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WO2008038965A1 - Dérivés de 7alpha-aminostéroïde ou leurs sels pharmaceutiquement acceptables, leurs procédés de préparation et composition anticancéreuse ou antibiotique les contenant agissant comme ingrédient actif - Google Patents

Dérivés de 7alpha-aminostéroïde ou leurs sels pharmaceutiquement acceptables, leurs procédés de préparation et composition anticancéreuse ou antibiotique les contenant agissant comme ingrédient actif Download PDF

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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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PCT/KR2007/004649
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English (en)
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Hong-Seok Kim
Nam Ju Cho
Sharaf Nawaz Khan
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Kyungpook National University Industry-Academic Cooperation Foundation
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    • 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

L'invention concerne des dérivés de 7α-aminostéroïde ou leurs sels pharmaceutiquement acceptables, leurs procédés de préparation et des compositions anticancéreuses ou antibiotiques les comprenant agissant comme ingrédient actif. L'amination réductrice avec un amine en présence d'un agent réducteur permet d'introduire un groupe amino à une position α d'un squelette stéroïde au cours d'étapes uniques et, donc, à haut rendement. Grâce à l'agencement à la position α, les groupes amino des dérivés de Ia- aminostéroïde présentent des activités physiologiques intenses. Capables de bloquer l'activation induite par le facteur de croissance endothélial vasculaire de la kinase MAP, les dérivés de 7α-aminostéroïde ou leurs sels pharmaceutiquement acceptables peuvent s'appliquer à une composition utilisée dans le traitement du cancer, tel que le cancer du poumon et le cancer des ovaires, et à une composition antibiotique pour lutter contre les bactéries Gram positif et Gram négatif.
PCT/KR2007/004649 2006-09-26 2007-09-21 Dérivés de 7alpha-aminostéroïde ou leurs sels pharmaceutiquement acceptables, leurs procédés de préparation et composition anticancéreuse ou antibiotique les contenant agissant comme ingrédient actif WO2008038965A1 (fr)

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JP2014530191A (ja) * 2011-09-13 2014-11-17 ブリガム・ヤング・ユニバーシティＢｒｉｇｈａｍ Ｙｏｕｎｇ Ｕｎｉｖｅｒｓｉｔｙ 骨疾患および破断骨治療のための組成物
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