• 专利附录
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    • 专利摘要:
    Certain 2-deoxystreptamine aminoglycoside antibiotics, substituted on the 1-amino group by an alkyl group bearing one or more hydroxy groups, are useful antibacterial agents. The 2-deoxystreptamine aminoglycoside compounds which are substituted in this manner include the kanamycins, the gentamicins, tobramycin, ribostamycin, the neomycins, and 6'-N-alkyl derivatives thereof.
    公开号:SU865128A3
    申请号:SU772494017
    申请日:1977-06-15
    公开日:1981-09-15
    发明作者:Ричардсон Кеннет；Маргарет Пльюс Роуна；Роберт Райт Джеймс
    申请人:Пфайзер Корпорейшн (Фирма)；
    IPC主号:
    专利说明:

    The invention relates to a process for the preparation of novel 2-deoxyrtreptamine aminoglycosides with valuable pharmacological properties. The purpose of the invention is to obtain new useful compounds, which expand the arsenal of means of action on a living organism, is obtained by synthesizing the latter, based on the known reaction of reductive alkylation of tlj. The proposed antibacterial agents are a series of 2-deoxystreptamine-aminoglycosides in which the amino group in position 1 is replaced by an alkyl group. Such compounds are effective in combating various gram-positive and gram-negative bacterial infections and are less toxic than the original aminoglycoside. A method is proposed for the preparation of 2 deoxistreptaminoglycosides of the general formula II HHg-HHB Cr O-L-O alkyl, substituted with 2 to 5 hydroxyl groups; - C-Su-alkyl substituted with 1-5 oxyl groups - C-Su-alkyl, non-substitutable or schenny 1-5 hydroxyl groups, amino or hydroxyl rpyntia; hydrogen or hydroxyl group under the condition that R is an amino group and R is hydrogen, C; is Su-gshkil, at least one of the carbon
    Dov which has a hydroxyl i ynny; - hydrogen or C-alkane, or their salts, which consists in the fact that the compound of formula C
    in-ijr-r
    NgVN-B
    -0 / O H 0 - () Ng
    ) BUT
    .
    HOHjC; -4 -OR x
    BUT
    Wh-b
    R
    de r
    have the indicated meanings
    fL
    - hydroxy or MHR group; - selected from the group including
    formyl and acetyl R is selected from the group including
    hydrogen, formyl and acetyl, are reacted with an alkylating agent of the formula
    ,ten
    O CH-R or O
    ,eight
    about 10
    where r
    in the presence of sodium cyanoborohydride in a reaction-inert solvent at a temperature of from room temperature to 90 ° C, followed by removal of the formyl or acetyl groups by hydrolysis at a temperature of from room temperature to 90 ° C or by reaction with hydrazine at a temperature of about.
    The compounds of Formulas 1 and I can occur in different conformations. Typically, each ring is in the shape of a chair, and each of the substituent groups is located equatorially with respect to the ring.
    The glycosidic linkage between the hexopyranosyl ring and the 2-deoxistreptamine ring is usually the oL link in relation to the latter.
    The additional Rxy-substituted alkyl substituent on the amino group at position 1 has one or more optically active centers, and each may be in the R or S configuration or may be present in a mixture of optical isomers.
    When evaluating compounds as antibacterial agents in vitro, the minimum inhibitory concentration (MIK) of the test compound is determined in a suitable environment in which the growth of specific microorganisms can be observed. Agar medium plates, each of which contains the HcnHTyeNroe compound at a specific concentration, are inoculated with the standard cell number of the test microorganism, and then each plate is incubated for 24 hours at. The plates are then examined for the presence or absence of bacterial growth, and the corresponding M.I.K. value is calculated. Microorganisms investigated in this test include Escherichia coli, Klebsiella pneumoniae, Proteus niirabilis, Pseudomonas aerupinosa, Staphu ococcus aureu and Streptococcus faecalis strains.
    The in vivo assessment is carried out by subcutaneous administration of the compounds to mice infected with Escherichia coli. -Each compound is administered in different doses to a group of mice, and its activity is determined as the level at which it gives 50% protection against lethalcoe outcome from Escherichia col i in 72 hours.
    The proposed antibacterial compounds can be administered to a human separately, but they are usually taken in a mixture with a pharmaceutical carrier selected in accordance with q, the usual method of administration and standard pharmaceutical practice. For example, they can be administered orally in the form of tablets containing such inert excipients as starch or lactose, separately in capsules, in admixture with an excipient, in the form of elixirs or suspensions containing perfuming or coloring agents. They can be administered parenterally, for example, intravenously, intramuscularly or subcutaneously. For parenteral administration, it is better to use them in the form of sterile aqueous solutions, which may contain other solutes, for example, a sufficient amount of salt or glucose to form an isotonic solution.
    When administering the drug to patients, it should be borne in mind that the daily dose of the antibacterial compound will be comparable to the dose of the aminoglycoside antibacterial agents already in use, i.e. 0.1–50 mg / kg (in divided doses) when administered parenterally or 10,100 mg / kg (in divided doses) when administered orally.
    Chromatography in a thin layer is carried out on silica plates using the indicated solvent system. The spots are developed after drying the plates by spraying a 5% solution of tert-butyl hypochlorite in cyclohexane, drying the plates for 10 minutes in a ventilated oven, cooling, and spraying the solution of starch-potassium iodide.
    Example 1. 1-N (S) -2,3 Dioxypropyl kanamycin A.
    3.3.6 - Three-GT e-formyl-kanamycin A (100 mg; 0.18 mmol), D -glyceraldehyde (31.6 mg; 0.36 mmol) and sodium cyanoborohydride (33 mg; 0.52 mmol ) dissolved in aqueous methanol (10 ml of methanol; 2 ml of water) and set (pH 6.0 is compressed with 5N hydrochloric acid. The solution is held at room temperature for 40. Then the solvent is evaporated under reduced pressure and the residue the samples are treated with 1N sodium hydroxide (), then left at inepaxype for 20 hours at room temperature. After concentration under reduced pressure, the residue is chromatographed on an ion exchange column Amberlite C6-5 resin (NHf form), using an ammonium hydroxide gradient of ammonium with an increasing concentration of O 0, 1N, as a solvent, resulting in 1 NC (S) -2, 3-dioxypropyl D kanami Cy (66 mg) 67%), Rf 0.27 in 1 M in a nominal solution of sodium chloride (Kanmycin A gives Rf value 0.21), Rf 0.70 in methanol; 0.88 with hydroxy ammonium 1: 2 (kanamycin A gives Rf 0.70). Found: C 40.1; H 7.0; N 8.3 941 N4. 2HiC03 calculated: C 40.5; H 6.8; N 8.2. The sample is converted into a volatile tetra-N-acetypone-0-trimethylsilyl derivative by treatment with acetic anhydride in methanol at a carbonate temperature for 24 hours, and then reacted with a mixture of hexamethyldisilane and tr methylchlorosilane 2: 1 at room temperature. for 24 hours. Found: 1285. without one group, CjHgOSi gives m / e 1285 .. Example 2.1-M-t (S) (R) 2, 3,4-Trioxybutyl Zcanamycin A. Solution 3.3, three-N - formylkanamycin A (100 mg; 0.18 Vlolla), D-erythrosis (107 mg; 0.90 mmol) and sodium cyanoborohydride (66 mg; 1.02 mmol) in a mixture of methanol (10 ml) and s (2 ml) at pH 6.0 was heated at for 50 h {solution was concentrated under reduced pressure. The residue is dissolved in 10% hydrazine hydrate (12 mp), the pH of the solution is adjusted to 6.0 with glacial acetic acid and then the solution is boiled under reflux for 6 hours. The solvent is evaporated under reduced pressure, and the resulting is evaporated. ocTiaTOK chromium is screened on Amberlite CG5O column as in Example 1. At the same time, the main fraction containing the product is chromatographed on a Sephadex CM25 column (NH form), washing it with an ammonium hydroxide gradient, resulting in 1 - N G (5) (R) 2 , 3,4-trioxybutyl kanamycin. A (37 mg; 36%), R 0.29 in methanol; 0.88 ammonium hydroxide 2: 2 (kanamycin A, R f 0, 32). found: C 41.6; H 6.6; N 7.9 C4aH44M4-0 | 42NaCO. Calculated: C 40.5; H 6.8; N 7.9. -example 3. 1 - N - (SySj (R) 2, 3, 4,5-Tetro-axipentyl-J-kangili. cin A.- Prepared analogously to example 2, however, 0-rybose is used as starting compound. Rf 0.68 in methanol; 0.88 ammonium hydroxide 1: 2 (kanamycin A, RC 0.70). Example 4. 1-N -T (S) (R) 3,4,5-TrioxypentylZkanamycin A is prepared analogously to Example 2, but in 2-deoxy-D-ribose, Rf 0.68 in methanol, 0.88 ammonium hydroxide 1: 2 (kanamycin A,, 70) is used as the starting material of the compound x Ex. 1 1 - N - G (5) (R) ( R) (R) 2,3,4,5, b-Pentaoyi Hexyl kanamycin A is prepared as in Example 2; however, as the starting compound use D-glucose, R $ 0.55 in methanol; 0.88 ammonium hydroxide 1: 2 (kanamycin A, Re 0.71). Example 6. 1-N- (R) (S) tl () 2, 3 , 4,5-TetaroxypentylJ kanamycin A is obtained analogously to Example 2, however, D-arabinose Rf 0.34 in methanol is used as the starting compound: 0.88 ammonium hydroxide 1: 1 (kanamycin A, R 0.49). Example 7. 1 - N 1 (5) (R) (R) 2,3,4,5-Tetrooxypentyl Kangshitsin A. Solution 3,3,6-tri-N formyl-kanamycin A (100 mg; 0.18 mmol), D-xylose (79 mg; 0.53 "mol) and cyaioborohydride, sodium (44 mg; 0.68 mmol) injected (10 ml) at pH 4.6 are heated at 31/2 h. Solvent It is evaporated under reduced pressure, and the residue is dissolved in 5N hydrochloric acid (10 ml) and stirred for 16 hours. The solvent is then evaporated and the residue is chromatographed on a column of Amberlite CG50 (NH form) ion exchange resin. Moreover, the gradient zlation is carried out with an increase in the concentration of ammonium hydroxide from O to 0.2 n, resulting in 1 - N - (SHR) (R) 2,3,4, 5-tetraoxypentyl kanamycin A (56 mg; 51% ), R {0.59 in methanol: 0.88 ammonium hydroxide 1: 2 (kanamycin A, R 0.66). Example 8. 1 - N - (R) (S) (S) 2,3,4,5-Tetraoxypentyl1 canamycin A was prepared as in Example 7, however, L-xylose was used as the starting compound. R 0.34 in methanol: 0.88 ammonium hydroxide 1: 2 (kanamycin A, R 0.50). Example 9. 1 g — N — r (R) (R) (S) 2,3,4,5-Tetraoxyl1-kanamycin A is prepared as in Example 7, one, using L-ribose as the starting compound, R 0, 38 in methanol: 0.88 ammonium hydroxide 1: 1
    (kanamycin A, R 0,51), m / e (field insorption) M + 1 found 619.
    Example 10. lNr (R) (R) (R) 2,3,4,5-Tetraoxypentyl kanamycin was prepared as in Example 7, however, O-xylose was used as the starting compound, R 0.37 in methanol: 0.88 ammonium hydroxide 1: 1 (kanamycin A, Rf 0.48).
    Example 11. 1 -N-f (5) 2,3-oxypropyl Dcanamycin B .. "
    A solution of D-glycerol aldehyde (45 mg; 0.5 mmol in methanol (1 ml) was added to a solution of 2.3, C (b tetraM-formyl-kanamycin B (100 mg; 0.17 mmol) in methanol (5 ml ) and water (1 ml). Sodium cyanoborohydride (20 mg; 0.3 mmol), pH 6.0 is added to the stirred solution, adjusted with 5N hydrochloric acid, and the resulting solution is stirred at room temperature overnight. 20 Then the solution is evaporated to dryness under reduced pressure, and the residue is placed in 5N hydrochloric acid, and the solution is left overnight at room temperature. The pH of the solution is set to 25 6.0 s using the sodium hydroxide solution and then. the resulting solution is rotographed on a column with Amberlito Sb50 as indicated in Example 1. After lyophilization of the corresponding Q fraction, 1-N- (S) 2, 3-dioxypropyl} kanamycin B (53 mg; 56% Rf 0.51 in 3 M aqueous solution of sodium chloride (kanamycin B, R 0.42). RjO, 54 in methanol: 0.88 hydroxide, 5 ammonium 1: 1 (kanamycin B, R 0.58). - spectrometric method by the field of desorption gives a strong M + 1 peak at m / e 558. For CH -lNsOa.
    Example 12.) (R) 2,3,4-Trioxybutile kanamycin In is prepared as in Example 11, however, D-erythrosis is used as the starting compound. R 0.60 in a ZM solution of sodium chloride (kanamycin B, Rg 0.45)., 45
    Example 13. 1 - N - (S) (S) t R) 2,3,4,5-Tetraoxypentyl kanamycin B was prepared analogously to Example 11, however, D-ribose was used as the starting compound, R 0.3 2M 50 solution of sodium chloride (kanamycin B, R 0,2).
    Example14. lNr (S) (R) 3,4,5-TrioxypentylZcanamycin B is prepared as in Example 11, however, as a starting compound, 2-deoxy-D-ribose, R 0.3 in 2m sodium chloride solution (kanamycin B, RP 0, 2).
    Example 15. 1-N- (S) (R) (R) (R) 2,3,4,5,6-Pentaoxyhexyl canamine-60 is prepared as in Example 11, however, D-glucose is used as the starting compound. R 0.25 in methanol: 0.88 ammonium hydroxide 1: 1 (kanamycin B, Rf 0.42). 65
    Example 16. 1 - N, 3-Dioxy-2-oximethylenopropyl j Kanamycin B was prepared analogously to Example 11, however, 01-2-oxymethyl-2.3-0isopropylidene-glycerol aldehyde was used as the starting compound, R 0.55 in a 3M chloride solution sodium (kanamycin c; R 0,42), m / e (field desorption) M + l found 588. For C, j2 O., c M + 1 588.
    Example 17. 1 - N - (R) 2,3 Dioxipropyl J canamycin B was prepared as in Example 11, however, L-glyceroldehyde was used as the starting compound. According to thin layer chromatography, the product is identical to the product obtained in Example 11.
    PRI me R 18. 1 - N, 3-Dioxy-2-propyl kanamycin A.
    3, 3, b, -Tri-m-formyl-kanamycin A (200 mg; 0.36 mmol), dioxyacetone (9.5 mg; 1.05 mmol, and sodium cyanoborohydride (88 mg; 1.40 mmol)) are dissolved in aqueous methanol (20 mp of methanol, 4 ml of water), and the pH of the solution was adjusted to 6.6 with 5N hydrochloric acid. The solution was heated under reflux for 22 hours. Then more dioxiacetone (95 mg) and cyanoborohydride were added sodium (88 mg) and the pH is adjusted to 5.5. The refluxing is continued for another 24 hours, after which the solvent is evaporated under reduced pressure. The resulting residue is treated with 10% hydrazine hydra Acetic acid at pH 6.0 (20 ml) was added and refluxed for 6 hours. After concentration under reduced pressure, the residue was chromatographed on an Amberlite CG50 ion exchange resin (NH form), and gradient elution with an increase in the concentration of ammonium hydroxide from O to 0.1 N. The fractions in which (according to TLC) contains the product are combined, evaporated and the product re-chromatographed on a column of Sephadex CM25 (in the form of ammonium ion), the same elution , as before. Get 1 - N - 11 3-dioxy2-propyl} kanamycin A (0.11 g; 57%), R 0.40 in methanol: O, 88 ammonium hydroxide 2: 1 (kanamycin A, R 0.30).
    Found: C 40.6; H 6.5; N 8.4.
    C ,. 2H COjV.Penp: C 40.5; H 6.8; N 8.2
    Example 19, 1 - N - 1, 3-Dioxy-2-propyl kanamycin B.
    Sodium cyanoborohydride (88 mg; 1.40 mmol) is added to a solution of 2, 3, 3B-tetra-N-formyl-kanamycin B (200 mg; 0.33 mmol) and dioxyacetone (95 mg; 1.05 mmol) in methanol (12 ml) and water (3 ml), the pH of the solution was adjusted to 4.5 with 2N hydrochloric acid, and the solution was boiled with reverse
    refrigerating for 20 hours. Then the solvent is evaporated under reduced pressure, and the residue is treated with water (10 ml). Hydrainehydrate (2 ml; 60%) is added, the pH of the solution is adjusted to 6.0 with glacial acetic acid (2 ml). The resulting solution was heated at reflux for an hour and then evaporated to a gummy residue under reduced pressure. The product is then dissolved in water (8 ml), the pH is adjusted to 5.5 with 0.2 N hydrochloric acid. The solution is chromatographed on an Amberlite CG50 ion exchange resin (in the form of ammonium ion), first being eluted with water, and then gradient elution with an increase in the concentration of ammonium hydroxide to 0.25 n. The fractions which, according to TLC, contain the product, are combined, evaporated, and the product is rechromatographed on a Sephadex CM25 column (in the ammonium ion form), and the elution is carried out as before, resulting in 1 - N - f1, 3-dioxy 2propyl kanamycin B (59 mg; 32%).
    R 0.55 in methanol: 0.88 ammonium hydroxide 1: 1 (kanamycin B, Rj 0.47, 37 in a 2 M solution of sodium chloride (kanamycin B, R 0.26).
    Found: C, 37.6: n, 6,3; N 9.2.
    CnHxiiNeO-ia x3H2x: og, H, J.O calculated: C 37.8; H 6.8; N 9.2%.
    Example 20. 1-N-G1 oxy2-propyl7canamycin B. 2, 3, C b -tetra-N-formyl-kanamycin B (200 mg; 0.36 mmol), oxyacetone {78 mg; Sulfur sodium cyanoborbride (88 mg; 1.40 mmol) was dissolved in aqueous methanol (20 ml of methanol, 4 ml of water), and the pH of the solution was adjusted to 6.0 with 5N hydrochloric acid. The solution is boiled under reflux for 22 hours. Then more hydroxyacetone (23 mg) and sodium cyanoborohydride (30 mg) are added, after which boiling under reflux is continued for 24 hours. Then the solvent is evaporated under reduced pressure, and the residue is treated with 10% hydrazine hydrate, adjusted to pH 6 with glacial acetic acid (20 ml), and the solution is boiled under reflux for 6 hours. After concentration under reduced pressure, the residue is chromatographed on Amberlite CG50 ion exchange resin ( form NHj) gradient elution is performed with increasing concentration of ammonium hydroxide 0.1 N from O JXO. The fractions which, according to TLC, contain the product, are combined and evaporated, resulting in 1 - N - G1-OXI-2-propyl kanamycin B (0.11 g; 50%). R 0.55 in a ZM solution of sodium chloride (kanamycin B, Rf 0.47).
    found: C 39.6: H 6.8; N 10.5.
    C2iH4jNyO x2VaHa.C03. - -
    . Calculated: C 40.5; H 6.9; N 10.0%.
    m / 1 (field desorption) M + 1 found 542. For С21Щ-5 О-11 М + 1 542.
    Example: - and mmep 21. 1 - N - fl-Oxy2-propyl kanamycin A was prepared as in Example 20, however, 3.3, b-three - N -vOmyl-kanamycin A. were used as starting compound. 3 in methanol, chloroform, 8% ammonium hydroxide (4: lt2) (kanamycin A, R 0.20).
    Example 22. 1-N EI-OKCH2-propyl} tobramycin.
    b - N-tert-butyloxycarbonyl5 tobramycin (2.0 g; 3.5 mmol), hydroxyacetone (0.78 g; 10.6 mmol) and sodium cyanoborohydride (0.89 g; 14.0 mmol) are dissolved in a mixture methanol (150 ml) and water (30 ml), the pH of the solution was adjusted to
    0 to 6.0 using 5n. hydrochloric acid. The resulting mixture was heated under reflux for 72 hours. Then the solvent was evaporated under reduced pressure, and the residue was treated with trifluoroacetic acid (20 ml),
    5 stirring for 15 minutes at room temperature. Then the solution is again evaporated to dryness-under reduced pressure, the residue is treated with a small amount of water ,. The pH is adjusted to 6.0 with ammonium hydroxide. The resulting solution is chromatographed on an Amberlite CG50 ion exchange resin (in the form of NHj), gradient wire eluted with hydro5 ammonium oxide. The fractions containing the product are combined, evaporated and the product rechromatographed on a Sephadex CM25 column (in the form of ammonium ion), elution being carried out as before. As a result, 1 - N - G1-hydroxy-2-propyl} tobramycin (8 mg; 04%) was obtained. , 68 in III solution of sodium chloride (tobramycin. R {0.60), m / e (field desorption) M + 1 found 526. For C2- (H43N5O-JO M -f
    5 II 526.
    Example 23. 1 - N -; (5) 2,3 Dioxypropyl tobramycin is prepared analogously to Example 22, but using a D-glycerol aldeo O guide instead of hydroxyacetone. R 0.55 in a ZM solution of sodium chloride (tobramycin, RI 0.45), R 0.37 in a mixture of methanol: 0.88 ammonium hydroxide 2: 1 (tobrgiiitsin, R "0.35).
    five
    Example 24. 1 - N - ri3 Dioxy-2-propyl Zkanamycin A. 6, N-Acetyl-kanamycin A (500 mg; 0.88 mmol), 1,3-dioxyacetone {237 mg 2.64 mmol) and cyanoborohydride Wat-, and (181 mg; 2.64 mmol) is dissolved with introductory methanol (45 ml of methanol, 5 ml of water) and the pH of the solution is adjusted to 6.0 with 2N hydrochloric acid.
    5 The solution was left to stand at room temperature for 3 days. Using those (methanol, chloroform / 1N ammonium hydroxide 4: 2: 1), two main components are found: R {0.17 and O,. The solution is evaporated, and the products are separated by ion exchange chromatography on a column. Sephadex CM25 (in the form of an ammonium ion, gradient elution with increasing concentration of ammochi hydroxide. From the slower component (which is eluted from the column secondarily) is removed protective groups by heating the product in an acid solution of sodium hydroxide at BO-EO C for 4 hours. After neutralization and purification using ion exchange chromatography on Amberlite CG50 column (in the form of ammonium ion / after elution, The behavior of / as before, to give 1 - N - G1, .3-dihydroxy-2-propilZkanamitsin A / identical product obtained in Example 18..
    Example 25. 1 - N - 1/3 Dioxy-2-propyl 2 canamycin B sulfate.
    Solution 1 - N - 1, 3-diox-2propyl Dkanamycin B (1.64 kg) in water
    Example
    is l) acidified to pH 6.4 / by adding concentrated sulfuric acid (0/38 l) in water (1.64 l). Charcoal (0.15 kg) is added and the mixture is stirred for 1 h, then filtered. The filter cake was washed with water (2x0.75 L), the combined filtrate and washes (8.5 L) were added to commercial methylated alcohol (70 L) during stirring. The precipitated sulphate salt is collected | They are filtered and dried under vacuum at 50 ° C. The output of 2.46 kg (90% of the regenerated activity of the antibiotic). I {0.47 (in chloroform, methanol concentrated ammonium hydroxide, water 1: 4: 2: 1).
    Found: C 33/46; E 6/70; N 8.09.
    (H4% N rO-fa 2HiO vl SC-jH OH X X2H2S64. 0 I
    Calculated: C 33/57; H 6/99 N 8/16.
    The test results of compounds on the antibacterial activity of 5 in vitro by the proposed method are given in the table.
    M.I.K., mg / m
    Table continuation
    R C / j - Ci-alkyl, substituted by 2-5 hydroxyl groups; ft - C- (- Su-alkyl, substituted by 1-5 hydroxyl groups; K - C - Cj-alkyl, unsubstituted or substituted by 1-5 hydroxyl groups; RU - amino or hydroxyl group R - hydrogen or hydroxyl group, provided when an amino group and R is in the genus, R ° is C4-C; -alkyl, at least one of the carbons of which has a hydroxyl group; R is hydrogen or C-C-alkyl, or their salts, characterized by the fact that the compound of the hydrogen formula, formyl and acetyl, is reacted with an alkylating agent of the formula C 1 H - T O-I and 9 to where R, R and R have the indicated values in the presence of sodium cyanoborohydride in a reaction-inert solvent at a temperature from room temperature to the subsequent removal of the formyl or acetyl groups by hydrolysis at a temperature from room temperature to or interaction with hydrazine at a temperature of about 100 ° C, followed by isolation of the desired product in the free state or as a salt 15 86512 DIRP op and those acknowledged 16.06.76 with R-CHaR. where R is c - C, -ALKIL / substituted with 2-5 hydroxyl groups. f 09.29.76 g. / R o vrt When R x-da R 1 816 alkyl, substituted by 1-5 hydroxyl groups. 08.12.76 at R -, where R - (Lf y-aaikyl, one of the carbon of which has a hydroxyl group, R - С-С alkyl. Sources of information taken into account during the examination 1. Nenitsescu KD Organic Chemistry, M., 1963, pp. 660.
    权利要求:
    Claims (2)
    [1]
    Claim
    1. The method of obtaining 2-deoxystreptaminaminoglycosides of the common morgue forde
    B - K - B 7 (1Ng NH-B * 'I
    R * - CH a - R® or CH H
    C a - Su-alkyl substituted
    R® hydroxyl groups;
    R® - C - Cy-alkyl substituted with 1-5 hydroxyl groups;
    R · * 0 - C - Cy-alkyl, unsubstituted or substituted by 1-5 hydroxyl groups;
    R a is an amino or hydroxyl group;
    R *
    [2]
    2-5
    R 7
    - hydrogen or hydroxy group, provided that when R 7 February amino group, a R a - hydrogen, R '10 - Sd - Cj-alkyl, at least one of which carbon has a hydroxyl group;
    - hydrogen or C-Cd-alkyl, or a salt thereof, characterized in that the compound is form 65 <1 -t where R and R have the indicated meanings;
    • R 5 - hydroxy or NHR ”group;
    R 1 'is selected from the group consisting of formyl and acetyl;
    R '' 2 · - is selected from the group consisting of hydrogen, formyl and acetyl; they are reacted with an alkylating agent of the formula o = Cn-a and a 10 * where R, R and R have the indicated meanings in the presence of sodium cyanoborohydride in the reaction inert solvent at a temperature from room temperature to 90 ° C followed by removal of formyl or acetyl groups by hydrolysis at a temperature from room temperature to 90 ° C or by reaction with hydrazine at a temperature of about 100 ° C followed by isolation of the target product in a free state or in the form of a salt.
    Feature Priority · *
    06/16/76 at R-CHDy, where R 8 - - C 5 -alkyl substituted with 2-5 hydroxyl groups.
    09/28/76 at R 'where R e and R y0 -C ^, 10 is alkyl substituted with 1-5 hydroxyl groups.
    12/08/76 at R.'CHR 9 R ' , < ', where R 9 is C = -Cj-alkyl, one of the carbons of which has a hydroxyl group, R 10 is -C $ · alkyl.
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    US4008218A|1977-02-15|1-N-|-α-substituted-ω-aminoacyl)-neamine or -ribostamycin and the production thereof
    EP0173614B1|1988-10-19|3&#39;-fluoro-3&#39;-deoxykanamycin a and the production thereof
    KR820000753B1|1982-05-04|Process for preparing a 2-deoxystreptamine aminoclycosides
    US4380581A|1983-04-19|Istamycins and streptomyces culture for the production thereof
    同族专利:
    公开号 | 公开日
    BG28071A3|1980-02-25|
    IL52181A|1981-03-31|
    YU132577A|1982-06-30|
    NZ184213A|1980-05-27|
    MX4323E|1982-03-24|
    DK147942B|1985-01-14|
    JPS52153943A|1977-12-21|
    JPS5713556B2|1982-03-17|
    CH606079A5|1978-10-13|
    IE45389B1|1982-08-11|
    RO73516A|1981-08-30|
    IE45389L|1977-12-16|
    NL7706514A|1977-12-20|
    SE7706944L|1977-12-17|
    HU179054B|1982-08-28|
    DE2726839C3|1980-05-14|
    FR2355029B1|1980-04-18|
    GR66411B|1981-03-20|
    CS203157B2|1981-02-27|
    NL170736C|1982-12-16|
    AT350722B|1979-06-11|
    DK265577A|1977-12-17|
    PL198872A1|1978-03-13|
    IL52181D0|1977-07-31|
    FR2355029A1|1978-01-13|
    FI771873A|1977-12-17|
    NO144851B|1981-08-17|
    LU77557A1|1979-03-26|
    ATA414277A|1978-11-15|
    PH14663A|1981-10-20|
    DD131019A5|1978-05-24|
    PL108094B1|1980-03-31|
    PT66669B|1978-11-13|
    DE2726839A1|1978-03-09|
    ES459832A1|1978-12-16|
    EG12742A|1979-12-31|
    US4214074A|1980-07-22|
    PT66669A|1977-07-01|
    NO772089L|1977-12-19|
    DE2726839B2|1979-08-30|
    NO144851C|1981-11-25|
    CA1075235A|1980-04-08|
    AR222781A1|1981-06-30|
    DK147942C|1985-09-02|
    AU2551177A|1978-04-13|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    GB1033394A|1962-04-03|1966-06-22|Rit Rech Ind Therapeut|New therapeutic agents|
    US4002742A|1974-03-19|1977-01-11|Schering Corporation|1-N-alkyl-4,6-di--1,3-diaminocyclitols, methods for their manufacture, methods for their use as antibacterial agents, and compositions useful therefor|
    US4000262A|1974-11-29|1976-12-28|Schering Corporation|5-epi-amino and 5-epi-azido-4,6-di-o--2,5-dideoxystreptamines 1-n-alkyl-5-epi-amino and 1-n-alkyl-5-epi-azido-4,6-di-o--2,5-dideoxystreptamines|
    US4000261A|1974-11-29|1976-12-28|Schering Corporation|5-epi-4,6-di-o--2-deoxystreptamines, methods for their manufacture and intermediates useful therein, methods for their use as antibacterial agents and compositions useful therefor|
    US4062947A|1975-11-04|1977-12-13|Schering Corporation|Di-N-alkylaminoglycosides, methods for their manufacture and novel intermediates useful therein, method for their use as antibacterial agents and pharmaceutical compositions useful therefor|
    US4085208A|1976-06-21|1978-04-18|Schering Corporation|Process for preparing 4,6-di-O--1,3-diaminocyclitols and novel 1-epimers and 1-N-alkyl derivatives produced thereby; methods for the use of the 1-epimer derivatives as antibacterial agents and compositions useful therefor|DK308878A|1977-08-18|1979-02-19|Pfizer|AMINOGLYOSIDE DERIVATIVES AND PROCEDURES FOR THEIR PREPARATION|
    DE2832268A1|1978-07-22|1980-01-31|Bayer Ag|PSEUDOTRISACCHARIDE|
    DE2928183A1|1979-07-12|1981-01-29|Bayer Ag|1-N-ALKYLSISOMICIN DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS MEDICINAL PRODUCTS|
    JPS5931266A|1982-08-11|1984-02-20|Hitachi Ltd|Controller for elevator|
    US7794713B2|2004-04-07|2010-09-14|Lpath, Inc.|Compositions and methods for the treatment and prevention of hyperproliferative diseases|
    KR100450607B1|2002-07-11|2004-09-30|경동제약 주식회사|Process for preparing Galamin|
    US7862812B2|2006-05-31|2011-01-04|Lpath, Inc.|Methods for decreasing immune response and treating immune conditions|
    SI2217610T1|2007-11-21|2017-03-31|Achaogen, Inc.|Antibacterial aminoglycoside analogs|
    CA2761756A1|2009-05-14|2010-11-18|Achaogen, Inc.|Treatment of urinary tract infections with antibacterial aminoglycoside compounds|
    WO2010132765A2|2009-05-15|2010-11-18|Achaogen, Inc.|Antibacterial aminoglycoside analogs|
    WO2010132768A1|2009-05-15|2010-11-18|Achaogen, Inc.|Antibacterial derivatives of sisomicin|
    WO2010132760A1|2009-05-15|2010-11-18|Achaogen, Inc.|Antibacterial derivatives of tobramycin|
    WO2010132757A2|2009-05-15|2010-11-18|Achaogen, Inc.|Antibacterial aminoglycoside analogs|
    WO2010132759A1|2009-05-15|2010-11-18|Achaogen, Inc.|Antibacterial derivatives of dibekacin|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    GB24989/76A|GB1530202A|1976-06-16|1976-06-16|Aminoglycosides|
    GB4014576|1976-09-28|
    GB5129476|1976-12-08|
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