NL8103639A - NEW 1-N (ALFA-HYDROXY-OMEGA-AMINOALKANOYL) DERIVATIVES OF 5.3 ', 4'-TRIDEOXY, 5.3', 4'-TRIDEOXY-6'-METHYL-OR 5.3 ', 4 6 "-TETRADEOXYKANAMYCIN-B, AND METHOD FOR PREPARING THEREOF. - Google Patents

Description

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I

Lx 5871

New 1-N- (α-hydroxy - --aminoalkanoyl) derivatives of 5,3 ', 4'-tri-deoxy, 5 * 3' - 'trideoxy-1'-N-methyl- or 5i3 * » Bn * = tetradeoxy-kanamycin-B, and process for its preparation.

This invention relates to new semisynthetic aminoglycoside antibiotics, including 1-N- (α-hydroxy-ω-aminoalka-noyl) -5,3 ^ 41-trideoxykanamycin-B, 1-N-Ca -hydroxy- »- aminoalkanoyl) “3 * 3 ', 4', 6H-tetradeoxykanamycin-B and -5,3 ', 4', 6n-tetradeoxykanamycin-5B, as well as 1-N- (α-hydroxy-ul-aminoalkanoyl) -5, 31 '- trideoxy-N-methyl-kanamycin-B and 5,3'-trideoxy-N-methyl-kanamycin-B, all of which are new compounds useful as bactericidal agents. The invention further relates to a method of preparing these new compounds. The invention further relates to a bactericidal agent which contains at least one of these new compounds as the active ingredient.

Dibekacin, ie 3 ', 4 * -dideoxykanamycin-B has already been semisynthetically prepared from kanamycin-B, see JP-A 7593/75, JP-B 794 612, 15 and IS 3 753 973- Dibekacin has already been extensively used for treating of various bacterial infections as a chemotherapeutic agent active against kanamycin sensitive bacteria, and also against various kanamycin resistant bacteria. Furthermore, habekacin, ie 1-N- (L-4-amino-2-hydroxybutyryl) dibekacin, which is an effective chemotherapeutic agent against dibekacin resistant bacteria, has already been prepared in a semi-synthetic manner, see JP-A 33 629 / 77 and US 4 107 424. Furthermore, semisynthetic 1-N- (α-hydroxy-α-amino-alkanoyl) -6 '-N-methyl-dibekacin has been prepared, which is highly effective against many different strains of bacteria. bleaching, see JP-A 115 199/74, GB 1475 481, and IS 147 861. Further investigation has prepared synthetic 6H-deoxy or 4 ", 6M-dideoxy derivatives of dibekacin and habekacin. It has further been found that the 6 "-deoxy derivatives and 4", 6M-dide oxide derivatives of dibekacin or habekacins not only exhibit low ototoxicity, but also show a bactericidal activity as strong as dibekacin or habekacin, see JP-A 119323/79, GB-A 2 058 774, and IIS application 174 630.

5.3 ', 4-trideoxykanamycin-B has also been prepared as a further deoxy derivative of dibekacin (see Jap. J. Antibiot. 32, (1979) S-78). However, this compound has been found to 81 ° J39 * tw 2 * is less effective than dibekacin.

It may be added that further deoxy derivatives of 1-N- (L-4-amino-2-hydroxybutyryl) -kanamycin-A (so-called amikacin) have been prepared, including 3'-deoxyamikacin, see JP-A 4 9 105/3 75 and US ^ 104 372, 3 '' ^ '-dideoxyamikacin, see JP-A 11 ^ 02/79, GB-A 2 0 ^ 3 03b and US application -114 7791 6 ”-deoxyamikacin, see JP-A 5 ^ 733/79 »* 1”, 6 ”-dideoxyamikacin, see JP-A 5½733 / 79 * 3 '' V, 4”, 6 ”-tetra-deoxyamikacin, see JP-A 138 685/79 , and 3 ', **' '6 "-trideoxyamikacin, see JP-A 5657/80, as well as 3', 6" -dideoxyamikacin, 5 "3'-dideoxyamicacin-10 cine and 5 * 3 ', 6" - trideoxyamikacin, see JP-A 107 202/80, all of which exhibit low acute toxicity and low ototoxicity, while their beneficial bactericidal activity is as strong as that of amikacin ·

In further development of these studies on deoxy derivatives of dibekacin or habekacin, it has now been possible to prepare a new compound, 5.3 ", 6" -tetradeoxykanamycin-B, which has been shown to be clearly effective against certain types of bacteria, while on the other hand, 5 * 3 ', Λ'-trideoxykanamycin-B does not show any bactericidal activity. Furthermore, a new compound 5 * 3', * 1 '-trideoxy-6'-N-methyl-kanamycin-B has been prepared, which also exhibits a bactericidal activity which is stronger than that of 5 * 3 ', -' - trideoxykanamycin-B, especially against certain resistant strains, in an attempt to find such new derivatives of 5 * 3 ', V-trideoxykanamycin - B, 5 * 3 '***', 6 "-tetradeoxykanamycin-B or 25" 3 '* ^' - trideoxy-6 * -N-methylkanamycin-B, which have a better bactericidal action, are now new 1 -N- (cc-hydro xy-ίύ -aminoalkanoyl) derivatives of these deoxykanamycins-B synthesized by acylating the 1-amino group of deoxykanamycin-B with a ce-bydroxy-a) -aminoalkanoic acid. It has further been discovered that the newly obtained 1-N- (cc-hydroxy-α-aminoalkanoyl) derivatives of 5 * 3, -, - - trideoxykanamycin-B, 5 * 3 '* -' - trideoxy -6'-N-methylkanamycin-B, and 5 * 3 't1 * ·', 6 "-tetradeoxykanamycin-B are highly effective against kana-mycine sensitive and resistant bacteria, while further providing strong bacterial activity over a wide range 35 of bacteria.

According to a first most general aspect of this invention, as a new compound 1-N- (cc-hydroxy-α-aminoalkanoyl) ~5i3 ', ^-trideoxy- or 1-N- (cc-hydroxy-ω-aminoalkanoyl) - 5.3, Λ'-tri-deoxy-6'-N-methyl-kanamycin-B, or 5 * 3'-trideoxy-6'-N-methyl-kan- 8103639 \ x

* J

• 3 - mycine-B, or 1-N- (cί-hydroxy-öi-aminoalkanoyl) -5,3, »4 · *» 6w-tetradeo3Ey-kanamycin-B, or 5i3 '> 4 *, 6u-tetradeoxykanamycin- B provides, represented by the formula- (1) R- H0— “w 2 * 4 * HN 11 Γ ~~~ ° QH 6 4 '(ν ^ γ - ^^ V · 0 nhr2

RtHN Λ - '"'" 5 \\ ^ nh2 1 3 3 where R is a hydroxy group or a hydrogen atom, and R ^ is a hydrogen atom or an α-hydroxy-6-aminoalkanoyl group of the formula -CO-CH- (CH-, ) -NH0 I c. n c.

OH

where n is 1, 2 or 3, and R2 is a hydrogen atom or a methyl group, provided that R2 is not a methyl group when R is a hydrogen-10 atom, also including a pharmaceutically suitable acid addition salt of this compound by the invention

According to a first preferred embodiment, the invention provides a new compound which satisfies the aforementioned formula (1), and a 1 -N- (α-hydroxy-α> -amino alkanoyl) -5,31 -41 -tri de oxy- ' 13 is kanamycin-B or a 1-N - (<x-hydroxy-6) -aminoalkanoyl) -3,3'Λ ', 6n-tetradeoxykanamycin-B, as represented by the formula (2) 6 »R λ 2' 4f

° \ H2N

H2KV ^ 0hV '', T

\ C2) ΗΝ- ~ γ 3

CO

CHOH

i 81 0 3 6 3 9 (cH2) nNH2 ♦ ♦. V »*. (- k - where H represents a hydroxyl group or a hydrogen atom, and n represents 1, -. 2 or 3, while R is a hydroxyl group, when this compound is 1-N- (oc-hydroxyl-ω-aminoalkanoyl) -5 * 31 * 4 '-trideoxykanamycin-B, while R is a hydrogen atom, when this formula is 1-N- (a-hy-5-droxy-w-aminoalkanoyl) -5,31,4 *, 6'-tetradeoxykanamycin-B , further, this embodiment also includes a pharmaceutically suitable acid addition salt of the compound (2).

According to a second preferred embodiment, there is provided a new compound represented by the formula (1) which is 5 * 3'* * 16M-tetradeoxykanamycin-B as represented by the formula (3) 6 '2' 4 «CH3 / 0 h2'n \ i__ '5' NHo HPN- \ X OH I 6 3" 0 ^ \ \ \ NH 2 <3) H2N- ^ q

1 J

or a pharmaceutically acceptable acid addition salt of this compound.

13 Ce physicochemical and biological properties of the new compounds of formulas (2) and (3) are as follows: (1) 1-N - ((S) -1-amino-2-hydfoxybutyryl) -513,4 trideoxy-kanamycin B monocarbonate monohydrate is a substance in the form of a colorless powder, which decomposes at 163 ° C 166 ° C, and which has an identical optical rotation [a] ^ = +8? (c 1, water). Its elemental analysis corresponds to C ^ H ^ NgQ ^ .HgCO ^ .E ^ O (C 44.80 #, H 7 »85%, N 13 * 63%) · This fabric gives a single stain (positive for Ninhydrin) at Rf 0.05 and Rf 0.09 on thin layer chromatography on silica gel developed with butanol-ethanol-chloroform-17% amonia 25 (4.5-2: 5 by volume), respectively. with chloroform-methanol-conc. amonia water (1: 4: 2: 1 by volume) as the appropriate developing solution; (2) 1-N - ((RS) -3 ”aMiπo-2-hydroxypropionyl) -5 ^ 3,4'-triodeoxykanamycin B monocarbonate is a substance in the form of a colorless powder, which decomposes at 113-1116 ° C, and which exhibits an unconventional optical rotation [cc] ^ = +120 (c1, water). The element- 8103639 - 5 - 4

analysis corresponds to C21I42N609 * H2C ° 3 H? i 19 N

13.63 ¢). This substance gives a single spot (positive for ninhydrin) at Hf 0.12 and Hf 0.35 in the aforementioned silica gel thin layer chromatography developed with butanol-ethanol-chloroform-17% ammonia 5 (4: 5: 2: 5 volume) or with chloroform-methanol-conc. ammonia water (1: 4: 2: 1 by volume) as the appropriate developing solution: (3) 1-N - ((S) -4-amino-2-hydroxybutyryl) -5 »3 * 4 ', 6H-tetradeoxykanamycin B-dicarbonate is a substance in the form of a color

10 devoid powder, which decomposes at 131-135 ° C, and exhibits a specific optical rotation [et] + 90 ° (c 1, water). The elemental analysis corresponds to C;>? Hj1 j ^ Oq. 2H ^ CQ ^ (C 44.71 H 7.30 #, N

13.04%). This substance gives up a single spot (positive for ninhydrin) at Hf 0.07 and Hf 0.23 in the aforementioned thin layer chromatography, silica gel, developed with butanol-ethanol-chloroform-17% ammonia (4: 5 * 2: 5 in volume) resp. with chloroform-methanol-conc. ammonia water (1: 4: 2: 1 by volume) as the respective developing solution} (4) 5 »3 '14', tetradeoxykanamycin-B-dicarbonate monohydrate is a substance in the form of a colorless powder which decomposes at 128 · 23 o 136 ° C, and exhibits a specific optical rotation [«] ^» +102 (c 1, water). The elemental analysis corresponds to C18H37N5 ° 6 · 2H2CO3.H2 O (C 42.77%, H 7.72 N 12.47 #). This substance gives a single spot (positive for ninhydrin) at Hf 0.42 and at Hf 0.56 * 25 in the aforementioned silica gel thin layer chromatography, developed with butanol-ethanol-chloroform-17 #'s ammonia (4: 5 · 2 : 5 ia volume) resp. with chloroform-methanol-conc. ammonia water (1: 4: 2: 1 by volume) as the appropriate developing solution.

The minimum suppression concentration (pg / ml) of 1-N - ((s) 30 -4-amino-2-hydroxybutyryl) -5 * 3 ', 4f-trideoxykanamycin-B. (Abbreviated as .AHB-trideoxy-KMB), 1-N - ((ES) -3-amino-2-hydroxypropionyl) -5 »3l» 4'-tri-deoxykanamycin-B (abbreviated as AHP-trideoxy-KMB), and 1-N - ((S) - 4-amino-2-hydroxybutyryl) -5,3'Λ ', 6 "-tetradeoxykanamycin-B (abbreviated as" AHB-tetradeoxy-KMB) of the formula (2) according to the invention, as well as of the new compound 5, 3 * 4f, 6H-tetradeoxykanamycin-B (abbreviated as tetradeoxy-KMB) of the formula (3) of the invention, against various microorganisms, were determined by the serial dilution method on an agar medium at 37 ° C, making the estimate after an incubation time of 18 h For comparison, the 8103639 * t - 6 minimum suppression concentrations of habekacin were determined in the same manner.

The bacterial control spectra of these new and known substances follow from Table A.

According to a third preferred embodiment of the invention, there is provided a new compound which satisfies the formula (1) and 1-N- (cc-hydroxy-o-aminoalkanoyl) -5'3 * tV-trideoxy-6 '. -N-methylkanamycin-B is represented by the formula (4); _ .....- ΗΟ'-Λ6 "2 'Η2Ν \ τ ^ ν ^ ιη 6" Ί "^^ hch3! 1 3 i) co

CHOH

(CH2) nNH2 wherein n is 1, 2 or 3, while this embodiment also includes pharmaceutically acceptable acid addition salts of this compound.

According to a fourth preferred embodiment, there is provided a new compound, which also satisfies the formula (1), which is 5 * 3'-trideoxy-1'-N-methyl-kanamycin-B represented by the formula (5) s ? i 6 "'. [ΗΟ ^ Λ 2' 4» i \ H2Ny \ 3> ^ 3 "OH 6 5 Λ - 0 NHCH3 Η ^ Λ ^ ν” 2 (5)

1 J

8103639 £ $ -7 - or a pharmaceutically acceptable acid addition salt thereof ·

The physicochemical and biological properties of the new compounds of formula (4) or (5) are as follows: (5) 1-N - ((s) -4-amino-2-hydro2-butyryl) -5 »3 ', 4 '-trideoxy-56'-N-methylkanamycin-B monocarbonate is a substance in the form of a colorless powder, which decomposes at 162 · 165 ° C, and a specific optical rotation [os] ^ = + 88 ° (c 1, water) exhibits its elemental analysis corresponds to C ^ H ^ gNgO ^ .H ^ CO ^ (C 47.05 #, H 7 * 90 # »N 13» 72%) · This substance forms a single stain (positive for ninhydrine 10 at Rf 0.05 and Bf 0.08 by thin layer chromatography on silica gel, developed with butanol-ethanol-chloroform-17% ammonia (4: 5: 2: 5 volume) resp.with chloroform- methanol-conc. ammonia water (1: 4: 2: 1 by volume) as developing solution · (6) 1-N - ((RS) -3-amino-2-hydroxypropionyl) -5 »3,» 4, - trideo: xy-15 61 -N-methyl-kanamycin-B-monocarbonate monohydrate is a substance in the form of a colorless powder, which decomposes at 1 ° -2164 ° C, and which has a similar optical rotation. g [«J ^ = +30 (c 0.3» water). The elemental analysis corresponds to CggH ^ N ^ Og .H ^ CO ^ .HgO (C 44.80 #, H 7 * 33 # »N 13 * 32 #). This substance forms a single spot 20 (positive for ninhydrin) at Rf 0.03 and Rf 0.14 in the aforementioned silica gel thin layer chromatography developed with butanol-ethanol-chloroform-17 #'s ammonia (4: 5: 2: 5 volume) resp. with chloroform-methanol-conc. ammonia water (1: 4: 2: 1 by volume) as developing solution · 25 (7) 1-N - ((S) -5-amino-2-hydroxyvaleryl) -3 »3,» 4'-trideoxy- 6 * -N-methylkanamycin-B-monocarbonate monohydrate is a colorless powder material which decomposes at 163 · 166 ° C and has a specific optical rotation [cc j ^ = +84 (c 0, 3 »water) change ** 'shows. Its elemental analysis corresponds to Cg ^ H ^ gNgO ^. HgCOj.

30 Η ^ Ο (C 46.57 H 8.13%, N 13 * 03%) · This substance forms a single spot ^ (positive for ninhydrin) at Rf 0.03 and Rf 0.08 in the aforementioned thin layer chromatography on silica gel , developed with butanol-ethanol-chloroform-17 #'s ammonia (4 3 2: 3: 3 volume) resp. with chloroform-methanol-concemmonia water (1: 4: 2: 1 by volume) as a developing 33 solution.

(3) 5 * 3 *, 4, -trideoxy-6, -N-methyl-kanamycin-B-monocarbonate monohydrate is a colorless powder material which decomposes at 140 ° C 140 ° C and which has a similar optical rotation [cc] shows 25 - +66 (c 1, water). Its elemental analysis comes across- 81 03 6 39 Μ- * * '- δ - one with C ^ H ^ N ^ .H ^ O ^^ O (C 45.36 96, Η 8.18%, N 13.23 %) · This substance forms a single stain (positive for ninhydrin) at Bf 0.22 and Rf 0.49 in the aforementioned thin layer chromatography of silica gel, de | wrapped with butanol-ethanol-chloroform-1? % b ammonia (4: 5: 2: 5 by volume) resp. chloroform-methanol-conc. ammonia water ¢ 1: 4: 2: 1! in volume) as a development solution.

The minimum suppression concentrations ζμg / ml) of. 1-N-; ((S) -4-amino-2-hydroxybutyryl) -5,3 ', 4 * -trideoxy-6'-N-methylkanamycin-, B (abbreviated as AHB-trideoxy-MKMB), 1-N - ((RS 3-amino-2-hydroxy- [1-propionyl] -5,3'-3-trideoxy-1'-N-methyl-kanamycin-B (abbreviated as AHP-trideoxy-MKMB), and 1N-USi ^ -amino ^ -hydroxyvaleryl) ^^ ', 4'-trideoxy-6'-N-methylkanamycin-B (abbreviated as AHV-trideoxy-MKMB) of the formula (4) according to the invention, as well as the new compound 5.3 4'-trideoxy-6'-N-methylkanamycin-B (abbreviated as trideoxy-15 MKMB) of the formula (5) of the invention against various microorganisms were determined by the series connection method on an agar medium at 37 ° C, the estimate being performed after 18 h incubation. For comparison, the minimum suppression concentrations of 1-N-II-Si-amino-hydroxy-butyryl, 4'-20-dideoxy-kanamycin-B (i.e. habekacin) were also determined in the same manner.

The bacterial control spectra of these new and known compounds are shown in Table B.

Tables A and B show that the novel compounds according to the invention, which satisfy the formula (1), including the compounds of the formulas (2), (3), (4) and (5), the growth of many strains of bacteria. The new compounds according to the invention show a low acute toxicity to animals and also to humans. It has been found that the new compounds of formula (2) and (3), such as 1-N - ((S) -4-amino-2-hydroxy-, butyryl) -5,3 ', 4 1'-Trideoxy-kanamycin-B, 1-N- (3 ** amino-2-hydroxypropionyl) -5,3 ', 4'-Trideoxy-kanamycin-B, 1-N - ((S) -4-amino- 2-hydroxybutyryl) “5.3 ', 4', 6M-tetradeoxykanamycin-B, and 5.3 ', 4', 6" -tetradeoxykanamycin-B have an LD 2 value of 25 · 50 mg / kg when acute toxicity is determined by intravenous injection in mice, and it has been found that the new compounds of formula (5) and (4), such as 1-N - ((S) -4-amino-2-hydroxybutyryl) - 5,3 ', 4'-trideoxy-6'-N-methyl-kana-mycine-B, 1-N- (3-amino-2-hydroxypropionyl) -5,3', 4'-trideoxy-6'-N- methylkanamycin-B, 1-N - ((S) -5-araino-2-hydroxyvaleryl) -5,3 ', 4'-tri-8103639' '- 9 - deoxy-β'-N-methylkanamycin-B, and 5-3-3-trideoxy-N-methyl-canca-mycine-B have an LD, -Q value of 50, 100 mg / kg, also determined by intravenous injection in mice.

The new compounds of the invention are usually obtained in the form of the free base or a hydrate or carbonate thereof. These compounds can each easily be converted into a pharmaceutically acceptable acid addition salt, such as the hydrochloride, hydrobromide, sulfate, phosphate, nitrate, acetate, maleate, citrate, ascorbate, methanesulfonate and the like, by reaction with the corresponding pharmaceutically acceptable inorganic or organic acid in a watery center.

The new compounds of formulas (1), (2), (3) »(4) or (5) and their pharmaceutically acceptable acid addition salts may be in any desired manner, such as oral, intraperitoneal, intravenous, subcutaneous or administered intramuscularly, using the form suitable for such administration, as is also the case with the known kanamycins. For example, these compounds can be administered orally using any form suitable for this mode of administration, such as powders, capsules, tablets, syrup or the like. An appropriate dose of these compounds for the effective treatment of bacterial infections is 0.1 to 1 g per person per day when administered orally. It is preferable to administer such a dose in three or four portions per day. These new compounds can also be administered * 25 intramuscularly at a dose of 50,500 mg per person and 2.Λ times per day. Furthermore, these compounds can be incorporated into an external ointment in which the active compound is present in a concentration of 0.5% by weight mixed with a known ointment carrier such as polyethylene glycol. Furthermore, these 50 new compounds are useful for sterilizing surgical instruments and nursing equipment.

According to a second aspect of the invention, there is provided a bacterial control composition comprising as active ingredient 1-N- (cc-hydroxy-ω-aminoalkanoyl) -5,3,1,5-trideoxykanamycin-B, 55 1-N- (a- hydroxy-ea-aminoalkanoyl) -5,3 '* 4 ·', 6n-tetradeoxykanamycin-B, or contains a pharmaceutically acceptable acid addition salt thereof, according to formula (2), or 5.3 '*, 6H- tetradeoxy-kanamycin-B or a pharmaceutically acceptable acid addition salt thereof, in accordance with formula (5), by an effective amount for bacterial control, in order to prevent the growth of bacteria, together with a carrier for the active compound, as well as a bacterial control composition, comprising as active ingredient 1N-Ca -hydroxyr-amino-aminoalkanoyl-1, V-trideoxy-6'-N-methyl-kanamycin-B, or a pharmaceutically acceptable acid addition salt thereof, in accordance with of the formula (4), or 5 »3 '» ^' - tri-> deoxy-ó'-N-methylkanamyci ne-B, or a pharmaceutically acceptable acid addition salt thereof, in accordance with formula (5), in an amount effective for bacterial control to prevent the growth of bacteria, and together with a carrier j for the active compound.

The preparation of the new compound of the formula (2) * according to the invention will now be described. The new compound of the formula (2), such as 1-N - ((S) -4-amino-2-hydroxybutyryl) -5 »3 '» 15 ^' - trideoxykanamycin-B and 1-N - ((S) -4-amino-2-hydroxybutyryl) -5,3 '' V, 6'-tetradeoxykanamycin-B, can be synthesized starting from either the known substance 5 * 3'-trideoxykanamycin-B (Jap. J.

Antibiot. 32 (1979) S-178), or of the new compound 5 * 3'Λ ', 6 "-tetradeoxykanamycin-B obtained according to the invention, and condensing the 1-20 amino group of the starting compound with a corresponding α-hydroxy- amino-amino-alkanoic acid as an equivalent compound.

According to a third aspect of the invention there is provided a process for preparing 1-N- (α-hydroxy-O) -amino-25-alkanoyl) -5,3 '' V-trideoxykanamycin-B or 1-N- (cs -hydroxy-o--amino-alkanoyl) -5,3 '*', 6M-tetradeoxykanamycin-B of the formula (2); "Fli%" HN ^ ά I (2)

CO

CHOH

81 0 3 6 3 9 (CH2) nNH2 • t ^ $ - 11 - wherein B is a hydroxyl group or a hydrogen atom, and n is 1, 2 or 3 »comprising: (a) acylating the 1-amino group of 5.3 *, V-trideoxy-kanamycin-B or 5.3 ', ** ·', 6H-tetradeoxy-kanamycin-B according to the formula (6): _______ NH2 h2n \ ^ VNH2 (S) «where H is the same or is a derivative with partial amino protection of 5.3 *, - '- trideoxykanamycin-B or of 5.3' - '-' tetradeoxykanamycin-B according to formula (61) s

10 B / 0H

Where B is a hydroxyl group or a hydrogen atom, and A is a hydrogen atom, while at least one B is a monovalent amino protecting group, and the others represent a hydrogen atom, or at least one pair of A and B together represent a divalent amino protecting group while the other A and B are each a hydrogen atom, the amino protecting groups represented by A and B may be the same or different, which is accomplished by a reaction with an α-hydroxy-o-aminoalkanoic acid or an amino-protected derivative thereof, represented by the formula (7) ï A *

X> N (CHO) CHClOH

2 “I (7) 81 0 3 6 3 9 oh - * * - * · - 12 - where A 'is a hydrogen atom, and B' is a hydrogen atom or a monovalent amino protecting group, or where A * and B ' together form a divalent amino protecting group, while n is Tr 2 or 3i while an equivalent compound may also be used to form the 1-N-acylated product represented by the formula (2 '): 6 »\

HN

| (20

CO

CHOH

I a r (0Η2) ηΝ <Β 'r or by the formula (2n):

N rA

GO% '| (2 »)

CHOH

I A * (CH2) c u B "1G where R, A, B, A ·, B" and n have the same meaning as above; and (b) removing the remaining amino protecting groups, where present, from the 1-N-acylated product of formula (2 ') or (2 ”), which is done in the known manner, at 8103639 f To obtain the compound of formula (2).

This method may include an additional step of converting the compound (2) into a pharmaceutically acceptable acid addition salt thereof by a known reaction with a suitable inorganic or organic acid, if desired.

In carrying out this process, it is possible to use as starting compound 5 »3 ', 4'-trideoxykanamycin-B or 5' 3 '' V, 6" -tetra-deoxykanamycin-B (6), the amino groups of which are not at all are protected in the form of the free base or in the form of an acid addition salt with a suitable acid such as hydrochloric or sulfuric acid, however, it is preferred as starting compound a partially protected derivative of 5i3 ', 4 ·-·ί- deoxykanamyciae-B or 5i3 ', 4 *, 6H-tetradeoxykanamycin-B of the formula (6'), in which at least part of the amino groups.

Other than the 1-amino group are protected with known protecting groups, which can be obtained by introducing a known amino protecting group into the compound of the formula (6) by a known method previously used in the synthesis of some known deoxy derivatives of kanamycin-B. For the preparation of these partially protected compounds of the formula (6 '), use can be made of the amino protection methods which have already been used to prepare the 6 * -N-benzyl-oxycarbonyl derivative of kanamycin-B, as described in US 3,781,268 and US 3,929,762, or in the preparation of 2 ', 6'-di-N-tert-butoxycarbonyl-25-kanamycin-B or ö'-N-benzyloxycarbonyl-kanamycin-B, or the mono-N- or di-N-tert-butoxycarbonyl or even tri-N-tert-butoxycarbonyl derivative of 6'-N-benzyloxycarbonylkanamycin-B, separated or in a mixture thereof, as described in GB 1 426 908 or US 3 939 143, or in the preparation of the 2 ', 3 "3" * 6, tetra-N-formyl derivative of kanamycin-B, as described in BE 817546.

In general, suitable examples of amino protecting groups that can be used for the present purpose are the common amino protecting groups, including an alkoxycarbonyl group, such as tert-butoxycarbonyl and tert-amyloxycarbonyl, a cycloalkyloxycarbonyl group such as cyclohexyloxycarbonyl, a aralkyloxycarbonyl group such as benzyloxycarbonyl, an acyl group such as trifluoroacetyl and o-nitrophenoxyacetyl, a phosphinothioyl group such as diphenylphosphinothioyl and dimethylphosphinothioyl, a phosphinyl group such as diphenylphinyl, and the like. Preferred forms of the divalent 81 03 639 ___ -1½ - amino protecting group are the phthaloyl group and a group of the Schiff base species such as salicylidene. The introduction of an amino protecting group of this kind can be effected by a reaction between a compound of the formula (6) and a suitable known reagent 5 for the introduction of such a group, for example in the form of an acid halide, an acid azide , an active ester, or an acid anhydride or the like, as is known in the conventional synthesis of peptides. When choosing the amount of reagent to enter an amino protecting group in a ratio of 0.5 * 10 6 mol / mol relative to the compound of formula (6), it is possible that a mixture of different derivatives (6 ') with arbitrary ratio is obtained, due to differences in reactivity of the different amino groups of the compound (6).

In carrying out this process, it makes sense to start from a 5 * 3'Λ'-trideoxykanamycin B or 5 * 3 ', 6 "tetradeoxy-kanamycin B derivative with amino protection, in which at least part of the amino groups other than the 1-amino group is blocked, for example with 3i2V, 6 ', 3 "-tetra-N-, 3» 2 ", 6'-tri-N-, 2', 6, -5" -tri- K-, 20 2 ', 6'-di-N or ö'-mono-N protection * Furthermore, a mixture of two or more of these partially N-protected derivatives can be used for the 1-N- without further purification acylation step of the present process.

To ensure that the desired product of the general formula (2) can be obtained in high yield using this process, it is only necessary that the 1-amino group of the compound of the formula (6), namely, 5> 3 ', V-trideoxykanamycin-B or 5.3 * -tetradeoxykanamycin-B, is acylated selectively with cc-hydroxy-amino-aminoalkanoic acid (7). It will be appreciated that preferably a derivative with 3,2 ', 6', 3 ,, - tetra-N-protection of the compound (6), ie the derivative with amino protection of the compound (61), in which all amino groups except the 1-amino group with the protecting groups are blocked when the starting compound to be acylated is used.

For example, to prepare the protected derivative of the formula (6 ') of the compound of the formula (6), proceed as follows. A known method according to US k 136 25 ^ can be used, according to which a 3, 2 ', 6'-tri-N-acylated protected derivative of kaamycin-B is prepared by a reaction 8103639 r.

-lotuses kanamycin-B and a bivalent transition-metal cation, for example of Cu (II), Ni (II), Co (II) etc., to form a metal complex of kanamycin-B, after which this complex with an acylating agent prior to introducing an amino protecting group, is reacted to protect all the amino groups except the 1-amino and 3n-amino groups of the kanamycin B portion of this complex (which amino groups are blocked by complexing with the divalent metal cation in this complex), after which the divalent metal cation is removed from the complex, for example, by treatment with hydrogen sulphide or with ammonia. A method according to JP-A 138 * f02 /? 8 (corresponding to US application 90591, GB-A 2036020 and BE 879 925) can also be used, wherein a 3.2 ', 6 * -tri-N-acylated protected derivative of kanamycin-B is prepared in a manner substantially similar to the foregoing, except that a zinc cation is used in place of a divalent transition metal cation. In this way, a protected derivative of the formula (6 ') can be prepared in high yield from the compound of the formula (6). The 3 "amino group of this protected derivative (6), prepared in this manner, can be further protected by selective acylation according to the aforementioned JP-A 73 064/79 (and claim 15 of BE 879 923) for preparing an amino-protected derivative of an aminoglycoside antibiotic, of which all amino groups except the 1-amino group are selectively protected, so that a derivative with 3.2 ', 6', 3n-tetra-N-25 protection of the compound (6 ) can be obtained in high yield, thereby reacting the aforementioned 3,2'-tri-N-protected derivative of the compound (6) with a formic acid alkyl ester, a di- or tri-halogen alkanoic acid alkyl ester, formyl-imidazole or an N-alkanoyl-imidazole as an acylating agent, the 3M amino group being selectively acylated with the acyl moiety of the acylating agent to give a high yield without the 1-amino group of the aforementioned derivative is acylated.

The 3.2 ', 2 * ^ "- tetra-N-acylated derivative, for example 3,2', 6'-tri-N-benzyloxycarbonyl-3" -N-trifluoroacetyl derivative of 5.3 ', V-tri-35 deoxykanamycin-B or of 5,3'-1,6,6-tetradeoxykanamycin-B, obtained by using the aforementioned processes according to US 4 136 25 and BE 879923, forms a preferred starting compound for selective acylation with cc- hydroxy-α-aminoalkanoic acid (7) in the 1-N-acylation step of the present process.

8103639 'I,%, s - 16 -

In the present process, the 1-amino group of the compound of formula (6) or (6 '), individually or in mixtures of two or more such compounds, is acylated with the oc-1-hydroxy-amino-aminoalkanoic acid with the formula (7): A '^ 5 y: N- (CH-) -CHCOOH (7) B- ^ 2n |

OH

wherein A 'and B' have the meanings mentioned above, and n is 1, 2 or 5, while the amino group is protected or not. This acid can be 3-amino-2-hydroxypropionic acid (ie the compound of formula (7) »where n equals 1, and A 'and 10 B' are hydrogen atoms), 4-amino-2-hydroxybutanoic acid (id. with n equal to 2), or 5-amino-2-hydroxypentanoic acid (id.with n equal to 3). The (S) isomer is preferred.

The 1-N-acylation with os-hydroxy-co-aminoalkanoic acid (7) can be carried out in the manner usual for synthesizing peptides, for example according to the known dicyclohexylcarbodiimide process, the known mixed acid anhydride process the known azide process, or the active ester process or the like, wherein the aforementioned acid is used as such or in the form of an equivalent reactive derivative. To protect the amino group of this acid, a protecting group equal to or different from the group present in the starting compound (6) can be used. A preferred protecting group is, for example, the tert-butoxycarbonyl group, which can be easily removed by treatment with aqueous trifluoroacetic acid-acetic acid or water-dilute hydrochloric acid. A benzyloxycarbonyl group, which can be removed from the usual hydrogenolysis in the presence of a catalyst such as palladium or platinum oxide, is a suitable N-protecting group.

The 1-N-acylation is preferably carried out in an aqueous organic solvent according to the active ester process, using an os-hydroxy-co-aminoalkanoic acid in the form of its active ester. For example, the N-hydroxysuccinimide ester of L-1-benzyloxycarbonylamino-2-hydroxybutanoic acid can be used as the active ester, which can be prepared in the usual manner. This active ester is preferably used in a ratio of 0.5% to 3% and preferably of 1, 1.5 mol / eq. per mole of the starting compound (6) or (6 ') to be acylated. The watery 81 0 3 6 3 3 ___________________ e>

1 I

Organic solvent, which is used in the reaction medium, can be a water-miscible organic solvent such as dioxane, 1,2-dimethoxyethane, dimethylformamide, tetrahydrofuran, etc. The acylation can take place at the ambient temperature, but can also be carried out at a higher temperature if desired. temperature, for example from 20 ·.

90 ° C, this with a reaction time of several h, and preferably 5..6 h.

When the acylation is carried out with a starting compound, such as a partially amino-protected derivative, in which at least 10 amino groups other than the 1-araino group are protected, such as, for example, the 6'-N -protected derivative of the starting compound (6), the acylation products formed can be partially purified by column chromatography, for example on silica gel, to remove the unreacted starting material, thereby obtaining a mixture of the desired 1-N-monoacylated product with other N-acylated products as in the case of habekacin, namely 1-N - ((S) -4-amino-2-hydroxybutyryl) -3'-41-dideoxy-kanamycin-B according to K 107 ^ 2½. These mixed acylation products can be immediately subjected to the following deprotection processing step without purification and / or separation, after which purification and separation take place to obtain the desired 1-N-monoacylated product.

In the second step of the process under consideration, the 1-N-acylation product (including the mixed acylation products) is subjected to the removal of the amino protecting groups, if they are still present in the product. These protection groups are removed in the usual way. Thus, the amino protecting group of the alkoxycarbonyl type is removed by hydrolysis with a weak acid in an aqueous solution of trifluoroacetic acid or acetic acid or the like, or with a dilute aqueous solution of an inorganic acid such as hydrochloric acid.

The aralkyloxycarbonyl group, such as benzyloxycarbonyl, can be removed by ordinary catalytic reduction (hydrogenolysis). If a phthaloyl group is present in the protecting group, it can be removed by heating in a solution of hydrazine hydrate in a lower alkanol.

The acylation product thus treated after carrying out this second step can form the desired 1-N-acylation product with the formulation.

V

mule (2) together with some isomers thereof. The desired 1-N- (oc-hydroxy- <u-arainoalkanoyl) derivative (2) can be chromatographically separated and purified using a cation exchanger containing carboxyl functions such as 5 Amberlite CG-50 (Rohm & Haas Co.) or CM-Sephadex C-25 (Pharmacia Co.), after which the bactericidal activity of the washout fractions can be determined using a suitable kanamyein-sensitive resp. resistant bacterial strain.

The 5.3 ', **', 6H-tetradeoxykanamycin-B, which is used as starting compound in the process for preparing a 1-N- (cc-hydroxy-6) -aminoalkanoyl) -5.3 ' , ** · '^ "- tetradeoxykanaraycine-B is used, can be prepared starting from 3', ** · ', 6" -trideoxykanamycin-B, which has been synthesized previously (and 6u-deoxydibekacin is mentioned in the aforementioned JP-A 119 323/79 or GB-A 2 058 77 ** ·) »or an N, 0-protected derivative thereof precolled by the formula (8 *): CH3 a \ n

OH JV

B 0D \\ Νζ (8 ') wherein A is a hydrogen atom and B is a monovalent amino protecting group, or A and B together form a divalent amino protecting group, while D is a hydroxyl protecting acyl group.

According to a fourth aspect of the invention, there is provided a process for preparing 5'3 '' ** * ', 6' -tetradeoxykanamycin-B of the aforementioned formula (3), which comprises: (a) the ^ ' -'-hydroxyl group of a penta-N-protected and 2n-O-protected derivative of 3 ', **', 6u-trideoxykanamycin-B according to the formula (8): n ^ a

\ 5 ^ \ XB

81 0 3 6 3 9 b ^ n Cb • », ft - 19" where A is a hydrogen atom and B is a monovalent amino protecting group, or A and B together form a divalent amino protecting group, while D is a hydroxyl protecting acyl group, having a monovalent hydroxy protecting acyl group of the same kind as the group D in the 2 ”position, in order to obtain the V'-O-protected compound of the formula C8 ')? ^ Cli3 η A ^ (8 *) in which A, B and D have the aforementioned meaning; (b) reacting the 10 -O-protected compound of the formula (80 with sulfuryl chloride to replace its 5-hydroxyl group with a chlorine atom to form the corresponding 5-chloro derivative (c) reducing this 5-chloro derivative to remove the 5 "* chloro group and forming a protected derivative of 5 * 3 ', 4', 6H-tetradeoxykanamycin-B of the formula (9)? CH3 OA ^ ΛΤ \ B- "7 ^ - ^ / (,) - in which A, B and D have the same meaning again; and (d) in the known manner removing the remaining hydroxyl and amino protecting groups from the compound (9) to obtain the compound of the formula (3).

In this method, the amino protecting groups, which are in penta-N-protected and 2n-0-protected 3 '**,' 6 '- trideoxykanamycin-B

8103639 ___ \ Λ%, 'V' - 20 - of the formula (8), which are used as starting material *, are of the same kind as those in the starting compound of the formula (6 *) described in the previously described method were used. The preparation of the starting compound of the formula (8) 5 will now be described.

As a first step, the 4H-hydroxyl group of the starting compound (8) is protected with a monovalent hydroxyl protecting group of the acyl species, which may be a lower alkanoyl group such as an acetyl or aroyl group, for example benzoyl. The introduction of such a hydroxyl-protecting acyl group into the 1-hydroxyl group of the starting compound (8) can be accomplished in a known manner by reacting the starting compound (8) with a suitable acylating agent, such as an anhydride, acid halide or active ester, for example in an organic solvent such as pyridine, and at a temperature of 10-50 ° C, preferably the ambient temperature. Preferably, acetyl chloride or benzoyl chloride is used for this purpose. In this reaction, the 5-hydroxyl group of the starting compound (8) is hardly acylated because of the low reactivity of this group.

In this way, the 1.5 * 2 ', 6', 3 "-penta-N- and 2", A "-dio-protected derivative of 5" ** "," 6 "-trideoxykanamycin- B of the formula (8 ').

As a second step, the protected derivative (8 ') thus obtained is subjected to deoxygenation in its 5-hydroxyl group, as described in Bull. Chem. Soc. Jap. 51. (1978) 2351 * The protected derivative (8 ') is reacted with 1.5 mol of sulfuryl chloride in an organic solvent such as dry pyridine at a temperature lower than the ambient temperature for 2 20 h with stirring to give the 5-chloro derivative 50.

The third step of this method involves reducing the derivative thus obtained to dehalogenate it. The 5-chloro group can be removed by reaction with a metal hydride, for example tributyltin hydride, as described in the latter article, or by a conventional catalytic hydrogenation in the presence of Eaney nickel. In this manner, the Ν, Ο -protected derivative of 5.3 ', 4', 6 "-tetradeoxykanamycin-B of the formula (9) is obtained.

The fourth step involves removing the protection in 8103639

* A

- 21 - derivative (9) thus obtained · The monovalent hydroxyl protection acyl groups (D) in the 5-deoxygenated compound (9) can be easily removed by basic hydrolysis at the ambient temperature, for example by the compound (9) in an ammonia- .

5 methanol mixture to be dissolved · The amino protecting group present in the starting compound (8) is of the aralkyloxycarbonyl type, whereby a group of this nature can be subjected simultaneously to the catalytic hydrogenation to which the 5-chloro derivative is subjected during the third step. deleted. The other amino protection groups can be easily removed in a known manner, for example by hydrolysis in a weak acid. When the amino protecting group is a lower alkoxycarbonyl group, such as ethoxycarbonyl, it can be removed by basic hydrolysis with barium hydroxide.

Hereby. The method may also be changed.

15 operation, in which 3't ^ ', 6M-trideoxykanamycin-B is used as the starting material, its five amino groups are protected, and then the two 2 "and 4" hydroxyl groups simultaneously with the same monovalent hydroxyl protecting groups (D ) are protected to obtain the Ν, Ν -protected derivative of the formula (8 ').

The preparation of the penta-N-protected and 2 "-O-protected derivative of 3 ', 6" - trideoxykanamycin-B of the formula (8), * used as starting compound, can be carried out in GB-A 2 058 77 ^ described in the manner described. A penta-N-protected derivative of 3 ', V-dideoxykanamycin-B is then obtained, which is represented by the formula H0 ^ \ 0 oh i

B 1 3 B

wherein A and B have the same meaning as in formula (8), while both their bn and 6 "hydroxyl groups are protected simultaneously with a divalent hydroxyl protecting group, such as the isopropylidene group, while the 2" hydroxyl group is protected with 8103639

* V

<* "- 22 - a monovalent hydroxyl protecting acyl group, such as benzoyl or acetyl, where a 2M ^" tri-O protected derivative of the formulas 6 "y / \ 0 4» γ ^ 2 "\

B OD ^ 1 OH N "" 'B

a ---__ \ ^ ^ (b)

3 "~" B

in which A and B have the aforementioned meaning, and the group X ^ 5 y ^ ^ is a divalent hydroxyl protecting group, in which X and Y is a hydrogen atom, an alkyl group with 1.Λ C atoms, an aryl group such as t phenyl, or an alkoxyl group having 1 ... 4 C atoms, which group may also represent a cyclohexylidene group or a tetrahydropyranylidene group, and D is a monovalent hydroxy protecting acyl group * The derivative of the formula (b) is then treated with an aqueous acetic acid solution to remove the aforementioned group protecting the kH and 6n-hydroxyl groups, after which the thus partially unprotected product is reacted with a suitable sulfonylating agent such as p-toluenesulfonyl chloride in pyridine, in order to remove the 6 " -sulfonylation of its hydroxyl group, to form a 6n-O-sulfonylated derivative having the following formula: GSOg -'A 'A.

(o - 8103639 - 23 - wherein A, B and D have the meanings mentioned above, and G is a lower alkyl group, in particular with 1 ... 4 C atoms, or an aryl group such as phenyl or p-methylphenyl or an aralkyl group such as benzyl. The derivative thus obtained is then treated with an alkali metal iodide or bromide to replace the 6n-sulfonyloxy (GSO2) group to replace the iodine or bromine group and the iodine or bromide. bromo derirate of the corresponding formula, which is later reduced with hydrogen in the presence of a known hydrogenation catalyst, such as palladium, which results in dehalogenation, whereby the penta-N is protected and 2n-0 is protected. 6n-Trideoxykanamycin B derivative of the formula (8) is obtained as intended.

The formation of the new compound of the formula (4) according to the invention will now be described · This new compound such as 1-N - ((S) -ίi-amino-2 = hydroxybutyryl) -5ί3, V- trideoxy-6'-N = methyl kanamycin-B and 1-N - ((S) -5-amino-2-hydroxyvaleryl) -5,31, - * - tri-deoxy-6'-N-methylkanamycin-B can be synthesized by using as starting compound the new compound 5,3 ', ^' - trideoxy-6'-N-raethyl-kanamycin-B according to the invention, and condensing its 1-amino group 20 with a corresponding os-hydroxy-w aminoalkanoic acid or an equivalent compound.

As a fifth aspect of the invention, a process for forming 1N-Ca-hydroxy-α-aminoalkanoyl-S-1-β-trideoxy-'-N-methyl-kanaraycine-B of the formula (* 0 provides *0 * ~ "Λ ΗΟ-γΛ ^ Λ OH NHCHo

HN

CO (.k)

CHOH

(CH2) nNH2 8103639 - 2b - where n equals 1, 2 or 3 »which method includes! (a) acylating the 1-amino group of 5i3'-trideoxy-6'-N-methylkanamycin-B of the formula (5): HO * - ho h2n

η2Α-άΑ I

2 OH x NHCH, l'VA0 5 or a partially amino-protected derivative thereof of the formula (5 '):

r ° A

(5,) where A is a hydrogen atom, and at least one B is a monovalent amino protecting group, while the others represent a hydrogen atom, or at least a pair of A and B together form a divalent amino protecting group, while the others are each represent a hydrogen atom, while the amino protecting groups formed by these A and B may be the same or different, which is accomplished by a reaction with an α-hydroxy---aminoalkanoic acid or an amino-protected derivative thereof, represented by the formula (7) A | ^^ NCCEL) GHGOOH (7)

/ I

B 'OH

wherein A 'is a hydrogen atom and B' is a hydrogen atom or a monovalent amino protecting group, or A 'and B' together form a divalent 81 p 3 6 3 9 τ * »Λ * -25- amino protecting group, and n is 1, 2 or 3, or with an equivalent compound, · to form the 1-N-acylated product of the formula (4 ') ί ΗζΝΛ ^ HN - ^ (Ιμ) co

CHOH

I A * (CH2) nN <; Bf 3 or with the formula (4 · 1): ,, i

CO

CHOH

I Ar (CH2) nN \ gt wherein A, B, A ', B' and n have the aforementioned meaning; and (b) removing the remaining amino protecting groups of the 1-N-acylated product of the formula (V) or (4M) in a known manner to obtain the compound of the formula (4). further comprising an additional step, wherein the compound (6) is converted into a pharmaceutically acceptable acid addition salt thereof by reaction with an acceptable inorganic or organic acid, if desired.

8103639 \ - 26 -

This method can be agitated in the same manner as described under the third aspect of the invention.

When carrying out the process according to the fifth aspect of the invention, it is useful to use as starting compound% 5,3'A'-trideoxy-''-N-methyl-kanamycin-B of the formula (5), the amino groups of which in the not protected at all, either in the form of a free base or of an acid addition salt with a suitable acid such as hydrochloric acid. However, it is preferable to use as starting compound a partially amino-protected derivative of 5.3 ', V-trideoxy-''-N-methyl-kanamycin-B of the formula (5'), in which at least some of the three amino groups and methylamino groups, except the 1-amino group, are protected with known amino protecting groups, which can be done by introducing a known amino protecting group into the compound (5), as described in detail in connection with the third aspect of the invention.

In the process under consideration, the steps for 1-N-acylation of the starting compound (4) or (V) and deprotection of the 1-N-acylated product (V) or 20 (VO), as well as purification of the deprotected product is carried out in the same manner as described with reference to the third aspect of the invention.

The new compound of the formula (5), namely 5, 3, 3, 3, tri-deoxy-6'-N-methylkanamycin-B, which is used as starting compound in the present process, can be prepared by going from a known compound such as 5> 3'i ^ '- trideoxykanamycin-B (see Jap. J. Antibiot. 32 (1979) S-178), wherein the N-methylation of the 6'-amino group of this compound is the same manner as described in JP-Λ 83 671/72, US 3 925 353 and J. Antibiot. 30 £ 2, (1972) 7 ^ 3-

According to a sixth aspect of the invention, a process for producing 5.3, V-trideoxy-6-N-methylkanamycin. -B provides that the formula (5) has: 8103639

* - I.

- 27 -

HO --— V

HO H2N

H2N \ NHCH3 H2nV / "- ^ NH2 (5) which process comprises the following steps: (a) introducing an alkyloxycarbonyl group, a cycloalkyloxycarbonyl group or an aralkyloxycarbonyl group into the 6'-amino-5 group of 5» 3 ', V-trideoxykanamycin-B of the formula (10): HO --- Λ h2n \ ^ vA r0 '^ / 0H ^ nh2 η2ν ^^^ Λ ^ nh2 (10) to form the compound of the formula (11) : ': Λ ^ \ T ^ Z.

NHCORo 0H s 3 h2n \ - ^ vV - 'h2 (11) in which an alkyl group with 1..6 C atoms, a cycloalkyl group with 10 3..6 C atoms or an aralkyl group, in particular a phenyl -C 1 -C 1 -C 4 alkyl group such as benzyl; and (b) reducing the compound (11) with a metal hydride in an anhydrous organic solvent to form the compound of the formula (5) · 81 0 3 6 3 9.

- 28 -

The implementation of this method will now be described in more detail. In a first step, an alkyloxycarbonyl group, a cycloalkyloxycarbonyl group or an aralkyloxycarbonyl group is introduced into the 6'-amino group of the starting compound (10), which may be a group such as the urethane-type amino protecting group. Entering the roach group (-0 = 0.OR ^) into the 6'-amino group of the starting compound (10). is obtained in the same manner as described above for the preparation of the amino-protected derivative of the starting material (6 ') according to the third aspect of the invention. The selective protection of the 6'-amino group can take place because the 6'-amino group is the most reactive of the amino groups of the compound (10). The group to be introduced can preferably be a methoxycarbonyl group, an ethoxycarbonyl group or a benzyloxycarbonyl group. In this manner, the 6'-N-alkylphoxy, the 6'-N-cycloalkyloxy or ó'-N-aralkyloxy-carbonylated product of the formula (11) is formed.

The 6'-N-alkyloxy, ö'-N-cycloalkyloxy or 6'-N-aralkyloxy-carbonyl group introduced in this manner is converted by reduction to obtain the 6'-N-methylation. This can be done by reducing the compound of formula (11) with a metal hydride such as lithium aluminum hydride and diboran in an anhydrous organic solvent such as tetrahydrofuran. This reduction will usually be carried out at a temperature of 40-9 ° C for at least 10 hours.

The invention will be elucidated hereinbelow on the basis of some non-limiting examples. Examples I..III relate to the first and third viewpoints of the invention, example IV to the first and fourth viewpoints, example V to the sixth, and examples VI..VIII to the fifth viewpoint of the invention.

Example I:

Synthesis of 1-N-UsJ-A-amino-H-hydroxybutyryl) .beta.-trideoxy-kanamycin-B.

(a) 4.36 g (10 mmol) of 5.3 ', 4'-trideoxykanamycin-B was dissolved in 100 ml of dry dimethyl sulfoxide, to which then 10.5 g (48 mmol) of zinc acetate, ZniCH 2 CO 2 ^ H ^ O, was added. The resulting mixture was stirred at ambient temperature for 20 hours to form a complex of 5.3 ', 4'-trideoxykanamycin-B with a zinc cation. After adding 12.0 g (39.5 mmol) of paramethoxy-8103639 * * · .. Λ -29-benzyl-S-4,6-dimethylpyrimid-2-ylthiocarbonate (supplied by Kokusan Kagaku KK), the resulting mixture was at 50 ° C for 7.5 h. stirred to obtain the N-p-methoxybenzyloxycarbonylation. The resulting reaction solution was then poured into 1000 ml of water, adjusting the pi to 11 by adding ammonia to obtain the decomposition of the zinc complex, resulting in a precipitate. The precipitate was filtered off, washed with 500 ml of water and dissolved in 60 ml of a mixed solvent of chloroform-methanol-17% ammonia (50: 10: 1 by volume). This solution was chromatographed on a 500 g column of silica gel (Wako gel C-200), developing with the same mixed solvent, yielding up to 1.1 g (.bb #) of a 3.2 colorless powder 61-tri-N-paramethoxybenzyloxycarbonyl-5,31, b1-trideoxykanamycin-B.

15-3.7 g (b mmol) of this colorless powder were dissolved in 50 ml dimethyl sulfoxide and 0.95 ml (8 mmol) ethyl trifluoroacetate was added to the solution. The resulting mixture was stirred at room temperature for 5 h to obtain the 3u-N-trifluoroacetylation, whereby 3 * 2 ', 6,6-tri-N-paramethoxybenzyloxycarbonyl-20', N-trifluoroacetyl-5,3 ' Trideoxykanamycin-B was obtained.

(b) To the reaction solution thus obtained, containing the N-protected kanamycin B derivative, 0.6 ml (b, b mmol) of triethylamine was added, followed by a 1.9 g solution (6 mmol) N-hydrosuccinimide ester of (S) -4-tert-butoxycarbonylamino-2-25 hydroxybutyric acid in 20 ml of dioxane. This mixture was stirred at room temperature for 19 h, after which the reaction solution was poured into 500 ral water to separate a precipitate. The precipitate was filtered off and washed with 100 ml of water to give 10.9 g of colorless powder. This powder was dissolved in 20 ml of 90 tri-30 fluoroacetic acid and the solution was allowed to stand at room temperature for J + 5 min to obtain removal of the amino protecting groups. The solution was then dried and the residue was taken up in 100 ral water. The aqueous solution was adjusted to pH 10.5 by the addition of ammonia, and stirred at room temperature for 20 h to obtain removal of the trifluoroacetyl group. The resulting reaction solution was concentrated to about 20 ml, adjusted to a pH of 7.5 by adding ammonia, diluted with 50 nil water, and then passed through a column of 150 ml Amberlite CG-50 resin (in the NH ^ form, 8103639.3 * - 30 - supplied by Bohm & Haas Co.). This column was washed successively with 750 ml of water and 500 ml of 0.5 N ammonia, and rinsed with 0.8 N ammonia. The fractions containing the desired product were combined and dried, yielding 1.76 g (72%) of 1-N - ((S) -4-amino-2-5 hydroxybutyryl) -5,3 ', V-trideoxykanamycin -B-monoarbonate monohyrate as a colorless powder. The total yield was 32%.

Example II;

Synthesis of 1-N- (3-amino-2-hydroxypropionyl) -5'3 ', 4'-trideoxykana-10 raycine-B.

(a) 435 (5 (1mmol) 5 * 3 ', 4'-trideoxykanamycin-B was dissolved in 10ml of dry dimethyl sulfoxide, then 1.05B (4.8mmol) zinc acetate, Zn (CH 2 CO., 2 ^ 0 was added. The resulting mixture was stirred at room temperature for 23 h. Then, a solution of 937i3 mg (3, 9 mmol) of tert-butyl-S-4,6-dimethylpyrimid-2-ylthiocarbonate in 5 ml of dimethyl sulfoxide was added and the resulting mixture was added at 50 ° C for 24 h was stirred to obtain the N-tert-butoxycarbonylation. The resulting solution was mixed with 15 ml of water, adjusted to pH 11 with ammonia, followed by addition of 6.4 g of sodium chloride and extraction with ethyl acetate (2 x 15 ml). The ethyl acetate extracts were combined and dried, and the residue was dissolved in 6 ml of dimethyl sulfoxide. The solution was mixed with 0.125 ml (1 mmol) ethyl trifluoroacetate, which mixture was stirred at room temperature for 4 h to obtain the 3n ** N-trifluoroacetylation.

(b) To the aforementioned reaction solution, containing 3'2f, 6'-tri-N-tert-butoxycarbonyl-3H-N-trifluoroacetyl-5,3'14'-trideoxykanamycin-B, was added 0.1 ml (0.7 mmol) triethylamine and 3 ^ 4 mg (1.05 mmol) 30 N-hydroxysuccinimide ester of paramethoxybenzyloxycarbonylisoserine added. The resulting mixture was stirred at room temperature for 20 h, after which the reaction solution was mixed with 10 ml of water and extracted with ethyl acetate (2 x 10 ral). The combined extracts were concentrated to a low content, followed by the addition of 20 ml of 3N-hydrochloric acid-50% b methanol. The mixture was stirred at room temperature for 2 h to obtain the simultaneous removal of both the tert-butoxycarbonyl and paramethoxybenzyloxycarbonyl groups and the amino protection groups. The resulting solution was adjusted to a pH of 10 by adding ammonia to 8103639-31%, and then stirred at ambient temperature for 21 h to obtain removal of the trifluoroacetyl group. The reaction solution was evaporated and diluted with water, after which the resulting aqueous solution was passed through a column of 25 ral Diaion-WK-10S (in the ΝΗ ^ + - νοπη supplied by Mitsubishi Kasei K.K). This column was washed with 125 ml of water, then rinsed with 0.4 N ammonia. The fractions containing the desired product were combined and dried to 257 mg of 1-N- (3-amino-2-hydroxypropionyl) -5,3 '' 4'-trideoxykanamycin B monocarbonate 10 as a colorless powder. Total yield was 42%

Example III: Synthesis of 1-N - ((S) -4-amino-2-hydroxybutyryl) -5,31,4 ', 6 "-tetradeoxykanamycin-B.

(a) 419.5 mg (0.75 mraol) 5.3 '| 4', 6H-tetradeoxykanamycin B-dicarbonate monohydrate was dissolved in 10 ml of dry dimethyl sulfoxide, to which then 1.05 g (4.8 ramol) Zinc acetate, ZnCH 2 CO 2, 22 2, 22 0 0 was added, which mixture was stirred at ambient temperature for 18 h. Then a solution of 1.44 g (6.0 mmol) of terto-butyl-S-4,6-dimethylpyrimid-2-ylthiocarbonate in 5 roll dimethylsulfoxide was added, which mixture was stirred at 50 ° C for 25 h . The resulting reaction solution was mixed with 15 ml of water, adjusted to pH 11 with ammonia, and extracted with ethyl acetate (2 x 15 ml). The aqueous layer was mixed with 6.4 g of sodium chloride, and further extracted with 20 ml of ethyl acetate. The ethyl acetate extracts were combined and dried, after which the residue was dissolved in 6 ml of dimethyl methyl sulfoxide. This solution was mixed with 0.125 ml (1 mmol) ethyl trifluoroacetate, which was stirred at ambient temperature for 4 h.

(b) To the aforementioned reaction solution, containing 3 * 2 ', 6'-toll ”1 *” tert-butoxycarbonyl-3w-N-trifluoroacetyl-5,31,4 *, 6f, -tetradeoxykana-30 mycine- B, 0.1 ml (0.7 mmol) of triethylamine and 399 µg (1.05 mmol) of N-hydroxy succinimide ester of (S) -4-p-methoxybenzyloxy-carbonylamino-2-hydroxybutyric acid were added. The resulting mixture was stirred at ambient temperature for h8 h, then the solution was mixed with 10 ml of water, and extracted with ethyl acetate (2 x 10 ml). The combined extracts were concentrated to a low content, followed by the addition of 20 ml of 3N-chloro-hydrochloric acid-50% methanol. The mixture was stirred at ambient temperature for 2 h to obtain removal of both the tert-butoxy and the paramethoxybenzyloxycarbonyl groups. The "" ^ .........................

The resulting solution was adjusted to pH 10 by addition of ammonia, then stirred at ambient temperature for 20 h to remove the trifluoroacetyl group. The solution thus obtained was evaporated to a low content, then diluted with 3 water, after which this solution was passed through a column of 25 µl Diaion-VK-10S (NH 2 form). This column was washed with 125 al water, then rinsed with 0.32 N ammonia. The fractions containing the desired product were combined and then dried to 303 µg of 1N-iisO-amino-B-hydroxybutyryl) 6,6-10 tetradeoxykanaraycine B-dicarbonate in the form of a colorless powder The total yield was 63%

EXAMPLE 4 Synthesis of 5.31-6.6-tetradeoxykanamycin-B.

(a) Preparation of 1, 3.2 ', 6' ^ "- penta-N-ethoxycarbonyl ^" dideoxykanamycin-B.

15 g (10.3 moles) of 3'-dideoxykanamycin-B were dissolved in a mixture of ^ 5 al water and ^ 5 al methanol, to which was added 8 g (95 2 moles) sodium bicarbonate, followed by the slow addition of 7 .2 ml (75.6 mmol) of ethyl chloroformate under ice-cooling. The resulting mixture was stirred at ambient temperature for 18 h to obtain the N-ethoxycarbonylation. The resulting solution was mixed with 500 ml of water to separate a precipitate. This was filtered and washed with water to yield 6 9 g (78%) of colorless powder of the above composition.

(B) Preparation of 1,3,2 ', 6' ^ "- penta-N-ethoxycarbonyl -", 6n-O-isopropylidene-3 ', V' -dideoxykanamycin-B.

4.83 g (5.93 moles) of the product of step (a) were dissolved in 50 ml of dimethylformamide, to which 30 mg (0.16 mmol) p-toluene sulfonic acid and 1.1 ml (9.0 moles) 2,2-dimethoxypropane was added.

The resulting mixture was stirred at ambient temperature for 25 h (to obtain the 4 *, 6, - Q isopropylidenation), then the solution was mixed with 1 ml (7.2 mmol) of triethylamine, after which the solution was dried to 5.1 g (100%) of the above compound as a pale yellow powder.

(C) Preparation of 1,3,2 ', 6', 3 "-Penta-N-ethoxycarbonyl-4n, 6'-O-isopropylidene-2" -O-benzoyl-3,4,4-dideoxykanamycin- B.

5.1 g (6.0 mmol) of the product of step (b) were dissolved in 75 ml of pyridine, to which 1 ml (8.6 mmol) of benzoyl chloride was then added, which mixture was left at room temperature for - - - -T-33-5L was stirred to obtain the 2 "-Q-benzoylation. The solution thus obtained was mixed with 10 ml of water, stirred at ambient temperature, then dried. The residue was dissolved in 250 ml of chloroform , which solution was washed successively with 100 ml of 5,2 N hydrochloric acid and 2 x 100 ml of saturated aqueous sodium bicarbonate The chloroform layer was separated, dried over anhydrous sodium sulfate, and further dried to 5.7 g (99 #) of the above compound in the form of a pale yellow powder.

(D) Preparation of 1; 3.2 ·, 6 * ^ "- penta-N-ethyoxycarbonyl ^ *" -

O-benzoyl-3 ', 4'-dideoxykanamycin-B

5 * 3 g (5.5 mmol) of the product thus obtained were dissolved in 80 ml of a mixture of acetic acid-methanol-water (2 s 1 s 1 by volume), which solution was left at the ambient temperature for 21 h, after which this was dried to 4.9 g (97%) of the above compound as a pale yellow powder.

(e) Preparation of 1,3,2 ', 6', 3 "-penta-N-ethoxycarbonyl-2" - 0-

benzoyl-6n-0-tosyl-3 ', 4'-dideoxykanamycin-B

1.5 g (1.63 mmol) of the product thus obtained were dissolved in 28 ml of pyridine, to which 374 mg (1.96 mmol) of para-toluenesulfonyl chloride was then added, which mixture was stirred at ambient temperature for 28 h to effecting the-tosylation. The solution was then dried, dissolving the powdered residue (2.3 g) in 12.5 ml of dichloroethane, which solution was subjected to silica gel column chromatography (Wako gel C-200, 200 g). The column was washed with 1000 ml of dichloromethane-ethanol (60: 1) and developed with dichloromethane-ethanol (50: 1) to yield 1.0 g (60%) of a colorless powder of the above compound.

(F) Preparation of 1.3 * 2 ', 6', 3 "-Penta-N-ethoxycarbonyl-2" -O-benzoyl-6 "-iodine-31.4 * -dideoxykanamycin-B 900 mg ( 0.84 mmol) of the aforementioned product was dissolved in 18 ml of dimethylformamide, after which 12.6 g (84 mmol) of sodium iodide was added, and stirred at 95 ° C for 2 h to give the 6-yd. The resulting solution was poured into 250 ml of water, the precipitate formed was filtered off, and then dissolved in 100 ml of chloroform This solution was washed with 100 ml of 20 s aqueous sodium thiosulfate and 100 ml of saturated aqueous sodium chloride. above 8103639 "ί -e - 34 -

V

anhydrous sodium sulfate, and further dried to 817 (95%) of the above compound as a colorless powder.

(g) Preparation of 1.3 * 2 ', 6', 3n-penta-N-ethoxycarbonyl-2n-Q-3 benzoyl-3 *, 4 ', 6M-trideoxykanamycin-B.

773 rag (0.75 mmol) of the aforementioned product * was dissolved in 20 ml of dioxane, to which a small amount. Haney nickel -2 -2 was added, which mixture was hydrogenated under a hydrogen pressure of 0.35 MPa for 23.5 h using a Parr-10 device. The resulting solution was filtered to remove the catalyst, then dried to 655 mg (97%) of a colorless powder of the above compound.

(h) Preparation of 1.3 * 2 ', 6', 3 "-penta-N-ethoxycarbonyl-2", M, "di-O-benzoyl-3", 4 ", 6'-trideoxykanamycin-B.

622 mg (0.69 mmol) of the aforementioned product was dissolved in 30 ml of pyridine, followed by the addition of 0.1 ral (0.86 mmol) of benzoyl chloride, which mixture was stirred at ambient temperature for 25 h every 4 h. "-O-benzoylation. The resulting solution was dried and the residue was dissolved in 50 ml of chloroform 20. The solution was successively saturated with 20% aqueous potassium bisulfate (2 x 30 ral) saturated aqueous sodium bicarbonate (2 X 30 ml), and saturated aqueous sodium chloride (1 x 30 ml), then dried over anhydrous sodium sulfate, and dried to 663 mg (96%) of the aforementioned compound as a colorless powder.

(j) Preparation of 1,3,2 ', 6', 3'-penta-N-ethoxycarbonyl-2M, V'-di-O-benzoyl-5-chloro-3 ', 4'-3-trideoxykanamycin- B.

600 mg (0.6 mmol) of the aforementioned product were dissolved in 12 ml of pyridine, 0.1 ml (1.24 mmol of sulfururyl chloride was added under ice-cooling under cooling with ice, the mixture was stirred at ambient temperature for 18 h every 5 hours). Chlorination The solution thus obtained was mixed with 100 ml of water and extracted with 60 ml of chloroform The extract was successively mixed with 60 ml of 10 # aqueous potassium bisulfate, 60 ml of saturated aqueous sodium bicarbonate and 60 ml of saturated aqueous sodium chloride, then dried over anhydrous sodium sulfate, and finally dried in. The obtained powdery residue (572 mg) was dissolved in 5 ml of dichloroethane, and chromatographed on a column of silica gel (Wako gel C-200, 50 g). This column was washed with 500 ml of dichloromethane and a dichloromethane-ethanol mixture (100 µl) developed into 356 mg (58%) colorless powder of the above compound.

(k) Preparation of 1.3> 2 ', 6', 3 '- penta-N-ethoxycarbonyl-2n, V'-5-di-O-benzoyl-5,3'> S 6 '- tetradeoxykanamycin- B.

308 mg (0.13 mmol) of the aforementioned product were dissolved in 5 ml of dioxane, to which a small amount of Eaney nickel W-2 was then added, which mixture was hydrogenated under hydrogen pressure of 0.35 MPa for 23> 5 h , using a Parr-10 device to effect dechlorination. The resulting solution was filtered to remove the catalyst, then dried to 295 mg (100 #) of colorless powder of the above compound.

(1) Preparation of 5,31,6 "-tetradeoxykanamycin-B.

120 mg (0.12 mmol) of the aforementioned product were dissolved in a mixture of 1 ml of dioxane and 1 ml of water, to which was then added 100 mg (1.27 mmol) of barium hydroxide, BaCOH2). which mixture was then subjected to a deprotecting treatment by heating to 110 ° C for 15 h under reflux. Carbon dioxide gas was then introduced into the reaction solution to precipitate barium carbonate, which was filtered off. The filtrate was mixed with 30 ml of water, then passed through a column of 20 ml Amberlite CG-50 (NH 4 form, Eohm 8th Haas Co.). This column was washed with 100 ml of water and 75 ml of 0.1-N ammonia solution, then rinsed with 0.3 N ammonia. The rinse fractions containing the desired product were combined and dried to 19 * 5mg (29 #) 5.3 ", 6" - tetradeoxykanamycin B-dicarbonate monohydrate as a colorless powder.

Example Vt Synthesis of 5 * 3'V-trideoxy-ö'-N-methyl-kanamycin-B.

30 (a) A-, 0g (9.18mmol) 5 »3 ', 4'-trideoxykanamycin-B was dissolved in a mixture of 40ml water and kOml methanol, then added a 5 * 8ml solution (9.18 mmol) triethylamine and 2.72 g (11.02 mmol) 2- (tert.-butoxycarbonyloxyimino) -2-phenylacetonitrile (commercially available under the name B0C-0N from Aldrich Co.) in 35 4- 0 ml of methanol was added. The resulting mixture was stirred at ambient temperature for 3 h, after which the solution containing 6'-N-tert-butoxycarbonyl-5.3 ', V-trideoxykanamycin-B was mixed with 2 ml of 17 Se's aqueous ammonia, and then dried. The residue was dissolved in 100 ml of water, which solution was brought to a pH of - 36 - 7.4 with 6 N hydrochloric acid, then washed with JO 2 in 1 ethyl ether, and finally passed through a column (20 mm internal diameter) of 100 ml Amberlite CG-50 (NH ^ + - form Rohm & Haas Co ·). This column was washed with 300 ml of water and 150 ml of 0.1 M aqueous ammonia, and then rinsed with 0.2 M aqueous ammonia. The rinsing liquid was collected in 5 µl aliquots, after which parts 11..24 were combined and dried to 2.1 g (42.5%) 6'-N-tert-butoxycarbonyl-5.3 ' 4'-trideoxykanamycin-B. Drying of pooled parts 2β-33 gave 1.4-2 g of 10 (35.6%) unreacted having 5.3'-trideoxy-kanamycin-B.

(b) 1.86 g (314 mmol) of 6'-N-tert-butoxycarbonyl-4'-triodeoxykanamycin-B obtained in the aforementioned manner was dissolved in 60 ml of dry tetrahydrofuran, followed by the addition of 1.31 g (34.5 mmol) of lithium aluminum hydride, after which the whole was heated at 80 ° C under reflux for 20 h. The resulting mixture was added dropwise to 200 ml of water, separating a precipitate, which was filtered off. The filtrate was evaporated to remove the tetrahydrofuran, then adjusted to a pH of 6.5 by adding hydrochloric acid. The solution thus obtained was passed through a column (12 mm internal diameter) of 30 ml Amberlite CG-50 (NH ^ +), which column was washed with 150 ml water, and successively with 0.2 M aqueous ammonia (150 ral ), 0.3 M aqueous ammonia (150 ml), and 0.4 M aqueous ammonia was rinsed. The rinsing liquid was collected in 6 ml portions, after which the parts 11..1? were combined, and dried to 40 rag (39 9%) unreacted having N-tert-butoxycarbonyl-5-3-trideoxykanaraycine-B. Parts 37 · 55 were also dried, yielding 592 mg (32.4%) of the above compound 5.3 ", 4" -trideoxy-6 * -N-raethylkanamycin-B.

Example VI; Synthesis of 1-N - ((S) -4-amino-2-hydroxybutyryl) -5,3 ', 4'-trideoxy-6'-N-methylkanamycin-B.

583 mg (1.10 mmol) of 5.3'14'-trideoxy-6'-N-methylkanamycin-B, prepared as in Example V, were dissolved in 10 ml of 90% aqueous dimethyl sulfoxide, to which 1 16 g (5.28 mmol) of zinc acetate, ZincCH 2 CO 2 J SHGO, were added. The mixture was added to the. stirred at ambient temperature for 20 h, followed by adding a solution of 1.06 g (4.29 mmol) of 2- (tert.-butoxycarbonyloxyimino) -2-phenylacetonitrile in 5 ml of dimethyl sulfoxide, then at 50 ° for 6 h C was further stirred to obtain the N-tert-butoxy-8103639-37 carbonylation. The resulting solution was mixed with 2 ml of 17% aqueous ammonia, then with 100 ml of water, and the solution was washed with 50 ml of ethyl ether. The separated aqueous layer was adjusted to a pH of 11 with 17% aqueous ammonia, 5 and mixed with 2 g of sodium chloride, and the resulting solution was extracted with ethyl acetate (3 x 100 ml). The ethyl acetate extracts were combined, dried over anhydrous sodium sulfate, and then dried. a chloroform-methanol-conc. aqueous ammonia (30: 10 t 1 by volume) was used. The rinsing liquid was collected in 10 ml aliquots, after which the aliquots of 25 ·· 50 were combined and dried to 607 mg (73.6%) of 3.2 ', 6'-tri-N-tert-butoxycarbonyl- 5.3'-3'-trideoxy-6'-N-methyl-15-kanamycin-B.

590 mg (0.787 mmol) of the latter product was dissolved in 10 ml of dimethyl sulfoxide and 0.1½ ml (1.18 mmol) of ethyl trifluoroacetate was added to the solution. The mixture was stirred at ambient temperature for 1.5 h to obtain the 3u "N" tri-20 fluoroacetylation. The resulting solution, containing 3, 2,6, tri-N-tert-butoxycarbonyl-3-N-trifluoroacetyl-5,31-1-trideoxy-6'-N-methylkanamycin-B, was used with both 0.16 ml (1.18 mmol) triethylamine as * f20 mg (1.18 mmol) N-hydroxysuccinimide ester of (S) -p-methoxybenzyloxycarbonylamino-2-hydroxybutyric acid, dissolved in 25 ^ ml tetrahydrofuran, mixed , which mixture was stirred at ambient temperature for 1 hr to effect the 1-N-acylation, then 100 ml of water was added and the mixture was extracted with ethyl acetate (2 x 100 ml) The combined extracts were dried over anhydrous sodium sulfate and further dried to the 1-N-acylated product in the form of an amino-protected derivative thereof.

The 1-N-acylated product thus obtained was dissolved in 10 ml of 90% aqueous trifluoroacetic acid, which solution was left at ambient temperature for 5 b. was stirred to remove the tert-butoxy-35 carbonyl and p-methoxybenzyloxycarbonyl groups and the solution was dried. The residue was dissolved in 30 ml of water and the pH adjusted to 10 with 17% aqueous ammonia, followed by stirring at ambient temperature for 18 h to remove the trifluoroacetyl group. The solution thus obtained 8103639 - 38 - was brought to a pH of 7 »5 by adding 6 N hydrochloric acid, and then through a column (13 mm internal diameter) of 20 ml Amberlite CG-50 (NH 2 +). shape). This column was washed with 100 ml water and rinsed successively with 160 ml 0.3 M water-3 rig ammonia and 100 ml 0.8 M aqueous ammonia. The rinsing liquid was collected in 4 ml aliquots, after which the aliquots 27.62 were pooled and then dried to 3 ^ 6 mg (71.8%) of the aforementioned compound 1-N - ((S 4-araino-2-hydroxybutyryl) -5i3 'A -'-trideoxy-1'-N-raethylkanamycin-B in the form of its monocarbonate.

Example VII: Synthesis of 1-N- (3-amino-2-hydroxypropionyl) -5, 3, V-trideoxy-61-N-methylkanaraycine-B.

102 mg (0.136 mmol) of 312,6,6-tri-K-tert-butoxycarbonyl-5,3 *, 41-trideoxy-61-N-methylkanaraycine-B, prepared in the manner of Example VI, was prepared in 3 nil dimethyl sulfoxide dissolved and 0.02 ml (0.204 mmol) ethyl trifluoroacetate added. The mixture was stirred at ambient temperature for 1 h. The solution containing the formed 3, 2, 6, tri-N-tert-butoxycarbonyl-3n-N-trifluoroacetyl-5,3'-trideoxy-6'-N-methyl-kanamycin-B was used with both 0 0.03 ml (0.204 mmol) of triethylamine as 73 mg (0.204 mmol) of N-hydroxy-succinimide ester of 3-, P "-methoxybenzyloxycarbonyl-amino-2-hydroxy-propionic acid dissolved in 0.5 ml of tetrahydrofuran, which mixture was stirred at ambient temperature for 7 h to effect the 1-N acylation, then 10 ml of water was added and the solution was extracted with ethyl acetate (2 x 10 ral).

The combined extracts were dried over anhydrous sodium sulfate, then dried to 136 mg of the 1-N-acylated product as its amino-protected derivative.

This acylated product was dissolved in 3 ml of 90% aqueous tri-fluoroacetic acid, then stirred at ambient temperature for 2 h to remove the tert-butoxycarbonyl and p-methoxybenzyl-oxycarbonyl groups and the solution was dried. The residue was dissolved in 10 ml of water and its pH was adjusted to 10 with 17% aqueous ammonia, followed by stirring at ambient temperature for 16 h to remove the trifluoroacetyl group. The solution thus obtained was brought to a pH of 6.4 by adding 6 N hydrochloric acid, and then passed through a column (11 mm internal diameter) of 10 ml Amberlite CG-50 (NH. + Form). This column was washed with 3 ° ml of water and 8103639 - 39 - 30 ml of 0.2 M aqueous ammonia, then rinsed with 0.5 M aqueous ammonia. The rinsing liquid was collected in 1 ml aliquots, then aliquots 4..7 were combined, and dried to 38.1 mg (45, ½ #) of the desired 1-N- (3-amino-2-hydroxypropionyl) -5.53 ', 4'-trideoxy-6'-N-methyl-kanamycin-B in the form of its monocarbonate.

Example VIII: Synthesis of 1-N - ((S) -5-araino-2-hydroxyvaleryl) -5, 3, 4'-trideoxy-6'-N-methylkanamycin-B

The same operations as in Example 7 were carried out, but using 76 mg (0.204 mmol) of the N-hydroxysuccinimide ester of (S) -5-p-methoxybenzyloxycarbonylamino-2-hydroxyvaleric acid instead of the corresponding ester of 3- p-methoxybenzyl "oxycarbonylamino-2-hydroxy-propionic acid, which ester was reacted with the 3 * 2 ', 6'-tri-N-tert-butoxycarbonyl-3" -N-trifluoro-15-acetyl-5 » 3 ', 4'-trideoxy-6'-N-methylkanamycin-B.

After washing the Amberlite CG-50 column, parts 2218 were combined, and dried to 47.2 mg (53 * 8 #) of the above compound in the monocarbonate form.

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Claims (14)

1. Compound of formula (1): H-.6 "Xcit ^ O, 2 '4' ΗΟΐΓ ^^ \ h2 h2nA ^^^ \ ^ ~ \." vf ~ 3 "0H \ o 5 'NHRj ^ ΗΝ - ^^^ ν4 * 112 C1 where R is a hydroxyl group or a hydrogen atom, R ^ is a hydrogen atom or an o: -hydroxy-ω-aminoalkanoyl group of the formula: -CO-CH - (CH_) -NH-5, 2 n is 2 OH, where n is 1, 2 or 3 »and R ^ is a hydrogen atom or a raethyl group, provided that R ^ is not a methyl group when R is a hydrogen atom, and a pharmaceutically acceptable acid addition salt of this compound. 2. A compound according to claim 1, characterized in that it comprises 1-N- (α-hydroxy-ω-aminoalkanoyl) -5, 3 ', 4' -trideoxykanamycin-B or 1 -N- (ot - hydroxy-amino-alkanoyl) -5,3 ', 4', 6 "-tetradeoxykanamycin-B of formula (2) is: 6" • R ^ \ 2 "^ \ Ή-2 ^ 7" H_N '—η ii ^ Mu- 2 3 '' OH j1 g 4 o 5 JNh2 HN-Af 3 I (2) CO CHOH 81 0 3 6 3 9 (cH2) nNH2 - 49 - where S is a hydroxyl group or a hydrogen atom, and n is equal to 1, 2 or 3) as well as a pharmaceutically acceptable acid addition salt of this compound. 3- A compound according to claim 1, characterized in that it is 1N-Coc-hydroxy---aminoalkanoyl) ^-^-trideoxy-1'-N-methyl-canarycine-B of the formula (4) : 6 »HO \ 2 '4» _ \ «t h2n-t \ 3' ho4" V ^^ T \ X0 / * on OH 4 I 5 NHCHg Λη0 I 1 3 (4) CO CHOH i (CH2) nNH2 where n equals 1, 2 or 3, as well as a pharmaceutically acceptable acid addition salt of this compound. Compound according to claim 2, characterized in that it contains 1-N - ((S) -4-amino-2-hydroxybutyryl) -5,3'-trideoxykanamycin-B, 1-N- (3-amino-2-hydroxypropionyl) -5,3 ', 4'-trideoxykanamycin-B, or 1-N - ((S) -4-amino-2-hydroxybutyryl) -3,3', 4 ', 6u-tetradeoxykanamycin-B. 5 * A compound according to claim 3, characterized in that it contains 1-N- (3-amino-2-hydroxypropionyl) -5,31-trideoxy-6-N-methyl-kanamycin-1,1-N - ((S) -4-amino-2-hydroxybutyryl) -5,3,4,4-trideoxy-''-N-methyl-kanamycin-B, or 1N-CCSJ-amino-hydroxy-valeryl) ^ ^ 4 "-trideoxy-6'-N-methylkanamycin-B. 6. A compound according to claim 1, characterized in that it is 3.3 '»41 ^" - tetradeoxykanamycin-B of the formula (3): 8103639 t -50 - 4 6 "2' 4» Cft .0 \ [0] X / wM 1 "** q" 5 ^ "NH 2 H 2 3" 0 / \ ^ \ HgNjy ^ 2 "Y 2 (3) as well as a pharmaceutically acceptable acid addition salt of this compound. Compound according to claim 1, characterized in that it is 5.3 'jV-trideoxy-ó'-N-methylkanamycin-B of formula (5): 6 "ΗΟ- ^ Λ 2t Zf · ΗΟ'γΛγ0 ^ Η2Ν · γ \ 3 ^^ HonY- ^ V ^ Ai "lr | '^^ 7> nhch3 2 au OH. fr 4 50 ΛΛ - ^ \ ° H2n \ ^^ 2 ^^ nh2 C5) 1 3 as well as a pharmaceutically acceptable acid addition salt of this compound. A process for preparing the compound according to claim 2 of the formula (2), characterized by: (a) acylating the 1-amino group of 5'3f, 4'-trideoxykanamycin-B or 5 »3 '» 4 · * ^' '- Tetradeoxykanamycin-B of the formula (6): ° ™ 2 H2n \ - ^ A ^ -NH2 (6) in which E has the same meaning as in the formula (2), or of a 15 amino-protected derivative of 5 »3» «^ '- tri- or 5» 3, 4', βΜ- 8103639-51 - tetradeoxykanamycin-B of the formula (β1). .. in which. R is a hydroxyl group or a hydrogen atom, and A is a hydrogen atom, and at least one B is a monovalent amino protecting group 5, while every other B is a hydrogen atom, or at least one pair of A and B together form a divalent amino protecting group, while the other A and B each being a hydrogen atom, these amino protecting groups being mutually the same or different, by reaction with an οί-hydroxy-α-aminoalkanoic acid or an amino-10 protected derivative thereof of the formula (7): A »NV'S 'N (CH_) -CHC00H (7) / 22 B 'OH in which A' is a hydrogen atom, and B 'is a hydrogen atom or a monovalent amino protecting group, or A' and B 'together form a divalent amino protecting group, and n is 1, 2 or 3, or 15 with an equivalent compound to form the 1-N-acylated product of the formula (2 ') - =. ¾¾ HN— ^ (2') CO CHOH IA * 81 03 63 9 (CH2) nN <· B '^ · ƒ · (-52 - or with the formula (2M): R "" q As ΗΟ ^ ~ Λ ^ \ B / / ^^^ 7 b / ~ ^ oh ^ "" -b (2 "> I ^ B co CHOH 'x" A' <CH2 nNCB, wherein R, A, B, A ', B' and n have the aforementioned meaning, and by (b) removing the remaining 5 amino protecting groups, if any, from the 1-N-acylating in known manner. the product of formula (2 ') or (2H) to form the compound of formula (2). A method of forming the compound according to claim 3 of the formula (* 0, characterized by: IQ (a) acylating the 1-amino group of 5 * 3 ', V-trideoxy-6'-N- methylkanamycin-B of the formula (5) H0 - ^. ^ oh ^^ nnhch3 (5) or a partially amino-protected derivative thereof of the formula (5 ') 8103639 - 53 - «f ° ^ <? 0 ^ \ ^^ <B (5I) where A is a hydrogen atom, and at least one B is a monovalent amino protecting group, while the other B are each a hydrogen atom, or at least a pair of A and B together form a divalent amino-5 protecting group, and the the others A and B are each a hydrogen atom, which amino protecting groups may be the same or different from each other by reaction with a ce-hydroxy-amino amino-carboxylic acid or an amino-protected derivative thereof of the formula (7): A *> SS ^ N (CH,) (CHCOOH (7) / 2 n B »OH IQ where A 'is a hydrogen atom, and B' is a hydrogen atom or a monovalent amino protecting group, or A 'and B' together ee n to form a divalent amino protecting group, while n is 1, 2 or 3 »or an equivalent compound, to form the 1-N-acylated product of the formula (4 ') X rX, HN - COCO 1 ( ift) CHOH I ^ A * (CH2) nN <B, 8103639 »'^» rt - 5 * - or with the formula (V1): H ° ^ a ^ n Av * \ r ^ 0v' \ ^ C ^ ch3 oh | ^ B ο / νΛ - hn \ ^ '~' '^' n'v'b CO (4n) CHOH, x ^ A '(0H2) nN ^ ^ B' where A, B, A ', B' and n have the aforementioned meaning, and by (b) removing the other amino-protecting groups, if present, from the ΙτΝ-acylated product of the formula (Λ1) or (A ") in a known manner to form the compound of the formula (½)., 10. A method of forming the compound of claim 6 of the formula (3) characterized by: 10 (a) protecting the hydroxyl group of a penta-N-protected and 2n-Q-protected derivative of 3'Λ ', 6 "-trideoxykanamycin-B of the formula (8): 4" CH.3 λ a B / N OD I OH | AA \ N ~ i ^ \ ^. N ^ (8) wherein A is a hydrogen atom, and B is a monovalent amino protecting group, or A and B together form a divalent amino protecting group, while D is a hydroxyl protecting acyl group having a monovalent hydroxyl protection acyl group of the same kind as the 8103639-5? - hydroxyl protection group CD) at the 2 "position of the compound C $), to form the 4f, -O * protected compound of the formula C8 '>: CH3 oh r ° ^ <: (8f) B5 where A , B and D have the aforementioned meaning, by (b) reacting the ^ -O-protected compound of the formula (8 ') with sulfuryl chloride to replace its 5-hydroxyl group with a chlorine atom to form the corresponding 5-chloro derivative, by 10 (c) reducing this 5-chloro derivative to remove the 5-chloro group and forming a protected derivative of 5.3, 4'-tetradeoxykanamycin-B with the formula (9) ï CH3 η A ^ (9) in which A, B and D have the aforementioned meaning, and by removing (d) the residual hydroxyl protecting groups and amino protecting groups from the compound of the formula (9) to forming the compound of the formula (3) A process for preparing the compound according to claim 7 of the formula (3), characterized by: Ca) introducing an alkyl, a cycloalkyl or an aralkyl-oxycarbonyl group into the 6'-amino group of 5.3 ', V-trideoxykana-mycine-B of the formula C10): 8103639-56 φ «* · T 'c« HO --- Λ, 0i ° ^ NH2 (10) to form the compound of the formula (11): ^ V "nh2 (11) wherein R ^ is an alkyl group with 1 .. 6 C atoms, a cycloalkyl group with 5 3..6 C atoms, or an aralkyl group, especially a phenyl (0 ^ ... 0 ^) alkyl group, and more particularly benzyl, and by (b) reducing the compound of formula (11) with a raetal hydride in an anhydrous organic solvent to form the compound of formula (5) Bacteria control composition, comprising as the active ingredient 1N-C-hydroxy---aminoalkanoyl), 4 * -trideoxy-kanamycin-B, 1-N- (ce-hydroxy-α-aminoalkanoyl-5,3 ') * T ^ "- tetradeoxy-kanamycin-B or a pharmaceutically acceptable acid addition salt thereof according to claim 2 or 5" 3 "» T ^ -deoxykanaraycine-B or a pharmaceutically acceptable acid addition salt thereof as claimed in claim 6 for bacterial control effective amount for growth of bacteria along with a carrier for this active compound. Bacteria control composition, characterized in that it is as the active ingredient 1-N- (cc-hydroxy-ω-aminoalkanoyl) -5131-trideoxy-61-N-methyl-kanamycin-B or 3 * 3 ', V trideoxy-6'-N-methylkanamycin-B or a pharmaceutically acceptable acid addition salt 8103639 - 57 - β thereof according to claim 3 or 7 in an amount effective for bacterial control to prevent the growth of bacteria, together with a carrier for this active compound. 1 8103639