Amycomycin, method for its preparing and its applying as pharmaceutical agent

FIELD: biotechnology, medicine, antibiotics.

SUBSTANCE: invention proposes to the new compound amycomycin of the molecular formula C65H115NO18 (structural formula is given on the invention claim) that shows an antibacterial activity. Amycomycin, its pharmaceutically acceptable salts and derivatives in all their stereoisomeris and tautomeric forms can be obtained by culturing microorganism Amycolatopsis sp. ST 101170 (DSM 12216) under aerobic conditions on the nutrient medium containing the necessary nutrient components. The end product is isolated and purified and converted if necessary to its pharmacologically acceptable salt, ester, ether and other chemical derivatives and eliciting the same spectrum of antibacterial activity. Amycomycin is a component of the pharmaceutical composition eliciting an antibacterial activity. Amycomycin acts as an antibiotic. Invention provides inhibition of microorganisms with resistance to vancomycin and teicoplanin used in treatment of infections caused by Staphylococcus aureus.

EFFECT: improved preparing method, valuable medicinal properties of amycomycin.

7 cl, 2 tbl, 4 ex

 

This invention relates to a compound called "amikacin", which can be obtained by culturing a microorganism Amycolatopsis sp., ST 101170 (DSM 12216), and its pharmaceutically acceptable salts and derivatives. This invention also relates to a method of obtaining micomicona, to use amikacin and its pharmaceutically acceptable salts and derivatives as pharmaceuticals, in particular to their use as antibiotics, as well as pharmaceutical compositions comprising amikacin, or its pharmaceutically acceptable salt, or a derivative thereof.

It is known that methicillin-resistant Staphylococcus aureus infection (MRSA) is dominated by some infectious conditions such as wounds and burns. Vancomycin, teicoplanin belonging to the class of glycopeptides are the only two antibiotics used in the clinic for the treatment of MRSA infections. However, due to the recent emergence of vancomycin - and teicoplanin-resistant strains reported that these infections have become threatening and fatal. So started an intensive search for structurally different class of compounds active against these vancomycin - and teicoplanin-resistant strains. For example, as an antibiotic, active against vancomycin - and teicoplanin-resistant strains has been described (EP-A-081853, filed July 11, 1996) methylsulfonyl I, cyclic dipeptide.

It was found that a new connection called "amikacin" has the activity of the antibiotic. Thus, the present invention relates to a compound of the formula:

and its pharmaceutically acceptable salts and derivatives, such as esters, ethers, and other obvious chemical equivalents, including all stereoisomeric forms and all tautomeric forms.

Amikacin has a characteristic residue Ternovoi acid with this highly oxidised side chain With45. He has the molecular formula C65H115NO18and can be obtained by culturing a microorganism Amycolatopsis species ST101170 (DSM 12216) in aerobic conditions and nutrient medium containing sources of carbon and nitrogen, with subsequent isolation and purification in the usual way. The microorganism ST101170 belongs to the order Actinomycetales, the genus Amycolatopsis, and June 4, 1998, he was deposited in the German collection of microorganisms and cell cultures (DSMZ-Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH, Braunschweig, Deutschland, and he was assigned a number DSM No. 12216.

The present invention also provides a method for obtaining compounds called "amikacin from Amycolatopsis species ST101170, its mutants and variants under aerobic conditions in a nutrient medium, the content is promoting one or more sources of carbon and one or more sources of nitrogen and optional nutrient inorganic salts and/or trace elements followed by separation of the compounds and purification in the usual way.

Mutants and variants of the microorganism ST101170 may also be able to synthesize the compound in accordance with the present invention. Such mutants can be obtained in a known manner by physical means, for example irradiation, such as ultraviolet or x-rays, or chemical mutagens such as ethylmethanesulfonate (EMS), 2-hydroxy-4-methoxybenzophenone (MOB) or N-methyl-N'-nitro-N-nitrosoguanidine (MNNG).

Screening of suitable mutants and variants, which can produce a connection in accordance with the invention, can be confirmed by determination of the biological activity of the active compounds accumulated in the culture broth, for example by testing antibacterial action, in particular against vancomycin-resistant strains (see table 2 below).

The preferred sources of carbon, suitable for aerobic fermentation, are assimilated carbohydrate and sugar alcohols such as glucose, lactose or D-mannitol, and uglevodsoderzhashchie natural products, such as malt extract. Suitable nitrogen sources include, for example, amino acids, peptides and proteins, including their degradation products, such as gelatin or tryptone, meat extract, crushed is the yemini, for example, corn, white beans, soybeans, or cotton plant, distillation residues from obtaining alcohol, meat flour and yeast extracts, and also ammonium salts and nitrates. Suitable inorganic salts, which may contain the nutrient solution are, for example, chlorides, carbonates, sulfates or phosphates of alkali or alkaline earth metals, zinc ions, cobalt or manganese.

The formation of micomicona going particularly well, for example, in a nutrient medium comprising about 0.5-5% starch (soluble), preferably 1-2%, about 0.5-5% glucose, preferably 1-3%, about 0.5-5% glycerol, preferably 1-2%, about 0.1-0.5% of corn extract, preferably of 0.2-0.3%, about 0.2-1% peptone, preferably 0.4 to 0.6%, about 0.1-0.5% of yeast extract, preferably of 0.2-0.4%, about 0.05-0.2% of sodium chloride, preferably 0.1 to to 0.2%, and about 0.1-0.5% of caso3, preferably of 0.2-0.3%. These quantities given in the calculation of the mass of the whole medium.

Cultivation ST101170 aerobic exercise, for example, by immersion with shaking or stirring in katalozhnyh flasks or laboratory fermenters, not necessarily with the introduction of air or oxygen. The cultivation of the fermentation can be carried out, for example, in a sterile wide-mouthed bottles or round-bottom flasks of various volumes in the glass is armentero or containers of V 2A-steel.

Cultivation ST101170 can be carried out at a temperature between about 20 and 35°C, preferably between about 25 and 30°and a pH between 4 and 10, preferably between 6 and 8. Under these conditions, the microorganism is cultivated in total over a period of time 20-200 hours, preferably 24-150 hours.

Cultivation is mainly carried out in several stages. First, in a liquid nutrient medium can be obtained one or more preculture. The main culture, the actual production environment, then inoculant precultural, for example, at a volume ratio of 1:10. Preculture receive, for example, inequilibrium nutrient medium mycelium with spores and leaving it for growth within from about 20 to about 120 hours, preferably 24-90 hours. The mycelium with spores can be obtained, for example, in the growth of the microorganism within about 1 to about 40 days, preferably 5-12 days, in solid or liquid nutrient medium such as malt-yeast agar or potato-dextrose agar.

The progress of fermentation and the formation of micomicona can be controlled by methods known in the art, such as measurement of the biological activity of the culture broth using biological assays, or chromatographic methods, tecimical thin layer chromatography (TLC) or high performance liquid chromatography (HPLC).

Connection amikacin present in the culture filtrate, and mycelium. Typically, however, the basic amount is present in the mycelium. The connection can be isolated using known methods of separation. So, it can be isolated from the culture filtrate, for example, by filtration or centrifugation. The filtrate may be extracted immiscible with water solvent, such as 1-butanol, ethyl acetate, chloroform, dichloromethane or similar, preferably butanol or ethyl acetate.

The active material can also be released from the mycelium extraction is mixed with water in a solvent such as methanol, acetone, acetonitrile, n-propanol or isopropanol, preferably methanol or acetone, or immiscible with water solvent, such as tert-butanol, ethyl acetate, chloroform, dichlormethane or similar, preferably butanol or ethyl acetate.

Extraction of the filtrate of the culture can be carried out in a wide range of pH. However, it is preferable to carry out the extraction in a neutral or weakly acidic medium, preferably at pH between 4 and 9. The organic extract may be concentrated in vacuum and dried, giving active raw material.

Selection or purification of micomicona can be carried out in a known manner with respect to chemical, physical and biological engineering the x characteristics of natural compounds.

One of the methods of allocation of amikacin in accordance with the invention is a distribution solution of a known per se manner.

Another way to clean micomicona is the absorption chromatography on resin such as Diaion® HP-20 (Mitsubishi Casei Corp., Tokyo), Amberlite® XAD 7 (Rohm and Haas, USA), on Amberchrom® CG (Toso Haas, Philadelphia, USA), or similar resins. The separation may be carried out in a wide range of pH. The range of pH is preferably from 1 to 9, more preferably from 2 to 8. Suitable are also numerous substrates with reversed phase, for example RP8RP18such as described in General in the context of high-performance liquid chromatography (HPLC). The next opportunity the cleaning compound in accordance with the invention consists in using the so-called "chromatographic substrates with normal phase, such as silica gel or Al2O3(aluminum oxide), or other method known per se. For this purpose suitable are many eluent, such as dichloromethane, chloroform, methanol, ethyl acetate, acetone, petroleum ether, or combinations thereof. the pH can be varied, for example, by the addition of triethylamine. An alternative method of allocation micomicona is to use molecular sieves, such as Fractogel® TSK HW-40, Sephadex® LH-20 and others, in a way known per se. Cu is IU, amikacin you can also select from the raw material with the help of crystallization. For this purpose, suitable are, for example, organic solvents and mixtures thereof, anhydrous or with the addition of water.

Further isolation and purification of compounds in accordance with the invention includes the use of-exchangers, preferably in the range of pH 7 to 10, and kationoobmennikom, preferably in the range of pH from 3 to 7. Particularly suitable for this purpose is the use of buffer solutions to which are added some amounts of organic solvents.

A possible method of cleaning is also a counter-current chromatography using a two-phase system eluent consisting of two or more solvents such as water, methanol, ethanol, butanol, isopropanol, acetone, dichloromethane, ethyl acetate or petroleum ether.

Amikacin or its chemical derivatives can be converted into the corresponding pharmaceutically acceptable salt by methods known to experts in this field.

Pharmacologically acceptable salts of the compounds according to the invention are inorganic or organic salts, such as described in Remington''s Pharmaceutical Sciences (17. Edition, page 1418 (1985)). Possible salts are alkali metal salts, ammonium salts, salts of alkaline earth metals,salts with physiologically acceptable amines and salts with inorganic or organic acids, such as HCl, HBr, H2SO4, maleic acid and fumaric acid.

Obvious chemical equivalents of the compounds of the invention are compounds with a small chemical differences, but having the same or a similar activity, or which may develop in soft conditions in the compounds according to the invention. Examples of obvious chemical equivalents are esters, ethers, amine derivatives, complexes or adducts of compounds or with compounds according to the invention.

Esters can be obtained, for example, the interaction of amikacin with carboxylic acids in the presence of reagents such as dicyclohexylcarbodiimide (DCC), or by treating compound allermuir agent such as acid chloride acid.

Ethers can be obtained, for example, from amikacin interaction with alkylating agents in basic terms.

Other methods of obtaining simple and complex esters described in the literature, for example, in Advanced Organic Synthesis, 4thEdition, J. March, John Wiley & Sons., 1992.

Chemical equivalents may represent a stable complexes with metal ions, such as transition metals, such as La3+Sm3+, Eu3+, Gd3+that are typical for derivatives Ternovoi acid and can be obtained by methods described in the literature (K. Tanaka et al., Chem. Pham. Bull. 1979, 27, 1901. K. Matsuo, Chem. Pharm. Bull. 1980, 28, 2494).

The double bond of alkyl side chain can be recovered by methods described in the literature, for example, in P. N. Rylander, "Hydrogenation Methods, Academic Press, New York (1985), Chpt. 2, or hydrohalogenation ways described N. O. House, "Modern Synthetic Reactions", W. A. Benjymin, Inc., New York (1972), pp.446-452. Gidroksilirovanii derivatives can be obtained by the interaction of the double bond with such reagents as OsO4as described in the literature, for example in Chem. Rev. 1980, 80, 187.

Derivatives can also be obtained by conversion of double bonds in the epoxy oxidation, for example, using MSRV, as described in Advanced Organic Synthesis, 4thEdition, J. March, John Wiley & Sons., 1992.

Amikacin according to the invention has the following physico-chemical and spectroscopic characteristics:

Appearance: colourless solid, soluble in methanol, DMSO, pyridine.

Molecular formula: C65H115NO18.

HPLC (high performance liquid chromatography):

Column: Purospher Star RP.18e (Merck), 55×4 mm, 3 µm

Eluent: CH3CN/a 0.01% N3PO4(85%)

Gradient:Time (min)% CH3CN
0,005,0
3,00 95,0
5,0095,0
6,005,0
10,005,0

Rate: 2 ml/min

Temperature: 40°

Detection: 210 nm, 254, 280, 320, 380

tR: to 2.67 min

Molecular weight: 1198,64 Da

HR-FAB-MS: 1220,801187 [M+Na]+

1H and13C-NMR: see table 1

UV/VIS: Meon,max(log)=229 nm(3,29), 281 (3,16)

Table 1

The chemical shift of amikacin in MeOD at 300 K
1H13
10,86of 14.76
20,9720,83
31,8931,20
43,4182,20
51,7039,55
60,7713,63
73,5480,19
81,6536,32
90,8612,71
101,4331,20
11the 1.4436,46
123,7571,98
131,62/,54 44,79
143,7472,22
151,58/1,3736,46
161,63/1,14to 29.27
171,5140,69
180,9015,70
193,7072,90
271,51/1,4642,12
284,0766,31
291,5242,12
303,8072,54
314,3373,26
326,62142,18
33-138,47
341,83was 12.75
35-206,04
364,2141,00
371,1417,77
38are 5.36128,37
39-138,72
401,69was 12.75
413,9880,54
421,6441,25
430,888,02
443,59 73,88
451,4936,46
461,62/1,3223,50
471.55V/1,3233,34
483,8075,09
491,7442,71
500,7711,92
513,4177,87
521,6136,46
530,86was 12.75
541.55V/1,3231,37
551,61/1,4436,46
56of 3.7771,83
571,6744,53
583,9271,12
592,30to 37.54
60of 5.84 (b)˜131,7 (C)
61-(C)
621,8213,81
63-(C)
64-(C)
653,24 (b)27,91
66-(C)
67-(C)
68 -(C)
695,50 (b)˜119,3 (C)
703,0926,52
711,1024,31
721,1024,31
b) Broad signals

c) Data signals invisible. C60 and C can only be obtained by using the HMQC spectrum.

Amikacin has an extremely high antibacterial activity, especially against gram-positive bacteria, such as, for example, Staphylo - and Enterococcen. The minimum inhibiting concentration Amikacin against wide range of bacteria are shown below in table 2. In particular, these strains have recently become increasingly problematic, i.e. microorganisms that have become resistant to existing antibiotics. The superiority of this compound in comparison with other antibiotics shown, for example, when the inhibition of vancomycin - and teicoplanin-resistant strains, such as, for example, .faecalis, E.faecium or .gallinarium.

Table 2

Minimum inhibitory concentration (mg/l) (test microrasbora)
The gram-positive strainCodeAmikacinvancomycin
S.aureus011HT3oxa S ery S0,080,3
S.aureus011HT18ATCC 13709 Smith0,080,3
S.epidermidis012G020oxa ery S S tet R0,30,6
S.aureus011HT1nov R<=0,040,08
S.aureus011DU5nov R tet R0,080,15
S.aureus011CB20oxa R ery Rc tet R0,080,15
S.aureus011G071ofl's oxa R ery S tet R0,150,6
S.aureus011G064ofl R oxa R ery tet Re R0,31,2
S. epidermidis012G042oxa R0,31,2
Staph. coag. Negative012HT5ofl R oxa R tet R0,150,6
S.aureus011GR91pri R oxa R ery R nov R1,21,2
Of these bacteria to antibioticsO2A1SJ1van S ery Rc0,30,15
Of these bacteria to antibioticsO2A1UC1van S ery Rc0,60,15
Of these bacteria to antibioticsO2A1F16 ery R0,60,08
Strepto gr.GO2GOCB2tet R rif R nov R0,60,15
S.pneumoniae030B12ery R0,150,15
S.milleri02milGR12ery S van S1,20,3
S.mitis02mitGR16ery Ri van S1,20,3
E.faecium02D3AP9nov S van R ery S tei R0,6>40
E.faecium02D3HT12tei R van R ery tet R R0,6>40
.faecium.O2D31P2tei R van R ery tet R Rnot ODA.>40
E.faeciumO2D3HM3nov S van A ery R tei R1,2>40
E.gallinariumO2DOHM8van With tet R ery S1,2>40
E.faecalisO2D2HM9nov R van In ery R tei S2,5>40
E.faecalisO2D2UC5ATCC 29212 nov R2,52,5
E.faecalisO2D2DU18tet R nov R1,20,3
E.faecalisO2D2HT10nov R van S tet R1, 0,6
The gram-negative strainCode
E.coliDB102501P5ery S fuc S nov Snot ODA.>40
P.aeruginosaNT>40>40
P.aeruginosa1771m391HT3mutant permissibly>40>40

Amikacin and its pharmaceutically acceptable salts and derivatives can be introduced to animals, preferably mammals, in particular humans, as pharmaceuticals by themselves, in mixtures with each other and in the form of pharmaceutical compositions, allowing you to enter their parenterally or by other means. Accordingly, the present invention also relates to amikacin and its pharmaceutically acceptable salts and derivatives for use as pharmaceuticals, and to the use of amikacin and its pharmaceutically acceptable salts and derivatives to obtain drugs, which have antibacterial activity. The present invention also relates to pharmaceutical compositions containing an effective amount of amikacin and/or one or more of its pharmaceutically acceptable salts, and/or produced in the water together with a pharmaceutically acceptable carrier.

Amikacin may be enterline (oral), parenteral (intravenous or intramuscular), rectally or locally (local administration). Pharmaceutical compositions containing amikacin or its pharmaceutically acceptable salt or derivative with other pharmaceutically active substances, can be obtained by mixing the active compounds with one or more pharmacologically portable assistive technology and/or excipients and converting the mixture into a suitable pharmaceutical form such as solutions, powders, tablets, capsules (including microcapsules), ointments (creams or gels), liposomal preparations, lipid complexes, colloidal dispersion or suppositories, suitable for injection.

Possible auxiliary and/or excipients for the finished forms of this type are conventional pharmaceutical solid or liquid fillers and extenders, solvents, emulsifiers, lubricity agents, taste corrigentov, dyes and/or buffer substances.

As usual, herbal form and route of administration, and doses that are appropriate for a particular case, depends on the species, against whom treatment, and the severity of the relevant condition or disease, and may be optimized using methods known in this field. In the operation example may be appropriate dosage of 0.001-10 mg, preferably 0.1 to 5 mg, more preferably 1.0 mg to weight about 75 kg Dose should be at least sufficient to achieve the desired effect.

The following examples illustrate the present invention but do not limit its scope.

Example 1

Obtaining seed

100 ml of nutrient solution (4 g/l yeast extract, 15 g/l soluble starch, 1 g/l To2HPO4, 0.5 g/l MgSO4×7H2Oh, supplemented with water to 1000 ml, pH 7.0 before sterilization) in a sterile Erlenmeyer flask inoculant strain of Amycolatopsis sp.(DSM 12216) and incubated for 5 days at 28°C and 180 rpm./min on a rotary shaker. 1.5 ml of this culture subsequently diluted with 1.5 ml of 99% glycerol and stored at 20°C.

Example 2

Culture or preculture Amycolatopsis sp., ST101170 (DSM 12216) in Erlenmeyer flasks

Sterile Erlenmeyer flask containing 100 ml of the following nutrient medium: 10 g/l starch solution, 10 g/l glucose, 10 g/l glycerol 99%, 2.5 g/l corn extract, or liquid, 5 g/l peptone, 2 g/l yeast extract, 1 g/l NaCl and 3 g/l caso3, inoculant full loop grown culture (the same nutrient solution, but with 2% agar) or 1 ml glycerol culture (see example 1) and incubated in a shaker at 180 rpm./min and 28°C. the Maximum production of compound amikacin h is achieved is through 72 hours.

72-Hour submerged culture (obtained in accordance with the described method for shaker culture, example 1, but with the following medium: 15 g/l glucose, 15 g/l soy flour, 3 g/l caso3and 5 g/l NaCl, pH 7.5) is sufficient for the inoculation of 10 and 200-l fermentors with inoculation amount of 10%.

Example 3

Getting connection amikacin

200-l fermentor was operated with the following settings:

Nutrient medium:10 g/l starch
10 g/l glucose
10 g/l glycerol 99%
2.5 g/l corn extract
5 g/l peptone
2 g/l yeast extract
7 g/l NaCl
3 g/l caso3
pH of 7.2 (before sterilization)
The AMF inoculum:10% of the volume of the fermenter
Incubation time:60-80 hours
Incubation temperature:28°
Mixing:50./min
Aeration:150 l/min

The addition of 1-2 ml of an ethanol solution of polyol, you can restrict education is the use of foam. The maximum production is achieved in 69 hours.

Example 4

Highlighting connections amikacin

200 l of a solution of the culture obtained in example 3, centrifuged and the mycelium completely extracted with methanol. The methanol extract was concentrated to a ratio of approximately 1:10, receiving a colorless precipitate, which is filtered off. This procedure is repeated up until leachate is no longer detected amikacin (HPLC). The remainder lyophilized, and then purified by HPLC:

1. Column: ®Fractogel TSK-HW 40 (4 l, 500×100 mm)

Eluent: Meon

Flow rate: 20 ml/min

Detection: 204 and 236 nm

Fractions enriched micomicona, suiryudan within 125 minutes. Faction merge together on the basis of HPLC (as indicated). Active combined fractions with the desired compound was concentrated in vacuo and lyophilized.

Active connection amikacin eluted through 42 minutes. Faction unite on the basis of HPLC (as indicated). Active combined fractions with the desired compound was concentrated in vacuo and lyophilized.

3. Column: ®Fractogel TSK-HW 40 (1 l, 500×50 mm)

Eluent: Meon

Flow rate: 5 ml/min

Detection: 204 and 236 nm

Active component amikacin eluted through 112 minutes.

In accordance with sunnym above process from 200 l of fermentation broth can be allocated 110 mg amikacin.

1. Amikacin formula

and its pharmaceutically acceptable salts, esters, ethers, and other obvious chemical equivalents in all their stereoisomeric and tautomeric forms.

2. The compound according to claim 1, characterized in that used as pharmaceuticals.

3. The compound according to claim 1, characterized in that is used as antibiotic.

4. Amikacin molecular formula C65H115NO18possessing antimicrobial activity obtained by cultivation of the microorganism Amycolatopsis species, ST101170 (DSM 12216) under aerobic conditions in a nutrient medium containing sources of carbon and nitrogen, with subsequent isolation and purification in the usual way, and its pharmaceutically acceptable salts and derivatives in all their stereoisomeric and tautomeric forms.

5. A method of obtaining a compound according to claim 1 or 2, comprising culturing a microorganism Amycolatopsis species, ST 101170 (DSM 12216) under aerobic conditions in a nutrient medium containing sources of carbon and nitrogen, with subsequent isolation and purification of compounds.

6. The method according to claim 5, characterized in that it comprises the additional step of transforming the obtained target product in a pharmacologically acceptable salt, ester, simple ether and other obvious chemical equivalents, the region is non antimicrobial activity.

7. Pharmaceutical composition having antimicrobial activity comprising an effective amount of a compound according to claim 1 or 2, and/or its pharmaceutically acceptable salt, ether complex, a simple ester or other obvious chemical equivalent, and a pharmaceutically acceptable carrier.



 

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FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to new substituted 7-sulfonyl-benzo[b][1,4]diazepines of the general formula (1) , their pharmaceutically acceptable salts, N-oxides or hydrates that elicit properties of a protein kinase inhibitor that can be used in pharmaceutical industry. In compounds of the general formula (1) R1 and R2 represent independently of one another hydrogen atom, inert substitute, optionally substituted carboxymethyl group, optionally substituted carbamoylmethyl group; R3 and R4 represent independently of one another hydrogen atom or inert substituted, or R3 and R4 in common with carbon atom to which they are bound form optionally substituted (C3-C7)-cycloalkyl, optionally substituted (C4-C7)-heterocyclyl or optionally substituted ethylene group; R5 represents optionally substituted amino-group or optionally substituted azaheterocyclyl. Also, invention relates to sulfochlorides of the general formula (2) that are used for preparing compound of the formula (1), and to methods for preparing compounds of general formulae (1) and (2). Also, invention relates to a pharmaceutical composition in form of tablets, capsules or injection formulations placed into pharmaceutically acceptable package, and to the focused library for the search of biologically active compound-leaders.

EFFECT: improved preparing method, valuable medicinal and biochemical properties of compounds.

7 cl, 2 sch, 1 tbl, 3 ex

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