WO2008038965A1 - 7alpha-aminosteroid derivatives or pharmaceutically acceptable salts thereof, preparation method thereof and composition for anticancer or antibiotics containing the same as an active ingredient - Google Patents
7alpha-aminosteroid derivatives or pharmaceutically acceptable salts thereof, preparation method thereof and composition for anticancer or antibiotics containing the same as an active ingredient Download PDFInfo
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- WO2008038965A1 WO2008038965A1 PCT/KR2007/004649 KR2007004649W WO2008038965A1 WO 2008038965 A1 WO2008038965 A1 WO 2008038965A1 KR 2007004649 W KR2007004649 W KR 2007004649W WO 2008038965 A1 WO2008038965 A1 WO 2008038965A1
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- chemical formula
- compound
- group
- cholestane
- aminosteroid
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- 239000000203 mixture Substances 0.000 title claims abstract description 28
- 239000004480 active ingredient Substances 0.000 title claims abstract description 10
- 230000001093 anti-cancer Effects 0.000 title claims abstract description 10
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- 238000002360 preparation method Methods 0.000 title abstract description 35
- 229940088710 antibiotic agent Drugs 0.000 title description 3
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- 125000003277 amino group Chemical group 0.000 claims abstract description 28
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- 206010058467 Lung neoplasm malignant Diseases 0.000 claims abstract description 7
- 201000005202 lung cancer Diseases 0.000 claims abstract description 7
- 208000020816 lung neoplasm Diseases 0.000 claims abstract description 7
- 206010061535 Ovarian neoplasm Diseases 0.000 claims abstract description 6
- 206010033128 Ovarian cancer Diseases 0.000 claims abstract description 5
- 239000000126 substance Substances 0.000 claims description 97
- -1 tert-butyloxycarbonyl (Boc) -amino group Chemical group 0.000 claims description 82
- 150000001875 compounds Chemical class 0.000 claims description 70
- 238000006243 chemical reaction Methods 0.000 claims description 43
- 238000000034 method Methods 0.000 claims description 28
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 17
- 239000007858 starting material Substances 0.000 claims description 15
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 10
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 claims description 10
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 claims description 10
- 230000002401 inhibitory effect Effects 0.000 claims description 8
- 239000005695 Ammonium acetate Substances 0.000 claims description 7
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- 239000012321 sodium triacetoxyborohydride Substances 0.000 claims description 7
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 claims description 6
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 claims description 6
- YCNIBOIOWCTRCL-UHFFFAOYSA-N azane;2,2,2-trifluoroacetic acid Chemical compound [NH4+].[O-]C(=O)C(F)(F)F YCNIBOIOWCTRCL-UHFFFAOYSA-N 0.000 claims description 6
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- 239000002243 precursor Substances 0.000 claims description 5
- RDRAQCPEBAHCJV-GPQDHHOHSA-N tert-butyl N-[(5R,8R,9S,10S,13S,14S,17R)-10,13-dimethyl-17-[(2R)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-16-yl]carbamate Chemical compound C(C)(C)(C)OC(=O)NC1[C@@H]([C@]2(CC[C@@H]3[C@]4(CCCC[C@@H]4CC[C@H]3[C@@H]2C1)C)C)[C@H](C)CCCC(C)C RDRAQCPEBAHCJV-GPQDHHOHSA-N 0.000 claims description 5
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- 125000005196 alkyl carbonyloxy group Chemical group 0.000 claims description 2
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
Definitions
- the present invention relates to 7 ⁇ -aminosteroid derivatives, pharmaceutically acceptable salts thereof, a method for preparing the same, and an anticancer or antibiotic composition comprising the same as an active ingredient.
- a steroid is characterized by a large, firm and flat carbon skeleton, which itself is structured as to be able to achieve molecular recognition.
- the highly lipophilic region of the steroid skeleton provides high solubility in organic solvents while the functional groups thereof, which are attached to the steroid skeleton and react with various substrates, vary.
- steroids are advantageous in that the stereochemistry thereof can be easily modified [Diedrich, F.; Walliman, P.; Marti, T. Chem. Rev. (1997), 97, 1567]. Being superior in ionic selectivity and physiological activity, therefore, steroid compounds with hydrogen bond-forming functional groups, such as amine, carbamate, urea, and so on, attached thereto, are used as starting materials for the development of new drugs.
- the compound represented by Chemical Formula a is a triaminocholanoate transformed from cholic acid by substituting amino groups for hydroxyl groups at positions 3, 7 and 12, and has been used for the synthesis of cyclooligomer hosts [Davis, A. P.; Walsh, J. J. Chem. Commun. (1996), 449], anion, amino acid derivatives [Davis, A. P.; Perry, J. J.; Williams, R. P. J. Am. Chem. Soc. (1997), 119, 1793], and receptors [Cheng, Y. A.; Suenaga, T.; Still, W. C. J. Am. Chem. Soc. (1996), 118, 1813] .
- the compound of Chemical Formula b is known to destroy lipid membranes and control the migration of ions across cell membranes so as to regulate the fluidity and transmembrane transportation of glucose, which results in inhibition of the growth of Gram-positive bacteria and yeasts [Kihel, L. E.; Choucair, B.; Dherbomez, M.; Letourneux, Y. Eur. J. Org. Chem. (2002), 4075; Fouace, S.; Kiehl, E.; Dherbomez. M.; Letourneux, Y. Bioorg. Med. Chem. Lett. (2001), 11, 3011].
- the compound of Chemical Formula c found in the stomach tissue of sharks, is known to have inhibitory activity over a broad spectrum of Gram-positive and Gram-negative bacteria, fungi and yeasts [Wherli, S. L.; Moore, K. S.; Roder, H.; Durell, S.; Zasloff, M. Steroids (1993), 58, 370; Stone, R. Science (1993), 259, 1125].
- the compound of Chemical Formula d is a tetramine which is known to strongly associate with DNA thanks to its increased lipophilicity, based on the fusion of two steroid skeletons.
- the amines arranged in ⁇ -positions play an important role in the function of the aminosteroid compounds.
- the amines arranged in ⁇ - positions provide little or no physiological activity compared to those arranged in ⁇ -positions [Burrows, J. C; Hsieh, H. P.; Muller, J. G. Bioorg. Med. Chem. (1995), 3, 823].
- aminosteroid compounds are synthesized, hence, it is very important to regulate the stereochemistry thereof. That is, amino groups must be readily introduced into steroid compounds at ⁇ positions in order to provide them with enhanced molecular recognition and physiological activity.
- It is a further object of the present invention to provide an anticancer or antibiotic composition comprising the 7 ⁇ -aminosteroid derivative or a pharmaceutically acceptable salt thereof as an active ingredient .
- the present invention provides a 7 ⁇ -aminosteroid derivative or a pharmaceutically acceptable salt thereof.
- the present invention provides a method for preparing the 7 ⁇ -aminosteroid derivative.
- the present invention provides an anticancer or antibiotic composition
- an anticancer or antibiotic composition comprising the 7 ⁇ -aminosteroid derivative or a pharmaceutically acceptable salt thereof as an active ingredient.
- Reductive amination with amine in the presence of a reducing agent allows an amino group to be introduced at an ⁇ position of a steroid skeleton in single steps, and thus at higher yield, compared to conventional methods. Thanks to the arrangement at ⁇ position, the amino groups of the 7 ⁇ - aminosteroid derivatives in accordance with the present invention show high physiological activities. Able to block vascular endothelial growth factor-induced activation of MAP kinase, 7 ⁇ -aminosteroid derivatives or pharmaceutically acceptable salts thereof are applicable to a composition for the treatment of cancer, such as lung cancer and ovarian cancer, and to an antibiotic composition against Gram-positive and negative bacteria.
- the present invention pertains to a 7 ⁇ -aminosteroid derivative, represented by the following Chemical Formula 1, or a pharmaceutically acceptable salt thereof.
- R 1 is an amino group, a tert-butyloxycarbonyl (Boc) -amino group, a Ci-C 5 alkylamino group or polyamino group,
- R 2 is an amino group, a Boc-amino group, a Ci ⁇ Cs alkylamino group, a hydroxyl group, a Ci ⁇ Cs alkylcarbonyloxy group or a polyamino group, said polyamino group being
- n, m and 1 are independently an integer of 1 ⁇ 5 and R 3 and R 4 are independently H or Boc.
- R 1 is an amino group, a Boc-amino group, a butylamino group,
- R 2 is an amino group, a Boc-amino group, an acetoxy
- the derivatives represented by Chemical Formula 1 in accordance with the present invention may be in the form of pharmaceutically acceptable salts.
- acid addition salts formed with pharmaceutically acceptable free acids and metal salts formed with bases are included.
- Useful as the free acids are inorganic acids such as hydrochloric acid, sulfuric acid, bromic acid, sulfurous acid, and phosphoric acid, and organic acids such as citric acid, acetic acid, maleic acid, fumaric acid, gluconic acid and methane sulfonic acid.
- the metal salts useful in the present invention include alkali metal salts and alkaline earth metal salts, such as sodium, potassium and calcium salts.
- the present invention pertains to a method for preparing a 7 ⁇ -aminosteroid derivative, as illustrated in the following Reaction Scheme 1, comprising: reducing a double bond of a compound of Chemical Formula 2, as a starting material, to afford a 7-keto-compound of Chemical Formula 3 (step 1); and aminating the keto-compound of Chemical Formula 3 through reaction with an amine under a reductive condition to produce a compound of Chemical Formula Ia (step 2) .
- the method according to the present invention may further comprises: hydrolyzing the compound of Chemical Formula Ia of Step 2 into a compound of Chemical Formula Ib (step 3) .
- R 1 is as defined in Chemical Formula 1 and the compounds of Chemical Formulas Ia and Ib are included within the range of the derivative of Chemical Formula 1.
- the method according to the present invention may further comprise: oxidizing the compound of Chemical Formula Ib of Step 3 into a 3-keto compound of Chemical Formula 4 (step 4) ; and aminating the 3-keto compound of Step 4 through reaction with an amine (II) under a reductive condition to produce a 3 ⁇ , 7 ⁇ -diaminosteroid compound (1) (step 5).
- Step 1 Production of 7-Keto Compound
- step 1 the double bond between the 5- and 6-carbon of the compound of Chemical Formula 2, serving as a starting material, is reduced into the 7-keto compound of Chemical Formula 3.
- the starting material of Chemical Formula 2 can be obtained from commercially available cholesteryl acetate through allylic oxidation, as disclosed in Davis, A. P. et. al. f Synlett. (1999), 991.
- the double bond between carbon atoms at positions 5 and 6 be reduced and that the 7-keto group formed by allylic oxidation not undergo reduction.
- hydrogenation with the aid of a platinum catalyst may be applied to the reduction.
- the 7-keto group may be reduced into a 7-hydroxy group according to the reaction conditions. Even in this case, however, the reaction mixture can be oxidized with PCC, followed by purification to afford the 7- keto compound with the double bond reduced alone, at a high yield.
- Step 2 the 7-keto compound of Chemical Formula 3, prepared in Step 1 is reacted with a suitable reducing agent or an amine compound such that an amino group is arranged in the ⁇ -position on the steroid rings to produce the 7 ⁇ -aminosteroid derivative of Chemical Formula 1.
- amine compound examples thereof include ammonia precursors, such as ammonium acetate (CH 3 CO 2 NHJ , ammonium formate (HCO 2 NH 4 ) , ammonium trifluoroacetate (CF 3 CO 2 NH 4 ) , and ammonium trifluoromethanesulfonate (NH 4 OT f ) , Ci ⁇ Cs alkylamines, polyamines and the like.
- ammonia precursors such as ammonium acetate (CH 3 CO 2 NHJ , ammonium formate (HCO 2 NH 4 ) , ammonium trifluoroacetate (CF 3 CO 2 NH 4 ) , and ammonium trifluoromethanesulfonate (NH 4 OT f )
- Ci ⁇ Cs alkylamines such as Ci ⁇ Cs alkylamines, polyamines and the like.
- the arrangement in which an amino group is introduced at the ⁇ -position in accordance with the present invention is based on the fact that the aminosteroid compounds with an amino group arranged in ⁇ -position exhibit more potent physiological activity than do those with an amino group at the ⁇ - position. This stereoselection depends on the reducing agents or amine compounds .
- sodium cyanoborohydride is a preferable reducing agent
- the amine compound is preferably selected from among ammonium acetate, ammonium formate, ammonium trifluoroacetate, ammonium trifluoromethanesulfonate, n-butyl amine, tert-butyloxycarbonyl spermidine (Boc-spermidine) , and tert-butyloxycarbonyl spermine (Boc-spermine) .
- the pH of the reaction mixture is preferably adjusted to be within the range from 5.5 to 6.5, so that hydroxyl compounds can be prevented from being generated as by-products .
- the generation of the hydroxyl compound can be further prevented by reaction with a suitable reducing agent or a suitable amine compound.
- the reducing agent is preferably sodium cyanoborohydride
- the amine compound is preferably selected from among ammonium acetate, ammonium formate and ammonium trifluoroacetate.
- the reducing agent is preferably used in an amount from 1 to 3 equivalents, and the amount of the amine compound preferably falls within the range from 25 to 35 equivalents.
- the reductive amination is not completed, or requires a long period of time to reach completion when the reductive agent is used in an amount less than 1 equivalent.
- Step 2 may further comprise protecting the amino group in order to prevent side reaction due to the polarity of the amino group itself.
- Step 3 Hydrolysis
- Step 3 the ester bond of the acetoxy group at position 3 of the 7 ⁇ -aminosteroid prepared in Step 2 is converted into a hydroxyl group through hydrolysis.
- This hydrolysis may be conducted under typical conditions for the hydrolysis of an ester without special limitations.
- Step 4 the 3-hydroxy compound of Chemical Formula Ib prepared in Step 4 is oxidized into the 3-keto compound of
- Step 5 is adapted for reductive amination, in which the 3-keto compound of Chemical 4, prepared in Step 4, is reacted with an amine compound in the presence of a reducing agent to produce the 3 ⁇ , 7 ⁇ -diaminosteroid compound (1).
- the reducing agent is selected from among sodium triacetoxyborohydride, sodium cyanoborohydride, sodium tris (ethylhexanoxy)borohydride (NaBH (OEh) 3 ) , and sodium tris (isovaleroxy)borohydride (NaBH (OIv) 3) and examples of the amine compound useful in the present invention include ammonia precursors, such as ammonium acetate, ammonium formate, ammonium trifluoroacetate, and ammonium trifluoromethanesulfonate, Ci ⁇ C 5 alkylamines, and polyamines .
- ammonia precursors such as ammonium acetate, ammonium formate, ammonium trifluoroacetate, and ammonium trifluoromethanesulfonate, Ci ⁇ C 5 alkylamines, and polyamines .
- Step 2 While the amine compounds useful in this step may be the same as those used in Step 2, in this step, large-size reducing agents are preferred over small-size sodium cyanoborohydride in contrast to Step 2. Thanks to its small size, sodium cyanoborohydride can attack the 3-keto compound in both the axial and the equatorial direction to afford 3 ⁇ -aminosteroid compounds with the concomitant production of a significant amount of 3 ⁇ -aminosteroid compounds (refer to Experimental Example 3) .
- the reducing agent suitable for this step is more preferably selected from among sodium triacetoxyborohydride, sodium tris (ethylhexanoxy)borohydride (NaBH (OEh) 3 ) , and sodium tris (isovaleroxy) borohydride (NaBH (0Iv) 3 ) .
- Step 2 With regard to the amounts of the reducing agent, the amine compound, and pH, the same conditions as in Step 2 are applicable.
- the present invention pertains to a method for preparing a 7 ⁇ - aminosteroid derivative, as illustrated in the following Reaction Scheme 4, comprising: reducing a double bond of a compound of Chemical Formula 2, as a starting material, to afford a 7-keto-compound of Chemical Formula 3 (step a) ; reducing the acetoxy group of the compound of Chemical Formula 3, prepared in Step a, to afford a 3, 7-diketo-compound of Chemical Formula 5 (step b) ; subjecting the keto-compound of Chemical Formula 5, prepared in Step b, to reductive amination (DI) to afford a compound of Chemical Formula 6 (step c) ; and subjecting the compound of Chemical Formula 6 prepared in Step c to reductive amination (IV) to produce 7 ⁇ - aminosteroid (step d) .
- Reaction Scheme 4 comprising: reducing a double bond of a compound of Chemical Formula 2, as a starting material, to afford a 7-keto-compound of Chemical Formula 3 (step a)
- Step a Production of 7-Keto Compound
- step a the compound of Chemical Formula 2, serving as a starting material, is reduced at the double bond between 5- and 6-carbon into the 7-keto compound of Chemical Formula 3.
- the starting material of Chemical Formula 2 can be obtained from commercially available cholesteryl acetate through allylic oxidation, as disclosed in Davis, A. P. et. al., Synlett. (1999), 991. It is preferred that the double bond between carbon atoms at positions 5 and 6 be reduced and that the 7-keto group formed by allylic oxidation not undergo reduction. For example, hydrogenation with the aid of a platinum catalyst may be applied to the reduction. The 7-keto group may be reduced into a 7-hydroxy group according to the reaction conditions. Even in this case, however, the reaction mixture can be oxidized with PCC, followed by purification to afford the 7- keto compound with the double bond reduced alone, at a high yield.
- Step b the 3-acetoxy compound of Chemical Formula 3, prepared in Step a, is reacted with a strong base to convert the acetoxy group into a ketone group to afford the 3,7-diketo compound (5) .
- This oxidation may be conducted under typical conditions well known in the art without special limitations.
- Step c the 3,7-diketo compound of Chemical Formula 5, prepared in Step b, is reacted with an amine compound in the presence of a reducing agent to afford the 3 ⁇ -aminosteroid compound (6) .
- the reducing agent is selected from among sodium triacetoxyborohydride, sodium cyanoborohydride, sodium tris (ethylhexanoxy) borohydride (NaBH (OEh) 3 ) , and sodium tris (isovaleroxy)borohydride (NaBH(OIv) 3 ) and examples of the amine compound useful in the present invention include ammonia precursors, such as ammonium acetate, ammonium formate, ammonium trifluoroacetate, ammonium trifluoromethanesulfonate,
- Ci-C 5 alkylamines and polyamines.
- Step 2 With regard to the amounts of the reducing agent and the amine compound and pH, the same conditions as in Step 2 are applicable.
- Step d the 3 ⁇ -aminosteroid compound of Chemical Formula 6, prepared in Step c, is reacted with an amine compound in the presence of a reducing agent to afford the 3 ⁇ , 7 ⁇ -diaminosteroid compound (1).
- a reducing agent preferably applicable to those for the reducing agent and the amine compound.
- this step may further comprise adding an acid or a base to yield an acid addition salt or free base.
- the present invention pertains to an anticancer composition
- an anticancer composition comprising the 7 ⁇ -aminosteroid derivative or a pharmaceutically acceptable salt thereof as an active ingredient .
- Squalamine a kind of aminosteroid derivatives analogous to the 7 ⁇ -aminosteroid derivatives or pharmaceutically acceptable salts thereof in accordance with the present invention, is known to significantly block vascular endothelial growth factor-induced activation of MAP kinase and induce endothelial cells to undergo apoptosis, thus inhibiting angiogenesis.
- Squalamine is found to have significant inhibitory activity against angiogenesis in brain tumors, breast cancer and lung cancer [Schiller J. H. and Bittner G. (1999), Clin. Cancer Res., 5, 4287-4294] and is being studied in clinical practice.
- a study of mice suffering from ovarian cancer showed that squalamine inhibited the growth of ovarian tumors, caused apoptosis and decreased the density of newly formed blood vessels, thus having anticancer activity [Dan Li, Jon I Willians and Richard J Pietras, (2002), Oncogene, 21, 2805- 2814] .
- aminosteroids Korean Li, Jon I Willians and Richard J Pietras, (2002), Oncogene, 21, 2805- 2814
- the 7 ⁇ -aminosteroid derivatives or pharmaceutically acceptable salts thereof according to the present invention which have the same steroid skeleton as squalamine with an active amino group arranged at the ⁇ -position on carbon 7 can be useful in the treatment of cancers including lung cancer, ovarian cancer, etc.
- the present invention pertains to an antibiotic composition
- an antibiotic composition comprising the 7 ⁇ -aminosteroid derivative of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient.
- the 7 ⁇ -aminosteroid derivatives according to the present invention or pharmaceutically acceptable salts thereof are found to have an MIC (Minimum Inhibitory Concentration; MIC) of 0.78 100 ⁇ g/ml, as measured on Gram-positive and Gram- negative bacteria (Experimental Example 4) . Therefore, the 7 ⁇ - aminosteroid derivatives or pharmaceutically acceptable salts thereof have potential antibiotic activity against a broad spectrum of microorganisms including bacteria and fungi .
- the composition may be administered orally or non- orally. It is usually formulated in combination with a diluent or excipient, such as a filler, a thickening agent, a binder, a wetting agent, a disintegrant, a surfactant, etc.
- Solid agents intended for oral administration of the compound of the present invention may be in the form of tablets, pills, powders, granules, capsules, and the like. These solid agents are formulated in combination with at least one excipient, such as starch, calcium carbonate, sucrose, lactose, or gelatine. In addition, a lubricant, such as magnesium stearate, talc and the like, may also be added. Liquid agents intended for oral administration include suspensions, internal use solutions, emulsion, syrups, and the like.
- non-oral dosage forms of the compound of the present invention include sterile aqueous solutions, non-aqueous solutions, suspensions and emulsions for injection, freeze-dried agents, and suppositories.
- nonaqueous solutions and suspensions made from propylene glycol, polyethylene glycol, vegetable oils, such as olive oil, and esters such as ethyl oleate may be used.
- the basic materials of suppositories include Witepsol, macrogol, tween 61, cacao butter, laurin, glycerol, and gelatine.
- the effective dosage of the compound or pharmaceutically acceptable salts thereof in accordance with the present invention depends on various factors, including the patient's weight, age, gender, state of health, diet, the time of administration, route of administration, etc.
- the compound in accordance with the present invention may be administered in a single dose or in multiple doses per day, each dose ranging from 0.001 ⁇ 10 mg/day for an adult patient weighing 70kg.
- Step 1 Production of 3 ⁇ -acetoxy-5 ⁇ -cholestan-7-one
- 3 ⁇ -acetoxy- cholest-5-en-7-one 400 mg, 0.90 mmol
- the reaction was completed, as determined by thin layer chromatography (TLC)
- TLC thin layer chromatography
- Step 2 Production of 7 ⁇ -tert-butyloxycarbonylamino-3 ⁇ - acetoxy-5 ⁇ -cholestane
- the organic layer thus formed was washed with a saturated aqueous sodium hydrogen carbonate solution and an aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After the removal of the solvent in a vacuum, the concentrate was dissolved in methanol (20 ml) without further purification and reacted with BoC 2 O (489 mg, 2 equivalents) at room temperature for 1 hour with stirring. When TLC indicated the disappearance of the starting material, the solvent was removed in a vacuum and the concentrate was dissolved in ethyl acetate.
- the organic layer thus formed was dried over anhydrous sodium sulfate, followed by the removal of the solvent in a vacuum.
- the concentrate was dissolved in anhydrous dichloromethane (5 ml) without purification and oxidized with PCC (297 mg, 1.5 equivalents) in the presence of CHaCO 2 Na (38 mg, 0.5 equivalents) at room temperature for 2 hours .
- Step 5 Preparation of 3 ⁇ , 7 ⁇ -bis (Boc-amino) -5 ⁇ - cholestane
- the 7 ⁇ -Boc-amino-5 ⁇ -cholestan-3-one (200 mg, 0.40 mmol) prepared in Step 4 and NH 4 OT f (2.01 g, 30 equivalents) were dissolved in anhydrous THF (30 ml) at room temperature for 30 min with stirring.
- NaBH (OEh) 3 (1 ml, 1 eq.
- 2-ethylhexanoic acid (3 eq.) in dichloromethane
- Step 1 Preparation of 3 ⁇ -acetoxy-5 ⁇ -cholestan-7-one The same procedure as in Step 1 of Example was conducted to prepare the object compound.
- Step 2 Preparation of 7 ⁇ -butylamino-3 ⁇ -acetoxy-5 ⁇ - cholestane
- EXTiMPLE 5 Preparation of 7 ⁇ -spermidyl-3 ⁇ -acetoxy-5 ⁇ -cholestane
- Step 1 Preparation of 3 ⁇ -acetoxy-5 ⁇ -cholestan-7-one The same procedure as in Step 1 of Example 1 was conducted to afford the object compound.
- Step 2 Preparation of 7 ⁇ -spermidyl-3 ⁇ -acetoxy-5 ⁇ - cholestane
- the organic layer thus formed was washed with a saturated aqueous sodium hydrogen carbonate solution and an aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After the removal of the solvent in a vacuum, the concentrate was purified using a Chromatotron (elution solvent: 2% ethyl acetate-hexane) to yield 564 mg of the object compound (0.73 mmol, 65%).
- Step 3 Preparation of 7 ⁇ -spermidyl-3 ⁇ -hydroxy-5 ⁇ - cholestane
- EXAMPLE 7 Preparation of 3 ⁇ , 7 ⁇ -bis (Boc-amino) -5 ⁇ -cholestane 2
- Step a Preparation of 3 ⁇ -acetoxy-5 ⁇ -cholestan-7-one In ethyl acetate (15 ml) was dissolved 3 ⁇ -acetoxy- cholest-5-en-7-one (10 g, 2.26 mmol) , followed by stirring at room temperature over 10 hours in a 1 atm hydrogen atmosphere in the presence of 5 % Pt/C (30 mg) .
- Step d Preparation of 3 ⁇ , 7 ⁇ -bis (Boc-) amino-5 ⁇ - cholestane
- the 7-keto compound of Chemical Formula 3, prepared in Step 1, was subjected to reductive amination (I) , in which 30 equivalents of NH 4 OT f was used as an amine compound in the presence of 2 equivalents of a reducing agent selected from among NaBH(OAc) 3 , NaBH 3 CN, NaBH 2 (OAc) 2 , NaBH 3 (OAc) and picoline borane under the conditions listed in Table 1, below.
- a reducing agent selected from among NaBH(OAc) 3 , NaBH 3 CN, NaBH 2 (OAc) 2 , NaBH 3 (OAc) and picoline borane under the conditions listed in Table 1, below.
- the reductive amination (I) although actively conducted in the presence of NaBH(OAc) 3 and NaBH 3 CN, was also found to yield hydroxyl compounds as side products at ratios of NH 2 /OH 10/1 and 2.5/1, respectively.
- the concomitant production of hydroxyl compounds in the reductive amination (I) of Step 2 is believed to be attributed to the fact that the reduction of the keto group into alcohol takes place preferentially over the formation of an imine and subsequent conversion to an amino group.
- the 7-keto compound of Chemical Formula 3, prepared in Step 1, was subjected to reductive amination (I), in which it was reacted with 30 equivalents of each of CH 3 CO 2 NH 4 , HCO 2 NH 4 , CF 3 CO 2 NH 4 , NH 4 OT f and NH 4 Cl in the presence of 2 equivalents of NaBH 3 CN as a reducing agent in a mixed solvent of THF/MeOH(l:l) .
- the reductive amination ( II ) with NH 4 OT f or NH 4 OAc was conducted in a mixed solvent of THF:MeOH (1:1) in the presence of various reducing agents under the conditions of Table 3, below.
- the reducing agents were obtained by reacting NaBH 4 with organic acids different in molecular size in dichloromethane to synthesize triacyloxyborohydride, as illustrated in Reaction Scheme 5, below. Comparison was made between the results from the use of these reducing agents and the reducing agents for the reductive amination (I) of Step 2, NaBH(OAc) 3 and NaBH 3 CN.
- RCOOH is isovaleric acid ( Iv) and 2-ethylhexanoic acid (Eh) when R is -CH 2 CH (CH 3 ) 2 and - CH 2 CH 2 CH 2 CH 2 CH (CH 2 CH 3 ) 2 , respectively .
- NaBH(OEh) 3 synthesized from 2- ethylhexanoic acid, allowed a higher yield (85%) and a higher ⁇ / ⁇ ratio (9:1) than did any other reducing agent.
- the aminosteroid compound was produced at the lowest yield, 55%, with an ⁇ / ⁇ ratio of 4:6.
- the data of Table 3 show that a greater proportion of ⁇ -oriented amino compounds is produced in the presence of a reducing agent having a larger molecular size.
- the product was produced at a high yield when using 30 equivalents of NH 4 OT f .
- the reaction time period was also increased.
- the compounds prepared in Examples 4, 6 and 8 were applied to 8 bacteria species.
- the bacteria tested in this example were obtained from the ATCC (Rockville, MD, U.S.A.) and can be divided into Gram-positive species including Streptococcus pyogenes 308A (S. pyogenes 308A), Streptococcus pyogenes 11A (S. pyogenes 11A) and Staphylococcus aureus 503 (S. aureus 503) , and Gram-negative species including E. CoIi DC2, Pseudomonas aeruginosa 9027 (P. aeruginosa 9027), Pseudomonas aeruginosa 1771M (P.
- aeruginosa 1771M Salmonella typhimurium (S. typhimurium) and E. cloacae 1321E.
- MICs Minimum Inhibitory Concentrations
- the strains were cultured at 37 0 C for 20 hours and diluted to 3*10 6 CFU/ml, and inocula of about 104 cfu per spot were applied with Microplanter onto agar plates containing twofold serial dilutions of each of the compounds prepared in Examples 4, 6 and 8, followed by incubation at 37 0 C for 20 hours .
- the MICs were defined as the minimum drug concentrations which completely inhibited the growth of bacteria, as observed with the naked eye.
- the 7 ⁇ - aminosteroid derivatives or pharmaceutically acceptable salts thereof in accordance with the present invention have MICs of 0.78 - 100 ⁇ g/mg, thus showing inhibitory activity against various bacteria.
- the compounds of the present invention have an MIC of 3.12 ⁇ g/ml or less, thus showing potent antibiotic activity.
- the 7 ⁇ -aminosteroid derivatives or pharmaceutically acceptable salts thereof can be used as antibiotics against bacteria and fungi.
- the compound of Chemical Formula 1 was dissolved in a suitable volume of a NaCl BP injection, and the solution was adjusted to a pH of 3.5 with diluted HCl BP and to a desired volume with NaCl BP injection, followed by sufficient mixing.
- the solution was loaded into transparent 5 ml type I ampules which were hermetically sealed by melting, followed by autoclaving at 120 0 C for 5 min to prepare injections.
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Abstract
Disclosed are 7α-aminosteroid derivatives or pharmaceutically acceptable salts thereof, preparation methods thereof, and anticancer or antibiotic compositions comprising the same as an active ingredient. Reductive amination with amine in the presence of a reducing agent allows an amino group to be introduced at an α position of a steroid skeleton in single steps, and thus at high yield. Thanks to the arrangement at α position, the amino groups of the Ia- aminosteroid derivatives show high physiological activities. Able to block vascular endothelial growth factor-induced activation of MAP kinase, 7α-aminosteroid derivatives or pharmaceutically acceptable salts thereof are applicable to a composition for the treatment of cancer, such as lung cancer and ovarian cancer, and to an antibiotic composition against Gram-positive and negative bacteria.
Description
[DESCRIPTION]
[invention Title]
7ALPHA-AMINOSTEROID DERIVATIVES OR PHAMACEUTICALLY ACCEPTABLE SALTS THEREOF, PREPARATION METHOD THEREOF AND COMPOSITION FOR ANTICANCER OR ANTIBIOTICS CONTAINING THE SAME AS AN ACTIVE INGREDIENT
[Technical Field]
The present invention relates to 7α-aminosteroid derivatives, pharmaceutically acceptable salts thereof, a method for preparing the same, and an anticancer or antibiotic composition comprising the same as an active ingredient.
[Background Art]
A steroid is characterized by a large, firm and flat carbon skeleton, which itself is structured as to be able to achieve molecular recognition. In addition, the highly lipophilic region of the steroid skeleton provides high solubility in organic solvents while the functional groups thereof, which are attached to the steroid skeleton and react with various substrates, vary. Furthermore, because functional groups are introduced into a steroid with their stereochemistry already determined, steroids are advantageous in that the stereochemistry thereof can be easily modified [Diedrich, F.;
Walliman, P.; Marti, T. Chem. Rev. (1997), 97, 1567]. Being superior in ionic selectivity and physiological activity, therefore, steroid compounds with hydrogen bond-forming functional groups, such as amine, carbamate, urea, and so on, attached thereto, are used as starting materials for the development of new drugs.
Conventional aminosteroid compounds to which functional groups, capable of forming hydrogen bonds, are introduced may be exemplified by the following Chemical Formulas .
[Chemical Formula a]
The compound represented by Chemical Formula a is a triaminocholanoate transformed from cholic acid by substituting amino groups for hydroxyl groups at positions 3, 7 and 12, and has been used for the synthesis of cyclooligomer hosts [Davis, A. P.; Walsh, J. J. Chem. Commun. (1996), 449], anion, amino acid derivatives [Davis, A. P.; Perry, J. J.; Williams, R. P.
J. Am. Chem. Soc. (1997), 119, 1793], and receptors [Cheng, Y. A.; Suenaga, T.; Still, W. C. J. Am. Chem. Soc. (1996), 118, 1813] .
[Chemical Formula b]
The compound of Chemical Formula b is known to destroy lipid membranes and control the migration of ions across cell membranes so as to regulate the fluidity and transmembrane transportation of glucose, which results in inhibition of the growth of Gram-positive bacteria and yeasts [Kihel, L. E.; Choucair, B.; Dherbomez, M.; Letourneux, Y. Eur. J. Org. Chem. (2002), 4075; Fouace, S.; Kiehl, E.; Dherbomez. M.; Letourneux, Y. Bioorg. Med. Chem. Lett. (2001), 11, 3011].
The compound of Chemical Formula c, found in the stomach tissue of sharks, is known to have inhibitory activity over a broad spectrum of Gram-positive and Gram-negative bacteria, fungi and yeasts [Wherli, S. L.; Moore, K. S.; Roder, H.; Durell, S.; Zasloff, M. Steroids (1993), 58, 370; Stone, R. Science (1993), 259, 1125].
[Chemical Formula d]
The compound of Chemical Formula d is a tetramine which
is known to strongly associate with DNA thanks to its increased lipophilicity, based on the fusion of two steroid skeletons.
Being capable of donating electrons, the amines arranged in α-positions play an important role in the function of the aminosteroid compounds. In contrast, the amines arranged in β- positions provide little or no physiological activity compared to those arranged in α-positions [Burrows, J. C; Hsieh, H. P.; Muller, J. G. Bioorg. Med. Chem. (1995), 3, 823]. When aminosteroid compounds are synthesized, hence, it is very important to regulate the stereochemistry thereof. That is, amino groups must be readily introduced into steroid compounds at α positions in order to provide them with enhanced molecular recognition and physiological activity.
There are many processes for converting a hydroxyl group into an amino group, including conversion from hydroxyl group to amino group via the formation of azide, followed by hydrogen reduction [Davis, A. P.; Brodevick, S.; Williams, R. P. Tetrahedron Lett. (1998), 39, 6083], via the formation of phthalimide through a Mitsunobu reaction, followed by hydrolysis [Davis, A. P./ Dresen, S.; Lawless, L. J. Tetrahedron Lett. (1997), 38, 4305], and via the formation of oxime through oxidation with ketone, followed by reduction [Zhou, X. T.; Rehman, A.; Li, C; Savage, P. B. Org. Lett. (2000), 2, 3015] .
However, these processes do not produce amines in one single step, but require multiple steps, including the formation of intermediates, such as oxime, azide and phthalimide, from hydroxyl groups and the transformation of these intermediates to amino groups, thus suffering from the disadvantage of being as low as 40% in overall production yield. In addition, the Mitsunobu reaction requires expensive reagents for the conversion of hydroxyl groups into amino groups [Davis, A. P.; Dresen, S.; Lawless, L. J. Tetrahedron Lett. (1997), 38, 4305].
Leading to the present invention, intensive and thorough research into novel 7α-aminosteroid derivatives with an increase in the overall production yield and α arrangement, conducted by the present inventors, resulted in the finding that amino groups can be introduced at α positions of a steroid skeleton in single steps and thus at high yield, through reductive amination with amines under a reductive condition. It was also found that the 7α-aminosteroid derivatives synthesized through reductive amination have inhibitory activity against cancer and microbes including bacteria and fungi .
[Disclosure] [Technical Problem]
It is therefore an object of the present invention to provide 7α-aminosteroid derivatives or pharmaceutically acceptable salts thereof.
It is another object of the present invention to provide a method of preparing the 7α-aminosteroid derivatives.
It is a further object of the present invention to provide an anticancer or antibiotic composition comprising the 7α-aminosteroid derivative or a pharmaceutically acceptable salt thereof as an active ingredient .
[Technical Solution]
In order to accomplish the above object, the present invention provides a 7α-aminosteroid derivative or a pharmaceutically acceptable salt thereof.
Also, the present invention provides a method for preparing the 7α-aminosteroid derivative.
Further, the present invention provides an anticancer or antibiotic composition comprising the 7α-aminosteroid derivative or a pharmaceutically acceptable salt thereof as an active ingredient.
[Advantageous Effects]
Reductive amination with amine in the presence of a reducing agent allows an amino group to be introduced at an α position of a steroid skeleton in single steps, and thus at
higher yield, compared to conventional methods. Thanks to the arrangement at α position, the amino groups of the 7α- aminosteroid derivatives in accordance with the present invention show high physiological activities. Able to block vascular endothelial growth factor-induced activation of MAP kinase, 7α-aminosteroid derivatives or pharmaceutically acceptable salts thereof are applicable to a composition for the treatment of cancer, such as lung cancer and ovarian cancer, and to an antibiotic composition against Gram-positive and negative bacteria.
[Best Mode]
In accordance with an aspect thereof, the present invention pertains to a 7α-aminosteroid derivative, represented by the following Chemical Formula 1, or a pharmaceutically acceptable salt thereof.
[Chemical Formula 1]
R1 is an amino group, a tert-butyloxycarbonyl (Boc) -amino
group, a Ci-C5 alkylamino group or polyamino group,
R2 is an amino group, a Boc-amino group, a Ci~Cs alkylamino group, a hydroxyl group, a Ci~Cs alkylcarbonyloxy group or a polyamino group, said polyamino group being
In a preferable compound of Chemical Formula 1, R1 is an amino group, a Boc-amino group, a butylamino group,
R2 is an amino group, a Boc-amino group, an acetoxy
group, a hydroxyl group,
,
l°c H
Concrete examples of the derivatives of Chemical Formula 1 in accordance with the present invention include:
1) 7α-amino-3β-acetoxy-5α-cholestane;
2) 7α-tert-butyloxycarbonyl (Boc) amino-3β-acetoxy-5α- cholestane;
3) 7α-butylamino-3β-acetoxy-5α-cholestane;
4) 7α-butylamino-3β-hydroxy-5α-cholestane;
5) 7α-spermidyl-3β-acetoxy-5α-cholestane;
6) 7α-spermidyl-3β-hydroxy-5α-cholestane; 7) 3α, 7α-diamino-5α-cholestane;
8) 3α, 7α-bis (Boc-amino) -5α-cholestane;
9) 3α,7α-bis (spermidyl) -5α-cholestane/ and
10) 3α, 7α-bis (sperminyl) -5α-cholestane.
The derivatives represented by Chemical Formula 1 in accordance with the present invention may be in the form of pharmaceutically acceptable salts. Within the range of these salts are included acid addition salts formed with pharmaceutically acceptable free acids and metal salts formed with bases . Useful as the free acids are inorganic acids such as hydrochloric acid, sulfuric acid, bromic acid, sulfurous acid, and phosphoric acid, and organic acids such as citric acid, acetic acid, maleic acid, fumaric acid, gluconic acid and methane sulfonic acid. Examples of the metal salts useful in the present invention include alkali metal salts and alkaline earth metal salts, such as sodium, potassium and calcium salts.
In accordance with another aspect thereof, the present invention pertains to a method for preparing a 7α-aminosteroid derivative, as illustrated in the following Reaction Scheme 1, comprising: reducing a double bond of a compound of Chemical Formula 2, as a starting material, to afford a 7-keto-compound of Chemical Formula 3 (step 1); and aminating the keto-compound of Chemical Formula 3 through reaction with an amine under a reductive condition to produce a compound of Chemical Formula Ia (step 2) .
[Reaction Scheme 1]
(wherein, R1 is as defined in Chemical Formula 1, and the compound of Chemical Formula Ia is included within the range of the derivatives of Chemical Formula 1)
Further, the method according to the present invention, as illustrated in the following Reaction Scheme 2, may further comprises: hydrolyzing the compound of Chemical Formula Ia of Step 2 into a compound of Chemical Formula Ib (step 3) .
[Reaction Formula 2]
Step 3
(wherein, R1 is as defined in Chemical Formula 1 and the compounds of Chemical Formulas Ia and Ib are included within the range of the derivative of Chemical Formula 1.)
Furthermore, the method according to the present invention, as illustrated in the following Reaction Scheme 3, may further comprise: oxidizing the compound of Chemical Formula Ib of Step 3 into a 3-keto compound of Chemical Formula 4 (step 4) ; and aminating the 3-keto compound of Step 4 through reaction with an amine (II) under a reductive condition to produce a 3α, 7α-diaminosteroid compound (1) (step 5).
[Reaction Scheme 3]
(wherein, R1 and R2 are each as defined in Chemical Formula 1 and the compounds of Chemical Formulas Ia and Ib are included within the range of the derivative of Chemical Formula D
Below, a stepwise description will be given of the preparation method according to the present invention.
Step 1: Production of 7-Keto Compound In step 1, the double bond between the 5- and 6-carbon of the compound of Chemical Formula 2, serving as a starting material, is reduced into the 7-keto compound of Chemical Formula 3.
The starting material of Chemical Formula 2 can be obtained from commercially available cholesteryl acetate through allylic oxidation, as disclosed in Davis, A. P. et. al.f Synlett. (1999), 991.
It is preferred that the double bond between carbon atoms at positions 5 and 6 be reduced and that the 7-keto group
formed by allylic oxidation not undergo reduction. For example, hydrogenation with the aid of a platinum catalyst may be applied to the reduction. The 7-keto group may be reduced into a 7-hydroxy group according to the reaction conditions. Even in this case, however, the reaction mixture can be oxidized with PCC, followed by purification to afford the 7- keto compound with the double bond reduced alone, at a high yield.
Step 2: Reductive Amination (I)
In Step 2, the 7-keto compound of Chemical Formula 3, prepared in Step 1 is reacted with a suitable reducing agent or an amine compound such that an amino group is arranged in the α-position on the steroid rings to produce the 7α-aminosteroid derivative of Chemical Formula 1.
Sodium triacetoxyborohydride (NaBH(OAc)3) and sodium cyanoborohydride (NaBH3CN) are suggested as reducing agents suitable for this reductive amination. As for the amine compound, examples thereof include ammonia precursors, such as ammonium acetate (CH3CO2NHJ , ammonium formate (HCO2NH4) , ammonium trifluoroacetate (CF3CO2NH4) , and ammonium trifluoromethanesulfonate (NH4OTf) , Ci~Cs alkylamines, polyamines and the like.
The arrangement in which an amino group is introduced at the α-position in accordance with the present invention is
based on the fact that the aminosteroid compounds with an amino group arranged in α-position exhibit more potent physiological activity than do those with an amino group at the β- position. This stereoselection depends on the reducing agents or amine compounds .
In this regard, sodium cyanoborohydride is a preferable reducing agent, and the amine compound is preferably selected from among ammonium acetate, ammonium formate, ammonium trifluoroacetate, ammonium trifluoromethanesulfonate, n-butyl amine, tert-butyloxycarbonyl spermidine (Boc-spermidine) , and tert-butyloxycarbonyl spermine (Boc-spermine) .
For the reductive amination of Step 2, the pH of the reaction mixture is preferably adjusted to be within the range from 5.5 to 6.5, so that hydroxyl compounds can be prevented from being generated as by-products .
The production of the hydroxyl compounds in the reductive amination of Step 2 is believed to be attributed to the fact that the reduction of the keto group into alcohol takes place preferentially over the formation of an imine and subsequent conversion to an amino group. Hence, it is very important in the production of the amino compound at high yield to effectively generate imine at an early stage of the reaction. When the reductive amination is conducted at pH
values outside the pH range, the generation of the hydroxyl compounds cannot be prevented.
Moreover, the generation of the hydroxyl compound can be further prevented by reaction with a suitable reducing agent or a suitable amine compound. In this context, the reducing agent is preferably sodium cyanoborohydride, and the amine compound is preferably selected from among ammonium acetate, ammonium formate and ammonium trifluoroacetate. The reducing agent is preferably used in an amount from 1 to 3 equivalents, and the amount of the amine compound preferably falls within the range from 25 to 35 equivalents. The reductive amination is not completed, or requires a long period of time to reach completion when the reductive agent is used in an amount less than 1 equivalent. In the presence of less than 25 equivalents of the amine compound, a hydroxyl compound is produced as a side product, or the reaction time is increased. On the other hand, even when the reducing agent and the amine compound are used in amounts greater than 3 and 35 equivalents, respectively, the production yield is not increased further.
Optionally, Step 2 may further comprise protecting the amino group in order to prevent side reaction due to the polarity of the amino group itself.
Step 3: Hydrolysis
In Step 3, the ester bond of the acetoxy group at position 3 of the 7α-aminosteroid prepared in Step 2 is converted into a hydroxyl group through hydrolysis. This hydrolysis may be conducted under typical conditions for the hydrolysis of an ester without special limitations.
Step 4 : Production of 3-Keto Compound
In Step 4, the 3-hydroxy compound of Chemical Formula Ib prepared in Step 4 is oxidized into the 3-keto compound of
Chemical Formula 4. This oxidation can be conducted under typical conditions for the oxidation of alcohol without special limitations.
Step 5 : Reductive Amination ( II)
Step 5 is adapted for reductive amination, in which the 3-keto compound of Chemical 4, prepared in Step 4, is reacted with an amine compound in the presence of a reducing agent to produce the 3α, 7α-diaminosteroid compound (1). For use in the reductive amination, the reducing agent is selected from among sodium triacetoxyborohydride, sodium cyanoborohydride, sodium tris (ethylhexanoxy)borohydride (NaBH (OEh) 3) , and sodium tris (isovaleroxy)borohydride (NaBH (OIv) 3) and examples of the amine compound useful in the present invention include ammonia precursors, such as ammonium
acetate, ammonium formate, ammonium trifluoroacetate, and ammonium trifluoromethanesulfonate, Ci~C5 alkylamines, and polyamines .
While the amine compounds useful in this step may be the same as those used in Step 2, in this step, large-size reducing agents are preferred over small-size sodium cyanoborohydride in contrast to Step 2. Thanks to its small size, sodium cyanoborohydride can attack the 3-keto compound in both the axial and the equatorial direction to afford 3α-aminosteroid compounds with the concomitant production of a significant amount of 3β-aminosteroid compounds (refer to Experimental Example 3) . In order to produce only a minimum of β-oriented compounds, the reducing agent suitable for this step is more preferably selected from among sodium triacetoxyborohydride, sodium tris (ethylhexanoxy)borohydride (NaBH (OEh) 3) , and sodium tris (isovaleroxy) borohydride (NaBH (0Iv) 3) .
With regard to the amounts of the reducing agent, the amine compound, and pH, the same conditions as in Step 2 are applicable.
In accordance with another alternative aspect thereof, the present invention pertains to a method for preparing a 7α- aminosteroid derivative, as illustrated in the following Reaction Scheme 4, comprising: reducing a double bond of a compound of Chemical Formula
2, as a starting material, to afford a 7-keto-compound of Chemical Formula 3 (step a) ; reducing the acetoxy group of the compound of Chemical Formula 3, prepared in Step a, to afford a 3, 7-diketo-compound of Chemical Formula 5 (step b) ; subjecting the keto-compound of Chemical Formula 5, prepared in Step b, to reductive amination (DI) to afford a compound of Chemical Formula 6 (step c) ; and subjecting the compound of Chemical Formula 6 prepared in Step c to reductive amination (IV) to produce 7α- aminosteroid (step d) .
(wherein R1 and R2 are as defined in Chemical Formula 1)
Below, the preparation method is described in a stepwise manner with reference to Reaction Scheme 4.
Step a: Production of 7-Keto Compound
In step a, the compound of Chemical Formula 2, serving as a starting material, is reduced at the double bond between 5- and 6-carbon into the 7-keto compound of Chemical Formula 3.
The starting material of Chemical Formula 2 can be obtained from commercially available cholesteryl acetate through allylic oxidation, as disclosed in Davis, A. P. et. al., Synlett. (1999), 991. It is preferred that the double bond between carbon atoms at positions 5 and 6 be reduced and that the 7-keto group formed by allylic oxidation not undergo reduction. For example, hydrogenation with the aid of a platinum catalyst may be applied to the reduction. The 7-keto group may be reduced into a 7-hydroxy group according to the reaction conditions. Even in this case, however, the reaction mixture can be oxidized with PCC, followed by purification to afford the 7- keto compound with the double bond reduced alone, at a high yield.
Step b: Production of 3,7-Diketo Compound
In Step b, the 3-acetoxy compound of Chemical Formula 3, prepared in Step a, is reacted with a strong base to convert the acetoxy group into a ketone group to afford the 3,7-diketo compound (5) . This oxidation may be conducted under typical
conditions well known in the art without special limitations.
Step c: Reductive Amination (III)
In Step c, the 3,7-diketo compound of Chemical Formula 5, prepared in Step b, is reacted with an amine compound in the presence of a reducing agent to afford the 3α-aminosteroid compound (6) .
For use in the reductive amination, the reducing agent is selected from among sodium triacetoxyborohydride, sodium cyanoborohydride, sodium tris (ethylhexanoxy) borohydride (NaBH (OEh) 3) , and sodium tris (isovaleroxy)borohydride (NaBH(OIv)3) and examples of the amine compound useful in the present invention include ammonia precursors, such as ammonium acetate, ammonium formate, ammonium trifluoroacetate, ammonium trifluoromethanesulfonate,
Ci-C5 alkylamines, and polyamines.
With regard to the amounts of the reducing agent and the amine compound and pH, the same conditions as in Step 2 are applicable.
Step d: Reductive Amination (IV)
In Step d, the 3α-aminosteroid compound of Chemical Formula 6, prepared in Step c, is reacted with an amine compound in the presence of a reducing agent to afford the 3α, 7α-diaminosteroid compound (1).
The same conditions as in Step c with regard to the amounts of the reducing agent and the amine compound and pH are preferably applicable to those for the reducing agent and the amine compound. Optionally, this step may further comprise adding an acid or a base to yield an acid addition salt or free base.
In accordance with a further aspect thereof, the present invention pertains to an anticancer composition comprising the 7α-aminosteroid derivative or a pharmaceutically acceptable salt thereof as an active ingredient .
Squalamine, a kind of aminosteroid derivatives analogous to the 7α-aminosteroid derivatives or pharmaceutically acceptable salts thereof in accordance with the present invention, is known to significantly block vascular endothelial growth factor-induced activation of MAP kinase and induce endothelial cells to undergo apoptosis, thus inhibiting angiogenesis.
Squalamine is found to have significant inhibitory activity against angiogenesis in brain tumors, breast cancer and lung cancer [Schiller J. H. and Bittner G. (1999), Clin. Cancer Res., 5, 4287-4294] and is being studied in clinical practice. A study of mice suffering from ovarian cancer showed that squalamine inhibited the growth of ovarian tumors, caused apoptosis and decreased the density of newly formed blood vessels, thus having anticancer activity [Dan Li, Jon I
Willians and Richard J Pietras, (2002), Oncogene, 21, 2805- 2814] . Besides, there have been many research reports on the pharmaceutical uses of aminosteroids [Karigiannis, G., Papaioannou, D. (2000) Structure, biological activity and synthesis of polyamine analogues and conjugates. Eur. J. Org. Chem. 1841-1863; Sillas, A. K., Williams, J. I., Tyler, B. M., Epostein, D. S., Sipos, E. P., Davids, J. D., McLane, M. P., Pitchford, S., Cheshire, K., Gannon, F. H., Kinney, W. A., Chao, T. L., Donowitz, M., Laterra, J., Bern, H. (1998) Squalamine inhibits angiogenesis and solid tumor growth in vivo and perturbs embryonic vasculature. Cancer Res. 58, 2784- 2792; Bhargava, P., Marshall, J. L., Dahut, W., Rizvi, N., Trocky, N., Williams, J. I., Hait, H,. Song, S., Holroyd, K. J., Hawkins, M. J. (2001) A Phase I and pharmacokinetic study of squalamine, a novel antiangiogenic agent, in patients with advanced cancers. Clin. Cancer Res. 7, 3912-3919; Hao, D., Hammond, L. A.; Eckhardt, S. G., Patnaik, A., Takimoto, C. H., Schwartz, G. H., Goetz, A. D., Tolcher, A. W., McCreery, H. A., Mamun, K., Williams, J. I., Holroyd, K. J., Rowinsky, E. K. (2003) . A Phase I and Pharmacokinetic Study of Squalamine, an Aminosterol Angiogenesis Inhibitor. Clin. Cancer Res. 9, 2465- 2471; Sridhar, S. S., Shepherd, F. A. (2003) Targeting angiogenesis: a review of angiogenesis inhibitors in the treatment of lung cancer. Lung cancer. 42, 81-91] . Thus, the 7α-aminosteroid derivatives or pharmaceutically acceptable
salts thereof according to the present invention, which have the same steroid skeleton as squalamine with an active amino group arranged at the α-position on carbon 7 can be useful in the treatment of cancers including lung cancer, ovarian cancer, etc.
In accordance with still a further aspect thereof, the present invention pertains to an antibiotic composition comprising the 7α-aminosteroid derivative of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient.
The 7α-aminosteroid derivatives according to the present invention or pharmaceutically acceptable salts thereof are found to have an MIC (Minimum Inhibitory Concentration; MIC) of 0.78 100 μg/ml, as measured on Gram-positive and Gram- negative bacteria (Experimental Example 4) . Therefore, the 7α- aminosteroid derivatives or pharmaceutically acceptable salts thereof have potential antibiotic activity against a broad spectrum of microorganisms including bacteria and fungi . The composition may be administered orally or non- orally. It is usually formulated in combination with a diluent or excipient, such as a filler, a thickening agent, a binder, a wetting agent, a disintegrant, a surfactant, etc. Solid agents intended for oral administration of the compound of the present invention may be in the form of tablets, pills, powders,
granules, capsules, and the like. These solid agents are formulated in combination with at least one excipient, such as starch, calcium carbonate, sucrose, lactose, or gelatine. In addition, a lubricant, such as magnesium stearate, talc and the like, may also be added. Liquid agents intended for oral administration include suspensions, internal use solutions, emulsion, syrups, and the like. In addition to a simple diluent such as water or liquid paraffin, various excipients, such as wetting agents, sweetening agents, aromatics, preservatives, and the like may be contained in the liquid agents for the oral administration of the compound of the present invention. Also, non-oral dosage forms of the compound of the present invention include sterile aqueous solutions, non-aqueous solutions, suspensions and emulsions for injection, freeze-dried agents, and suppositories. For injections, nonaqueous solutions and suspensions made from propylene glycol, polyethylene glycol, vegetable oils, such as olive oil, and esters such as ethyl oleate may be used. The basic materials of suppositories include Witepsol, macrogol, tween 61, cacao butter, laurin, glycerol, and gelatine.
The effective dosage of the compound or pharmaceutically acceptable salts thereof in accordance with the present invention depends on various factors, including the patient's weight, age, gender, state of health, diet, the time of administration, route of administration, etc. In general, the
compound in accordance with the present invention may be administered in a single dose or in multiple doses per day, each dose ranging from 0.001 ~ 10 mg/day for an adult patient weighing 70kg.
[Mode for Invention]
A better understanding of the present invention may be obtained through the following examples, which are set forth to illustrate, but are not to be construed as the limit of, the present invention.
EXAMPLE 1 : Preparation of 7α-tert-Butyloxycarbonylamino- 3β-acetoxy-5α-cholestane
Step 1: Production of 3β-acetoxy-5α-cholestan-7-one In ethyl acetate (10 ml) was dissolved 3β-acetoxy- cholest-5-en-7-one (400 mg, 0.90 mmol), followed by stirring at room temperature for 48 hours in a 1 atm hydrogen atmosphere in the presence of a catalytic amount of 5 % Pt/C. When the reaction was completed, as determined by thin layer chromatography (TLC) , the reaction mixture was filtered through a celite column to remove the inorganic materials. After the removal of the solvent from the filtrate in a vacuum, the concentrate was dissolved in dichloromethane without further filtration and reacted with CH3CO2Na (37 mg, 0.5 equivalents)
and PCC (116 mg, 1.5 equivalents) at room temperature for 2 hours. When TLC indicated the completion of the reaction, the reaction mixture was dissolved in diethyl ether (40 ml) with stirring, and was passed through a celite column to remove the inorganic materials therefrom. The solvent of the filtrate was removed in a vacuum to afford 387 mg of the subject compound
(0.87 πrmol, 97 %) .
TLC: Rf 0.50 (ethyl acetate-hexane 1:4); mp: 142 - 143 0C (dichloromethane-hexane) ; IR (KBr): 2967, 1728, 1469, 1369, 1265, 1027, 739 cm"1;
1H NMR: δ 2.02 (s, 3H, -OCOCH3), 1.10 (s, 3H, 19-CH3), 0.90 (d, J = 6.6 Hz, 3H, 21-CH3), 0.87 (d, J = 6.7 Hz, 3H, 26- CH3), 0.85 (d, J= 6.7 Hz, 3H, 27-CH3), 0.65 (s, 3H, 18-CH3);
13C NMR δ 211.7, 170.4, 72.7, 55.0, 49.9, 48.8, 46.5, 45.8, 42.5, 39.4, 38.7, 36.1, 35.9, 35.6, 33.8, 28.4, 28.0, 27.1, 25.0, 23.7, 22.8, 22.5, 21.7, 21.3, 18.7, 12.0, 11.7;
MS (relative intensity, %) (m/z) : 444 (M+, 89), 426 (M- H2O, 22), 290 (81), 236 (100).
Step 2 : Production of 7α-tert-butyloxycarbonylamino-3β- acetoxy-5α-cholestane
In a mixture of tetrahydrofuran-methanol (30 ml, 1:1, v/v) were dissolved 3β-acetoxy-5α-cholestane-7-one (500 mg, 1.12 mmol) and NH4OAC (2.59 g, 30 equivalents), and a small amount of bromocresol green was added to the solution, followed
by stirring at room temperature for 30 min. While the reaction mixture was stirred for 3 hours with the pH thereof adjusted using acetic acid, reduction was induced in the presence of NaBH3CN (209 mg, 3 equivalents) . When the reaction was completed, as determined using TLC, the solvent was removed in a vacuum, followed by extraction with ethyl acetate. The organic layer thus formed was washed with a saturated aqueous sodium hydrogen carbonate solution and an aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After the removal of the solvent in a vacuum, the concentrate was dissolved in methanol (20 ml) without further purification and reacted with BoC2O (489 mg, 2 equivalents) at room temperature for 1 hour with stirring. When TLC indicated the disappearance of the starting material, the solvent was removed in a vacuum and the concentrate was dissolved in ethyl acetate.
The organic layer thus formed was dried over anhydrous sodium sulfate, followed by the removal of the solvent in a vacuum.
The residue thus obtained was purified using a Chromatotron
(elution solvent: 2% ethyl acetate-hexane) to yield 524 mg of the object compound (0.96 mmol, 86%).
TLC: Rf 0.55 (ethy lacetate:hexane=l: 4) ; mp: 154-156 0C (dichloromethane-hexane) ;
IR (KBr): 3323, 2941, 1735, 1686, 1525, 1456, 1364, 1240, 1169, 1026 cm"1; 1H NMR δ 4.65 (m, 2H, 3α-H, NH), 3.66 (bs, IH, 7β-H) ,
1.95 (s, 3H, -COCH3), 1.39 (s, 9H, -COC (CH3) 3), 0.83 (d, J= 6.6 Hz, 3H, 21-CH3), 0.79 (d, J= 6.6 Hz, 3H, 26-CH3), 0.79 (d, J = 6.5 Hz, 3H, 27-CH3), 0.77 (s, 3H, 19-CH3), 0.58 (s, 3H, 18-CH3);
13C NMR δ 171.0, 155.7, 79.5, 74.0, 56.9, 54.1, 48.5, 43.3, 40.2, 40.0, 39.1, 38.0, 37.4, 36.8, 36.5, 36.3, 35.1, 34.2, 30.4, 29.1, 28.8, 28.7, 28.0, 24.6, 23.5, 23.2, 22.1, 21.8, 19.3, 12.6, 12.2;
MS (relative intensity, %) m/z 445 (M+, 16), 428 (19), 342 (11), 95 (31), 43(100); Elemental Analysis for C34H59NO4: C, 74.81; H, 10.89; N, 2.57 (calculated); C, 74.63; H, 11.64; N, 2.23 (found).
EXAMPLE 2: Preparation of 3α, 7α-bis (Boc-amino) -5α-cholestane 1
Steps 1 and 2 ; Preparation of 7α-Boc-amino-3β-acetoxy-5α- cholestane
The same procedures as in Steps 1 and 2 of Example 1 were conducted.
Steps 3 and 4 ; Preparation of 7α-Boc-amino-5α-cholestan-3-one
In 5 % potassium hydroxide/ethanol (50 ml) was dissolved the 7α-Boc-amino-3β-acetoxy-5α-cholestane (500 mg, 0.92 mmol) prepared in Step 2, and the solution was refluxed for 10 hours with stirring. The solvent was removed in a vacuum before extraction with ethyl acetate. The organic layer thus formed
was washed with a saturated aqueous NaCl solution, dried over anhydrous sodium sulfate, and concentrated in a vacuum. The concentrate was dissolved in anhydrous dichloromethane (5 ml) without purification and oxidized with PCC (297 mg, 1.5 equivalents) in the presence of CHaCO2Na (38 mg, 0.5 equivalents) at room temperature for 2 hours . When the reaction was completed as monitored by TLC, the reaction mixture was mixed with diethyl ether (100 ml) by stirring, and passed through a celite column to remove inorganic materials. After the removal of the solvent from the eluate, the silica gel purification (elution solvent: ethyl acetate :hexane=l : 4 ) of the residue yielded 425 mg of the object compound (0.85 mmol, 92 %) .
TLC: Rf 0.54 (ethyl acetate :hexane=l : 2) ; mp: 103-105 0C (dichloromethane-hexane) ;
IR (KBr) : 3997, 2952, 2383, 1708, 1456, 1355, 1173 cm"1; 1H NMR δ 4.73 (d, J = 8.4 Hz IH, NH), 3.77 (bs, IH, 7β- H), 1.45 (s, 9H, -COC (CH3) 3) , 1-03 (s, 3H, 19-CH3), 0.91 (d, J = 6.5 Hz, 3H, 21-CH3), 0.86 (d, J= 6.5 Hz, 6H, 26, 27-CH3), 0.69 (s, 3H, 18-CH3);
13C NMR δ 211.9, 155.7, 79.7, 56.6, 53.8, 51.8, 48.0, 47.7, 44.5, 43.0, 41.0, 39.8, 39.9, 38.8, 38.5, 37.6, 36.5, 36.2, 36.1, 35.0, 28.8, 28.5, 28.4, 24.3, 23.9, 23.2, 22.9, 21.7, 19.0, 12.3, 11.2; Elemental analysis for C32H55NO3 : C, 76. 60, H, 11 . 05, N,
2.79 (calculated) ; C, 75.16, H, 11.60, N, 2.74 (found).
Step 5 : Preparation of 3α, 7α-bis (Boc-amino) -5α- cholestane The 7α-Boc-amino-5α-cholestan-3-one (200 mg, 0.40 mmol) prepared in Step 4 and NH4OTf (2.01 g, 30 equivalents) were dissolved in anhydrous THF (30 ml) at room temperature for 30 min with stirring. To this solution was added NaBH (OEh) 3 (1 ml, 1 eq.), which could be prepared by reacting NaBH4 (1 eq.) and 2-ethylhexanoic acid (3 eq.) in dichloromethane, and the solution was stirred for 3 hours . When TLC indicated the completion of the reaction, the solvent was removed in a vacuum, followed by extraction with ethyl acetate. The organic solvent thus formed was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate before the removal of the solvent in a vacuum. The residue thus obtained was dissolved in methanol (20 ml) without purification, and reacted with BoC2O (131 mg, 1.5 eq.) at room temperature for 1 hour with stirring. When TLC indicated the disappearance of the starting material, the solvent was removed in a vacuum, followed by extraction with ethyl acetate. The extraction was dried over anhydrous sodium sulfate before the removal of the solvent in a vacuum. The residue thus obtained was was purified using a Chromatotron (elution solvent: 5 % ethyl acetate-hexane) to yield 180 mg of an α-isomer (0.30
mmol, 75%) and 24 mg of a β-isomer (0.04 mmol, 10%) .
TLC: Rf 0.5 (ethyl acetate:hexane=l : 4 ) ; mp: 97-99 0C (dichloromethane-hexane) ;
IR (KBr): 3460, 3366, 2934, 2868, 1718, 1699, 1496, 1365, 1245, 1168, 1084, 1022, 866, 780 cm"1;
1H NMR δ 4.73 (d, J = 9.0 Hz, IH, 3α-NH, 7α-NH) , 3.76
(bs, IH, 3β-H), 3.67 (bs, IH, 3β-H) , 1.40 (s, 9H, -COC (CH3) 3),
1.39 (s, 9H, -COC(CH3)3) 0.83 (d, J = 6.5 Hz, 3H, 21-CH3), 0.80
(d, J = 6.5 Hz, 3H, 26-CH3), 0.79 (d, J = 6.5 Hz, 3H, 27-CH3), 0.73 (s, 3H, 19-CH3), 0.58 (s, 3H, 18-CH3);
13C NMR δ 155.7, 147.1, 85.5, 79.5, 56.6, 52.0, 46.1, 43.0, 39.8, 37.7, 36.5, 36.2, 34.7, 33.3, 33.2, 30.1, 28.8, 28.4, 27.8, 26.6, 25.3, 23.9, 23.2, 22.9, 21.0, 19.0, 12.3, 11.1; MS (relative intensity, %) m/z 402 (M+, 40), 385 (M-OH, 25), 353 (20), 137 (46), 95 (59), 43(100);
Elemental analysis for C37H66N2O4: C, 73.71, H, 11.03, N, 4.65 (calculated) ; C, 72.80, H, 11.59, N, 4.70 (found).
EXAMPLE 3: Preparation of 7α-butylamino-3β-acetoxy-5α- cholestane
Step 1: Preparation of 3β-acetoxy-5α-cholestan-7-one The same procedure as in Step 1 of Example was conducted to prepare the object compound.
Step 2 : Preparation of 7α-butylamino-3β-acetoxy-5α- cholestane
To a mixture of THF-methanol (30 ml, 1:1, v/v) were dissolved the 3β-acetoxy-5α-cholestan-7-one (500 mg, 1.12 mmol) prepared in Step 1 and n-butyl amine (2.45 g, 33.6 mmol), and then a small amount of bromocresol green at room temperature for 30 min with stirring. Thereafter, the solution was added with NaBH3CN (222 mg, 3 eq.) and stirred over 8 hours with the pH thereof adjusted with acetic acid. When the reaction was completed as monitored by TLC, the solvent was removed in a vacuum, followed by extraction with ethyl acetate. The organic layer thus formed was washed with a saturated aqueous sodium hydrogen carbonate solution and an aqueous sodium chloride, dried over anhydrous sodium sulfate and concentrated in a vacuum. The residue thus obtained was dissolved in methanol
(10 ml) without purification and reacted with BoC2O (489 mg, 2 eq.) at room temperature for 1 hour with stirring. When TLC indicated the disappearance of the starting material, the solvent was removed in a vacuum, followed by extraction with ethyl acetate. The organic layer thus formed was dried over anhydrous sodium sulfate and concentrated in a vacuum. The residue thus obtained was purified using a Chromatotron (elution solvent: 2% methanol-dichloromethane) to produce 422 mg of the object compound as a liquid (0.84 mmol, 75%).
TLC: Rf 0.63 (Methanol :dichloromethane=l: 9) 1H NMR δ 4.69 (septet, J = 5.5 Hz, IH, 3α-H) , 2.62 (bs, IH, 7β-H), 2.35 (m, IH, 7α-NH) , 2.01 (s, 3H, -COC(CH3), 0.90 (d, J = 6.5 Hz, 3H, 21-CH3), 0.87 (d, J = 6.5 Hz, 3H, 26-CH3), 0.86 (d, J = 6.5 Hz, 3H, 27-CH3), 0.83 (s, 3H, 19-CH3), 0.65
(s, 3H, 18-CH3)
13C NMR δ 170.7, 73.9, 56.3, 54.7, 50.7, 50.1, 47.8, 46.0, 42.8, 39.7, 39.6, 39.2, 36.7, 36.3, 36.0, 35.9, 34.0, 32.6, 31.8, 28.3, 28.1, 27.6, 24.0, 23.8, 23.0, 22.7, 21.6, 21.3, 20.8, 18.8, 14.2, 11.9, 11.7.
EXAMPLE 4: Preparation of 7α-butylamino-3β-hydroxy-5α- cholestane
Steps 1 and 2: Preparation of 7α-butylamino-3β-acetoxy- 5α-cholestane
The same procedures as in Steps 1 and 2 of Example 1 were conducted to afford the object compound.
Step 3 : Preparation of 7α-butylamino-3β-hydroxy-5α- cholestane
The 7α-butylamino-3β-acetoxy-5α-cholestane (2.25 mmol) prepared in Step 2 and potassium hydroxide (250 mg) was dissolved in ethanol and the solution was refluxed over 1 hour with stirring. The solvent was removed before neutralization
with IN hydrochloric acid. The residue was washed with sodium hydrogen carbonate, followed by extraction with dichloromethane. Recrystallization in acetone-methanol mixture afforded the object compound. 1H NMR δ 5.07 (bs, IH, NHBoc) , 4.69 (m, IH, 3α-H) , 2.58 (bs, IH, 7β-H), 2.32 (m, IH, 7α-NH) , 0.89 (d, J = 6.6 Hz, 3H, 21-CH3), 0.83 (d, J = 6.5 Hz, 3H, 26-CH3), 0.82 (d, J= 6.5 Hz, 3H, 27-CH3), 0.79 (s, 3H, 19-CH3), 0.61 (s, 3H, 18-CH3)
13C NMR δ 71.2, 56.3, 54.9, 50.7, 47.8, 46.2, 42.9, 39.7, 39.6, 39.3, 38.2, 36.9, 36.8, 36.4, 36.0, 35.9, 31.6, 28.3, 28.2, 24.0, 23.8, 23.0, 22.7, 21.3, 20.8, 18.8, 14.2, 11.9, 11.7.
EXTiMPLE 5: Preparation of 7α-spermidyl-3β-acetoxy-5α-cholestane
Step 1 : Preparation of 3β-acetoxy-5α-cholestan-7-one The same procedure as in Step 1 of Example 1 was conducted to afford the object compound.
Step 2 : Preparation of 7α-spermidyl-3β-acetoxy-5α- cholestane
In a mixture of tetrahydrofuran-methanol (30 ml, 1:1, v/v) were dissolved 3β-acetoxy-5α-cholestane-7-one (500 mg, 1.12 mmol) and Boc-spermidine (1.93 g, 5 equ.), and a small amount of bromocresol green was added to the solution, followed
by stirring at room temperature for 30 min. Thereafter, the solution was added with NaBH3CN (222 mg, 3 eq. ) and stirred over 8 hours with the pH thereof adjusted with acetic acid. When the reaction was completed as determined using TLC, the solvent was removed in a vacuum, followed by extraction with ethyl acetate. The organic layer thus formed was washed with a saturated aqueous sodium hydrogen carbonate solution and an aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After the removal of the solvent in a vacuum, the concentrate was purified using a Chromatotron (elution solvent: 2% ethyl acetate-hexane) to yield 564 mg of the object compound (0.73 mmol, 65%).
TLC: Rf 0.60 (methanol : dichloromethane=l : 9) ;
1H NMR δ 4.69 (s, IH, 3α-H) ; 3.15-3.08 (bm, 6H, HN(BoC)CH2, H2CN(BoC)CH2), 2.57 (bs, IH, 7β-H) , 1.97 (s, 3H, - COC(CH3), 1.41 (s, 18H, t-Bu) 0.85 (d, J = 6.5 Hz, 3H, 21-CH3), 0.82 (d, J= 7.0 Hz, 3H, 26-CH3), 0.81 (d, J = 6.5 Hz, 3H, 27- CH3), 0.78 (s, 3H, 19-CH3), 0.60 (s, 3H, 18-CH3)
13C NMR δ 170.8, 156.1, 155.8, 79.3, 79.1, 73.8, 56.3, 54.8, 50.7, 47.2, 45.5, 42.9, 42.7, 40.5, 39.6, 39.1, 36.7, 36.3, 36.0, 35.9, 33.9, 29.8, 28.7, 28.6, 28.2, 28.1, 27.5, 26.1, 23.9, 23.8, 23.0, 22.7, 21.6, 21.2, 18.8, 11.9, 11.7.
EXAMPLE 6: Preparation of 7α-spermidyl-3β-hydroxy-5α-cholestane
Steps 1 and 2: Preparation of 7α-spermidyl-3β-acetoxy- 5α-cholestane
The same procedures as in Steps 1 and 2 of Example 5 were conducted to afford the object compound.
Step 3 : Preparation of 7α-spermidyl-3β-hydroxy-5α- cholestane
The 7α-spermidyl-3β-acetoxy-5α-cholestane (2.25 mmol) prepared in Step 2 and potassium hydroxide (250 mg) was dissolved in ethanol and the solution was fluxed over 1 hour with stirring. The solvent was removed before neutralization with IN hydrochloric acid. The residue was washed with sodium hydrogen carbonate, followed by extraction with dichloromethane. Recrystallization in acetone-methanol mixture afforded the object compound.
1H NMR δ 5,24 (bs, IH, NHBoc) , 4.85 (m, IH, 3α-H) , 3.55
(bs, IH, 7α-NH), 3.12 (m, IH, 7β-H) , 3.15-3.05 (bm, 6H,
HN(BoC)CH2, H2CN(BoC)CH2), 2.57, 0.82 (d, J = 6.6 Hz, 3H, 21-
CH3), 0.81 (d, J = 6.5 Hz, 3H, 26-CH3), 0.78 (d, J = 6.5 Hz, 3H, 27-CH3), 0.74 (s, 3H, 19-CH3), 0.58 (s, 3H, 18-CH3).
13C NMR δ 156.2, 155.8, 79.6, 79.4, 71.4, 56.2, 54.8,
50.7, 47.4, 45.5, 42.9, 40.4, 39.6, 39.2, 36.9, 36.3, 36.0,
35.8, 31.5, 28.6, 28.6, 28.1, 26.1, 23.9, 23.8, 23.0, 22.7, 21.3, 18.8, 11.9, 11.7.
EXAMPLE 7: Preparation of 3α, 7α-bis (Boc-amino) -5α-cholestane 2 Step a: Preparation of 3β-acetoxy-5α-cholestan-7-one In ethyl acetate (15 ml) was dissolved 3β-acetoxy- cholest-5-en-7-one (10 g, 2.26 mmol) , followed by stirring at room temperature over 10 hours in a 1 atm hydrogen atmosphere in the presence of 5 % Pt/C (30 mg) . The reaction mixture was filtered through a celite column to remove the catalyst. The filtrate was dried. The residue was purified using column chromatography ethyl acetate:hexane=l : 4 ) to afford the object compound as a white solid (1.0 g, 2.25 mmol, yield 99%). mp: 142 - 143 0C (dichloromethane-hexane) ; IR (KBr): 2967, 1728, 1469, 1369, 1265, 1027, 739 cm"1; 1H NMR δ 0.65 (s, 3H, 18-CH3), 0.85 (d, J = 6.5 Hz, 3H, 27-CH3), 0.87 (d, J = 6.5 Hz, 3H, 26-CH3), 0.90 (d, J= 6.5 Hz, 3H, 21-CH3), 1.10 (s, 3H, 19-CH3), 2.02 (s, 3H, -OCOCH3);
13C NMR δ 11.7, 12.0, 18.7, 21.3, 21.7, 22.5, 22.8, 23.7, 25.0, 27.1, 28.0, 28.4, 33.8, 35.6, 35.9, 36.1, 38.7, 39.4, 42.5, 45.8, 46.5, 48.8, 49.9, 55.0, 72.7, 170.4, 211.7.
Step b: Preparation of 5α-cholestan-3, 7-dione
The 3β-acetoxy-5α-cholestan-7-one (1.0 g, 2.25 mmol) prepared in Step a and KOH (250 mg) were dissolved in ethanol and the solution was refluxed over 1 hour with stirring. The solvent was removed before neutralization with IN hydrochloric acid. The residue was washed with sodium hydrogen carbonate,
followed by extraction with dichloromethane . The extraction was dissolved in anhydrous dichloromethane (5 ml) and oxidized with PCC (297 mg, 1.5 equivalents) for 6 hours. After the reaction was terminated with diethyl ether (50 ml) , the reaction mixture was purified through a celite column. Column chromatography ethyl acetate:hexane=l: 4) with the residue afforded the object compound as a white solid (780 mg, 1.95 mmol, yield 82%) . mp: 178 - 179 0C; IR (KBr) 2949, 1713, 1467, 1437, 1265, 772, 738 cm"1;
1H NMR δ 0.68 (s, 3H, 18-CH3), 0.86 (d, J = 6.5 Hz, 3H, 27-CH3), 0.87 (d, J = 6.5 Hz, 3H, 26-CH3), 0.91 (d, J= 6.5 Hz, 3H, 21-CH3), 1.08 (s, 3H, 19-CH3), 2.40 (m, 3H, 2, 4, 6-CH);
13C NMR δ 11.0, 12.0, 18.7, 22.2, 22.5, 22.8, 23.7, 24.9, 28.0, 28.3, 35.6, 36.0, 36.1, 36.9, 37.5, 38.6, 39.4, 42.4, 44.1, 45.7, 47.8, 48.7, 49.7, 54.1, 54.9, 209.7, 210,5.
Step c: Preparation of 3α-Boc-amino-5α-Cholest-7-one
The 5α-cholestan-3,7-dione (200 mg, 0.50 mmol) prepared in Step b was dissolved, together with NaBH(OEh)3 (4 ml, 2.0 eq.) and NH4OTf (501 mg, 3.00 eq. ) , in anhydrous THF (30 ml) at room temperature for 1 hour with stirring. After the removal of the solvent, the residue was extracted with ethyl acetate, washed, dried and concentrated. The residue was dissolved in methanol (20 ml) without further purification, and reacted with
Boc-anhydride (169 mg, 1.5 eq.) for 3 hours with stirring. To this reaction mixture was added an aqueous 2N NaOH solution.
Then, the solvent was removed, followed by extraction with ethyl acetate, washing, drying and concentration in that order. The residue thus obtained was purified using a Chromatotron
(elution solvent: 5% ethyl acetate-hexane) to afford the object compound (205 mg, 0.41 mmol, yield 82%).
1H NMR δ 0.59 (s, 3H, 18-CH3), 0.80 (d, J = 6.5 Hz, 3H,
27-CH3), 0.84 (d, J= 6.5 Hz, 3H, 26-CH3), 0.86 (d, J = 6.5 Hz, 3H, 21-CH3), 1.00 (s, 3H, 19-CH3), 1.40 (s, 9H, -COC (CH3) 3),
3.83 (s, IH, 3β-H) , 4.88 (s, IH, 3α-NH) ;
13C NMR δ 11.0, 12.2, 14.2, 18.9, 21.3, 22.6, 22.9, 23.8,
25.0, 26.2, 28.1, 28.5, 29.2, 30.2, 32.9, 33.5, 35.7, 36.2,
36.5, 38.8, 39.6, 42.6, 43.1, 46.0, 49.1, 50.3, 55.1, 55.9, 65.3, 79.2, 155.3, 212.1.
Step d: Preparation of 3α, 7α-bis (Boc-) amino-5α- cholestane
The 3α-Boc-amino-5α-cholest-7-one (200 mg, 0.40 mmol) prepared in Step c was dissolved, together with NaBH3CN (79 mg,
1.20 mmol) and ammonium acetate (925 mg, 12.00 mmol), in a mixture of THF-methanol (1:1) at room temperature for 2 hours with stirring. Simultaneously, the pH of the solution was adjusted to 6 with acetic acid. When TLC indicated the disappearance of the starting materials, the solvent was
removed, followed by extraction with dichloromethane . The organic layer thus formed was washed, dried and concentrated. The residue thus obtained was dissolved in methanol (10 ml) and treated with BoC2O (131 mg, 0.60 mrnol) . One hour later, an aqueous 2N NaOH solution was dropwise added to the reaction mixture which was then stirred over 5 hours. After the removal of the solvent, the residue was washed with sodium hydrogen carbonate and extracted with ethyl acetate. The residue was purified using a column chromatography (ethyl acetate:hexane=l : 9) to afford the object compound (175 mg, yield 71%) .
TLC Rf 0.33 (ethyl acetate-hexane 1:9, 4 times dropwise added) ; mp: 97-99 0C (CH2Cl2-hexane) ; IR (KBr) 780, 866, 1022, 1084, 1168, 1245, 1365, 1496,
1699, 1718, 2868, 2934, 3366, 3460 cm"1;
1H NMR δ 0.58 (s, 3H, 18-CH3), 0.73 (s, 3H, 19-CH3), 0.79
(d, J = 6.5 Hz, 3H, 27-CH3), 0.80 (d, J = 6.5 Hz, 3H, 26-CH3),
0.83 (d, J= 6.5 Hz, 3H, 21-CH3), 1.39 (s, 9H, -COC (CH3) 3), 1.40 (s, 9H, -COC(CH3)3), 3.67 (bs,lH, 7β-H) , 3.76 (bs, IH, 3β-H) ,
4.73 (d, J= 9.0 Hz, 2H, 3α-NH, 7α-NH) ;
13C NMR δ 11.1, 12.3, 19.0, 21.0, 22.9, 23.2, 23.9, 25.3,
26.6, 27.8, 28.4, 28.8, 30.1, 33.2, 33.3, 34.7, 36.2, 36.5,
37 . 7 , 39. 8 , 43. 0 , 46. 1 , 52 . 0, 56. 6, 79. 5, 85. 5, 147 . 1 , 155. 7 ; Elemental analysis for C37H66N2O4 : C, 73. 71, H, 11 . 03, N,
4.65 (calculated) ; C, 73.52, H, 11.24, N, 4.77 (found).
EXAMPLE 8 : Preparation of 3α, 7α-bisamino-5α-cholestane chloride
In a mixture of methanol (1.0 ml) and anhydrous dichloromethane (10 ml) was dissolved the 3α, 7α-bis (Boc) amino-
5α-cholestane (200 mg, 0.33 rnmol) prepared in Example 7 and then added thionyl chloride (0.24 ml, 3.3 mmol) . The resulting mixture was overnight stirred. After the removal of the solvent, the residue thus obtained was recrystallized in a mixture of acetone-methanol . Purification and subsequent oven-drying afforded 3α, 7α-bisamino-5α-cholestane chloride as a white solid.
Elemental analysis for C27H52Cl2N2 : C, 68 . 18 ; H, 11. 02 ; N, 5. 89 (calculated) , C, 67 .81; H, 11. 54 ; N, 5. 94 ( found) .
EXAMPLE 9: Preparation of 3α, 7α-bisamino-5α-cholestane
To a solution of the 3α, 7α-bisamino-5α-cholestane chloride (200 mg, 0.42 mmol) prepared in Example 8 in methanol (2 ml) was added a saturated aqueous sodium hydrogen carbonate (10 ml), followed by stirring at room temperature over 5 hours. The reaction mixture was extracted with ethyl acetate, dried and concentrated. The recrystallization of the residue afforded 3α, 7α-bisamino-5α-cholestane.
EXPERIMENTAL EXAMPLE 1: Effect of Reducing Agent and Amine Compound on Reductive Amination (I) 1
The following experiments were performed in order to examine the effect of reducing agents on the production yield and the formation of the hydroxyl compound in the reductive amination (I) of Step 2 in accordance with the present invention.
The 7-keto compound of Chemical Formula 3, prepared in Step 1, was subjected to reductive amination (I) , in which 30 equivalents of NH4OTf was used as an amine compound in the presence of 2 equivalents of a reducing agent selected from among NaBH(OAc)3, NaBH3CN, NaBH2(OAc)2, NaBH3(OAc) and picoline borane under the conditions listed in Table 1, below.
TABLE 1
When NaBH2(OAc)2, NaBHs(OAc) or picoline borane was used as a reducing agent, as seen in Table 1, reductive amination (I) was conducted at a very low yield or did not occur.
However, the production yields amounted to as high as 86% and 78%, respectively, in the presence of NaBH(OAc)3 and NaBH3CN. Thus, it can be seen that NaBH(OAc)3 and NaBH3CN are useful as reducing agents for reductive amination (I) according to the present invention.
However, the reductive amination (I), although actively conducted in the presence of NaBH(OAc)3 and NaBH3CN, was also found to yield hydroxyl compounds as side products at ratios of NH2/OH 10/1 and 2.5/1, respectively. The concomitant production of hydroxyl compounds in the reductive amination (I) of Step 2 is believed to be attributed to the fact that the reduction of the keto group into alcohol takes place preferentially over the formation of an imine and subsequent conversion to an amino group.
Accordingly, new amine compounds were employed, as illustrated in Experimental Example 2, in order to search for the condition under which no hydroxyl compounds are formed.
EXPERIMENTAL EXAMPLE 2: Effect of Reducing Agent and Amine Compound on Reductive Amination (I) 2
The 7-keto compound of Chemical Formula 3, prepared in Step 1, was subjected to reductive amination (I), in which it
was reacted with 30 equivalents of each of CH3CO2NH4, HCO2NH4, CF3CO2NH4, NH4OTf and NH4Cl in the presence of 2 equivalents of NaBH3CN as a reducing agent in a mixed solvent of THF/MeOH(l:l) .
TABLE 2
Results of reductive amination with various amine compounds in the presence of NaBH3CN are summarized in Table 2. As seen in Table 2, amino compounds were produced at yields of 89% and 85% within 5 hours without the concomitant production of hydroxy compounds when CH3CO2NH4 and HCO2NH4 were used, respectively. As for CF3CO2NH4, it allowed the production of exclusive amino compounds at a yield of 48%, although the reaction time period was elongated. The use of NH4OTf increased the production yield to as high as 78%, but with hydroxy compounds amounting to about 30%. Reductive amination with NH4Cl did not take place. Like NH4OTf, NaBH(OAc)3, acting as a reducing agent, allowed the production of hydroxyl
compounds in a manner similar to that seen in Tables 1 and 2.
From the data obtained in the examples, it can be inferred that reductive amination with NaBH(OAc)3 occurs less readily at position 7 due to greater steric hindrance than at position 3 because NaBH(OAc)3 is larger in molecular size than is NaBH3CN.
EXPERIMENTAL EXAMPLE 3: Effect of Reducing Agent and Amine Compound on Reductive Amination ( II )
It was found that when 3-keto aminosteroid compounds, which exhibit less steric hindrance than do 7-keto aminosteroid compounds, were subjected to the reductive amination (II) in the presence of NaBH3CN, β-oriented aminosteroid was produced in a greater proportion than α-oriented aminosteroid because the reducing agent could attack 3-keto aminosteroid in both the axial direction and the horizontal direction due to the small molecular size thereof. Thus, the following experiment was conducted in order to search for a reducing agent that would allow the synthesis of a greater proportion of α-oriented aminosteroid.
The reductive amination ( II ) with NH4OTf or NH4OAc was conducted in a mixed solvent of THF:MeOH (1:1) in the presence of various reducing agents under the conditions of Table 3, below. The reducing agents were obtained by reacting NaBH4
with organic acids different in molecular size in dichloromethane to synthesize triacyloxyborohydride, as illustrated in Reaction Scheme 5, below. Comparison was made between the results from the use of these reducing agents and the reducing agents for the reductive amination (I) of Step 2, NaBH(OAc)3 and NaBH3CN.
[Reaction Scheme 5]
CH2CI2 NaBH4 + 3RCOOH ► NaBH(OCOR)3 + 3H2
In this reaction scheme, RCOOH is isovaleric acid ( Iv) and 2-ethylhexanoic acid (Eh) when R is -CH2CH (CH3) 2 and - CH2CH2CH2CH2CH (CH2CH3) 2, respectively .
TABLE 3
As seen in Table 3, NaBH(OEh)3, synthesized from 2-
ethylhexanoic acid, allowed a higher yield (85%) and a higher α/β ratio (9:1) than did any other reducing agent. In the presence of NaBH3CN as a reducing agent, the aminosteroid compound was produced at the lowest yield, 55%, with an α/β ratio of 4:6. Thus, the data of Table 3 show that a greater proportion of α-oriented amino compounds is produced in the presence of a reducing agent having a larger molecular size.
Although not given in the table, the product was produced at a high yield when using 30 equivalents of NH4OTf. Upon a reaction with 20 equivalents of NH4OTf, not only was the production yield decreased due to the side production of hydroxyl compounds, the reaction time period was also increased.
EXPERIMENTAL EXAMPLE 4: Antibiotic Effect of 7α-Aminosteroid Derivatives and Pharmaceutically Acceptable Salts thereof
7α-Aminosteroid derivatives or pharmaceutically acceptable salts thereof in accordance with the present invention were assayed for antibiotic activity as follows.
The compounds prepared in Examples 4, 6 and 8 were applied to 8 bacteria species. The bacteria tested in this example were obtained from the ATCC (Rockville, MD, U.S.A.) and can be divided into Gram-positive species including Streptococcus pyogenes 308A (S. pyogenes 308A), Streptococcus
pyogenes 11A (S. pyogenes 11A) and Staphylococcus aureus 503 (S. aureus 503) , and Gram-negative species including E. CoIi DC2, Pseudomonas aeruginosa 9027 (P. aeruginosa 9027), Pseudomonas aeruginosa 1771M (P. aeruginosa 1771M) , Salmonella typhimurium (S. typhimurium) and E. cloacae 1321E. MICs (Minimum Inhibitory Concentrations) were determined by the twofold agar dilution method with Muller-Hinton agar. In detail, the strains were cultured at 370C for 20 hours and diluted to 3*106 CFU/ml, and inocula of about 104 cfu per spot were applied with Microplanter onto agar plates containing twofold serial dilutions of each of the compounds prepared in Examples 4, 6 and 8, followed by incubation at 370C for 20 hours . The MICs were defined as the minimum drug concentrations which completely inhibited the growth of bacteria, as observed with the naked eye.
TABLE 4
E. cloacae 132IE 100 .00 12 .50 3 .12
As understood from the data of Table 4, the 7α- aminosteroid derivatives or pharmaceutically acceptable salts thereof in accordance with the present invention have MICs of 0.78 - 100 μg/mg, thus showing inhibitory activity against various bacteria. Particularly, with regards to S. pyogenes 308A and S. aureus 503, the compounds of the present invention have an MIC of 3.12 μg/ml or less, thus showing potent antibiotic activity.
Therefore, the 7α-aminosteroid derivatives or pharmaceutically acceptable salts thereof can be used as antibiotics against bacteria and fungi.
PREPARATION EXAMPLE 1: Preparation of Pharmaceutical Formulations
1-1. Preparation of Powder
7α-Aminosteroid Derivative of Chemical Formula 1 2g Lactose Ig
The above ingredients were mixed and loaded into an airtight sac to produce powder.
1-2. Preparation of Tablet
7α-Aminosteroid Derivative of Chemical Formula 1 lOOmg Corn Starch lOOmg
Lactose lOOmg
Mg Stearate 2mg These ingredients were mixed and prepared into tablets using a typical tabletting method.
1-3. Preparation of Capsule
7α-Aminosteroid Derivative of Chemical Formula 1 lOOmg Corn Starch lOOmg
Lactose lOOmg
Mg Stearate 2mg
These ingredients were mixed and loaded into gelatin capsules according to a typical method to produce capsules .
1-4. Preparation of Injection
7α-Aminosteroid Derivative of Chemical Formula 1 10 μg/ml
Diluted HCl BP added to form pH 3.5 NaCl BP injection up to 1 ml
The compound of Chemical Formula 1 was dissolved in a suitable volume of a NaCl BP injection, and the solution was adjusted to a pH of 3.5 with diluted HCl BP and to a desired volume with NaCl BP injection, followed by sufficient mixing. The solution was loaded into transparent 5 ml type I ampules
which were hermetically sealed by melting, followed by autoclaving at 1200C for 5 min to prepare injections.
Claims
[CLAIMS]
[Claim 1]
A 7α-aminosteroid derivative, represented by the following Chemical Formula 1, or a pharmaceutically acceptable salt thereof:
[Chemical Formula 1]
(wherein,
R1 is an amino group, a tert-butyloxycarbonyl (Boc) -amino group, a Ci~C5 alkylamino group, or a polyamino group,
R2 is an amino group, a Boc-amino group, a Ci~C5 alkylamino group, a hydroxyl group, a Ci~Cs alkylcarbonyloxy group or a polyamino group, said polyamino group being
wherein n, m and 1 are independently an integer of 1 ~ 5 and R and R4 are independently H or Boc) .
[Claim 2]
The 7α-aminosteroid derivative or the pharmaceutically acceptable salt according to claim 1, wherein R1 is an amino group, a Boc-amino group, a butylamino group,
R2 is an amino group, a Boc-amino group, an acetoxy
[Claim 3]
The 7α-aminosteroid derivative or the pharmaceutically acceptable salt according to claim 1, wherein the 7α- aminosteroid derivative is selected from a group consisting of:
1) 7α-amino-3β-acetoxy-5α-cholestane;
2 ) 7α-tert-butyloxycarbonylamino-3β-acetoxy-5α- cholestane;
3) 7α-butylamino-3β-acetoxy-5α-cholestane;
4) 7α-butylamino-3β-hydroxy-5α-cholestane;
5) 7α-spermidyl-3β-acetoxy-5α-cholestane;
6) 7α-spermidyl-3β-hydroxy-5α-cholestane;
7) 3α, 7α-diamino-5α-cholestane; 8) 3α, 7α-bis (tert-butyloxycarbonylamino) -5α-cholestane;
9) 3α, 7α-bis (spermidyl) -5α-cholestane; and
10) 3α, 7α-bis (sperminyl) -δα-cholestane.
[Claim 4]
A method for preparing a 7α-aminosteroid derivative, as illustrated in Reaction Scheme 1, comprising: reducing a double bond of a compound of Chemical Formula 2, as a starting material, to afford a 7-keto compound of Chemical Formula 3 (step 1) ; and aminating the keto-compound of Chemical Formula 3 through reaction with an amine in the presence of a reducing agent (I) to produce a compound of Chemical Formula 1 (step 2) . [Reaction Scheme 1]
(wherein R1 is as defined in Chemical Formula 1, and the compound of Chemical Formula Ia is included within the range of the derivatives of Chemical Formula 1)
[Claim 5]
A method for preparing a 7α-aminosteroid derivative, as illustrated in Reaction Scheme 2, comprising: reducing a double bond of a compound of Chemical Formula 2, as a starting material, to afford a 7-keto compound of Chemical Formula 3 (step 1) ; aminating the keto-compound of Chemical Formula 3 through reaction with an amine in the presence of a reducing agent (I) to produce a compound of Chemical Formula Ia (step 2 ) ; and hydrolyzing the compound of Chemical Formula Ia of Step 2 into a compound of Chemical Formula Ib (step 3) .
[Reaction Formula 2 ]
(wherein R1 is as defined in Chemical Formula 1 and the compounds of Chemical Formulas Ia and Ib are included within the range of the derivative of Chemical Formula 1)
[Claim β]
A method for preparing a 7α-aminosteroid derivative, as illustrated in Reaction Scheme 3, comprising: reducing a double bond of a compound of Chemical Formula 2, as a starting material, to afford a 7-keto compound of Chemical Formula 3 (step 1) ; aminating the keto-compound of Chemical Formula 3 through reaction with an amine in the presence of a reducing agent (I) to produce a compound of Chemical Formula Ia (step 2); hydrolyzing the compound of Chemical Formula Ia of Step 2 into a compound of Chemical Formula Ib (step 3) ; oxidizing the compound of Chemical Formula Ib of Step 3 into a 3-keto compound of Chemical Formula 4 (step 4); and aminating the 3-keto compound of Step 4 through reaction with 'an amine in the presence of a reducing agent (II) to produce a 3α, 7α-diaminosteroid compound (1) (step 5).
[Reaction Scheme 3]
(wherein R1 and R2 are each as defined in Chemical Formula 1 and the compounds of Chemical Formulas Ia and Ib are included within the range of the derivative of Chemical Formula D
[Claim 7]
A method for preparing a 7α-aminosteroid derivative, as illustrated in Reaction Scheme 4, comprising: reducing a double bond of a compound of Chemical Formula 2, as a starting material, to afford a 7-keto compound of Chemical Formula 3 (step a) ; reducing the acetoxy group of the compound of Chemical Formula 3, prepared in Step a, to afford a 3, 7-diketo compound of Chemical Formula 5 (step b) ; aminating the keto compound of Chemical Formula 5, prepared in Step b, with an amine in the presence of a reducing agent (HI) to afford a compound of Chemical Formula 6 (step c) / and
arainating the compound of Chemical Formula 6, prepared in Step c, with an amine in the presence of a reducing agent (IV) to produce 7α-aminosteroid (step d) .
[Reaction Scheme 4]
5
(wherein R1 and R2 are as defined in Chemical Formula 1 )
[Claim 8]
The method according to claim 4 or 8, wherein the reducing agent of Step 2 is sodium triacetoxyborohydride or sodium cyanoborohydride .
[Claim 9]
The method according to claim 8, wherein the reducing agent is sodium cyanoborohydride.
[Claim lO]
The method according to claim 6, wherein the reducing agent of Step 5 is selected from a group consisting of sodium triacetoxyborohydride, sodium cyanoborohydride, sodium triethylhexyloxyborohydride and sodium tris (isovaleroxy)borohydride.
[Claim 11]
The method according to claim 10, wherein the reducing agent is selected from a group consisting of sodium triacetoxyborohydride, sodium triethylhexyloxyborohydride and sodium tris (isovaleroxy)borohydride.
[Claim 12]
The method according to claim 6, wherein the amine of Step 2 or 5 is selected from a group consisting of an ammonia precursor, a Ci~C5 alkylamine and a polyamine.
[Claim 13]
The method according to claim 12, wherein the ammonia precursor is selected from a group consisting of ammonium acetate, ammonium formate, ammonium trifluoroacetate and ammonium trifluoromethanesulfonate, the alkyl amine is ji-butyl amine, and the polyamine is tert-butyloxycarbonyl spermidine or tert-butyloxycarbonyl spermine .
[Claim 14]
The method according to claim 6, wherein Step 2 or 5 is conducted at a pH of 5.5 ~ 6.5.
[Claim 15] An anticancer composition, comprising the Ia- aminosteroid derivative of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient .
[Claim 16]
The anticancer composition according to claim 15, wherein the composition is useful in the treatment of lung cancer or ovarian cancer.
[Claim 17]
An antibiotic composition, comprising the 7α- aminosteroid derivative of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
[Claim 18]
The antibiotic composition according to claim 17, wherein the composition has inhibitory activity against bacteria or fungi .
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KR101013179B1 (en) * | 2008-03-17 | 2011-02-10 | 경북대학교 산학협력단 | 7alpha-aminobisnorsteroid derivative or pharmaceutically acceptable salt thereof, preparation method thereof and antibiotic composition containing the same as an active ingredient |
KR101427467B1 (en) * | 2012-07-24 | 2014-08-08 | 경북대학교 산학협력단 | Aminosteroid derivatives or pharmaceutically acceptable salts thereof and composition for antibiotics containing the same |
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