WO2009049490A1 - Use of aminoglycoside antibiotic in the preparation of pharmaceutical composition for treating drug-resistant bacterial infection - Google Patents

Abstract

The use of 2'-NH2-3',4'-dideoxy--1-N-acylated derivatives of aminoglycoside antibiotic in the preparation of pharmaceutical composition for treating drug-resistant bacterial infection, the preparation of the derivatives and the formulation thereof.

Description

 Application of an aminoguanidine antibiotic as a medicine for treating drug-resistant bacteria

Technical field

 The use of an aminoglycoside antibiotic in the preparation of a pharmaceutical composition for treating a drug-resistant bacterial infection belongs to the technical field of application of aminoglycoside antibiotics. The present invention relates to a mono-acylated derivative of an aminoglycoside antibiotic having a 2 '-NH -3 ', 4'-two deoxy structure and its use in the preparation of a pharmaceutical composition for antibiotic resistant bacteria.

Background technique

 Document 1 CN1420120A,

 Literature 2 ZL93112412.3,

 Literature 3 ZL01133701.X,

 Literature 4 USP4117221,

 Literature 5 USP4230847,

 Literature 6 USP5442047.

 Since the introduction of aminoglycoside antibiotics, its broad-spectrum antibacterial activity has shown strong antibacterial activity against Gram-negative bacteria, and has a good synergy with clinically widely used β-lactam antibiotics and their main ear. , nephrotoxicity is predictable, and thus become a clinically indispensable class of antibiotics.

 In order to reduce toxicity and enhance the activity against resistant bacteria, some semi-synthetic aminoglycoside antibiotics such as arbekacin, isepamicin, etimicin, and netilmicin have also been developed. Their structural formulas are as follows: AHB = (s) a 4-amino-2-hydroxybutanoyl group,

 AHP= (s) — 3-amino-2-hydroxypropanoyl,

 Abecin (1 - N - AHB - Dibeka Star):

Isepamicin (1N-AHP-gentamicin B) _: (s)-COCH(OH)CH ₂ NH etimicin (1 -N-ethylgentamicin Cla):

Netilmicin (1 -N-ethyl sisomicin):

In recent years, with the widespread use of various antibacterial drugs, many drug-resistant strains have been induced, resulting in a number of infectious diseases that are difficult for clinicians to treat effectively, especially for highly antihypertensive agents that exhibit high levels of multi-drug resistance. Xilin-resistant Staphylococcus aureus (MRSA) and methicillin-resistant coagulase-negative staphylococci (MRCNS) have become major obstacles in the treatment of clinical infections.

 The semi-synthetic aminoglycoside antibiotics developed above have an unambiguous effect on MRSA, except for arbekacin, which has a clear effect on SA.

A number of acyl derivatives such as 1-N-gentamicin and sisomicin are disclosed in Document 4, and these acylated derivatives have been reported to have good antibacterial activity against drug-resistant bacteria, and can be made into commercial antibiotic preparations. . However, the literature does not disclose the antibacterial activity of these derivatives on highly resistant bacteria such as MRSA and MRCNS, and not all of the derivatives disclosed in the literature have good antibacterial activity against MRSA, such as 1N-AHP Qingda There is no good antibacterial activity of MRSA on mesomycin B (isopamicin). Therefore, the above patent documents do not cover the inventive concept of the patent. Document 5 discloses the use of divalent metal ion complexation protection to synthesize a protective intermediate in which the mono-H ₂ position is in a free state, and further specifically derivatizes at the 1-N position, and Document 6 discloses the use of zinc ions. Complexation, formyl protected intermediates, a new method for the synthesis of isepamicin 63⁄4. However, the synthetic method of the present invention is not covered.

Summary of the invention

 SUMMARY OF THE INVENTION The object of the present invention is to provide an aminoglycoside antibiotic for use as a medicament for the treatment of a drug-resistant infection. The problem to be solved is to provide an aminoglycoside antibiotic having a strong antibacterial effect on MRSA and MRCNS and a low production cost.

 In order to solve this problem, the inventors carefully compared the antibacterial activity of clinically applied aminoglycoside antibiotics having different structural features to clinically isolated pathogenic bacteria. among them,

Structural features of etimicin: ethyl, 2'-NH ₂ , 3', 4'-dideoxy, 3"-N-p3⁄4, structural characteristics of isepamicin: 1-N-AHP, 2' -hydroxy, 3', 4'-dihydroxy, 3"-N-CH ₃ , structural characteristics of amikacin: 1-N-AHB, 2'-hydroxy, 3', 4'-dihydroxy, 3" -Li ₂ , structural characteristics of arbekacin: 1-N-AHB, 2'-N3⁄4, 3', 4'-dideoxy, 3"-ΝΉ ₂ , structural characteristics of netilmicin: 1-N -ethyl, 2'-Ν, 3', 4'-dideoxy, 3"-N-C3⁄4, 4'

=5' double bond structure,

 SK-701 = 1-N- (S) -3-amino-2-hydroxypropionyl gentamicin Cla;

SK-702 = 1-N- (S) -3-amino-2-hydroxypropanoyl- 3"-N-demethylgentamicin Cla. Structural characteristics of SK-701: 1- Ν-ΑΗΡ, 2 Structural characteristics of '- should be ₂ , 3', 4'-dideoxy, 3〃-N-CH ₃ , SK-702: 1-N-AHP, 2'π, 3', 4'-dide deoxidation, 3 " -ΝΉ ₂ .

 Table 1. Antibacterial activity of antibiotics against MRSA and MRCNS with various structural features

 By comparison, you can see:

1. The double bond structure of 4' = 5' (netilmicin) is not an essential antibiotic for MRSA; 2. 1-N acylation (amikacin, isepamicin) is not antibiotic resistant The only necessary structure of the MRSA; 3. The 1 -N alkylated product (netilmicin, etimicin) has little effect on MRSA.

Thus, we have surprisingly found that a 1-N acyl derivative synthesized by an antibiotic having a 2'-ΝΗ ₂ -3, 4'-dideoxy structure as a precursor has significant & anti-MR A and MRCNS activities, thereby completing The invention has been made.

The invention provides an aminoglycoside antibiotic 1 -N-acyl derivative having the characteristics of 2'-Η ₂ - 3 ', 4'-two deoxygenation structure as an application for preparing a pharmaceutical preparation for treating drug-resistant bacteria.

Technical Solution of the Invention: The use of an aminoglycoside antibiotic for preparing a pharmaceutical composition for treating a drug-resistant bacterial infection, the aminoglycoside antibiotic having the following structure:

R=CH ₃ CO, (S)-CH ₂ (NH ₂ )CH(OH)CO, or (S)-C3⁄4(NH ₂ )CH ₂ CH(OH)CO, =H or CH ₃ , R ₂ =H Or CH ₃ .

The aminoglycoside antibiotic is R=(S)-CH ₂ ( H ₂ )CH(OH)CO , =H, and R ₂ =CH ₃ has the following structure:

That is, the use of 1-N-(s)-3-amino-2-hydroxypropionyl gentamicin Cla in the preparation of a pharmaceutical composition for treating drug-resistant infections. Or the aminoglycoside antibiotic is R=(S)-CH ₂ (NH ₂ )CH(OH)CO , ==Η, and the structure is as follows:

That is, the use of 1-N-(s)-3-amino-2-hydroxypropanosyl- 3" demethylated gentamicin Cla in the preparation of a pharmaceutical composition for treating drug-resistant infections.

 The resistant bacteria are methicillin-resistant Staphylococcus aureus, or the resistant bacteria are methicillin-resistant coagulase-negative staphylococci. .

 The pharmaceutical composition comprising the 1-N acylated derivative or a pharmaceutically acceptable salt thereof as an active ingredient, and a pharmaceutically acceptable carrier, and 0.01% of the 1-N acylated derivative or a pharmaceutically acceptable salt thereof ~99.99% is composed of a weight ratio of 99.99% to 0.01% with a pharmaceutically acceptable carrier.

 The pharmaceutical composition is prepared by mixing an effective amount of a 1-N acylated derivative or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier, and subjecting it to conventional packaging and sterilization.

 The pharmaceutical composition is a tablet, an aqueous injection, a powder injection, an eye drop, an aerosol, a cream, or an aerosol.

 Method for preparing aminoglycoside antibiotic compound having the following structure

R=CH ₃ CO, (S)-CH ₂ (NH ₂ )CH(OH)CO, or (S)-CH ₂ (NH ₂ )CH ₂ CH(OH)CO

=Η or CH ₃ ,

 Including the following steps:

 1) using a divalent metal ion to form a complexation state of the amino group of the parent compound, followed by a formylation reaction, and the divalent metal ion used for complexation is a zinc ion, a cobalt ion or a nickel ion;

 2) removing metal ions;

 3) performing an R-based derivatization reaction at the 1-N position;

 4) specifically removing the formylation protecting group;

 5) Purification of the target product, purification of the product by cation exchange resin column chromatography, elution with different concentrations of aqueous ammonia solution; or purification of the product by adsorption resin column chromatography, with different concentrations of ethanol, methanol or acetone aqueous solution Elution is performed.

Method for preparing aminoglycoside antibiotic compound having the following structure

R-CH3CO, (S)-CH ₂ (N3⁄4)CH(OH)CO, or (S)-CH ₂ (NH ₂ )CH ₂ CH(OH)CO, =H or C3⁄4,

 Including the following steps:

 1) The mother core compound is subjected to 3"-N demethylation reaction with iodine or iodide and purified to obtain a 3"-N-demethylated product;

 2) using a divalent metal ion to form a complexation state of the amino group, followed by a formylation reaction, and the divalent metal ion used for complexation is a zinc ion, a cobalt ion or a nickel ion;

 3) removing metal ions;

 4) performing an R-based derivatization reaction at the 1-N position;

 5) specifically removing the formylation protecting group;

 6) Purification of the target product, purification of the product, elution with cation exchange resin column chromatography, elution with different concentrations of aqueous ammonia solution; or purification of the product by adsorption resin column chromatography, with different concentrations of ethanol, methanol or The aqueous acetone solution was eluted.

 The beneficial effects of the invention:

 Abecin has the same structural characteristics and also has significant anti-MRSA activity. However, arbekacin is a kanamycin-based aminoglycoside antibiotic, and it uses a complicated chemical method for 3', 4'-double deoxygenation, a long synthetic route, complicated process, and high cost.

In order to realize the present invention economically and efficiently, the present invention synthesizes 1-N-acylated derivatives from natural sources and economically available antibiotics having 2'-H ₂ -3', 4'-dideoxy structures. The invention has good industrial application value.

The invention selects a natural-derived 1-N-acylated derivative synthesized from gentamicin Cla having 2'-ΝΗ ₂ -3\ 4'-two deoxygenation structure as a raw material:

 SK-701 = 1 -N- (S) -3 - amino 2-hydroxypropionyl gentamicin Cla;

 SK-702 = 1 -N- (S ) -3 -amino- 2 -hydroxypropionyl- 3"-N-demethylgentamicin Cla.

However, it is not limited thereto, and the 1-N-(S)-4-amino-2-hydroxybutyryl derivative and the 1-N-acetyl derivative can also be synthesized by the method provided by the present invention. The structural measurements of SK-701 and SK-702 are as follows: l. MS: SK-701, M+1 = 537, its molecular weight is 536 SK-702, M+1=523, its molecular weight 522 2. ¹³ C - NMR measurement results are shown in Table 2.

 Table 2

NM characteristic data is shown in Table 3. SK-701, SK-702

 55.20 1H d Γ 55.20 1H d Γ

 55.10 1H d 1" 55.12 1H d \"

 64.18 1H t 2"' 54.19 1H t 2"'

52.50 3H s 3" -N-CH ₃

Δΐ.21 3H s 4" -C-CHj 51.18 3H s 4" -C-CH ₃ disclosed in the present invention has o

2'-NH ₂ -3', 4'-two deoxystructured aminoglycoside antibiotics 1-N-acyl derivatives not only show good antibacterial activity against MRSA and MRCNS, but also show against Gram The negative bacteria also have a good antibacterial effect.

Method for determination of susceptibility of bacteria: The minimum inhibitory concentration (MIC) of the sample for clinical isolates was determined according to the agar double dilution method recommended by CLSI (Clinical and Laboratory Standards Institute). The antibacterial concentration was 128mg/L - 0.06mg / L 12 dilutions of double dilution. The bacterial inoculum was 10 ⁴ CFU/dot. The quality control strains were: golden yellow grape ball ATCC29213 (MSSA), Escherichia coli ATCC25922, and P. acuminata ATCC27853. The drug sensitivity judgment standard of amikacin was according to the CLSI 2007 edition standard. The test results are shown in Table 4-8.

Table 4 Drug sensitivity of SK-701, SK-702 and other test drugs to aerobic Gram-positive cocci (MICmg/L) Bacteria (strain number) "~ Antimicrobial MIC range MIC ₅₀ MC ₉ o ~~

 (50) SK-702 8 32

 Etimicin 0.125— >128 〉128 >128 Isepamicin 1>128 64 128 Amikacin 1->128 >128 〉128

 MSSA 0.06-0.25 0.25 0.25

(20) SK-702 0.06-0.5 0.25 0.5 etimicin 0.06-4 0.25 0.5 isepamicin 1-8 2 4

 Amikacin 1—4 2 4

 MRCNS SK-701 0.06-0.25 0.06 0.125

(50) SK-702 0.06-4 2 4

 Etimicin 0.06-128 16 128 Isepamicin 0.5-32 4 16

Amikacin 0.5-128 8 64 MSCNS SK-701 0.06 0.125

(20) SK-702 0.06-4 0.125 1

Etimicin 0.06-64 0.125 8 Isepamicin 0.5-8 1 2 Amikacin 0.5-16 1 4 -701, SK-702 and other test drugs for aerobic Gram-negative bacilli (MICmgL) Bacteria (strain number) Antibacterial MIC range MIC ₅₀ MIC ₉₀ ~~

, SK-701 o 0.125 —>128 0.25 0.5 Escherichia coli SK-702 0.5- -> 128 0.5 1

 (50) Etimicin 0.25 d- ->128 2 32

 Isepamicin 0.125 ->128 0.5 1 Amikacin 0.5- ->128 1 4

SK-701 0.125 —>128 0.25 >128 Klebsiella pneumoniae SK-702 0.25- —>128 0.5 〉128

(50) Etimicin 0.25- ->128 0.5 〉128 Isepamicin 0.25- ->128 0.5 〉128 Amikacin .0.5- ->128 1 〉128

SK-701 0,25- ->128 1 4 Enterobacter cloacae SK-702 0.25- ->128 4 4

 (20) Etimicin 0.25- ->128 32 64

 Isepamicin 0.5- ->128 1 2 Amikacin 1 〉1.28 8 16

SK-701 0.5- ->128 1 >128 Serratia marcescens

1一>128 2 >128

(20) Etimicin 0.5- ->128 2 >128 Isepamicin 1 〉128 2 >128 Amikacin 2->128 4 >128

SK-701 0.5- ->128 2 8 Pseudomonas aeruginosa SK-702 0.06- ->128 1 4

 (20) Etimicin 0.125-> 128 4 16

Isepamicin 0.5- ->128 4 32 Amikacin 0.5- ->128 4 32 Cumulative inhibition rate (%) of bacterial strains against clinical isolates of SK-701 and SK-702, etc. (bacterial MIC (mg/L)

 (strain number) drug 0.5 1 2 4 8

MRSA SK-701 86 100 100 100 100

 (50) S v"K-702 6 8 20 38 58

 Etimicin 6 6 6 8 8

 Isopami O Star 0 2 2 4 8

 Amikacin 0 2 2 4 4

 MSSA 100 100 100 100 100

 (20) SK-702 100 100 100 100 100

 Etimicin 90 90 95 100 100 Isepamicin 0 15 75 95 100 Amikacin 0 15 65 100 100

 MRCNS SK-701 100 100 100 100 100

 ( 50) SK-702 22 40 84 100 100

 Etimicin 8 8 16 22 28 Isepamicin 4 16 18 56 74

 Amikacin 4 8 16 40 70

 MSCNS SK-701 100, 100 100 100 100

 (20) SK-702 85 95 95 100 100

 Etimicin 75 75 85 85 95 Isepamicin 20 60 95 95 100 Amikacin 25 65 85 95 95

 SK-701 92 96 98 98 98 Escherichia Eich SK-702 54 90 92 94 98

 Etimicin 46 48 50 50 58

 (50) Isepamicin 84 94 98 98 98

 Amikacin 4 58 88 90 94

 SK-701 70 70 70 72 72 Pneumonia Cray SK-702 70 70 72 72 72

 Helicobacter pylori 66 66 66 66 66

 ( 50) Isepamicin 70 70 70 70 70

Amikacin 10 66 70 70 70 2 Cumulative inhibition rate of SK-701 and SK-702 test drugs against 300 strains of clinical isolates (%) Bacterial MIC (mg/L)

 (strain number) drug 0.5 1 2 4 8

45 50 85 90 95 Enterobacter cloacae SK- 702 45 45 45 90 95

 (20) Etimicin 40 45 45 45 45

 Isepamicin 10 55 90 90 90

 o

 , Amikacin 0 30 45 45 80

 SK-701 20 50 65 80 80 Serratia marcescens SK-702 0 40 75 75 80

 (20) 'Ettemimiline 10 35 75 75 75

 Isepamicin 0 10 60 80 80 Amikacin 0 0 25 75 75

 SK-701 10 25 50 75 90 Pseudomonas aeruginosa SK-702 15 55 70 90 90

 (20) Etimicin 5 5 25 55 75

Isepamicin 5 5 30 55 75 Amikacin, 5 10 40 55 80

/ Os600iAV 03⁄46o/:/l£9s08005 /-/.

Table 8. Distribution of MICs and cumulative inhibition rate (%) of MRCNS 50 strains by SK-701 and SK-702, etc. Anti-drug MIC (mg/L)

 0.06 0.125 0.25 0.5 1 2 4 8 16 32 64 128 〉128

SK701 . Number of strains 28 18 4

 Cumulative strains 28 46 50

 Cumulative inhibition rate (%) 56.0 92.0 100.0

 SK702 Number of strains 3 1 6 1 9 22 8

 Cumulative number of strains 3 4 10 11 20 42 50

 Cumulative inhibition rate (%) 6.0 8.0 20.0 22.0 40.0 84.0 100.0 Number of etimicin strains 3 1 4 3 3 19 9 2 6 Cumulative strain number 3 - 4 8 11 14 33 42 44 50 Cumulative inhibition rate (%) 6.0 8.0 16.0 22.0 28.0 66.0 84.0 88.0 100.0 Number of isepamicin strains 2 6 1 19 9 9 4

 Cumulative strains 2 8 9 28 37 46 50

Cumulative inhibition rate (%) 4.0 16.0 18.0 56.0 74.0 92.0 100.0 Number of amikacin strains 2 2 4 12 15 5 4 3 3 Cumulative strain number 2 4 8 20 35 40 44 47 50 Cumulative inhibition rate (%) 4.0 8.0 16.0 40.0 70.0 80.0 88.0 94.0 100.0

The initial acute toxicity (LD ₅ .) of SK-701 and SK-702 showed that the LD _{5Q of} SK-701 and SK-702 are similar, 50-75mg/Kg, and the clinical use of aminoglycoside antibiotics is permitted. Within the scope.

It can be seen that SK-701 and SK-702 have significant anti-MRSA and MRCNS activities, and the LD ₅₀ results are within the scope of clinical application of aminoglycoside antibiotics, and thus can be used for the preparation of a medicament for treating drug-resistant infections.

 Synthesis method 1

R=CH ₃ CO,(S)-C3⁄4(NH ₂ )CH(OH)C〇(AHP) or (S)- CH ₂ ( 3⁄4)CH ₂ CH(OH)CO(AHB) R1 =H or CH3 Synthesis method 2

R=CH ₃ CO, (S>CH ₂ (NH ₂ )CH(OH)CO(AHP), (S)-CH ₂ (NH ₂ )CH ₂ CH(OH)CO(AHB) Rl =H or C3⁄4 Synthesis method 3

R=CH ₃ CO, (S)-CH ₂ (NH ₂ )CH(OH)CO(AHP) , (S)-CH ₂ (NH ₂ )CH ₂ CH(OH)CO(AHB) =H or CH ₃

 In order to specifically modify the target side chain at the N position, the present invention employs a formyl protecting intermediate, and the formyl form donor is 2-formyl hydrazinothiazole, and its structural formula is as follows:

When the present invention is used for preparing a pharmaceutical composition effective for treating a drug-resistant bacterial infection, it is first neutralized with a acid to form a salt which is easily soluble in water, wherein the acid may be a mineral acid such as hydrochloric acid, phosphoric acid, sulfuric acid, or the like. It may also be an organic acid such as maleic acid, lactic acid or tartaric acid, and the most commonly used sulfate is made of sulfuric acid.

The preparation method of the pharmaceutical preparations disclosed by the present invention, the specific method is an aminoglycoside antibiotic having a 2'-ΝΉ ₂ - 3 ', 4'-two deoxy structure structure, or a acyl derivative thereof or A pharmaceutically acceptable salt as an active ingredient and a pharmaceutically acceptable carrier such as a buffer, a lubricant, a disintegrant, a binder, a surfactant, a preservative, a sweetener, an isotonic agent, etc., in a weight ratio of an active ingredient It is prepared from 0.01-99.99% and the carrier is 99.99-0.01%, and is packaged and sterilized.

The pharmaceutical preparations of the present invention are used in a similar manner and dosage to other aminoglycoside antibiotics. For example, the most common application method is injection, and the dosage is 50-800 mg/day, which is used once or three times. detailed description

 Example 1 : Synthesis of 1 - N - (S) - 3 - amino - 2 -propionyl gentamicin Cla

1) Synthesis of 3, 2', 6'-three-one N-formyl gentamicin Cla

 25 g of gentamicin Cla (GMCla) was dissolved by stirring with 500 mL of dimethyl sulfoxide (DMS0), cooled to room temperature, and 100 mL of dichloromethane, 32 g of cobalt acetate tetrahydrate was added, and dissolved and complexed at room temperature with stirring. 40 g of 2-formylmercaptothiazole was added in portions and reacted for 1 hour with stirring. 500 mL of 5 Ό cold water was added to the reaction mixture, and the mixture was separated. The supernatant was added with 5 g of activated carbon and stirred for 20 minutes. The filtrate was extracted with 1 / 10 filtrate volume of dichloromethane and extracted twice.

 The upper aqueous phase was dynamically adsorbed by 800 mL HD-2 resin (ammonium type) column. After washing with DMSO, it was eluted with 0.4N ammonia water. After pH 9.5, the fractions were collected, the same components were combined, and concentrated to dryness. 100 mL of methanol was dissolved, evaporated to dryness and dehydrated, and once again, 20.5 g of a solid was obtained.

5 g of the above solid was purified by using a 200 mL HD-2 resin column (high I diameter > 10), eluted with a gradient of 0-0.4 N ammonia water, and the eluate was collected in portions, and the same fractions were combined, concentrated to dryness, and dissolved in methanol. Evaporation and dehydration were repeated once to obtain 2.8 g of the solid product 3, 2', 6'-tris-N-formyl gentamicin Cla. [a] ^D t = 154° _; elemental analysis: C: 44.32 H: 7.41 0: 12.35 (moisture: 5.6%, theoretical value: C: 44.22 H: 7.56 0: 12.31).

 2) Synthesis of 1 -N- (S) 3-amino- 2 -hydroxypropionyl gentamicin Cla

 15 g of the first solid obtained above was dissolved in 300 mL of methanol, and 10.5 g of phthalamide-α-hydroxypropionic acid (ΡΗΡΑ) and 5 g of 1-hydroxybenzotriazole monohydrate (5 g) were added at room temperature ( ΗΟΒΤ) Stirring was dissolved, and 8.4 g of cyclohexylcarbodiimide (DCC) was added in portions and reacted for 1 hour.

 The reaction solution was filtered, and the filtrate was concentrated to dryness under reduced pressure. Ethanol was evaporated under reduced pressure, dissolved in water, adsorbed with an HD-2 resin column, purified, eluted with 0-0.4N aqueous ammonia, fractionated, combined, and concentrated to dryness to give 7.2 g.

2 g of the above solid was taken, dissolved in 50 mL of water, filtered through a microporous membrane (0.45 μm), and the filtrate was freeze-dried to obtain 1.7 g of a solid of 1-N-(S)-3-amino-2-hydroxypropanoyl 5 g of the above solid was dissolved in 80 mL of water, and 6N H ₂ S0 _{4 was added} . The pH was adjusted to 4.5 to 7, and the activated carbon was decolorized by adding 2, activated carbon, filtered, and the filtrate was freeze-dried to obtain 7.1 g of l-N-(S)-3. - Amino-2-hydroxypropanomycin Cla sulfate.

 Example 2: Synthesis of 1-N-(S)-3-amino-2-hydroxypropanoyl- 3"-N-demethylgentinyl Cla

5 g of 3''-N-demethylgentamicin Cla was added to 20 mL of water and 100 mL of DMSO, and dissolved by stirring. For example, 10 g of zinc acetate was stirred and dissolved, and 8.5 g of 2-formylsulfonylthiazole was added in portions at room temperature to stir the reaction. Add 150 mL of cold water to the reaction mixture, mix well, and filter. The filtrate was dynamically attached with weakly acidic cationic resin D151. After washing with water, it was eluted with 0.4N ammonia water. At pH 9.5, the fractions were collected, the same components were combined, and the pressure was reduced. Evaporate to dryness to give a solid.

 The above solid was subjected to a 1-N acylation reaction by the method of Step 2) in Example 1 and purified to give 1-N-(S)-3-amino-2-hydroxypropanoyl- 3"-^-demethylated Toxin Cla base 1.8 g.

1.5 g of the above solid was dissolved in 30 mL of water, 6N H ₂ S0 _{4 was} adjusted to pH 4.5 to 7.0, decolorized by adding activated carbon, filtered, and the filtrate was freeze-dried to obtain 2.1 g of 1-N-(S)-3-amino-2-hydroxyl Propionyl-3"-N-demethylgentamicin Cla sulfate.

 Example 3: Synthesis of 1-N-(S)-3-amino-2-hydroxypropanoyl- 3"-N-demethylgentinyl Cla

1 -N- (S) — 3—Amino-2-hydroxypropionyl gentamicin Cla sulfate 8 g plus 100 mL water dissolved, add 10 g of sodium acetate, add 10 g of iodine (100 mL of dimethylformamide dissolved) ), the reaction was stirred at 50 to 70 ° C for 12 hours. The reaction solution was diluted with water to 400 mL, dynamically adsorbed with 100 mL of D151 resin, washed with 0.4 N aqueous ammonia after water washing, and fractionally collected at pH 9.5, and the same fractions were combined and evaporated to dryness under reduced pressure. The force n 50 mL water was dissolved, purified by HD-2 (weak acid cation resin) resin column (height/diameter > 10), eluted with 0-0.4N ammonia water, and collected in portions. The same components were combined, concentrated to dryness, dissolved in 30 mL of water, adjusted to pH 4.5~7 by adding 6N H ₂ S0 ₄ , decolorized with 1 g of activated carbon, filtered, and the filtrate was freeze-dried to obtain 3.1 g of 1-N-(S)- 3-amino-2-hydroxypropionyl- 3"-N-demethylgentamicin Cla sulfuric acid.

 Example 4. Antibiotic water injection

 Recipe:

 SK-701 grams

 Anhydrous sulfurous acid 0.4 g

 Water for injection 200 ml

 pH 4.5-7.0

 Process: Weigh the main and auxiliary materials according to the formula, dissolve in 160mL of water for injection, adjust the pH, add the appropriate amount of activated carbon, add water to a constant volume of 200mL, remove the charcoal, filter the microporous membrane to the net, pass the nitrogen encapsulation, 10CTC circulation steam Bacteria for 30 minutes.

Claims

Rights request

1. Use of an aminoglycoside antibiotic in the preparation of a pharmaceutical composition for treating a drug-resistant infection: the aminoglycoside antibiotic has the following structure:

R=CH ₃ CO, (S)-CH ₂ ( H ₂ )CH(OH)CO , or (S)-CH ₂ ( 3⁄4)CH ₂ CH(OH)CO,

=H or CH ₃ , R ₂ =H or CH ₃ .

2. Use according to claim 1, characterized in that the aminoglycoside antibiotic is R = (S) - CH ₂ (NH ₂ ) CH(OH) CO , = Η, R ₂ = C3⁄4, the structure is as follows:

That is, the use of 1-N-(s)-3-amino-2-hydroxypropionyl gentamicin Cla in the preparation of a pharmaceutical composition for treating drug-resistant infections.

3. The use according to claim 1, wherein the aminoglycoside antibiotic is R = (S)-CH ₂ (NH ₂ )CH(OH)CO , 3⁄4=3⁄4=Η, and the structure is as follows:

That is, the use of 1-N-(s)-3-amino-2-hydroxypropionyl- 3"-N-demethylgentamicin Cla in the preparation of a pharmaceutical composition for treating drug-resistant infections. 4. The use according to claims 1-3, characterized in that the resistant bacteria are methicillin-resistant Staphylococcus aureus

 5. Use according to claim 1 - 3, characterized in that the resistant bacteria are methicillin-resistant coagulase-negative staphylococci.

 The pharmaceutical composition according to any one of claims 1 to 3, which is characterized in that the 1-N acylated derivative or a pharmaceutically acceptable salt thereof as an active ingredient is composed of a pharmaceutically acceptable carrier, and The 1-N acylated derivative or a pharmaceutically acceptable salt thereof has a weight ratio of 0.01% to 99.99% and a pharmaceutically acceptable carrier of 99.99% to 0.01% by weight.

 The method for preparing a pharmaceutical composition according to claim 6, wherein an effective amount of the 1-N acylated derivative or a pharmaceutically acceptable salt thereof is mixed with a pharmaceutically acceptable carrier, and is conventionally packaged and destroyed. Made by bacteria.

 8. A pharmaceutical composition according to claim 6 wherein the pharmaceutical composition for the treatment of a drug resistant bacterial infection is a tablet, an aqueous injection, a powder injection, an eye drop, an aerosol, a cream, or Aerosol.

 The use according to claim 1, wherein the preparation of the aminoglycoside antibiotic is characterized by the preparation of the following structural compound

R=CH ₃ CO, (S)^CH ₂ (NH ₂ )CH(OH)CO, or (S)-C3⁄4(NH ₂ )CH ₂ CH(OH)C0;

RfH or CH ₃ ,

 Including the following steps:

 1) using a divalent metal ion to form a complexation state of the amino group of the parent compound, followed by a formylation reaction, and the divalent metal ion used for complexation is a zinc ion, a cobalt ion or a nickel ion;

 2) removing metal ions;

 3) performing an R-based derivatization reaction at the 1-N position;

 4) specifically removing the formylation protecting group;

 5) Purification of the target product, purification of the product, elution with cation exchange resin column chromatography, elution with different concentrations of aqueous ammonia solution; or purification of the product by adsorption resin column chromatography with different concentrations of ethanol, methanol or acetone The aqueous solution is eluted.

10. The use according to claim 1, wherein the preparation of the aminoglycoside antibiotic is characterized by the preparation of the following structural compound

R=CH ₃ CO, (S)-CH ₂ (NH ₂ )CH(OH)CO, or (S)-C3⁄4(NH ₂ )CH ₂ CH(OH)CO,

=H or CH ₃ ,

 Including the following steps:

 1) The mother core compound is subjected to 3"-N demethylation reaction with iodine or iodide and purified to obtain 3"-N-demethylated product;

 2) using a divalent metal ion to form a complexation state of the amino group, followed by a formylation reaction, and the divalent metal ion used for complexation is a zinc ion, a cobalt ion or a nickel ion;

 3) removing metal ions;

 4) performing an R-based derivatization reaction at the 1-N position;

 5) specifically removing the formylation protecting group;

 6) Purification of the target product, purification of the product by cation exchange resin column chromatography, elution with different concentrations of aqueous ammonia solution; or purification of the product by adsorption resin column chromatography, with different concentrations of ethanol, methanol or acetone aqueous solution Elution is performed. ;