimethylsilyloxy-23,24-bisnorcola-5-en-7-one of formula (2). .

< Examples 1 and 2> 3α-N- [t-butyl N (3- [4- aminobutyl ])-1,3 -diaminopropyl Di-carbamate] 22-hydroxy -23,24- bis Nord -5α- kolran and 3β-N- [t- butyl N (3- [4- amino-butyl]) in -7α--fluoro-1,3 Preparation of diaminopropyl dicarbamate] -7α-fluoro-22-hydroxy-23,24-bisnor-5α-cholan

Step 1: Preparation of 3 -dioxolane- 22-t- butylmethylsilyloxy- 23, 24bisnor-5α - cholan-7β- ol

30 ml of tetrahydrofuran (THF) was added to a three neck flask, cooled to -78 ° C, and 100 ml of liquid ammonia (NH ₃ ) was condensed. To the solution was added a piece of lithium (688 mg, 0.1 mol) and the solution was stirred until it turned blue. 3 -dioxolane-22-t-butyldimethylsilyloxy-23,24-bisnorcola-5-en-7-one (1 g, 1.98 mol) solution of Preparation Example 1 dissolved in THF (10 mL) and ethanol (0.4 mL, 7.9 mmol) was added sequentially to the reaction solution and stirred for 1 hour. The reaction was terminated with ammonium chloride (15 g), water and ethyl acetate. Ammonia was evaporated at room temperature, the residue was washed and extracted with ethyl acetate, and the organic layer was dried and concentrated. The residue was separated by column chromatography to give the product as a white solid (950 mg, 94%).

mp 120-121 ° C. (CH ₂ Cl ₂ -MeOH);

¹ H NMR δ 0.03 (s, 6H, Si (C H ₃ ) ₂ ), 0.69 (s, 3H, 18-CH ₃ ), 0.83 (s, 3H, 19-CH ₃ ), 0.89 (s, 9H, SiC (C H ₃ ) ₃ , 0.99 (d, J = 6.9 Hz, 3H, 21-CH ₃ ), 3.26 (dd, J = 9.6, 7.8 Hz, 1H, 22-H _a ), 3.38 (m, 1H, 7α -H), 3.48 (bs, 1H, 7β-OH), 3.60 (dd, J = 9.6, 3.2 Hz, 1H, 22-H _b ), 3.93 (m, 4H, -OCH ₂ CH ₂ O-);

¹³ C NMR δ -5.4, 11.5, 12.2, 17.0, 18.3, 21.3, 25.9, 27.0, 28.1, 31.1, 34.9, 35.9, 37.5, 37.9, 38.9, 39.8, 40.9, 43.4, 43.7, 51.7, 52.1, 55.4, 64.1 , 64.2, 67.9, 75.0, 109.1;

Elemental analysis of C ₃₀ H ₅₄ O ₄ Si: C, 71.09; H, 10.74. (Theoretical value); C, 71.17; H, 10.78 (experimental).

Step 2: Fluoro-22-hydroxy-7α- -23,24- bis Nord -5α- kolran 7β- fluoro-3-one and 22-hydroxy -23,24- bis Nord -5α- kolran -3 Manufacture of

3-dioxolane-22-t-butylmethylsilyloxy-23,24bisnor-5α-cholan-7β-ol (500 mg, 0.98 mmol) prepared in step 1 was added to n-pentane (10 mL). After thawing, diethylaminosulfur trifluoride (0.2 mL, 1.47 mmol) was added and stirred for 30 minutes. The solvent was removed in vacuo and p-toluenesulfonic acid (p-TSA, 20 mg, 0.11 mol) dissolved in acetone (20 mL) was added to the residue and stirred for 6 hours. After the reaction was completed, the solvent was removed in vacuo, washed with sodium hydrogen carbonate, extracted with ethyl acetate, and the organic layer was dried and concentrated. The residue was subjected to column chromatography to give 7α-fluoro-22-hydroxy-23,24-bisnor-5α-colan-3-one (163 mg, 47%) and 7β-fluoro- as a white crystalline solid. 22-hydroxy-23,24-bisnor-5α-cholan-3-one (127 mg, 36%) was obtained.

(One) 7α- Fluoro -22- Hydroxy -23,24- Visnor -5α-cholan-3-one

_{mp 177-178 ℃ (CH 2 Cl 2} - hexane);

¹ H NMR δ 0.63 (s, 3H, 18-CH ₃ ), 0.93 (s, 3H, 19-CH ₃ ), 0.98 (d, J = 6.5 Hz, 3H, 21-CH ₃ ), 3.29 (dd, J = 10.5, 7.0 Hz, 1H, 22-H _a ), 3.58 (dd, J = 10.5, 3.0 Hz, 1H, 22H _b ), 4.57 (bd, J _HF = 49.1 Hz, 1H, 7β-H);

¹³ C NMR δ 10.7, 12.1, 17.0, 21.5, 23.9, 28.0, 34.5 (d, J = 21.3 Hz), 35.6, 38.2, 38.3, 39.1, 39.5, 39.7, 39.8, 43.0, 44.1, 46.3, 50.0, 52.7, 68.2, 90.3 (d, J = 171.0 Hz), 211.6;

Elemental Analysis of C ₂₂ H ₃₅ FO ₂ : C, 75.39, H, 10.06 (theoretical); C, 75.10; H, 10.06 (experimental).

(2) 7β- Fluoro -22- Hydroxy -23,24- Visnor -5α-cholan-3-one

mp 168-169 ° C (CH ₂ Cl ₂ -hexanes);

¹ H NMR δ 0.65 (s, 3H, 18-CH ₃ ), 0.97 (s, 3H, 19-CH ₃ ), 0.99 (d, J = 6.5 Hz, 3H, 21-CH ₃ ), 3.29 (dd, J = 10.5, 7.0 Hz, 1H, 22-H _a ), 3.57 (dd, J = 10.5, 3.5 Hz, 1H, 22-H _b ), 4.13 (dm, J _HF = 49.0 Hz, 1H, 7α-H);

¹³ C NMR δ 12.4, 13.1, 17.8, 22.5, 27.0, 28.9, 35.8, 36.0, 38.7, 38.8, 39.6, 40.4, 42.1 (d, J = 16.5 Hz), 44.1, 44.2, 44.9, 51.6, 52.6, 55.7, 68.8, 96.4 (d, J = 174.0 Hz), 212.0;

Elemental Analysis of C ₂₂ H ₃₅ FO ₂ : C, 75.39, H, 10.06 (theoretical); C, 75.33, H, 10.10 (experimental).

Step 3: 3α-N- [t-butyl N (3- [4- aminobutyl ])-1,3 -diaminopropyl Dicarboxylic bar mate] -22- hydroxy -23,24- bis Nord -5α- kolran and 3β-N- [t- butyl N (3- [4- amino-butyl]) in -7α--fluoro-l, 3 Preparation of -diaminopropyl dicarbamate] -7α-fluoro-22-hydroxy-23,24-bisnor-5α-cholan

7α-fluoro-22-hydroxy-23,24-bisnor-5α-cholan-3-one (200 mg, 0.57 mmol) and Boc-spermidine (492 mg, 1.43 mmol) prepared in step 1 were prepared. After dissolving in THF (10 mL), NaBH ₃ CN (56 mg, 0.86 mmol) was added thereto, followed by stirring at room temperature for 6 hours. The solvent was removed in vacuo, washed with sodium hydrogen carbonate, extracted with ethyl acetate and dried. The residue was concentrated and chromatographed on silica gel to give 3α-N- [t-butyl N (3- [4-aminobutyl])-1,3-diaminopropyl dicarbamate] -7α-fluoro-22- Hydroxy-23,24-bisnor-5α-cholane (152 mg, 38%) and 3β-N- [t-butyl N (3- [4-aminobutyl])-1,3-diaminopropyl dicarba Mate] -7α-fluoro-22-hydroxy-23,24-bisnor-5α-cholan (228 mg, 56%) was obtained.

(1) 3α-N- [t-butyl N (3- [4- aminobutyl ])-1,3 -diaminopropyl Dicarboxylic carbamate] - Fluoro-22-hydroxy-7α- -23,24- bis Nord -5α- kolran

mp 48 ° C. (CH ₂ Cl ₂ -hexanes);

¹ H NMR δ 0.60 (s, 3H, 18-CH ₃ ), 0.73 (s, 3H, 19-CH ₃ ), 0.98 (d, J = 6.5 Hz, 3H, 21-CH ₃ ), 1.38 (s, 18H , t- Bu ), 3.05 (m, 6H, spermidine protons), 3.32 (dd, J = 10.5, 6.5 Hz, 1H, 22-H _a ), 3.55 (dd, J = 10.5, 3.0 Hz, 1H, 22 -H _b ), 4.04 (bs, 1H, 3β-H), 4.54 (d, J = 48.6 Hz, 1H, 7β-H);

¹³ C NMR δ 11.2, 11.9, 15.4, 16.8, 21.0, 23.7, 25.8, 27.5, 27.8, 28.5, 34.2, 34.4, 35.7, 36.9, 37.9, 38.9, 39.3, 39.5, 40.2, 42.8, 43.4, 44.0, 44.5, 45.2, 46.6, 46.8, 49.9, 52.5, 53.6, 57.4, 66.0. 67.8, 79.2, 79.5, 79.8, 90.9 (d, J = 170.0 Hz), 155.7, 156.1;

Elemental Analysis of C ₃₉ H ₇₀ FN ₃ O ₅ : C, 68.89, H, 10.38, N, 6.18 (theoretical); C, 68.93; H, 10.65, N, 6.32 (experimental).

(2) 3β-N- [t-butyl N (3- [4- aminobutyl ])-1,3 -diaminopropyl Dicarboxylic carbamate] - Fluoro-22-hydroxy-7α- -23,24- bis Nord -5α- kolran

mp 52 ° C (CH ₂ Cl ₂ -hexane);

¹ H NMR δ 0.60 (s, 3H, 18-CH ₃ ), 0.72 (s, 3H, 19-CH ₃ ), 0.97 (d, J = 6.5 Hz, 3H, 21-CH ₃ ), 1.38 (s, 18H , t- Bu ), 3.10 (m, 6H, spermidine protons), 3.27 (dd, J = 10.5, 6.5 Hz, 1H, 22-H _a ), 3.57 (dd, J = 10.5, 3.0 Hz, 1H, 22 -H _b ), 4.04 (bs, 1H, 3α-H), 4.54 (d, J = 49.1 Hz, 1H, 7β-H);

¹³ C NMR δ 11.2, 11.9, 15.4, 16.8, 21.0, 23.7, 25.8, 27.5, 27.8, 28.5, 34.2, 34.4, 35.7, 36.9, 37.9, 38.9, 39.3, 39.5, 40.2, 42.8, 43.4, 44.0, 44.5, 45.2, 46.6, 46.8, 49.9, 52.5, 53.6, 57.4, 66.0, 67.8, 79.2, 79.5, 79.8, 90.9 (d, J = 169.0 Hz), 155.7, 156.1;

Elemental Analysis of C ₃₉ H ₇₀ FN ₃ O ₅ : C, 68.89, H, 10.38, N, 6.18 (theoretical); C, 68.81; H, 10.47, N, 6.31 (experimental).

<Example 3 ~ 4> 3α-N- [ t- butyl N (3- [4- amino-butyl]) - 1,3-diamino-propyl Di-carbamate] 22-hydroxy -23,24- bis Nord -5α- kolran and 3β-N- [t- butyl N (3- [4- amino-butyl]) in -7β--fluoro-l, 3 Preparation of -diaminopropyl dicarbamate] -7β-fluoro-22-hydroxy-23,24-bisnor-5α-cholan

Step 1 and Step 2: Preparation of 22-hydroxy -23,24- bis Nord -5α- kolran 3-one as a fluoro 7β-

The target compound was obtained in the same manner as in Step 1 and Step 2 of Example 1.

Step 3: 3α-N- [t-butyl N (3- [4- aminobutyl ])-1,3 -diaminopropyl Dicarboxylic bar mate] -22- hydroxy -23,24- bis Nord -5α- kolran and 3β-N- [t- butyl N (3- [4- amino-butyl]) in -7β--fluoro-l, 3 Preparation of -diaminopropyl dicarbamate] -7β-fluoro-22-hydroxy-23,24-bisnor-5α-cholan

7β-fluoro-22-hydroxy-23,24-bisnor-5α-cholan-3-one (200 mg, 0.57 mmol) and Boc-spermidine (492 mg, 1.43 mmol) prepared in step 2 were prepared. After dissolving in THF (10 mL), NaBH ₃ CN (56 mg, 0.86 mmol) was added thereto, followed by stirring at room temperature for 6 hours. The solvent was removed in vacuo, washed with sodium hydrogen carbonate, extracted with ethyl acetate and dried. The residue was concentrated and chromatographed on silica gel to give 3α-N- [t-butyl N (3- [4-aminobutyl])-1,3-diaminopropyl dicarbamate] -7β-fluoro-22- Hydroxy-23,24-bisnor-5α-cholane (154 mg, 39%) and 3β-N- [t-butyl N (3- [4-aminobutyl])-1,3-diaminopropyl dicarba Mate] -7β-fluoro-22-hydroxy-23,24-bisnor-5α-cholan (225 mg, 55%) was obtained.

(1) 3α-N- [t-butyl N (3- [4- aminobutyl ])-1,3 -diaminopropyl Dicarboxylic carbamate] - Fluoro-22-hydroxy-7β- -23,24- bis Nord -5α- kolran

mp 63-64 ° C. (CH ₂ Cl ₂ -hexanes);

¹ H NMR δ 0.62 (s, 3H, 18-CH ₃ ), 0.76 (s, 3H, 19-CH ₃ ), 0.97 (d, J = 6.5 Hz, 3H, 21-CH ₃ ), 1.38 (s, 18H , t- Bu ), 3.06 (m, 6H, spermidine protons), 3.29 (dd, J = 10.5, 6.5 Hz, 1H, 22-H _a ), 3.56 (dd, J = 10.5, 3.0 Hz, 1H, 22 -H _b ), 4.14 (d, J = 49.1 Hz, 1H, 7α-H), 4.52 (bs, 1H, 3β-H);

¹³ C NMR δ 11.9, 12.4, 17.2, 20.9, 25.6, 25.8, 26.1, 26.4, 27.8, 28.3, 28.8, 29.8, 30.0, 32.7, 33.4, 35.2, 35.4, 36.5, 39.0, 39.9, 40.5, 41.6, 41.8, 43.5, 44.7, 45.3, 45.5, 47.1, 51.8, 52.1, 52.5, 53.3, 55.3, 68.2, 79.5, 80.0, 96.5 (d, J = 174.0 Hz), 155.8, 156.3;

Elemental Analysis of C ₃₉ H ₇₀ FN ₃ O ₅ : C, 68.89, H, 10.38, N, 6.18 (theoretical); C, 69.20, H, 10.44, N, 5.93 (experimental).

(2) 3β-N- [t-butyl N (3- [4- aminobutyl ])-1,3 -diaminopropyl Dicarboxylic carbamate] - Fluoro-22-hydroxy-7β- -23,24- bis Nord -5α- kolran

mp 57-58 ° C (CH ₂ Cl ₂ -hexane);

¹ H NMR δ 0.62 (s, 3H, 18-CH ₃ ), 0.76 (s, 3H, 19-CH ₃ ), 0.97 (d, J = 6.5 Hz, 3H, 21-CH ₃ ), 1.37 (s, 18H , t- Bu ), 3.06 (m, 6H, spermidine protons), 3.27 (dd, J = 10.5, 6.5 Hz, 1H, 22-H _a ), 3.56 (dd, J = 10.5, 3.0 Hz, 1H, 22 -H _b ), 4.10 (dm, J = 49.1 Hz, 1H, 7α-H), 4.56 (bs, 1H, 3α-H);

¹³ C NMR δ 12.4, 12.7, 17.2, 21.4, 26.1, 26.5, 27.7, 28.3, 28.5, 28.8, 30.0, 35.0, 35.3, 35.5, 35.7, 37.4, 39.0, 39.9, 40.5, 41.6, 41.7, 42.2, 42.3, 43.5, 43.9, 44.4, 45.4, 46.8, 51.9, 52.0, 52.1, 55.2, 57.6, 68.0, 79.4, 79.8, 96.5 (d, J = 174.0 Hz), 155.9, 156.3;

Elemental Analysis of C ₃₉ H ₇₀ FN ₃ O ₅ : C, 68.89, H, 10.38, N, 6.18 (theoretical); C, 69.32, H, 10.01, N, 5.92 (experimental).

<Example 5> 3α-N- [t- butyl N (3- [4- amino-butyl]) - 1,3-diamino-propyl Dicarboxylic carbamate Preparation of 22-sulfate -23,24- bis Nord -5α- kolran to -7α- fluoro

Steps 1-3: 3α-N- [t-butyl N (3- [4- aminobutyl ])-1,3 -diaminopropyl Dicarboxylic carbamate Preparation of 22-hydroxy -23,24- bis Nord -5α- kolran to -7α- fluoro

Example 1 was carried out in the same manner as in the steps 1 to 3 to obtain the target compound.

Step 4: 3α-N- [t-butyl N (3- [4- aminobutyl ])-1,3 -diaminopropyl Dicarboxylic bar mate Preparation of 22-sulfate -23,24- bis Nord -5α- kolran to -7α- fluoro

Prepared in step 3 3α-N- [t-butyl N (3- [4-aminobutyl])-1,3-diaminopropyl dicarbamate] -7α-fluoro-22-hydroxy-23,24-bisnor-5α -Colane (100 mg, 0.15 mmol) and SO ₃ -pyridine complex (81 mg, 0.23 mmol) were dissolved in pyridine (3 mL) and stirred at room temperature for 4 hours. The solvent was removed in vacuo, washed with 10% hydrochloric acid, extracted with ethyl acetate and dried. The residue was concentrated and chromatographed on silica gel to give the target compound (107 mg, 93%).

mp 233 ° C (CH ₂ Cl ₂ -hexane);

¹ H NMR δ 0.60 (s, 3H, 18-CH ₃ ), 0.72 (s, 3H, 19-CH ₃ ), 1.00 (d, J = 6.0 Hz, 3H, 21-CH ₃ ), 1.36 (s, 18H , t- Bu ), 2.80-3.33 (m, 6H, spermidine protons), 3.03 (dd, J = 12.0, 6.0 Hz, 1H, 22-H _a ), 3.53 (dd, J = 10.5, 3.0 Hz, 1H , 22-H _b ), 4.05 (bs, 1H, 3β-H), 4.56 (d, J = 48.6 Hz, 1H, 7βH).

<Example 6> 3β-N- [t- butyl N (3- [4- amino-butyl]) - 1,3-diamino-propyl Dicarboxylic carbamate Preparation of 22-sulfate -23,24- bis Nord -5α- kolran to -7α- fluoro

Steps 1-3: 3β-N- [t-butyl N (3- [4- aminobutyl ])-1,3 -diaminopropyl Dicarboxylic carbamate Preparation of 22-hydroxy -23,24- bis Nord -5α- kolran to -7α- fluoro

The target compound was obtained in the same manner as in the steps 1 to 3 of Example 2.

Step 4: 3β-N- [t-butyl N (3- [4- aminobutyl ])-1,3 -diaminopropyl Dicarboxylic bar mate Preparation of 22-sulfate -23,24- bis Nord -5α- kolran to -7α- fluoro

Prepared in step 3 3β-N- [t-butyl N (3- [4-aminobutyl])-1,3-diaminopropyl dicarbamate] -7α-fluoro-22-hydroxy-23,24-bisnor-5α -Target compound (108 mg, 95%) was obtained in the same manner as Step 4 of Example 5, except that colan (100 mg, 0.15 mmol) was used.

Decomposed at 285 ° C. (CH ₂ Cl ₂ -hexane);

¹ H NMR δ 0.60 (s, 3H, 18-CH ₃ ), 0.76 (s, 3H, 19-CH ₃ ), 0.99 (d, J = 5.5 Hz, 3H, 21-CH ₃ ), 1.36 (s, 18H , t- Bu ), 2.80-3.33 (m, 6H, spermidine protons), 3.05 (dd, J = 12.0, 6.0 Hz, 1H, 22-H _a ), 3.56 (dd, J = 10.5, 3.0 Hz, 1H , 22-H _b ), 3.91 (bs, 1H, 3α-H), 4.53 (d, J = 50.0 Hz, 1H, 7β-H).

<Example 7> 3α-N- [t- butyl N (3- [4- amino-butyl]) - 1,3-diamino-propyl Dicarboxylic carbamate Preparation of 22-sulfate -23,24- bis Nord -5α- kolran to -7β- fluoro

Steps 1-3: 3α-N- [t-butyl N (3- [4- aminobutyl ])-1,3 -diaminopropyl Dicarboxylic carbamate Preparation of 22-hydroxy -23,24- bis Nord -5α- kolran to -7β- fluoro

The target compound was obtained in the same manner as in the steps 1 to 3 of Example 3.

Step 4: 3α-N- [t-butyl N (3- [4- aminobutyl ])-1,3 -diaminopropyl Dicarboxylic bar mate Preparation of 22-sulfate -23,24- bis Nord -5α- kolran to -7β- fluoro

Prepared in step 3 3α-N- [t-butyl N (3- [4-aminobutyl])-1,3-diaminopropyl dicarbamate] -7β-fluoro-22-hydroxy-23,24-bisnor-5α Except for using the colan (100 mg, 0.15 mmol) in the same manner as in Step 4 of Example 5 to obtain the target compound (110 mg, 95%).

¹ H NMR δ 0.64 (s, 3H, 18-CH ₃ ), 0.78 (s, 3H, 19-CH ₃ ), 0.99 (d, J = 6.5 Hz, 3H, 21-CH ₃ ), 1.37 (s, 18H , t-Bu), 2.803.12 (bm, 6H, HN (Boc) CH ₂ , H ₂ CN (Boc) CH ₂ ), 3.05 (dd, J = 12.0, 6.0 Hz, 1H, 22-H _a ), 3.54 (dd, J = 10.5, 3.0 Hz, 1H, 22-H _b ), 4.01 (bs, 1H, 3β-H), 4.22 (dm, J = 51.6 Hz, 1H, 7α-H);

¹³ C NMR δ 11.5, 12.1, 14.2, 17.3, 20.6, 22.7, 23.2, 24.9, 25.7, 26.3, 27.4, 28.5, 29.2, 29.4, 29.8, 31.1, 32.0, 34.4, 34.6, 35.2, 36.8, 39.9, 40.2, 41.3, 41.5, 43.6, 44.4, 47.3, 50.4, 50.5, 52.7, 55.0, 55.6, 73.1, 79.1, 80.8, 95.4 (d, J = 174.0 Hz), 156.2, 157.5;

Elemental Analysis of C ₃₉ H ₇₀ FN ₃ O ₈ S: C, 61.63; H, 9. 28; N, 5.53; S, 4.22 (theoretical); C, 61.27; H, 9.07; N, 5.35; S, 4.29 (experimental).

<Example 8> 3β-N- [t- butyl N (3- [4- amino-butyl]) - 1,3-diamino-propyl Dicarboxylic carbamate Preparation of 22-sulfate -23,24- bis Nord -5α- kolran to -7β- fluoro

Steps 1-3: 3β-N- [t-butyl N (3- [4- aminobutyl ])-1,3 -diaminopropyl Dicarboxylic carbamate Preparation of 22-hydroxy -23,24- bis Nord -5α- kolran to -7β- fluoro

The target compound was obtained in the same manner as in the steps 1 to 3 of Example 4.

Step 4: 3β-N- [t-butyl N (3- [4- aminobutyl ])-1,3 -diaminopropyl Dicarboxylic bar mate Preparation of 22-sulfate -23,24- bis Nord -5α- kolran to -7β- fluoro

Prepared in step 3 3β-N- [t-butyl N (3- [4-aminobutyl])-1,3-diaminopropyl dicarbamate] -7β-fluoro-22-hydroxy-23,24-bisnor-5α Except for using the colan (100 mg, 0.15 mmol) in the same manner as in Step 4 of Example 5 to obtain the target compound (109 mg, 94%).

¹ H NMR δ 0.63 (s, 3H, 18-CH ₃ ), 0.77 (s, 3H, 19-CH ₃ ), 0.98 (d, J = 6.5 Hz, 3H, 21-CH ₃ ), 1.36 (s, 18H , t-Bu), 2.813.15 (bm, 6H, HN (Boc) CH ₂ , H ₂ CN (Boc) CH ₂ ), 3.06 (dd, J = 12.0, 6.0 Hz, 1H, 22-H _a ), 3.55 (dd, J = 10.5, 3.0 Hz, 1H, 22-H _b ), 4.05 (bs, 1H, 3α-H), 4.23 (dm, J = 50.2 Hz, 1H, 7α-H);

¹³ C NMR δ 11.4, 12.0, 14.3, 17.5, 21.1, 22.6, 23.5, 25.0, 25.8, 26.5, 27.5, 28.4, 29.3, 29.6, 29.8, 31.1, 32.2, 34.0, 34.6, 35.3, 36.9, 39.7, 40.2, 41.0, 41.5, 43.7, 44.5, 47.6, 50.0, 50.5, 52.4, 55.1, 55.6, 73.2, 79.3, 80.9, 95.5 (d, J = 174.1 Hz), 156.3, 157.4;

Elemental Analysis of C ₃₉ H ₇₀ FN ₃ O ₈ S: C, 61.63; H, 9. 28; N, 5.53; S, 4.22 (theoretical); C, 61.32; H, 9. 12; N, 5.29 S, 4.33 (experimental).

< Example  9-16 Example  Preparation of the hydrochloride of the compound of 1-8

After dissolving the compounds of Examples 1 to 8 in dichloromethane, thionyl chloride and methanol were added, stirred at room temperature for 5 hours, and then recrystallized with acetone to obtain the hydrochloride of the compounds of Examples 1 to 8.

< Comparative example  1 to 2

Prior Art [HS Kim, BS Choi, KC Kwon, SO Lee, HJ Kwak, CH Lee, Synthesis and antimicrobial activity of squalamine analogue. Bioorg . Med. Chem . 2000 , 8 , 2059-2065, squalane derivatives of the following formulas (5) and (6) were used.

< Experimental Example  1> antimicrobial activity test

In order to determine the antimicrobial activity of the 7-fluoro-3-aminosteroid derivatives according to the present invention, the following experiment was performed.

The minimum inhibitory concentration (MIC) values for Gram-positive bacteria and Gram-negative bacteria using the agar dilution method using the compounds of Examples 9 to 16 and Comparative Examples 1 to 2 Was measured.

The MIC means the minimum concentration of antibiotics that can inhibit the development of bacteria, the value is expressed in mg / ㎖, Gram-positive bacteria used are S. pyogenes 308A (a), S. pyogenes 77A (b) and S. aureus 503 (c) and Gram-negative bacteria are E. coli DC2 (d), P. aeruginosa 9027 (e), P. aeruginosa 1771M (f), S. typhimurim (g) and E. cloacae 1321 E (h) were used.

An overnight incubation Strain 3 × 10 ⁶ cluster forming unit (colony-forming units; CFU) / the embodiment and the comparative example compound (agar plate) The agar plate was added each of diluted step 2 from ㎖ 10 ⁴ CFU / ㎖ in After inoculation to be, after incubation for 20 hours at 37 ℃ to observe the formation of the colony of the bacteria with the naked eye to measure the MIC, the results are shown in Table 1.

division Antimicrobial Activity (MIC, mg / mL) a b c d e f g h Example 9 25.00 12.50 12.50 50.00 50.00 100.00 100.00 100.00 Example 10 12.50 12.50 6.25 12.50 12.50 6.25 50.00 50.00 Example 11 12.50 6.25 6.25 12.50 12.50 25.00 50.00 100.00 Example 12 12.50 12.50 6.25 12.50 12.50 6.25 100.00 100.00 Example 13 12.50 12.50 12.50 25.00 25.00 50.00 100.00 100.00 Example 14 50.00 50.00 25.00 50.00 12.50 25.00 100.00 100.00 Example 15 25.00 12.50 6.25 25.00 50.00 50.00 50.00 50.00 Example 16 50.00 50.00 50.00 25.00 50.00 50.00 50.00 50.00 Comparative Example 1 25.00 25.00 12.50 25.00 50.00 50.00 50.00 50.00 Comparative Example 2 NA 50.00 50.00 50.00 50.00 50.00 50.00 50.00

As shown in Table 1, the 7-fluoro-3-aminosteroid derivative according to the present invention exhibits the same or more antimicrobial activity compared to the antimicrobial activity of the conventional squalamine derivatives can be usefully used in various antibacterial agents.

< Formulation example  1> Preparation of Pharmaceutical Formulations

<1-1> Powder  Produce

2 g of 7-fluoro-3-aminosteroid derivative of Formula 1

1 g lactose

After mixing the above components, the airtight cloth was filled to prepare a powder.

<1-2> Preparation of Tablet

100 mg of 7-fluoro-3-aminosteroid derivative of Formula 1

Corn starch 100 mg

Lactose 100 mg

2 mg magnesium stearate

After mixing the above components, tablets were prepared by tableting according to a conventional method for producing tablets.

<1-3> Preparation of Capsule

100 mg of 7-fluoro-3-aminosteroid derivative of Formula 1

Corn starch 100 mg

Lactose 100 mg

2 mg magnesium stearate

After mixing the above components, the capsule was prepared by filling in gelatin capsules according to the conventional method for producing a capsule.

<1-4> Preparation of Injection Solution

10 μg / ml of 7-fluoro-3-aminosteroid derivative of Formula 1

Dilute hydrochloric acid BP until pH 3.5

Injectable sodium chloride BP up to 1 ml

Dissolve the 7-fluoro-3-aminosteroid derivative of Formula 1 in an appropriate volume of sodium chloride BP for injection, adjust the pH of the resulting solution to pH 3.5 with dilute hydrochloric acid BP, and use sodium chloride BP for injection. The volume was adjusted and mixed well. The solution was filled into a 5 ml Type I ampoule made of clear glass, encapsulated under an upper grid of air by dissolving the glass, and sterilized by autoclaving at 120 ° C. for at least 15 minutes to prepare an injection solution.

Claims (10)

7-fluoro-3-aminosteroid derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof. <Formula 1>

(In the above formula, R ¹ is H or BoC, R ² is H or SO ₃ H.) The method of claim 1, wherein the 7-fluoro-3-aminosteroid derivative is 1) 3α-N- [t-butyl N (3- [4-aminobutyl])-1,3-diaminopropyl dicarbamate] -7α-fluoro-22-hydroxy-23,24-bisnor -5α-cholan; 2) 3β-N- [t-butyl N (3- [4-aminobutyl])-1,3-diaminopropyl dicarbamate] -7α-fluoro-22-hydroxy-23,24-bisnor -5α-cholan; 3) 3α-N- [t-butyl N (3- [4-aminobutyl])-1,3-diaminopropyl dicarbamate] -7β-fluoro-22-hydroxy-23,24-bisnor -5α-cholan; 4) 3β-N- [t-butyl N (3- [4-aminobutyl])-1,3-diaminopropyl dicarbamate] -7β-fluoro-22-hydroxy-23,24-bisnor -5α-cholan; 5) 3α-N- [t-butyl N (3- [4-aminobutyl])-1,3-diaminopropyl dicarbamate] -7α-fluoro-22-sulfate-23,24-bisnor- 5α-cholan; 6) 3β-N- [t-butyl N (3- [4-aminobutyl])-1,3-diaminopropyl dicarbamate] -7α-fluoro-22-sulfate-23,24-bisnor- 5α-cholan; 7) 3α-N- [t-butyl N (3- [4-aminobutyl])-1,3-diaminopropyl dicarbamate] -7β-fluoro-22-sulfate-23,24-bisnor- 5α-cholan; And 8) 3β-N- [t-butyl N (3- [4-aminobutyl])-1,3-diaminopropyl dicarbamate] -7β-fluoro-22-sulfate-23,24-bisnor- 7-fluoro-3-aminosteroid derivative or a pharmaceutically acceptable salt thereof, characterized in that any one selected from the group consisting of 5α-cholan. As shown in Scheme 1 below, Preparing a 7β-OH compound of Formula 3 by reducing a double bond of a compound of Formula 2, which is a starting material (step 1); Preparing a compound of Chemical Formula 4 by fluorinating the compound of Chemical Formula 3 prepared in Step 1 (Step 2); And A method of preparing the 7-fluoro-3-aminosteroid derivative of claim 1, comprising the step (step 3) of preparing a compound of Formula 1 by reductive amination of the compound of Formula 4 prepared in Step 2. <Scheme 1>

Wherein R ¹ and R ² are as defined in Formula 1 above. The method according to claim 3, further comprising the step of reacting a compound subjected to reductive amination by step 3 with sulfur trioxide in a pyridine solvent to introduce a -SO ₃ H group to R ² of Formula 1 Method for preparing 7-fluoro-3-aminosteroid derivative. The method of claim 3, wherein the reduction in step 1 is dissolved in a metal-reducing agent solution. The method of claim 5, wherein the metal is any one selected from the group consisting of lithium, sodium and calcium, and the reducing agent solution is any one selected from the group consisting of liquid ammonia, ethanol and dichloromethane. Process for the preparation of fluoro-3-aminosteroid derivatives. According to claim 3, wherein the fluorinating agent used in step 2 is any one selected from the group consisting of DAST, KF / Ph ₃ SnF / sulfolane and KF / 18C6 / ionoc liq. Method for producing a 7-fluoro-3-aminosteroid derivative, characterized in that 1 to 2 equivalents. The method of claim 3, wherein the reducing agent used in step 3 is sodium cyanoborohydride, sodium 2-ethylhexanoic borohydride and sodium acetoxyborohydride A method for producing a 7-fluoro-3-aminosteroid derivative, characterized in that one is selected from the group consisting of 1 to 3 equivalents. The method according to claim 3, wherein the amine compound used in step 3 is any one selected from the group consisting of tert-butoxycarbonylspermidine, spermine and butylamine, and its amount is 25 to 35 equivalents. Method for preparing 7-fluoro-3-aminosteroid derivative. The antimicrobial pharmaceutical composition comprising the 7-fluoro-3-aminosteroid derivative of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.