JPH07252290A - 1-N- (5-amino-4-fluoro-2-hydroxyvaleryl) kanamycin - Google Patents

Abstract

(57) [Summary] (Modified) [Objective] To provide a novel kanamycin derivative having excellent antibacterial activity against various bacteria and a broad antibacterial spectrum, and having extremely low acute toxicity. [Structure] A compound represented by the general formula (I) and an acid addition salt thereof, an antibacterial composition containing the compound or a pharmaceutically acceptable acid addition salt thereof as an active ingredient, and the general formula (I) And the intermediate compounds that can be used in the production method. [In the formula, (i) R ¹ = R ² = R ³ = OH, and R ⁴ · R ⁵ = HF; (ii) R ¹ = H, F, R ² = R ⁵ =
H, R ³ = R ⁴ = OH; (iii) R ¹ = NH ₂ in (a)
R ² = R ³ = R ⁴ = OH, R ⁵ = H, (b) R ² = R ³
= OH, R ⁴ · R ⁵ = HF, (c) R ² = H, R ³ = R
⁴ = OH, R ⁵ = H; and so on]

Description

Detailed Description of the Invention

[0001]

The present invention relates to a novel semisynthetic antibiotic, kanamycin A or B, deoxykanamycin A or B, or deoxy-fluorokanamycin A or B 1-N-[(2S, 4R). -Or (2S, 4S)-
5-Amino-4-fluoro-2-hydroxyvaleryl]
Derivatives and methods for their production.

1-N-[(2S, 4R)-or (2S, 4S) -5-amino-of the novel kanamycins according to the invention.
4-Fluoro-2-hydroxyvaleryl] derivatives have excellent antibacterial activity against various bacteria, a broad antibacterial spectrum, and markedly reduced acute toxicity, and thus are useful for treating bacterial infections. It is an antibacterial agent.

Further, the present invention relates to an antibacterial agent composition containing the above novel kanamycin derivative as an active ingredient, and also relates to a novel intermediate compound which can be used for producing the novel kanamycin derivative.

[0004]

Various deoxykanamycin derivatives and deoxy-fluorokanamycin derivatives derived from kanamycins A and B are already known and have useful antibacterial activity. Further, kanamycin A or B, or deoxykanamycin A or B, or deoxy-fluorokanamycin A or B 1-N-[(S) -4-
It is also known that Amino-2-hydroxybutyryl] derivatives have useful antibacterial activity.

For example, 3'-deoxy-3'-fluorokanamycin A (JP-A-61-40297 and US Pat. No. 4,63).
4,688) and 3'-deoxy-3'-fluorokanamycin B (JP-A-61-140597), 3 ', 4'-dideoxy-3'-fluorokanamycin B (JP-A-62-51694).
And U.S. Pat. No. 4,845,082), and 1-N-
[(S) -4-Amino-2-hydroxybutyryl]-
3'-deoxy-3'-fluorokanamycin A or B
(JP-A 61-236791), 2 ', 3'-dideoxy-
2'-fluorokanamycin A (JP-A-61-143393)
And 1-N-[(S) -4-amino-2-hydroxybutyryl] -2 ', 3'-dideoxy-2'-fluorokanamycin A (JP-A-62-93296 and U.S. Pat.
No. 474) is known.

Further, 4 "-deoxy-4" -fluoro-
4 ″ -Epicanamycin A (“Journal of Carbohydrat
e Chemistry ", Vol. 1, p. 289 (1982), and 6"-
Deoxy-6 ″ -fluorokanamycin A, 5,6 ″-
Dideoxy-5,6 "-difluoro-5-epikanamycin A and 5-deoxy-5-fluoro-5,4" -diepikanamycin A [24 volumes of "Tetrahedron Letters",
No. 17, pp. 1763-1766 (1983)]) is also known.

[Chemical Abstracts] 90
Vol. 104, 301 (1979), 5-deoxy-5-epi-
5-fluorokanamycin A is described.

Furthermore, 5-deoxy-5-fluoro- or 5-epi-5-fluorokanamycin B, 5,3'-
Dideoxy-5-fluoro- or 5-epi-5-fluorokanamycin B, 5,4'-dideoxy-5-fluorokanamycin B and 5,3 ', 4'-trideoxy-5-fluoro- or 5-epi-5 -Fluorokanamycin B (JP-A-63-39891 and European Patent Application No. 0 259 01
4A2) is also known.

1-N-[(S) -4-amino-2-hydroxybutyryl] -3 ', 4'-dideoxykanamycin B (Japanese Patent Publication No. 52-33629 and US Pat. No. 4,107,424)
Is an antibacterial agent known as habekacin or arbekacin and widely used clinically.

Further, 1-N-[(2R, 3R) -4-amino-
3-Fluoro-2-hydroxybutyryl] kanamycin A or B, or their deoxy derivatives are known to have excellent antibacterial activity (JP-A-63-208598).
U.S. Pat. No. 4,873,225 and European Patent Application No. 0 285.
526 A2).

[0011]

Conventionally, aminoglycoside antibiotics are water-soluble and therefore have good permeability to human tissues, and clinically have a better therapeutic effect on bacterial infections than other antibiotics. showed that. As such, it has often been used to treat patients with severe bacterial infections where other antibiotics are ineffective. However, since this treatment is mainly performed by intravenous injection of an aqueous solution of an aminoglycoside antibiotic, acute toxicity to the patient is rapidly expressed, and therefore the dose is reduced.
Discontinuation of administration is often forced. Currently, aminoglycoside antibiotics tend to be considered highly toxic.

The above-mentioned habekacin or arbekacin are also not completely satisfactory in terms of toxicity. Therefore, it is always desired to create new kanamycin derivatives that have excellent antibacterial activity but exhibit reduced toxicity. The present inventors have been engaged in research over the past many years for the purpose of reducing the toxicity of this aminoglycoside antibiotic.

[0013]

From the background of recent research, the present inventors have determined that the 1-position amino group of kanamycin A or B, or a deoxy derivative or deoxy-fluoro derivative thereof is 5-amino-4-fluoro. It was conceived to synthesize novel kanamycin derivatives by a method involving acylation with 2-hydroxyvaleric acid.
Based on this idea, studies were repeated to synthesize 5-amino-4-fluoro-2-hydroxyvaleric acid having a specific steric structure using L-malic acid as a starting material through multiple steps. As a result, (2S, 4R)-or (2S, 4S) -5-
We have succeeded in synthesizing amino-4-fluoro-2-hydroxyvaleric acid and its O-benzyl protected derivative. In this connection, as a precursor, (2S, 4R)-or (2S, 4S)
We have succeeded in synthesizing -5-azido-4-fluoro-2-hydroxyvaleric acid and its O-benzyl protected derivative.

As a result of further research, the above (2S, 4R)-
Or (2S, 4S) -5-azido-4-fluoro-2-hydroxyvaleric acid, or (2S, 4R)-or (2S, 4S) -5-amino-4-fluoro-2-hydroxyvaleric acid or them 1-N-generally represented by the following general formula (I) by a method comprising selectively acylating the 1-position amino group of kanamycins using the O-benzyl protected compound.
We have succeeded in synthesizing [(2S, 4R)-or (2S, 4S) -5-amino-4-fluoro-2-hydroxyvaleryl] kanamycin as a new compound. Moreover, the novel kanamycin derivative represented by the general formula (I) described below not only has excellent antibacterial activity against various kinds of bacteria, but also has markedly reduced toxicity (LD) to mammals as compared to Arbekacin. ₅₀ ) was shown.

Therefore, according to the first aspect of the present invention, the following general formula (I) [Wherein (i) each of R ¹ , R ² and R ³ is a hydroxyl group, R ⁴ is a hydroxyl group or a fluoro group and R ⁵ is a hydrogen atom, or R ⁴ is a hydrogen atom; R ⁵ is a fluoro group, or (ii) R ¹ is a hydrogen atom or a fluoro group, and each of R ² and R ⁵ is a hydrogen atom, and R
³ and R ⁴ are each a hydroxyl group, or (iii) R ¹
Is an amino group, R ² , R ³ and R ⁴ are each a hydroxyl group and R ⁵ is a hydrogen atom, or R ² and R ³ are each a hydroxyl group and either R ^{4 or} R ⁵ One of them is a fluoro group and the other is a hydrogen atom, or (iv) R ¹ is an amino group, R ² is a hydrogen atom, each of R ³ and R ⁴ is a hydroxyl group, and R ⁵ is a hydrogen atom. Or R
³ is a hydroxyl group, one of R ⁴ and R ⁵ is a fluoro group and the other is a hydrogen atom, or (v) R ¹ is an amino group, and each of R ² , R ³ and R ⁵ is hydrogen. An atom and R ⁴ is a hydroxyl group, or each of R ² and R ³ is a hydrogen atom and one of R ⁴ and R ⁵ is a fluoro group and the other is a hydrogen atom] -N-[(2
S, 4R)-or (2S, 4S) -5-amino-4-fluoro-2
-Hydroxyvaleryl] kanamycin A or B or a derivative thereof, and an acid addition salt thereof are provided.

The novel kanamycin derivative of the general formula (I) according to the first aspect of the present invention is roughly classified into the following 5 groups (1) to (1).
It can be classified into the kanamycin A or B derivative of (5).

(1) The following general formula (I-i) (Wherein R ⁴ is a hydroxyl group and R ⁵ is a hydrogen atom, or R ⁴ is a fluoro group and R ⁵ is a hydrogen atom,
Or R ⁴ is a hydrogen atom and R ⁵ is a fluoro group) 1-N-[(2S, 4R)-or (2S, 4S) -5-amino-
4-Fluoro-2-hydroxyvaleryl] -kanamycin A or -5-deoxy-5-fluorokanamycin A
Alternatively, -5-deoxy-5-epi-5-fluorokanamycin A and an acid addition salt thereof.

(2) The following general formula (I-ii) (In the formula, R ¹ is a hydrogen atom or a fluoro group) 1-N-[(2S, 4R)-or (2S, 4S) -5-amino-
4-Fluoro-2-hydroxyvaleryl] -2 ', 3'
-Dideoxykanamycin A or -2 ', 3'-dideoxy-2'-fluorokanamycin A, and acid addition salts thereof.

(3) The following general formula (I-iii) (In the formula, R ⁴ is a hydroxyl group and R ⁵ is a hydrogen atom, or R ⁴ is a fluoro group and R ⁵ is a hydrogen atom, or R ⁴ is a hydrogen atom.
Is a hydrogen atom and R ⁵ is a fluoro group) 1-
N-[(2S, 4R)-or (2S, 4S) -5-amino-4-fluoro-2-hydroxyvaleryl] -kanamycin B or -5-deoxy-5-fluorokanamycin B or -5
-Deoxy-5-epi-5-fluorokanamycin B,
And acid addition salts thereof.

(4) The following general formula (I-iv) (In the formula, R ⁴ is a hydroxyl group and R ⁵ is a hydrogen atom, or R ⁴ is a fluoro group and R ⁵ is a hydrogen atom, or R ⁴ is a hydrogen atom.
Is a hydrogen atom and R ⁵ is a fluoro group) 1-
N-[(2S, 4R)-or (2S, 4S) -5-amino-4-fluoro-2-hydroxyvaleryl] -3'-deoxykanamycin B or -5,3'-dideoxy-5-fluorokanamycin B or -5,3'-dideoxy-5-epi-5-fluorokanamycin B, and acid addition salts thereof.

(5) The following general formula (Iv) (In the formula, R ⁴ is a hydroxyl group and R ⁵ is a hydrogen atom, or R ⁴ is a fluoro group and R ⁵ is a hydrogen atom, or R ⁴ is a hydrogen atom.
Is a hydrogen atom and R ⁵ is a fluoro group) 1-
N-[(2S, 4R)-or (2S, 4S) -5-amino-4-fluoro-2-hydroxyvaleryl) -3 ', 4'-dideoxykanamycin B or -5,3', 4'- Trideoxy-5-fluorokanamycin B or -5,3 ', 4'
-Trideoxy-5-epi-5-fluorokanamycin B, and its acid addition salts.

In the compounds of the above general formula (I) or general formulas (Ii) to (Iv), (2
S, 4R)-or (2S, 4S) -5-amino-4-fluoro-2
-Hydroxyvaleryl group has the formula (2S, 4R) -5-amino-4-fluoro-2-
A hydroxyvaleryl group, or Represented by (2S, 4S) -5-amino-4-fluoro-2-
It can be a hydroxyvaleryl group.

The novel kanamycin derivatives of general formula (I) or of general formulas (Ii) to (Iv) according to the invention are
It is obtained in the form of a free base or hydrate or carbonate, and can be converted into a pharmaceutically acceptable acid addition salt by a conventional method. Such acid addition salts include pharmaceutically acceptable inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid or acetic acid, malic acid, citric acid, ascorbic acid,
There are salts with pharmaceutically acceptable organic acids such as methanesulfonic acid.

The novel kanamycin A according to the first invention
Alternatively, examples of the B derivative include the following 14 compounds (a) to
There is (n), and all of these compounds are basic colorless powdery substances which do not show a clear melting point. The names of these compounds are given below and the values of the specific optical rotations of these compounds are given.

Compound (a): 1-N-[(2S, 4R) -5-
Amino-4-fluoro-2-hydroxyvaleryl] kanamycin A [In the general formula (Ii), the 1-N-acyl group is a (2S, 4R) -5-amino-4-fluoro-2-hydroxyvaleryl group. Wherein R ⁴ is a hydroxyl group and R ⁵ is hydrogen] [α] _D ²⁴ + 82 ° (c 0.5, water) Compound (b): 1-N-[(2S, 4R) -5- Amino-4-
Fluoro-2-hydroxyvaleryl] -5-deoxy-
5-fluorokanamycin A [1- in the general formula (Ii)
The N-acyl group is (2S, 4R) -5-amino-4-fluoro-
2-hydroxyvaleryl group, R ⁴ is fluorine and R ⁵
When α is hydrogen] [α] _D ²⁴ + 80 ° (c 0.5, water) Compound (c): 1-N-[(2S, 4R) -5-amino-4-
Fluoro-2-hydroxyvaleryl] -5-deoxy-
5-epi-5-fluorokanamycin A [general formula (I-
In i), the 1-N-acyl group is (2S, 4R) -5-amino-4-
A compound in which a fluoro-2-hydroxyvaleryl group is used, R ⁴ is hydrogen and R ⁵ is fluorine] [α] _D ²³ +82
° (c 1, water)

Compound (d): 1-N-[(2S, 4R) -5-
Amino-4-fluoro-2-hydroxyvaleryl]-
2 ', 3'-dideoxykanamycin A [general formula (I-
In ii), the 1-N-acyl group is (2S, 4R) -5-amino-4-
Compound in which R ¹ is hydrogen in fluoro-2-hydroxyvaleryl group] [α] _D ²³ + 85 ° (c 1, water) Compound (e): 1-N-[(2S, 4R) -5- Amino-4-
Fluoro-2-hydroxyvaleryl] -2 ', 3'-dideoxy-2'-fluorokanamycin A [general formula (I
-Ii) the 1-N-acyl group is (2S, 4R) -5-amino-4
A compound which is a fluoro-2-hydroxyvaleryl group and R ¹ is fluorine] [α] _D ²² + 83 ° (c 1, water)

Compound (f): 1-N-[(2S, 4R) -5-
Amino-4-fluoro-2-hydroxyvaleryl] kanamycin B [In the general formula (I-iii), the 1-N-acyl group is a (2S, 4R) -5-amino-4-fluoro-2-hydroxyvaleryl group. Wherein R ⁴ is a hydroxyl group and R ⁵ is hydrogen] [α] _D ²⁴ + 81 ° (c 1, water) Compound (g): 1-N-[(2S, 4R) -5- Amino-4-
Fluoro-2-hydroxyvaleryl] -5-deoxy-
5-fluorokanamycin B [1- in the general formula (I-iii)
The N-acyl group is (2S, 4R) -5-amino-4-fluoro-
2-hydroxyvaleryl group, R ⁴ is fluorine and R ⁵
When α is hydrogen] [α] _D ²³ + 79 ° (c 1, water) Compound (h): 1-N-[(2S, 4R) -5-amino-4-
Fluoro-2-hydroxyvaleryl] -3'-deoxykanamycin B [In the general formula (I-iv), the 1-N-acyl group is (2S, 4R) -5-amino-4-fluoro-2-hydroxyvaleryl] A compound in which R ⁴ is a hydroxyl group and R ⁵ is hydrogen] [α] _D ²² + 75 ° (c 0.5, water)

Compound (i): 1-N-[(2S, 4R) -5-
Amino-4-fluoro-2-hydroxyvaleryl]-
5,3'-dideoxy-5-fluorokanamycin B
[In the general formula (I-iv), the 1-N-acyl group is (2S, 4R) -5.
-Amino-4-fluoro-2-hydroxyvaleryl group, a compound in which R ⁴ is fluorine and R ⁵ is hydrogen] [α] _D ²⁴ + 78 ° (c 1, water) Compound (j): 1 -N-[(2S, 4R) -5-amino-4-
Fluoro-2-hydroxyvaleryl] -5,3'-dideoxy-5-epi-5-fluorokanamycin B [in the general formula (I-iv), the 1-N-acyl group is (2S, 4R) -5-amino] -4-fluoro-2-hydroxyvaleryl group,
Compound in which R ⁴ is hydrogen and R ⁵ is fluorine] [α] _D ²⁴ + 77 ° (c 1, water)

Compound (k): 1-N-[(2S, 4R) -5-
Amino-4-fluoro-2-hydroxyvaleryl]-
3 ', 4'-dideoxykanamycin B [general formula (I-
In v), the 1-N-acyl group is (2S, 4R) -5-amino-4-
A compound which is a fluoro-2-hydroxyvaleryl group, R ⁴ is a hydroxyl group and R ⁵ is hydrogen] [α] _D ²² + 81 ° (c 1, water) Compound (l): 1-N- [ (2S, 4S) -5-amino-4-
Fluoro-2-hydroxyvaleryl] -3 ', 4'-dideoxykanamycin B [in the general formula (Iv), 1-N-
The acyl group is (2S, 4S) -5-amino-4-fluoro-2-
Compound wherein hydroxyvaleryl group, R ⁴ is hydroxyl group and R ⁵ is hydrogen] [α] _D ²³ + 71 ° (c 1, water)

Compound (m): 1-N-[(2S, 4R) -5-
Amino-4-fluoro-2-hydroxyvaleryl]-
5,3 ', 4'-Trideoxy-5-fluorokanamycin B [in the general formula (Iv), the 1-N-acyl group is (2S, 4
R) -5-amino-4-fluoro-2-hydroxyvaleryl group, a compound in the case where R ⁴ is fluorine and R ⁵ is hydrogen] [α] _D ²³ + 81 ° (c 1, water) Compound ( n): 1-N-[(2S, 4R) -5-amino-4-
Fluoro-2-hydroxyvaleryl] -5,3 ', 4'
-Trideoxy-5-epi-5-fluorokanamycin B [in the general formula (Iv), the 1-N-acyl group is (2S, 4R)-
A compound in which 5-amino-4-fluoro-2-hydroxyvaleryl group, R ⁴ is hydrogen and R ⁵ is fluorine] [α] _D ²² + 80 ° (c 0.5, water).

The antibacterial activity of the novel kanamycin derivative of the general formula (I) according to the present invention is obtained by culturing at a minimum growth inhibitory concentration (MIC, mcg / ml) against various bacteria in Mueller Hinton agar medium at 37 ° C. for 18 hours. Was measured by the multiple dilution method. The medium to be measured is pH
It was 7.

In particular, the following equation 1-N-[(2S, 4R) -5-amino-4-fluoro-2-hydroxyvaleryl] -3 ', 4'-dideoxykanamycin B (the above compound k) and 1-N-[( 2
The MIC (mcg / ml) with S, 4S) -5-amino-4-fluoro-2-hydroxyvaleryl] -3 ', 4'-dideoxykanamycin B (the compound 1) was measured in detail.
The measured antibacterial spectrum is shown in Table 1 below. Also,
For comparison, 1-N-[(S) -4-amino-2-hydroxybutyryl] -3 ', 4'-dideoxykanamycin B (ie habekacin or arbekacin: abbreviation AB
The antibacterial spectrum of K) was similarly measured and is shown in Table 1.

[0033]

[0034] As can be seen from the antibacterial data in Table 1 above, compound (k), ie, 1 which is an example of a novel kanamycin derivative of the present invention.
-N-[(2S, 4R) -5-amino-4-fluoro-2-hydroxyvaleryl] -3 ', 4'-dideoxykanamycin B [abbreviation: (2S, 4R) -4-F-Val-DKB ] And compound (l), namely 1-N-[(2S, 4S) -5-amino-4-
Fluoro-2-hydroxyvaleryl] -3 ′, 4′-dideoxykanamycin B [abbreviation: (2S, 4S) -4-F-Val-DK
B] has a high antibacterial activity against various bacteria and also against resistant bacteria, and exhibits a broad antibacterial spectrum.

Further, in order to evaluate the acute toxicity of the kanamycin derivative of the general formula (I) according to the present invention, several aqueous solutions of the compound of the present invention (adjusted to pH 7 by adding hydrochloric acid) were added.
When a half-lethal dose (LD ₅₀ ) (mg / kg) was calculated by injecting intravenously into a mouse strain (male, 4-week-old, 1 group 4 mice), (2S, 4
R) -4-F-Val- DKB [Compound (k)] LD ₅₀ value of is 135mg / kg, (2S, 4S ) -4-F-Val-DKB [compound (l)] LD ₅₀ value of Was 125 mg / kg. For comparison, it was found that the toxicity was well reduced compared to the LD ₅₀ value of 80 mg / kg of Arbekacin (abbreviation: ABK) that was similarly tested.

The compounds (a), (b), which are examples of the kanamycin derivative of the general formula (I) according to the present invention,
(C), (d), (e), (f), (g), (h),
In order to evaluate the antibacterial activity of (i), (j), (k), (l), (m) and (n), Escherichia coli (E. coli) K-12 and Pseudomonas aeruginosa (Pseudomonas aeruginosa)
The MIC (mcg / ml) of each of the above compounds for A3 was measured by the same multiple dilution method as described above, in comparison with arbekacin (abbreviation: ABK). The results are shown in Table 2 below.

[0037]

The novel kanamycin derivative of the general formula (I) or the acid addition salt thereof according to the present invention can be compounded with a pharmaceutically acceptable liquid or solid carrier to prepare an antibacterial composition.

Therefore, according to the second invention, the following general formula (I) (In the formula, R ¹ , R ² , R ³ , R ⁴ , and R ⁵ have the same meanings as described above.) 1-N-[(2S, 4R)-or (2S, 4S) -5 -Amino-4-fluoro-2-hydroxyvaleryl] kanamycin A or B or a derivative thereof or a pharmaceutically acceptable acid addition salt thereof as an active ingredient and mixed with the active ingredient to be pharmaceutically acceptable. An antibacterial agent composition is provided, which comprises a possible carrier.

The dosage form of the kanamycin derivative of the present invention of general formula (I) can be by injection. In the case of preparing an injection, a pH adjusting agent, a buffer, a stabilizer, an excipient, etc. are added to the compound of the present invention of formula (I) or a salt thereof as an active ingredient, and the mixture is lyophilized and then lyophilized for injection. The agent can be manufactured. Further, by adding a pH adjusting agent, a buffering agent, a stabilizer, an isotonic agent, a local anesthetic and the like to the compound of the present invention, subcutaneous, intramuscular and intravenous injections can be produced by a conventional method.

The dose of the compound of the present invention varies depending on the disease to be treated and its symptoms, but an appropriate amount can be determined by an appropriate preliminary test.

Next, the synthesis of the novel kanamycin derivative of the general formula (I) according to the present invention, particularly the general formula (Ii), the general formula (I-ii), the general formula (I-iii) and the general formula (I). -Iv) or the synthesis of the kanamycin derivative of the general formula (Iv) will be described.

According to the third aspect of the present invention, the following general formula (II)

[Wherein (i) each of R ¹ , R ² and R ³ is a hydroxyl group, and R ⁴ is a hydroxyl group or a fluoro group;
⁵ is a hydrogen atom, or R ⁴ is a hydrogen atom and R
⁵ is a fluoro group, or (ii) R ¹ is a hydrogen atom or a fluoro group, R ² and R ⁵ are each a hydrogen atom, and R ³ and R ⁴ are each a hydroxyl group, or
(iii) R ¹ is an amino group, each of R ² , R ³ and R ⁴ is a hydroxyl group and R ⁵ is a hydrogen atom, or R ²
And R ³ are each a hydroxyl group, one of R ⁴ and R ⁵ is a fluoro group and the other is a hydrogen atom, or (i
v) R ¹ is an amino group, R ² is a hydrogen atom, R ³
And R ⁴ are each a hydroxyl group and R ⁵ is a hydrogen atom, or R ³ is a hydroxyl group and one of R ⁴ and R ⁵ is a fluoro group and the other is a hydrogen atom, or (v )
R ¹ is an amino group, each of R ² , R ³ and R ⁵ is a hydrogen atom and R ⁴ is a hydroxyl group, or R ² and R 5
Each of ³ is a hydrogen atom, one of R ⁴ and R ⁵ is a fluoro group and the other is a hydrogen atom], or kanamycin A or B or a derivative thereof, or a derivative of the general formula (II) The amino group at the 1-position of the amino-protected derivative in which all or part of the amino group other than the amino group at the position is protected by an amino-protecting group is represented by the following general formula (III) (In the formula, Y is a hydrogen atom or a hydroxyl protecting group which can be eliminated by catalytic reduction) (2S, 4
R)-or (2S, 4S) -5-azido-4-fluoro-2-hydroxyvaleric acid or a derivative protected with a hydroxyl group thereof, or a valeric acid derivative of the general formula (III) or a protected derivative thereof. Acylation with an active ester results in the following general formula (IV)

1-N represented by the formula: wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and Y have the meanings defined above.
- generating acylated product or its protected derivative, which is then in the catalytic reduction subjected to azide group (-N ₃₎ the converted and Y is catalytically reduced to the amino group of a compound of formula (IV) de If it is a releasable hydroxy protecting group, the group Y is also eliminated, whereby the following general formula (V) A compound of formula (V) wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ have the meanings defined above, or an amino protected derivative thereof, and then a compound of general formula (V) Has a residual amino-protecting group, the following general formula (I) comprising removing the residual amino-protecting group from the amino-protected derivative of the compound of general formula (V).

[Wherein (i) each of R ¹ , R ² and R ³ is a hydroxyl group, and R ⁴ is a hydroxyl group or a fluoro group;
⁵ is a hydrogen atom, or R ⁴ is a hydrogen atom and R
⁵ is a fluoro group, or (ii) R ¹ is a hydrogen atom or a fluoro group, R ² and R ⁵ are each a hydrogen atom, and R ³ and R ⁴ are each a hydroxyl group, or
(iii) R ¹ is an amino group, each of R ² , R ³ and R ⁴ is a hydroxyl group and R ⁵ is a hydrogen atom, or R ²
And R ³ are each a hydroxyl group, one of R ⁴ and R ⁵ is a fluoro group and the other is a hydrogen atom, or (i
v) R ¹ is an amino group, R ² is a hydrogen atom, R ³
And R ⁴ are each a hydroxyl group and R ⁵ is a hydrogen atom, or R ³ is a hydroxyl group and one of R ⁴ and R ⁵ is a fluoro group and the other is a hydrogen atom, or (v )
R ¹ is an amino group, each of R ² , R ³ and R ⁵ is a hydrogen atom and R ⁴ is a hydroxyl group, or R ² and R 5
Each of ³ is a hydrogen atom, one of R ⁴ and R ⁵ is a fluoro group, and the other is a hydrogen atom]
N-[(2S, 4R)-or (2S, 4S) -5-amino-4-fluoro-2-hydroxyvaleryl] kanamycin A or B
Alternatively, a method for producing the derivative is provided.

Examples of the kanamycins A or B of general formula (II) or their deoxy or deoxy-fluoro derivatives used as starting compounds in the third process of the invention include the following known compounds: (i) Kanamycin A,
5-deoxy-5-fluorokanamycin A and 5-deoxy-5-epi-5-fluorokanamycin A; (ii)
2 ', 3'-dideoxykanamycin A and 2', 3 '
-Dideoxy-2'-fluorokanamycin A; (iii)
Kanamycin B, 5-deoxy-5-fluorokanamycin B and 5-deoxy-5-epi-5-fluorokanamycin B; (iv) 3'-deoxykanamycin B (ie tobramycin), 5,3'-dideoxy-5- Fluorokanamycin B and 5,3'-dideoxy-5-
Epi-5-fluorokanamycin B, and (v) 3 ',
4'-dideoxykanamycin B (ie dibekacin), 5,3 ', 4'-trideoxy-5-fluorokanamycin B (ie 5-deoxy-5-fluorodibekacin) and 5,3', 4'-trideoxy-5 -Epi-5-fluorokanamycin B (i.e. 5-deoxy-5-epi-5-fluorodibekacin).

The starting compound used in the third method of the present invention may be an amino-protected derivative in which all or part of the amino group other than the 1-position amino group of the kanamycin derivative of the general formula (II) is protected. . The amino-protecting group that can be used here includes a usual amino-protecting group. For example, a monovalent amino group including an alkoxycarbonyl group such as a tertiary butoxycarbonyl group, an aralkyloxycarbonyl group such as a benzyloxycarbonyl group, and a substituted lower alkanoyl group which is easily removed by hydrolysis such as a trifluoroacetyl group. A phthaloyl group can be used as a protecting group as well as a divalent amino protecting group.

The introduction of these amino protecting groups can be carried out by a known method in peptide synthesis or the like, for example, by adding a known amino protecting group introducing agent in the form of an acylating agent such as an acid halide or an active ester of kanamycin of the general formula (II). It can be carried out by reacting with a compound.

In the third method of the present invention, the general formula (I
Examples of the amino-protected derivative in which all or part of the amino groups other than the 1-position amino group of the starting kanamycin compound of I) are protected include, for example, 3,2 ′, 6 ′, 3 ″ -tetra-N-
Protected body, 3,2 ', 6'-tri-N-protected body, 3,6'
-Or a 6 ', 3 "-di-N-protected form or a 6'-mono-N-protected form can be used.

In order to produce the target compound of the general formula (I) in a high yield by the third method of the present invention, basically, the 1-position amino group of the starting kanamycin compound of the general formula (II) is selectively selected. In addition, acylation with 5-azido-4-fluoro-2-hydroxyvaleric acid of the formula (III) may be followed by reduction of the azido group. Therefore, it is preferred to use as starting material an amino protected derivative of the starting kanamycin compound of formula (II) in which all amino groups other than the 1-position amino group are occluded with amino protecting groups.

The following method can be used, for example, to prepare an amino-protected derivative in which all amino groups other than the 1-position amino group of the kanamycin compound of the general formula (II) are protected. That is, the kanamycin compound of formula (II) is reacted with a cation of a divalent transition metal such as zinc to form a metal complex, and an amino-protecting group-introducing agent is allowed to act on this complex to form 1 and 3 positions of the kanamycin portion of the complex. Protecting all amino groups except the two amino groups at the ″ position (these are complexed with a divalent metal ion to be blocked) with an amino protecting group,
After that, divalent metal cations are removed from the complex by treating with, for example, a cation exchange resin or aqueous ammonia, and JP-B-63-1319 or U.S. Pat.
By applying the N-protection method described in claim 1 of claim 5, 3,6'-di-N-protected derivative or 3,2 ',
The 6'-tri-N-protected derivative is produced in high yield.

Next, Japanese Patent Publication No. 63-32799 or US Patent No.
A tri-N-protected or tetra-N-protected derivative in which all amino groups other than the 1-position amino group of compound (II) are protected by application of the method for producing an amino protected derivative described in claim 15 of 4,297,485. Can be prepared. That is, according to the method of JP-B-63-32799 or U.S. Pat. No. 4,297,485, the N-protected form of kanamycin in which all amino groups other than the 1-position and 3 "-position amino groups are protected is the 3" -position amino group. As a selective acylating agent of, for example, a trihalogenated alkanoic acid ester, particularly trifluoroacetic acid ethyl ester is allowed to act. By this, without acylating the 1-position amino group of the kanamycin compound,
The amino group at the 3 ″ position can be selectively protected with a trihaloalkanoyl group.

In the third method of the present invention, 2 of the general formula (III) is used.
Acylation of the 1-amino group of the starting kanamycin compound (II) or a partial amino-protected derivative thereof with 5-azido-4-fluoro-2-hydroxyvaleric acid with or without protection of the 2-hydroxyl group. Consisting of 1-N
The acylation reaction is carried out first. In this reaction, a reaction derivative of 5-azido-4-fluoro-2-hydroxyvaleric acid of the general formula (III) or a protected derivative thereof is converted into a starting compound (II) by a dicyclohexylcarbodiimide method or an active ester method at a reaction temperature of 0 ° C. It can be carried out by operating at -30 ° C. Expression (I
The amino protecting group of the N-protected derivative of the starting kanamycin compound of I) is a tertiary butoxycarbonyl group or paramethoxybenzyloxycarbonyl group, which can be easily deprotected with an acid,
Alternatively, a benzyloxycarbonyl group that can be deprotected by catalytic reduction is preferable.

The above 1-N-acylation reaction is preferably carried out by the active ester method in a water-containing organic solvent. For example, N-hydroxysuccinimide of the valeric acid compound of formula (III) is used as a solvent in dioxane, dimethoxyethane, dimethylformamide, or tetrahydrofuran.

1-N of the general formula (IV) thus generated
- converted to 1-N-terminus of the azide group of the acyl group (-N ₃₎ then catalytically reduced with an amino group of the acylated reaction product (-NH _2). At this time, if there is a hydroxy protecting group (Y),
This can also be detached.

When an amino-protecting group remains in the obtained reduction product of the general formula (V), the amino-protecting group is further eliminated by a conventional method. That is, the alkyloxycarbonyl group-type amino protecting group is eliminated by hydrolysis in hydrous trifluoroacetic acid. Further, when the amino protecting group is an aralkyloxycarbonyl group such as a benzyloxycarbonyl group, it can already be eliminated in the preceding catalytic reduction (hydrogenolysis) step, so it is not necessary to remove the special amino protecting group. .

(2S, 4R)-or (2
S, 4S) -5-Azido-4-fluoro-2-hydroxyvaleric acid or its 2-O-benzylated product is a novel compound synthesized by the present inventor this time. The method of synthesizing these compounds from L-malic acid in multiple steps is as described below.

Then, (2S, 4R)-or (2S, 4S) -5-azido-2-benzyloxy-4-fluorovaleric acid, and (2S, 4R)-or (2S, 4S) -5- Amino-4-fluoro-
A method for synthesizing 2-hydroxyvaleric acid will be briefly described. Details of the reaction in each reaction step are shown in Reference Examples 1 and 2 below.

(1) The following equation L-malic acid from "Journal of Molecular Structure"
Volume 12, page 71-78 (1972) by the method of the following formula (2R, 5S)
-5-methylcarboxy-2-trichloromethyl-1,
3-Dioxolan-4-one [Compound (1)] is synthesized.

(2) From compound (1) to “Justus Liebigs A
nnalen der Chemie ", Volume 677, pages 200-208 (1964), and the formula (2R, 5S) -5- (2
-Chloro-2-oxoethyl) -2-trichloromethyl-1,3-dioxolan-4-one [compound (2)] is synthesized.

(3) The carbon chain is extended by reacting the compound (2) with diazomethane to give a compound of the formula (2R, 5S)
-5- (3-Chloro-2-oxopropyl) -2-trichloromethyl-1,3-dioxolan-4-one [compound (3)] is synthesized [see Reference Example 1 (a) below].

(4) Compound (3) is azidated with sodium azide to give (2R, 5S) -5- (3-azido-2-oxopropyl) -2-trichloromethyl-1,3-dioxolane of the following formula: -4-one [compound (4)] is synthesized [see Reference Example 1 (b)].

(5) Compound (4) is reacted with zinc borohydride to carry out reduction of ketone and elimination of trichloroethylidene group, and cyclization accompanied therewith. As a result, two lactones of the following formula (2S, 4S) -4-azidomethyl-2-
Hydroxy-4-butanolide [Compound (5)] and its 4
Position epimer, that is, (2S, 4R) -4-azidomethyl-2-hydroxy-4-butanolide [compound (6)] is synthesized [see Reference Example 1].

(6) When the compound (5) is reacted with benzyl bromide to form a benzyl group, (2S, 4S) -4-azidomethyl-2-benzyloxy-4-butanolide of the formula:
(7)] is generated [see Reference Example 1 (d)]. (In the formula, Bzl represents a benzyl group, and so on).

(7) When the compound (7) is treated with a solution of hydrogen chloride in methanol to perform ring opening of lactone and methyl esterification, (2S, 4S) -5-azido-2-benzyloxy- Methyl 4-hydroxyvalerate [compound (8)] is produced [see Reference Example 1 (e)]. (In the formula, Me represents a methyl group, and the same applies hereinafter).

(8) The 4-position hydroxyl group of the compound (8) is fluorinated with diethylaminosulfur trifluoride or another fluorinating agent, and then (2S, 4R) -5-azido-
Methyl 2-benzyloxy-4-fluorovalerate [compound (9)] is produced [see Reference Example 1 (f)].

(9) When the compound (9) is hydrolyzed with an aqueous solution of alkali metal hydroxide, (2S, 4R) -5-azide-
2-benzyloxy-4-fluorovaleric acid [compound (1
0)] is generated [see Reference Example 1 (g)].

(10) The compound (10) is catalytically reduced with hydrogen for a sufficient time in the presence of a palladium catalyst to reduce an azide group and eliminate a benzyl group. (2S, 4R) -5 of the following formula
-Amino-4-fluoro-2-hydroxyvaleric acid [compound (13)] is produced [see Reference Example 1 (H)].

(11) Alternatively, the compound (6) of the above item (5)
Is reacted with benzyl bromide in the same manner as in the case of compound (5) to produce (2S, 4R) -4-azidomethyl-2-benzyloxy-4-butanolide of the following formula (compound (14)). [Refer to Reference Example 2 (a) below].

(12) The compound (14) is treated with a solution of hydrogen chloride in methanol in the same manner as in the case of the compound (7) to give (2S, 4R) -5-azido-2-benzyloxy-4 of the following formula. -Methyl hydroxyvalerate [compound (15)] is produced [see Reference Example 2 (b) below].

(13) When the 4-position hydroxyl group of the compound (15) is fluorinated with diethylaminosulfur trifluoride or another fluorinating agent, (2S, 4S) -5-azido-2-benzyloxy-4 -Methyl fluorovalerate [compound (16)] is produced [see Reference Example 2 (c)].

(14) When the compound (16) is hydrolyzed with alkali, (2S, 4S) -5-azido-2-benzyloxy-4-fluorovaleric acid [compound (17)] of the following formula is produced [ Refer to Reference Example 2 (d)].

(15) When the compound (17) is catalytically reduced with hydrogen for a sufficient time, (2S, 4S) -5-amino-4-fluoro-2-hydroxyvaleric acid [compound (18)] of the following formula is produced. [Refer to Reference Example 2 (e)].

By adjusting the reaction time of the hydrogen catalytic reduction of the compound (10) and the hydrogen catalytic reduction of the compound (17),
(2S, 4R) -5-amino-2-benzyloxy-4 of the following formula
-Fluorovaleric acid [compound (19)] and the following formula (2S, 4S)-
5-Amino-2-benzyloxy-4-fluorovaleric acid [compound (20)] can be produced respectively [Reference Example 1 described below].
See (h) and Reference Example 2 (e)].

Further, as another method for producing the kanamycin derivative of the general formula (I), according to the fourth invention, the following general formula (II)

[Wherein (i) each of R ¹ , R ² and R ³ is a hydroxyl group, and R ⁴ is a hydroxyl group or a fluoro group;
⁵ is a hydrogen atom, or R ⁴ is a hydrogen atom and R
⁵ is a fluoro group, or (ii) R ¹ is a hydrogen atom or a fluoro group, R ² and R ⁵ are each a hydrogen atom, and R ³ and R ⁴ are each a hydroxyl group, or
(iii) R ¹ is an amino group, each of R ² , R ³ and R ⁴ is a hydroxyl group and R ⁵ is a hydrogen atom, or R ²
And R ³ are each a hydroxyl group, one of R ⁴ and R ⁵ is a fluoro group and the other is a hydrogen atom, or (i
v) R ¹ is an amino group, R ² is a hydrogen atom, R ³
And R ⁴ are each a hydroxyl group and R ⁵ is a hydrogen atom, or R ³ is a hydroxyl group and one of R ⁴ and R ⁵ is a fluoro group and the other is a hydrogen atom, or (v )
R ¹ is an amino group, each of R ² , R ³ and R ⁵ is a hydrogen atom and R ⁴ is a hydroxyl group, or R ² and R 5
Each of ³ is a hydrogen atom, one of R ⁴ and R ⁵ is a fluoro group and the other is a hydrogen atom], or kanamycin A or B or a derivative thereof, or a derivative of the general formula (II) The amino group at the 1-position of the amino-protected derivative in which all or part of the amino group other than the amino group at the position is protected by an amino-protecting group is represented by the following general formula (VI):

(Wherein Y is a hydrogen atom or a hydroxyl protecting group which can be eliminated by catalytic reduction and Z is a hydrogen atom or an amino protecting group) (2S, 4R)
-Or (2S, 4S) -5-amino-4-fluoro-2-hydroxyvaleric acid or a derivative thereof protected with a hydroxyl group and / or an amino group, or a valeric acid derivative of the general formula (VI) or this Acylation with an active ester of a protected derivative of the compound of formula (VII) A 1-N-acylated product or an amino-protected derivative thereof represented by the formula: wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , Y and Z have the meanings defined above. Generate and also general formula
The formation of an amino-protected derivative of the compound of formula (VII) from which the residual hydroxyl- and amino-protecting groups are eliminated by the following general formula (I) (Wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ have the meanings defined above) 1-N-[(2S, 4R)-or (2S, 4S) -5 -Amino-4-fluoro-2-hydroxyvaleryl] kanamycin A or B or a derivative thereof is provided.

The general formula (I
The starting kanamycin compound of I) is the same as that which can be used in the third method of the present invention. The starting kanamycin compound of the general formula (II) is converted to (2S, 4R)-or (2S, 4S)-of the general formula (VI).
The reaction of 1-N-acylation with 5-amino-4-fluoro-2-hydroxyvaleric acid or a protected derivative thereof can be carried out in the same manner as in the third method of the present invention.

The 5-amino-4-fluoro-2-hydroxyvaleric acid of the general formula (VI) may have its 2-position hydroxyl group protected with a hydroxyl protecting group capable of leaving by catalytic reduction, for example, a benzyl group. it can. In addition, the general formula (V
The 5-position amino group of the valeric acid compound of I) is an amino protecting group which can be easily removed by acid hydrolysis, for example, an alkoxycarbonyl group such as tertiary butoxycarbonyl or an amino protecting group which can be removed by reduction, for example, a benzyloxycarbonyl group. Can be protected by.

1-N of the general formula (VII) thus produced
-When the acylation reaction product has a residual amino-protecting group (such as Z), the amino-protecting group is eliminated, and this elimination can be performed by a conventional method. That is, the alkoxycarbonyl group type amino protecting group is eliminated by hydrolysis with trifluoroacetic acid, acetic acid or dilute hydrochloric acid. When the amino-protecting group is an aralkyloxycarbonyl group such as a benzyloxycarbonyl group, it can be eliminated by ordinary catalytic reduction (hydrogenolysis). When the 1-N-acylated product of general formula (VII) has a residual hydroxyl protecting group (Y), it can be eliminated by catalytic reduction.

Thus, removal of all residual amino and hydroxyl protecting groups produces the desired kanamycin derivatives of general formula (I) above according to the invention.

In order to isolate and purify this objective kanamycin derivative, a chromatographic method in which a molecular eluent such as CM-Sephadex C-25 is used and gradient elution is carried out with aqueous ammonia is suitable.

The above-mentioned 5-azido-2-benzyloxy-
4-fluorovaleric acid, 5-azido-4-fluoro-2-
Hydroxyvaleric acid, 5-amino-4-fluoro-2-hydroxyvaleric acid and 5-amino-2-benzyloxy-
4-Fluorovaleric acid is a novel compound synthesized by the present inventors for the first time, and although it has no antibacterial activity itself, it is an intermediate compound useful for the production of the novel kanamycin derivative of the general formula (I). Is.

Therefore, according to the fifth aspect of the present invention, the following equation (VI
II) (Wherein Y'is a hydrogen atom or a benzyl group) or (2S, 4R)-or (2S, 4S) -5-azido-4-fluoro-2-hydroxyvaleric acid or (2S, 4R) -Or (2
S, 4S) -2-Benzyloxy-4-fluorovaleric acid is provided.

According to the sixth aspect of the present invention, the following formula (IX) (In the formula, Y ″ is a hydrogen atom or a benzyl group) or (2S, 4R)-or (2S, 4S) -5-amino-4-fluoro-2-hydroxyvaleric acid or (2S, 4R) -Or (2
S, 4S) -5-Amino-2-benzyloxy-4-fluorovaleric acid is provided.

Next, the present invention is represented by the general formula (VIII) or the general formula (I
Reference Examples 1 to 1 illustrating the synthesis of the novel valeric acid derivative of (X)
2, as well as examples illustrating the production of the novel kanamycin derivative of the general formula (I) will be specifically described.

Reference Example 1 (a) (2R, 5S) -5- (2-chloro-2-oxoethyl) -2-trichloromethyl-1,3-dioxolane-
From 4-one [compound (2)], (2R, 5S) -5- (3-chloro-2-oxopropyl) -2-trichloromethyl-
Synthesis of 1,3-dioxolan-4-one [compound (3)] (2R, 5S) -5- (2-chloro-2-oxoethyl) -2-trichloromethyl-1,3-dioxolan-4-one known in the literature, that is, 5.0 g of the compound (2) was added to 50 ml of diethyl ether. Dissolve it, add it to 730 ml of 0.05N diazomethane-diethyl ether solution, leave it for 5 minutes,
Add 1.2N hydrogen chloride-diethyl ether solution 70 to this solution.
ml was added and reacted at room temperature for 15 minutes (extension of carbon chain).
The reaction solution was concentrated, and the resulting residue was subjected to silica gel column chromatography (developing system; toluene-ethyl acetate = 6:
Purified in 1), 4. of the title compound (3) as colorless crystals.
I got 9g. Yield 93% mp. 75-76 ° C [α] _D ²⁴ + 33 ° (c 1, chloroform).

(B) (2R, 5S) -5- (3-azido-2-
Oxopropyl) -2-trichloromethyl-1,3-dioxolan-4-one [Compound (4)] 20.0 g of the compound (3) of the above (a) is added to 200 ml of methylene chloride.
6.4 g of sodium azide under cooling at 0 ° C.,
20.6 g of tetraethylammonium bromide and 140 ml of acetonitrile were added, and the mixture was reacted by stirring at the above temperature for 9 hours.

After adding 1.2 L of chloroform to the reaction solution, it was washed with water, dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified by silica gel column chromatography (developing system; toluene-ethyl acetate = 6: 1) to obtain 17.6 g of the title compound (4) as colorless crystals. Yield 86% IR: 2110 cm ^-1 (N ₃ ) mp. 105-106 ° C [α] _D ²³ + 38 ° (c 1, chloroform).

(C) (2S, 4S) -4-azidomethyl-2-
Hydroxy-4-butanolide [compound (5)] and its 4
Position epimer, ie (2S, 4R) -4-azidomethyl-2-
Synthesis of hydroxy-4-butanolide [compound (6)] 3.00 g of the compound (4) of the above (b) was dissolved in 80 ml of anhydrous tetrahydrofuran, and an excess diethyl borohydride solution of zinc borohydride was added to this solution under cooling at -20 ° C for reduction [ketone reduction, and Deprotection of the trichloroethylidene group proceeds, cyclization occurs between the resulting hydroxyl group and the released carboxyl group, and compounds (5) and (6) are obtained as two lactones].

Acetic acid was added to the reaction solution to decompose excess reagents,
Then, 300 ml of ethyl acetate was added, the solution was washed with an aqueous solution of sodium sulfate, dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified by high performance liquid chromatography using a silica gel column (developing system; hexane-ethyl acetate = 1: 3) to obtain 0.54 g of the title compound (5) as a colorless syrup. Yield 35%. At the same time, 0.87 g of colorless syrup-like compound (6) was obtained. Yield 56%.

Compound (5): [α] _D ²² + 59 ° (c 1, chloroform) IR: 2110 cm ⁻¹ (N ₃ ) ¹ H-NMR spectrum (in deuterated chloroform, TMS internal standard) δ2.10 (1H, dt, H-3a) 2.67 (1H, ddd, H-3b) 3.51 (1H, dd, H-5a) 3.62 (1H, dd, H-5b) 4.62 (1H, dd, H-2) Compound (6) : [Α] _D ²² -137 ° (c 1, chloroform).

(D) (2S, 4S) -4-azidomethyl-2-
Synthesis of benzyloxy-4-butanolide [compound (7)] 1.1 g of the compound (5) of the above (c) was dissolved in 22 ml of anhydrous DMF, 3.2 g of silver oxide and 1.6 ml of benzyl bromide were added, and the mixture was stirred at room temperature. After 3 hours, the reaction solution was filtered and the filtrate was concentrated. Chloroform (150 ml) was added to the obtained residue, this solution was washed successively with 0.05 N hydrochloric acid and water, dried over anhydrous sodium sulfate, and concentrated. The obtained residue is subjected to silica gel column chromatography (developing system; hexane-
Purification with ethyl acetate = 5: 2) gave 1.38 g of the title compound (7) as a colorless syrup. Yield 80%.

[Α] _D ²⁴ + 4 ° (c 1, chloroform) ¹ H-NMR spectrum (in deuterated chloroform, TMS internal standard) δ2.09 (1H, dt, H-3a) 2.52 (1H, ddd, H- 3b) 4.26 (1H, dd, H-2).

(E) Methyl (2S, 4S) -5-azido-2-benzyloxy-4-hydroxyvalerate [Compound (8)]
Synthesis of 2.0 g of the compound (7) of the above (d) was dissolved in 27 ml of anhydrous methanol, and 1N hydrogen chloride-methanol solution 3 was added to this solution.
ml was added and reacted at room temperature for 10 minutes (lactone ring opening and methyl esterification proceeded).

After adding 200 ml of chloroform to the reaction solution,
This was washed with water until it became neutral, dried over anhydrous sodium sulfate and concentrated. The obtained residue is subjected to silica gel column chromatography (developing system; toluene-ethyl acetate = 6:
Purified in 1), 1. of the title compound (8) in the form of colorless syrup.
80 g was obtained. Yield 80% ¹ H-NMR spectrum (in deuterated chloroform, TMS internal standard) δ 3.77 (3H, s, COOMe) 4.24 (1H, dd, H-2).

(F) Synthesis of methyl (2S, 4R) -5-azido-2-benzyloxy-4-fluorovalerate [compound (9)] 1.01 g of the compound (8) of the above (e) was dissolved in 24 ml of anhydrous benzene, and this was dissolved in anhydrous benzene-anhydrous pyridine (8:
Add to a solution of 1.4 ml of diethylaminosulfur trifluoride added to 27 ml of the mixed solution of 1), and leave at room temperature for 1 hour.
Heated at 60 ° C. for 2 hours.

The reaction solution was treated with a 5% aqueous sodium hydrogen carbonate solution 23
After adding 0 ml and stirring, 230 ml of toluene was added thereto, the organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated. The obtained residue is subjected to silica gel column chromatography (developing system; cyclohexane-chloroform-acetone = 10: 2:
51 of the title compound (9) in the form of a colorless syrup purified in 1).
2 mg was obtained. Yield 50%.

[Α] _D ²³ -61 ° (c 1, chloroform) IR: 2110 cm ^-1 (N ₃ ) ¹ H-NMR spectrum (in deuterated chloroform, TMS internal standard) δ 3.78 (3H, s, COOMe) 4.10 (1H, t, H-2 ) 4.87 (1H, double m, H-4) J 2,3a = J 2,3b = ~6Hz, J 4, F = 48Hz.

(G) Synthesis of (2S, 4R) -5-azido-2-benzyloxy-4-fluorovaleric acid [compound (10)] 350 mg of the compound (9) of the above (f) was dissolved in 72 ml of methanol, 1.8 ml of 1N aqueous sodium hydroxide solution was added thereto, and the mixture was reacted at room temperature for 1 hour for hydrolysis.

The reaction solution was concentrated, and when the amount became small, water was added.
35 ml was added, and a small amount of 1N hydrochloric acid was further added thereto under ice cooling to make the aqueous solution acidic (pH 1). This aqueous solution was extracted with ethyl acetate, and the obtained ethyl acetate solution was dried over anhydrous sodium sulfate and then concentrated. 315 mg of the title compound (10) was obtained as a colorless syrup. Yield 95%.

Elemental analysis Actual value C 54.15%, H 5.37%, F 7.12%, N 15.87% Calculated value as C ₁₂ H ₁₄ FN ₃ O ₃ C 53.93%, H 5.28%, F 7.11%, N 15.72% [ α] _D ²² -49 ° (c 1, chloroform) IR: 2110cm ^-1 (N ₃ ) ¹ H-NMR spectrum (in deuterated chloroform, TMS internal standard) δ 2.13 (1H, m, H-3a) 2.32 (1H , m, H-3b) 4.15 (1H, t, H-2) 4.93 (1H, double m, H-4) J 2,3a = J 2,3b = 6Hz, J 4, F = 48Hz.

(H) Synthesis of (2S, 4R) -5-amino-4-fluoro-2-hydroxyvaleric acid [compound (13)] 72 mg of the compound (10) of the preceding item (g) was dissolved in 2.5 ml of a mixed solution of methanol-water (3: 2), palladium black was added as a catalyst and hydrogen was blown at room temperature for 9 hours for catalytic reduction. After filtering the reaction solution, the filtrate was concentrated. The obtained solid was washed with a mixed solution of methanol-ethyl acetate (1: 2) (3
ml × 2) to obtain 37 mg of the title compound (13) as a colorless solid. Yield 91%.

[Α] _D ²³ -10 ° (c 0.5, water) ¹ H-NMR spectrum (heavy water, TMS internal standard) δ 4.15 (1H, t, H-2) 5.04 (1H, double m, H- 4) J _{4, F} = 50Hz.

When the reaction time of catalytic reduction of compound (10) was shortened to 1 hour and the above reduction step was carried out in the same manner and the reaction solution was treated in the same manner as above, it was converted into a colorless solid of the following formula:
(2S, 4R) -5-amino-2-benzyloxy-4-fluorovaleric acid [compound (19)] was obtained. Yield 95%.

[0107] Reference Example 2 (a) Synthesis of (2S, 4R) -4-azidomethyl-2-benzyloxy-4-butanolide [compound (14)] 390 mg of the compound (6) of Reference Example 1 (c) was dissolved in 8 ml of anhydrous DMF, 1.2 g of silver oxide and 0.6 ml of benzyl bromide were added, and the mixture was stirred at room temperature. After 3 hours, the reaction solution was filtered and the filtrate was concentrated. 60 ml of chloroform was added to the obtained residue,
This solution was washed successively with 0.05N hydrochloric acid and water, dried over anhydrous sodium sulfate, and concentrated. The obtained residue was purified by silica gel column chromatography (developing system; hexane-ethyl acetate = 5: 2) to obtain 485 mg of the title compound (14) as a colorless syrup. Yield 79% [α] _D ²¹ -161 ° (c 1, chloroform).

(B) Methyl (2S, 4R) -5-azido-2-benzyloxy-4-hydroxyvalerate [Compound (1
5)] Synthesis 4.5 g of the compound (14) of the above (a) is 63 ml of anhydrous methanol
The resulting solution was dissolved in the above solution, 7 ml of a 1N hydrogen chloride-methanol solution was added to the solution, and the mixture was reacted at room temperature for 10 minutes (opening of lactone and progress of methyl esterification).

After adding 500 ml of chloroform to the reaction solution,
This was washed with water until it became neutral, dried over anhydrous sodium sulfate and concentrated. The obtained residue is subjected to silica gel column chromatography (developing system; toluene-ethyl acetate = 6: 1).
Of the title compound (15) in the form of a colorless syrup.
4.17 g was obtained. Yield 82%.

(C) Methyl (2S, 4S) -5-azido-2-benzyloxy-4-fluorovalerate [Compound (16)]
Synthesis of 1.65 g of the compound (15) of the previous item (b) was added to 38 ml of anhydrous benzene.
Dissolved in anhydrous benzene-anhydrous pyridine (8:
To a solution prepared by adding 2.2 ml of diethylaminosulfur trifluoride to 45 ml of the mixed solution of 1), and leaving it at room temperature for 1 hour,
Heated at 60 ° C. for 2 hours.

The reaction solution was added with a 5% aqueous sodium hydrogen carbonate solution 3
After adding to 50 ml and stirring, 300 ml of toluene was added thereto, the organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated. The obtained residue is subjected to silica gel column chromatography (developing system; cyclohexane-chloroform-acetone = 10:
2: 1) and the title compound (1
6) 1.18g was obtained. Yield 71% [α] _D ²³ -74 ° (c 1, chloroform) IR: 2110 cm ^-1 (N ₃ ).

(D) Synthesis of (2S, 4S) -5-azido-2-benzyloxy-4-fluorovaleric acid [compound (17)] 1.80 g of the compound (16) of the above (c) was dissolved in 36 ml of methanol, 9 ml of 1N aqueous sodium hydroxide solution was added thereto, and the mixture was reacted at room temperature for 1 hour for hydrolysis.

The reaction solution was concentrated, and when the amount became small, water was added.
180 ml was added, and a small amount of 1N hydrochloric acid was further added thereto under ice cooling to make the aqueous solution acidic (pH 1). This aqueous solution was extracted with ethyl acetate, and the obtained ethyl acetate solution was dried over anhydrous sodium sulfate and then concentrated. 1.66 g of the title compound (17) was obtained as colorless crystals. Yield 97%.

Elemental analysis Measured value C 53.74%, H 5.18%, F 6.89%, N 15.92% Calculated value as C ₁₂ H ₁₄ FN ₃ O ₃ C 53.93%, H 5.28%, F 7.11%, N 15.72% [ α] _D ²² -81 ° (c 1, chloroform) IR: 2110 cm ^-1 (N ₃ ) mp. 99-100 ℃ ¹ H-NMR spectrum (in deuterated chloroform, TMS internal standard) δ 4.24 (1H, dd, H-2) 4.90 (1H, double m, H-4) J _2,3a = 11Hz, J _{2, 3b} = 3Hz, J _{4, F} = 49Hz.

(E) Synthesis of (2S, 4S) -5-amino-4-fluoro-2-hydroxyvaleric acid [compound (18)] The compound (17) of the preceding paragraph (d) was catalytically reduced in the presence of a palladium catalyst for 9 hours in the same manner as in Reference Example 1 (h), and the reaction solution was treated in the same manner to obtain the title compound (18). Yield 88% [α] _D ²¹ -25 ° (c 0.5, water).

When the reaction time of the catalytic reduction of compound (17) was shortened to 1 hour and the above reduction step was carried out in the same manner, and the reaction solution was treated in the same manner, a colorless solid of the following formula (2
S, 4S) -5-Amino-2-benzyloxy-4-fluorovaleric acid [compound (20)] was obtained. Yield 92%

Example 1 (a) (2S, 4R) -5-azido-2-benzyloxy-4
-Synthesis of N-hydroxysuccinimide ester of fluorovaleric acid [compound (11)]

300 mg of the compound (10) of Reference Example 1 (g) and 130 mg of N-hydroxysuccinimide were mixed with 1 part of anhydrous ethyl acetate.
It was dissolved in 2 ml, and dicyclohexylcarbodiimide (460 mg) was added thereto with stirring, and the mixture was stirred at room temperature for 1.5 hours (active esterification).

The white suspension obtained was filtered, insolubles were washed with anhydrous acetic ester, and the filtrate and washings were concentrated to obtain 400 mg of the title compound (11) as a colorless syrup.

(B) 1-N-[(2S, 4R) -5-azido-
2-benzyloxy-4-fluorovaleryl] -3,
2 ', 6'-tris (N-benzyloxycarbonyl)
Preparation of -3 ', 4'-dideoxy-3 "-N-trifluoroacetylkanamycin B [compound (22)] In the formula, Bzl represents a benzyl group, Z represents a benzyloxycarbonyl group, and TFA represents a trifluoroacetyl group.

3,2 ', 6'-Tris (N-benzyloxycarbonyl) -3', 4'-dideoxy-3 "-N
-Trifluoroacetyl kanamycin B [compound (2
800 mg of 1)] and 130 mg of sodium carbonate were dissolved in 60 ml of a mixed solution of tetrahydrofuran-water (1: 1). To this solution was added a solution prepared by dissolving 370 mg of the compound (11) obtained in (a) above in 10 ml of tetrahydrofuran. After 1 hour, 180 mg of the compound (11) was further added to 5 m of tetrahydrofuran.
A solution dissolved in 1 was added and the mixture was allowed to react at room temperature for 1 hour (1-N-acylation reaction). Then, the reaction solution was concentrated. The obtained residue was washed successively with water and ethyl acetate to obtain 610 mg of the title compound (22) as a colorless solid.
Yield 60%.

(C) 1-N-[(2S, 4R) -5-amino-
4-Fluoro-2-hydroxyvaleryl] -3 ', 4'
-Production of dideoxykanamycin B [compound (k)]

450 mg of the compound (22) of the above (b) was mixed with 3N aqueous ammonia-tetrahydrofuran (1: 2) mixture.
It was dissolved in 27 ml. Hydrolyzed at room temperature for 1 day 3 ″ -N
-The trifluoroacetyl group was eliminated. afterwards,
The solid obtained by concentrating the reaction solution was dissolved in 24.5 ml of a mixed solution of acetic acid-dioxane-water (1:16:32). Palladium black was added to the solution as a catalyst, hydrogen was blown into the solution at room temperature for 5 hours to carry out catalytic reduction to convert an azido group into an amino group and to eliminate an O-benzyl group and an N-benzyloxycarbonyl group. .

The reaction solution was filtered and then concentrated. The obtained solid was dissolved in water, passed through a column of CM-Sephadex C-25 (70 ml), and developed with 0 to 0.15N aqueous ammonia while gradually increasing the ammonia concentration. The eluent containing the target compound showing ninhydrin color was collected and concentrated to obtain 197.8 mg of the title compound (k) as a colorless solid. Yield 80%.

[Α] _D ²² + 81 ° (c 1, water) ¹ H-NMR spectrum (dihydrochloric acid-heavy water, pD 2.5, TMS internal standard) δ 4.40 (1H, dd, H-2 ″ ′) 5.12 (1H, double m, H-4 ''') 5.20 (1H, d, H-1 ") 5.81 (1H, d, H-1') J _{4 ''', F} = ~ 50Hz Elemental analysis (C ₂₃ H ₄₅ FN ₆ O ₁₀・ H ₂ CO ₃・ 0.5
H ₂ O as) Found C 43.94, H 7.51, F 3.04 , N 13.07% Calculated C 43.96, H 7.38, F 2.90 , N 12.82% Example 2 (i) (2S, 4S)-5-azido-2 -Benzyloxy-4
-Synthesis of N-hydroxysuccinimide ester of fluorovaleric acid [compound (12)]

200 mg of the compound (17) of Reference Example 2 (d) and 86 mg of N-hydroxysuccinimide were dissolved in 8 ml of anhydrous ethyl acetate, 270 mg of dicyclohexylcarbodiimide was added thereto with stirring, and the mixture was stirred at room temperature for 1.5 hours. (Active esterification).

The obtained white suspension was filtered, the insoluble matter was washed with anhydrous ethyl acetate, and the filtrate and washings were concentrated to obtain 270 mg of the title compound (12) as a colorless syrup.

(B) 1-N-[(2S, 4S) -5-azido-
2-benzyloxy-4-fluorovaleryl] -3,
2 ', 6'-tris (N-benzyloxycarbonyl)
Preparation of -3 ', 4'-dideoxy-3 "-N-trifluoroacetylkanamycin B [compound (23)] 3,2 ', 6'-Tris (N-benzyloxycarbonyl) -3', 4'-dideoxy-3 "-N-trifluoroacetylkanamycin B [compound (21)] (370 mg) and sodium carbonate (60 mg) were added to tetrahydrofuran- Water (1:
It was dissolved in 20 ml of the mixed solution of 1). To this solution, 200 mg of the compound (12) obtained in (a) above was added 5 ml of tetrahydrofuran.
The solution dissolved in was added. After 1 hour of the reaction, a solution of 70 mg of the compound (12) in 2 ml of tetrahydrofuran was added, and the reaction was terminated by leaving it at room temperature for 2 hours (1-N-acylation reaction). Then, the reaction solution was concentrated.
The obtained residue was washed successively with water and ethyl acetate to obtain 280 mg of the title compound (23) as a colorless solid. Yield 60%.

(C) 1-N-[(2S, 4S) -5-amino-
4-Fluoro-2-hydroxyvaleryl] -3 ', 4'
-Production of dideoxykanamycin B [compound (l)]

400 mg of the compound (23) of the above (b) was mixed with 3N aqueous ammonia-tetrahydrofuran (1: 2).
It was dissolved in 25 ml. Hydrolyzed at room temperature for 1 day 3 ″ -N
-The trifluoroacetyl group was eliminated. afterwards,
The solid obtained by concentrating the reaction solution was dissolved in 18.3 ml of a mixed solution of acetic acid-dioxane-water (1:20:40). Hydrogen was blown into the solution at room temperature using palladium black as a catalyst to carry out catalytic reduction for 5 hours to convert the azido group to an amino group and to eliminate the O-benzyl group and the N-benzyloxycarbonyl group.

The reaction solution was filtered and then concentrated. The obtained solid was dissolved in water, passed through 70 ml of a column of CM-Sephadex C-25, and developed with 0 to 0.15N aqueous ammonia while gradually increasing the ammonia concentration. The eluent containing the target compound showing ninhydrin color was collected and concentrated to obtain 163 mg of the title compound (l) as a colorless solid.

[Α] _D ²³ + 71 ° (c 1, water) ¹ H-NMR spectrum (dihydrochloric acid-heavy water, pD 2.8, TMS internal standard) δ 4.38 (1H, dd, H-2 ″ ′) 5.08 (1H, double m, H-4 ''') 5.19 (1H, d, H-1 ″) 5.81 (1H, d, H-1 ′).

Example 3 Preparation of 1-N-[(2S, 4R) -5-amino-4-fluoro-hydroxyvaleryl] -3 ', 4'-dideoxykanamycin B [compound (k)] (1) 2,3 ', 6'-tris (N-benzyloxycarbonyl) -3', 4-dideoxy-3 "-N-trifluoroacetylkanamycin B [compound (21)] 2
10 mg and 30 mg of sodium carbonate were dissolved in 10 ml of a mixed solution of tetrahydrofuran-water (1: 1). For this solution,
(2S, 4R) -5-amino-4-obtained in Reference Example 1 (HI)
A solution of 220 mg of N-hydroxysuccinimide ester of (2S, 4R) -5-benzyloxycarbonylamino-4-fluoro-2-hydroxyvaleric acid prepared from fluoro-2-hydroxyvaleric acid [compound (13)] in tetrahydrofuran ( 5 ml) was added. The reaction was terminated by leaving it at room temperature for 2 hours. Then, the reaction solution was concentrated. The obtained residue was washed successively with water and ethyl acetate to give a colorless solid.

The above colorless solid was 3,2 ', 6'-tris (N-benzyloxycarbonyl) -1-N-[(2S, 4
R) -5-Benzyloxycarbonylamino-4-fluoro-2-hydroxyvaleryl] -3 ', 4'-dideoxy-3 "-N-trifluoroacetylkanamycin B crude product.

(2) 215 mg of this solid was dissolved in 15 ml of a mixture of 3N aqueous ammonia-tetrahydrofuran (1: 2). After hydrolysis at room temperature for 1 day, the 3 ″ -N-trifluoroacetyl group was eliminated. After that, the reaction solution was concentrated to give a solid, which was added with acetic acid-dioxane-water (1:20:20). The mixture was dissolved in 12.3 ml, and hydrogen was blown into the solution at room temperature using palladium black as a catalyst for catalytic reduction for 1.5 hours.
-The benzyloxycarbonyl group was eliminated.

The reaction solution was filtered and then concentrated. The obtained solid was dissolved in water, passed through a 35 ml column of CM-Sephadex C-25, and developed with 0 to 0.15N ammonia water while gradually increasing the ammonia concentration. The eluent containing the target compound showing ninhydrin color was collected and concentrated to obtain 80 mg of the title compound (k) as a colorless solid. [Α] _D ²² + 81 ° (c 1, water).

Example 4 1-N-[(2S, 4R) -5-amino-4-fluoro-2-
Synthesis of hydroxyvaleryl] -5,3 ′, 4′-trideoxy-5-fluorokanamycin B [compound (m)] 3,2 ′, 6′-tris (N) shown in Example 1 (b).
-Benzyloxycarbonyl) -3 ', 4'-dideoxy-3 "-N-trifluoroacetylkanamycin B
Instead of [compound (21)], 3,2 ′, 6′-tris (N-benzyloxycarbonyl) -5,3 ′, 4′-
The procedure of Examples 1 (b) and (c) was repeated using 120 mg of trideoxy-5-fluoro-3 ″ -N-trifluoroacetylkanamycin B (compound described in US Pat. No. 4,873,225). 48 mg of the compound (m) of Example 1 was obtained as a colorless solid: [α] _D ²³ + 81 ° (c 1, water).

Example 5 1-N-[(2S, 4R) -5-amino-4-fluoro-2-
Hydroxyvaleryl] kanamycin A [compound (a)]
Synthesis of 3,2 ′, 6′-tris (N) shown in Example 1 (b)
-Benzyloxycarbonyl) -3 ', 4'-dideoxy-3 "-N-trifluoroacetylkanamycin B
In place of [Compound (21)], 150 mg of 3,6′-bis (N-benzyloxycarbonyl) -3 ″ -N-trifluoroacetylkanamycin A (compound described in US Pat. No. 4,297,485) was used. Then, the method of Example 1 (b) and (c) was repeated: 60.2 mg of the title compound (a)
Was obtained as a colorless solid. [Α] _D ²⁴ + 82 ° (c 0.5, water).

Example 6 1-N-[(2S, 4R) -5-amino-4-fluoro-2-
Synthesis of Hydroxyvaleryl] -5-deoxy-5-fluorokanamycin A [Compound (b)] 3,2 ′, 6′-Tris (N) shown in Example 1 (b).
-Benzyloxycarbonyl) -3 ', 4'-dideoxy-3 "-N-trifluoroacetylkanamycin B
Instead of [compound (21)], 3,6′-bis (N-benzyloxycarbonyl) -5-deoxy-5-fluoro-3 ″ -N-trifluoroacetylkanamycin A 17
The method of Example 1 (b) and (c) was repeated using 2 mg. 70.3 mg of the title compound (b) was obtained as a colorless solid. [Α] _D ²⁴ + 80 ° (c 0.5, water).

Example 7 1-N-[(2S, 4R) -5-amino-4-fluoro-2-
Hydroxyvaleryl] -5-deoxy-5-epi-5-
Synthesis of fluorokanamycin A [compound (c)] 3,2 ′, 6′-tris (N) shown in Example 1 (b)
-Benzyloxycarbonyl) -3 ', 4'-dideoxy-3 "-N-trifluoroacetylkanamycin B
Instead of [compound (21)], 3,6′-bis (N-benzyloxycarbonyl) -5-deoxy-5-epi-5
The procedure of Examples 1 (b) and (c) was repeated using 125 mg of -fluoro-3 "-N-trifluoroacetylkanamycin A. 47 mg of the title compound (c) was obtained as a colorless solid. [Α] _D ²³ + 82 ° (c 1, water).

Example 8 1-N-[(2S, 4R) -5-amino-4-fluoro-2-
Synthesis of Hydroxyvaleryl] -2 ', 3'-dideoxykanamycin A [Compound (d)] 3,2', 6'-Tris (N) shown in Example 1 (b).
-Benzyloxycarbonyl) -3 ', 4'-dideoxy-3 "-N-trifluoroacetylkanamycin B
Instead of [compound (21)], 3,6′-bis (N-benzyloxycarbonyl) -2 ′, 3′-dideoxy-
210 "of 3" -N-trifluoroacetyl kanamycin A
The procedure of Example 1 (b) and (c) was repeated using g. 86.7 mg of the title compound (d) was obtained as a colorless solid. [Α] _D ²³ + 85 ° (c 1, water).

Example 9 1-N-[(2S, 4R) -5-amino-4-fluoro-2-
Hydroxyvaleryl] -2 ', 3'-dideoxy-2'
-Synthesis of fluorokanamycin A [compound (e)] 3,2 ', 6'-tris (N) shown in Example 1 (b)
-Benzyloxycarbonyl) -3 ', 4'-dideoxy-3 "-N-trifluoroacetylkanamycin B
Instead of [compound (21)], 3,6′-bis (N-benzyloxycarbonyl) -2 ′, 3′-dideoxy-
The procedure of Examples 1 (b) and (c) was repeated using 183 mg of 2'-fluoro-3 "-N-trifluoroacetylkanamycin A. 81.7 mg of the title compound (e).
Was obtained as a colorless solid. [Α] _D ²² + 83 ° (c 1, water).

Example 10 1-N-[(2S, 4R) -5-amino-4-fluoro-2-
Hydroxyvaleryl] kanamycin B [compound (f)]
Synthesis of 3,2 ′, 6′-tris (N) shown in Example 1 (b)
-Benzyloxycarbonyl) -3 ', 4'-dideoxy-3 "-N-trifluoroacetylkanamycin B
In place of [Compound (21)], 95 mg of 3,2 ′, 6′-tris (N-benzyloxycarbonyl) -3 ″ -N-trifluoroacetylkanamycin B was used in Example 1 (b) and The method of (C) was repeated, and 31 mg of the title compound (f) was obtained as a colorless solid [α] _D ²⁴ + 81 ° (c 1, water).

Example 11 1-N-[(2S, 4R) -5-amino-4-fluoro-2-
Synthesis of Hydroxyvaleryl] -5-deoxy-5-fluorokanamycin B [Compound (g)] 3,2 ′, 6′-tris (N) shown in Example 1 (b).
-Benzyloxycarbonyl) -3 ', 4'-dideoxy-3 "-N-trifluoroacetylkanamycin B
Instead of [compound (21)], 3,2 ′, 6′-tris (N-benzyloxycarbonyl) -5-deoxy-5
The procedure of Examples 1 (b) and (c) was repeated using 118 mg of -fluoro-3 "-N-trifluoroacetylkanamycin B. 39.5 mg of the title compound (g) was obtained as a colorless solid. [Α] _D ²³ + 79 ° (c 1, water).

Example 12 1-N-[(2S, 4R) -5-amino-4-fluoro-2-
Hydroxyvaleryl] -3'-deoxykanamycin B
Synthesis of [Compound (h)] 3,2 ′, 6′-tris (N) shown in Example 1 (b)
-Benzyloxycarbonyl) -3 ', 4'-dideoxy-3 "-N-trifluoroacetylkanamycin B
Instead of [compound (21)], 3,2 ′, 6′-tris (N-benzyloxycarbonyl) -3′-deoxy-
250m of 3 "-N-trifluoroacetyl kanamycin B
The procedure of Example 1 (b) and (c) was repeated using g. 87.6 mg of the title compound (h) was obtained as a colorless solid. [Α] _D ²² + 75 ° (c 0.5, water).

Example 13 1-N-[(2S, 4R) -5-amino-4-fluoro-2-
Synthesis of Hydroxyvaleryl] -5,3′-dideoxy-5-fluorokanamycin B [Compound (i)] 3,2 ′, 6′-Tris (N) shown in Example 1 (b).
-Benzyloxycarbonyl) -3 ', 4'-dideoxy-3 "-N-trifluoroacetylkanamycin B
230 mg of 3,2 ′, 6′-tris (N-benzyloxycarbonyl) -5,3′-dideoxy-5-fluoro-3 ″ -N-trifluoroacetylkanamycin B in place of [compound (21)] The procedure of Example 1 (b) and (c) was repeated using 75.8 mg of the title compound (i).
Was obtained as a colorless solid. [Α] _D ²⁴ + 78 ° (c 1, water).

Example 14 1-N-[(2S, 4R) -5-amino-4-fluoro-2-
Synthesis of Hydroxyvaleryl] -5,3′-dideoxy-5-epi-5-fluorokanamycin B [Compound (j)] 3,2 ′, 6′-tris (N) shown in Example 1 (b).
-Benzyloxycarbonyl) -3 ', 4'-dideoxy-3 "-N-trifluoroacetylkanamycin B
Instead of [compound (21)], 3,2 ′, 6′-tris (N-benzyloxycarbonyl) -5,3′-dideoxy-5-epi-5-fluoro-3 ″ -N-trifluoroacetyl Example 1 using 105 mg of kanamycin B
The methods of (b) and (c) were repeated. 33 mg of the title compound (j) was obtained as a colorless solid. [Α] _D ²⁴ + 77 ° (c 1, water).

Example 15 1-N-[(2S, 4R) -5-amino-4-fluoro-2-
Synthesis of hydroxyvaleryl] -5,3 ', 4'-trideoxy-5-epi-5-fluorokanamycin B [compound (n)] 3,2', 6'- shown in Example 1 (b) Tris (N
-Benzyloxycarbonyl) -3 ', 4'-dideoxy-3 "-N-trifluoroacetylkanamycin B
Instead of [compound (21)], 3,2 ′, 6′-tris (N-benzyloxycarbonyl) -5,3 ′, 4′-
Using 370 mg of trideoxy-5-epi-5-fluoro-3 ″ -N-trifluoroacetylkanamycin B,
The method of Example 1 (b) and (c) was repeated. 124 mg of the title compound (n) was obtained as a colorless solid. [Α] _D ²² + 80 ° (c 0.5, water).

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Yoshiaki Takahashi 1-1-14 Yaguchi Ota-ku, Tokyo Yaheim Heim 201

Claims (13)

[Claims] 1. The following general formula (I): [Wherein (i) each of R ¹ , R ² and R ³ is a hydroxyl group, R ⁴ is a hydroxyl group or a fluoro group and R ⁵ is a hydrogen atom, or R ⁴ is a hydrogen atom; R ⁵ is a fluoro group, or (ii) R ¹ is a hydrogen atom or a fluoro group, and each of R ² and R ⁵ is a hydrogen atom, and R
³ and R ⁴ are each a hydroxyl group, or (iii) R ¹
Is an amino group, R ² , R ³ and R ⁴ are each a hydroxyl group and R ⁵ is a hydrogen atom, or R ² and R ³ are each a hydroxyl group and either R ^{4 or} R ⁵ One of them is a fluoro group and the other is a hydrogen atom, or (iV) R ¹ is an amino group, R ² is a hydrogen atom, each of R ³ and R ⁴ is a hydroxyl group, and R ⁵ is a hydrogen atom. Or R
³ is a hydroxyl group, one of R ⁴ and R ⁵ is a fluoro group and the other is a hydrogen atom, or (v) R ¹ is an amino group, and each of R ² , R ³ and R ⁵ is hydrogen. An atom and R ⁴ is a hydroxyl group, or each of R ² and R ³ is a hydrogen atom and one of R ⁴ and R ⁵ is a fluoro group and the other is a hydrogen atom] -N-[(2
S, 4R)-or (2S, 4S) -5-amino-4-fluoro-2
-Hydroxyvaleryl] kanamycin A or B or a derivative thereof, and an acid addition salt thereof. 2. The following general formula (I-i): (Wherein R ⁴ is a hydroxyl group and R ⁵ is a hydrogen atom, or R ⁴ is a fluoro group and R ⁵ is a hydrogen atom,
Or R ⁴ is a hydrogen atom and R ⁵ is a fluoro group) 1-N-[(2S, 4R)-or (2S, 4S) -5-amino-
4-Fluoro-2-hydroxyvaleryl] -kanamycin A or -5-deoxy-5-fluorokanamycin A
Alternatively, the compound according to claim 1, which is -5-deoxy-5-epi-5-fluorokanamycin A, or an acid addition salt thereof. 3. The following general formula (I-ii): (In the formula, R ¹ is a hydrogen atom or a fluoro group) 1-N-[(2S, 4R)-or (2S, 4S) -5-amino-
4-Fluoro-2-hydroxyvaleryl] -2 ', 3'
-Dideoxykanamycin A or -2 ', 3'-dideoxy-2'-fluorokanamycin A.
And the acid addition salts thereof. 4. The following general formula (I-iii): (In the formula, R ⁴ is a hydroxyl group and R ⁵ is a hydrogen atom, or R ⁴ is a fluoro group and R ⁵ is a hydrogen atom, or R ⁴ is a hydrogen atom.
Is a hydrogen atom and R ⁵ is a fluoro group) 1-
N-[(2S, 4R)-or (2S, 4S) -5-amino-4-fluoro-2-hydroxyvaleryl] -kanamycin B or -5-deoxy-5-fluorokanamycin B or -5
-Deoxy-5-epi-5-fluorokanamycin B, the compound according to claim 1, and an acid addition salt thereof. 5. The following general formula (I-iv): (In the formula, R ⁴ is a hydroxyl group and R ⁵ is a hydrogen atom, or R ⁴ is a fluoro group and R ⁵ is a hydrogen atom, or R ⁴ is a hydrogen atom.
Is a hydrogen atom and R ⁵ is a fluoro group) 1-
N-[(2S, 4R)-or (2S, 4S) -5-amino-4-fluoro-2-hydroxyvaleryl] -3'-deoxykanamycin B or -5,3'-dideoxy-5-fluorokanamycin The compound according to claim 1, which is B or -5,3'-dideoxy-5-epi-5-fluorokanamycin B, and an acid addition salt thereof. 6. The following general formula (Iv): (In the formula, R ⁴ is a hydroxyl group and R ⁵ is a hydrogen atom, or R ⁴ is a fluoro group and R ⁵ is a hydrogen atom, or R ⁴ is a hydrogen atom.
Is a hydrogen atom and R ⁵ is a fluoro group) 1-
N-[(2S, 4R)-or (2S, 4S) -5-amino-4-fluoro-2-hydroxyvaleryl] -3 ', 4'-dideoxykanamycin B or -5,3', 4'- Trideoxy-5-fluorokanamycin B or -5,3 ', 4'
-Trideoxy-5-epi-5-fluorokanamycin B, the compound according to claim 1, and an acid addition salt thereof. 7. The general formula (I) shown in claim 1 or the general formula (Ii) shown in each of claims 2 to 6.
A (2S, 4R)-or (2S, 4S) -5-amino-4-fluoro-2-hydroxyvaleryl group in the compound of the general formula (Iv) has the following formula (2S, 4R) -5-amino-4-fluoro-2-
A hydroxyvaleryl group, or Represented by (2S, 4S) -5-amino-4-fluoro-2-
The compound according to claim 1, which is a hydroxyvaleryl group. 8. The following formula 1-N-[(2S, 4R)-or (2S, 4S) -5-amino-4-fluoro-2-hydroxyvaleryl]-
7. The composition is 3 ', 4'-dideoxykanamycin B.
And the acid addition salt thereof. 9. The following general formula (I): [Wherein (i) each of R ¹ , R ² and R ³ is a hydroxyl group, R ⁴ is a hydroxyl group or a fluoro group and R ⁵ is a hydrogen atom, or R ⁴ is a hydrogen atom; R ⁵ is a fluoro group, or (ii) R ¹ is a hydrogen atom or a fluoro group, and each of R ² and R ⁵ is a hydrogen atom, and R
³ and R ⁴ are each a hydroxyl group, or (iii) R ¹
Is an amino group, R ² , R ³ and R ⁴ are each a hydroxyl group and R ⁵ is a hydrogen atom, or R ² and R ³ are each a hydroxyl group and either R ^{4 or} R ⁵ One of them is a fluoro group and the other is a hydrogen atom, or (iv) R ¹ is an amino group, R ² is a hydrogen atom, each of R ³ and R ⁴ is a hydroxyl group, and R ⁵ is a hydrogen atom. Or R
³ is a hydroxyl group, one of R ⁴ and R ⁵ is a fluoro group and the other is a hydrogen atom, or (v) R ¹ is an amino group, and each of R ² , R ³ and R ⁵ is hydrogen. An atom and R ⁴ is a hydroxyl group, or each of R ² and R ³ is a hydrogen atom and one of R ⁴ and R ⁵ is a fluoro group and the other is a hydrogen atom] -N-[(2
S, 4R)-or (2S, 4S) -5-amino-4-fluoro-2
-Hydroxyvaleryl] kanamycin A or B or a derivative thereof or a pharmaceutically acceptable acid addition salt thereof as an active ingredient, and a pharmaceutically acceptable carrier mixed with the active ingredient. An antibacterial composition. 10. The following general formula (II): [Wherein (i) each of R ¹ , R ² and R ³ is a hydroxyl group, R ⁴ is a hydroxyl group or a fluoro group and R ⁵ is a hydrogen atom, or R ⁴ is a hydrogen atom; R ⁵ is a fluoro group, or (ii) R ¹ is a hydrogen atom or a fluoro group, and each of R ² and R ⁵ is a hydrogen atom, and R
³ and R ⁴ are each a hydroxyl group, or (iii) R ¹
Is an amino group, R ² , R ³ and R ⁴ are each a hydroxyl group and R ⁵ is a hydrogen atom, or R ² and R ³ are each a hydroxyl group and either R ^{4 or} R ⁵ One of them is a fluoro group and the other is a hydrogen atom, or (iv) R ¹ is an amino group, R ² is a hydrogen atom, each of R ³ and R ⁴ is a hydroxyl group, and R ⁵ is a hydrogen atom. Or R
³ is a hydroxyl group, one of R ⁴ and R ⁵ is a fluoro group and the other is a hydrogen atom, or (v) R ¹ is an amino group, and each of R ² , R ³ and R ⁵ is hydrogen. An atom and R ⁴ is a hydroxyl group, or each of R ² and R ³ is a hydrogen atom and one of R ⁴ and R ⁵ is a fluoro group and the other is a hydrogen atom] A
Alternatively, the amino group at the 1-position of the amino-protected derivative, in which all or part of the amino group other than the amino group at the 1-position of B or its derivative or the derivative of the general formula (II) is protected by the amino group Formula (III) (In the formula, Y is a hydrogen atom or a hydroxyl protecting group which can be eliminated by catalytic reduction) (2S, 4
R)-or (2S, 4S) -5-azido-4-fluoro-2-hydroxyvaleric acid or a derivative protected with a hydroxyl group thereof, or a valeric acid derivative of the general formula (III) or a protected derivative thereof. Acylation with an active ester results in the following general formula (IV) Forming a 1-N-acylated product or a protected derivative thereof, wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and Y have the meanings defined above, Then, this is subjected to catalytic reduction to convert the azido group (—N ₃ ) of the compound of formula (IV) into an amino group, and when Y is a hydroxy protecting group which can be eliminated by catalytic reduction, a group Y is also added. Desorption, which gives the following general formula (V) A compound of formula (V) wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ have the meanings defined above, or an amino protected derivative thereof, and then a compound of general formula (V) Has a residual amino-protecting group, the following general formula (I) comprising removing the residual amino-protecting group from the amino-protected derivative of the compound of general formula (V). [Wherein (i) each of R ¹ , R ² and R ³ is a hydroxyl group, R ⁴ is a hydroxyl group or a fluoro group and R ⁵ is a hydrogen atom, or R ⁴ is a hydrogen atom; R ⁵ is a fluoro group, or (ii) R ¹ is a hydrogen atom or a fluoro group, and each of R ² and R ⁵ is a hydrogen atom, and R
³ and R ⁴ are each a hydroxyl group, or (iii) R ¹
Is an amino group, R ² , R ³ and R ⁴ are each a hydroxyl group and R ⁵ is a hydrogen atom, or R ² and R ³ are each a hydroxyl group and either R ^{4 or} R ⁵ One of them is a fluoro group and the other is a hydrogen atom, or (iV) R ¹ is an amino group, R ² is a hydrogen atom, each of R ³ and R ⁴ is a hydroxyl group, and R ⁵ is a hydrogen atom. Or R
³ is a hydroxyl group, one of R ⁴ and R ⁵ is a fluoro group and the other is a hydrogen atom, or (v) R ¹ is an amino group, and each of R ² , R ³ and R ⁵ is hydrogen. An atom and R ⁴ is a hydroxyl group, or each of R ² and R ³ is a hydrogen atom and one of R ⁴ and R ⁵ is a fluoro group and the other is a hydrogen atom] -N-[(2
S, 4R)-or (2S, 4S) -5-amino-4-fluoro-2
-Hydroxyvaleryl] kanamycin A or B or a derivative thereof. 11. The following general formula (II): [Wherein (i) each of R ¹ , R ² and R ³ is a hydroxyl group, R ⁴ is a hydroxyl group or a fluoro group and R ⁵ is a hydrogen atom, or R ⁴ is a hydrogen atom; R ⁵ is a fluoro group, or (ii) R ¹ is a hydrogen atom or a fluoro group, and each of R ² and R ⁵ is a hydrogen atom, and R
³ and R ⁴ are each a hydroxyl group, or (iii) R ¹
Is an amino group, R ² , R ³ and R ⁴ are each a hydroxyl group and R ⁵ is a hydrogen atom, or R ² and R ³ are each a hydroxyl group and either R ^{4 or} R ⁵ One of them is a fluoro group and the other is a hydrogen atom, or (iv) R ¹ is an amino group, R ² is a hydrogen atom, each of R ³ and R ⁴ is a hydroxyl group, and R ⁵ is a hydrogen atom. Or R
³ is a hydroxyl group, one of R ⁴ and R ⁵ is a fluoro group and the other is a hydrogen atom, or (v) R ¹ is an amino group, and each of R ² , R ³ and R ⁵ is hydrogen. An atom and R ⁴ is a hydroxyl group, or each of R ² and R ³ is a hydrogen atom and one of R ⁴ and R ⁵ is a fluoro group and the other is a hydrogen atom] A
Alternatively, the 1-position amino group of the amino-protected derivative in which all or part of the amino group other than the 1-position amino group of B or a derivative thereof or the derivative of the general formula (II) is protected by the following general formula (VI) (In the formula, Y is a hydrogen atom, or a hydroxyl protecting group which can be eliminated by catalytic reduction, and Z is a hydrogen atom or an amino protecting group.) (2S, 4R)-or (2S, 4R)
S) -5-Amino-4-fluoro-2-hydroxyvaleric acid or a derivative thereof in which a hydroxyl group and / or an amino group is protected, or an activity of a valeric acid derivative of the general formula (VI) or a protected derivative thereof Acylation with an ester results in the following general formula (VII) A 1-N-acylated product or an amino-protected derivative thereof, represented by the formula: wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , Y and Z have the meanings defined above. Generate and also
The formation of an amino-protected derivative of a compound of general formula (VII) from which residual residual hydroxyl- and amino-protecting groups are eliminated, the following general formula (I) [Wherein (i) each of R ¹ , R ² and R ³ is a hydroxyl group, R ⁴ is a hydroxyl group or a fluoro group and R ⁵ is a hydrogen atom, or R ⁴ is a hydrogen atom; R ⁵ is a fluoro group, or (ii) R ¹ is a hydrogen atom or a fluoro group, and each of R ² and R ⁵ is a hydrogen atom, and R
³ and R ⁴ are each a hydroxyl group, or (iii) R ¹
Is an amino group, R ² , R ³ and R ⁴ are each a hydroxyl group and R ⁵ is a hydrogen atom, or R ² and R ³ are each a hydroxyl group and either R ^{4 or} R ⁵ One of them is a fluoro group and the other is a hydrogen atom, or (iv) R ¹ is an amino group, R ² is a hydrogen atom, each of R ³ and R ⁴ is a hydroxyl group, and R ⁵ is a hydrogen atom. Or R
³ is a hydroxyl group, one of R ⁴ and R ⁵ is a fluoro group and the other is a hydrogen atom, or (v) R ¹ is an amino group, and each of R ² , R ³ and R ⁵ is hydrogen. An atom and R ⁴ is a hydroxyl group, or each of R ² and R ³ is a hydrogen atom and one of R ⁴ and R ⁵ is a fluoro group and the other is a hydrogen atom] -N-[(2
S, 4R)-or (2S, 4S) -5-amino-4-fluoro-2
-Hydroxyvaleryl] kanamycin A or B or a derivative thereof. 12. The following formula (VIII) (Wherein Y'is a hydrogen atom or a benzyl group) or (2S, 4R)-or (2S, 4S) -5-azido-4-fluoro-2-hydroxy-valeric acid or (2S, 4R). ) − Or (2
S, 4S) -5-Azido-2-benzyloxy-4-fluorovaleric acid. 13. The following formula (IX) (In the formula, Y ″ is a hydrogen atom or a benzyl group) or (2S, 4R)-or (2S, 4S) -5-amino-4-fluoro-2-hydroxyvaleric acid or (2S, 4R) -Or (2
S, 4S) -5-Amino-2-benzyloxy-4-fluorovaleric acid.