Derivatives of erythromycin, pharmaceutical composition, method of obtaining derivatives of erythromycin

 

(57) Abstract:

Describes derivatives of erythromycin formula 1, where m = 1,2, n = 1,2, Ar is phenyl, possibly substituted by halogen atoms, alkyl - or alkoxygroup, CF3group or a phenyl, A=B=H or A and B together form a carbon - carbon bond, Z = H or a residue of carboxylic acid C1-C18possessing antibiotic activity against gram-positive bacteria. Connection + get method, comprising the stage of acylation, amination and cyclization. The pharmaceutical composition as the active agent contains a compound 1 in an effective amount, can therefore be used as medicaments in the treatment of infections with susceptible microbes. 3 S. and 11 C.p. f-crystals, 6 PL.

The invention relates to new derivatives of erythromycin, to a method for their production and to their use as medicaments.

The object of the present invention is the products of formula (l):

< / BR>
where

R - radical , in which m and n, identical or different, are an integer value from 0 to 6;

and or A and B, identical or different, represent a hydrogen atom, halogen atom or alkyl radical comprising dug the relationship between carbon atoms, with which they are associated,

and Ar represents :

or carbocyclic aryl radical with up to 18 carbon atoms, with the possibility of substitution by one or more radicals selected from the group consisting of carboxyl radicals, free, converted into a salt, ester or aminirovaniya, hydroxyl radicals, halogen atoms, radicals of NO2C N radicals such as alkyl, alkanniny and alkynylaryl, O-alkyl, O-alkanniny and O-alkynylaryl, S-alkyl, S-alkanniny and S-alkynylaryl, N-alkyl, N-alkanniny and N-alkynylaryl, linear, branched or cyclic, comprising up to 12 carbon atoms, with the possibility of substitution by one or more halogen atoms, a radical , in which R1and R2identical or different, represent a hydrogen atom or an alkyl radical comprising up to 12 carbon atoms, aryl, O-aryl and S-carbocyclic aryl radicals and aryl, O-aryl and S-heterocyclic aryl radicals containing one or more heteroatoms; with the possibility of substitution of one or more substitutes of the numbers listed above;

or Ar is a heterocyclic aryl-Lami of the numbers listed above, and Z represents a hydrogen atom or the residue of carbocyclic acids comprising up to 18 carbon atoms, as well as added salts with acids of compounds of formula (I).

In the definition of substitutes:

carbocyclic aryl radical is, first and foremost, phenyl or nattily radical;

Under the heterocyclic aryl radical understand or monocyclic heteroaryl radical with 5 or 6 atoms, containing one or more heteroatoms, or a condensed polycyclic system, each cycle of which contains 5 or 6 atoms and possibly one or more heteroatoms:

heterocyclic aryl radical comprises one or more heteroatoms, selected primarily from oxygen, sulfur and nitrogen;

monocyclic heteroaryl radical with 5 atoms is, first and foremost, thienyl, purely, paralelly, diazolidinyl, peredelnyj, pyrimidinyl, pyridazinyl or personilnya radical;

condensed polycyclic heteroaryl radical may be, for example, indaily, benzofuranyl, benzothiazolyl or finalininkiu radical or residue purine bases such as adenine;

alkyl, alkenylsilanes, n-boutigny, isobutylene, tert-boutigny, decile or dodecylphenyl, vinyl, allyl, etinilnoy, prominently, propargyl, cyclobutenyl, cyclopentenyl or tsiklogeksilnogo:

halogen is, first and foremost, fluorine, chlorine or bromine;

alkyl radical substituted by a halogen atom, is primarily so radical as CHCL2, CHBr2, CHF2, CCl3, CBr3, CF3CH2CF3CH2CH2Cl3,

CH2CH2CF3;

carbocyclic acid residue is in the first place, acetyl, propylaniline, batilly, isobutyryloxy, n-valelly, isovaleryl, tert-weleily and picalilly.

The subject of the invention, in particular, are :

the compounds of formula (I) in which Z represents a hydrogen atom;

the compounds of formula (I) in which A and B represent a hydrogen atom or form a third bond between the carbon atoms to which they are linked;

the compounds of formula (I) in which m represents the number 1 or 2;

the compounds of formula (I) in which n represents the number 0 or 1;

the compounds of formula (I) in which Ar represents a carbocyclic aryl radical, followed substitution of a fluorine atom, the radical CF3, phenyl radical, and primarily those in which Ar represents an unsubstituted phenyl radical.

The object of the present invention, first and foremost, is the compound of Example 1 and its salts with acids.

The products of General formula (I) possess very high antibiotic activity against gram-positive bacteria, such as staphylococci, streptococci, pneumococci.

Therefore, compounds that are the subject of the present invention can be used as medicaments in the treatment of infections with sensitive germs, in particular in the treatment of staphylococcal infections, such as staphylococcal septicemia, facial or skin malignant staphylococcal infections, pyoderma, septic or suppurative wounds, furuncles, carbuncles, cellulitis, erysipelas and acne, such staphylococcal infection as primary or post-acute flu-like illness, pneumonia, pulmonary suppuration, such streptococcal infection, acute tonsillitis, otitis, sinusitis, scarlet fever, such pneumococcal infections like pneumonia, bronchitis, brucellosis, diphtheria, gonococcal disease.

The products that are the subject of this coplasma pneumoniae, Chlamydia, Legionella spp., Ureaplasma, Toxoplasma, or microbes such as mycobacteria, Listeria, meningococci and Campylobacter.

Thus, the object of the present invention on the medical level, in particular as antibiotic funds, are also the products of formula (I) as described above, as well as their added salt are acceptable from a pharmaceutical point of view, inorganic or organic acids.

The object of the present invention on the medical level, in particular as antibiotic funds, is also the product of Example 1 and its acceptable from a pharmaceutical point of view of salt.

The object of the present invention are also pharmaceutical compounds comprising, as an active start, at least one of the above medicines.

These compositions can be applied orally, by rectal, parenteral or local application to the skin or on the mucous membranes, but it is preferable to apply inside.

These compositions can be solid or liquid and can be any pharmaceutical form which is widely used in the treatment of the person, as, for example, simple or dragevent tablets, the Active principle (active start) is inserted into the base, usually used in the manufacture of pharmaceutical compositions, such as talc, Arabic gum, lactose, amide, magnesium stearate, cocoa butter, aqueous or anhydrous binder, fats of animal or vegetable origin, derived paraffin, glycols, various moisturizing, dispersion or emulsion agents, preservatives.

These compositions can also be in the form of a powder intended to be dissolved before taking in the appropriate binder, such as sterile pyrogen-free water.

Commonly used doses depend on the disease to be treated, the characteristics of the patient, method of application and the product. In the case of the product of Example 1, they can be, for example, from 50 to 300 mg per day for adults by ingestion.

The object of the present invention is also a method of obtaining compounds of formula (I), characterized in that the compound of formula (II):

< / BR>
in which Z' represents a residue of carboxylic acids comprising up to 18 carbon atoms, is exposed to agent that can selectively activate the hydroxyl in position 11 to obtain the compounds of formula (III):

< / BR>
in which R1representatives of the formula (IV):

< / BR>
after which the compound of formula (IV) is subjected to:

or the effects of the compounds of formula (V):

R-N=C=O

in which R has the above significance, to obtain the compounds of formula (VI):

< / BR>
which tsiklitiria either spontaneously by heating, or exposed to tsiklitiria means for obtaining compounds of formula (IA):

< / BR>
the corresponding product of formula (I) in which Z represents a hydrogen atom;

or the impact of carbonyldiimidazole to obtain the compounds of formula (VII):

< / BR>
then the effects of the compounds of formula (VIII):

RNH2< / BR>
in which R has the above significance, to obtain the above compounds of formula (VI), which spontaneously tsiklitiria by heating, or exposed to tsiklitiria means to obtain the corresponding compound of formula (IAthen, if necessary, the specified compounds of the formula (IA) is subjected to an allocator hydroxyl functional group in position 2' and/or, if necessary, the effects of acid to obtain the salt.

In preferred applications of the method, aplauses the AI 11, is sulfonovy anhydride, such as methanesulfonyl, paratoluenesulfonyl or triftormetilfullerenov anhydride;

the Foundation is able to create a double bond 10(11), is databaseconnection, such as DBU (1,8-diazabicyclo [5-4-0] undecyl-7-ene), Diisobutylene, 2,6-lutidine, 2,4,6-kallidin or tetramethylguanidine;

the reaction between the compound of formula (IV) and the compound of the formula (V) is carried out in the presence of a base, such as pyridine, triethylamine, morpholine, N-methylmorpholine, and cyclization of the compounds of formula (VI) occurs, either spontaneously or by heating at a temperature of from 50oC to 100oC;

the reaction between the compound of formula (IV) and carbonyl diimidazol proceeds in the presence of a base such as sodium hydride, triethylamine, sodium carbonate, sodium bicarbonate or potassium, or in the absence of a base in a solvent such as methylene chloride, tetrahydrofuran or dimethylformamide;

the reaction between the compound of formula (VII) and compound RNH2flows in the environment of a solvent, such as acetonitrile, dimethylformamide or tetrahydrofuran, dimethoxyethane or dimethylsulfoxide, and the cyclization of the compounds of formula (VI) is, as a rule, at potassium, in the environment of a solvent, such as tetrahydrofuran;

hydrolysis of the ester functional group in position 2' is carried out using methanol or aqueous solution of hydrochloric acid;

the salt formation is carried out by conventional methods using acid.

Compounds of the formula (II) used as starting products are known products which can be obtained as described in patent application EEC 0.487.411.

Compounds of the formula RN=C=0 and RNH2are also well-known products.

The compounds of formula RNH2can be obtained, for example by the method described in Ann. Chem. 690-98-114.

Example 1. 11,12-dideoxy 3-de ((2,6-dideoxy 3-C-methyl 3-O-methyl-L-abovecaptionskip) oxy) 6-0-methyl 3-oxo 12,11-(oxycarbonyl((4-phenyl 3-butenyl) imino)) - erythromycin.

Step A: 2'-acetate 3-de ((2,6-dideoxy 3-C-methyl 3-O - methyl-L-abovecaptionskip)oxy) 6-O-methyl-11-O-(methylsulphonyl) 3-oxo erythromycin.

In a nitrogen atmosphere with shaking in 17 g of 2'-acetate 3-de ((2,6-dideoxy 3-C-methyl 3-O-methyl-L-abovecaptionskip)oxy) 6-O-methyl 3-exoerythrocytic add 100 ml of pyridine. Then the mixture is cooled to +10oC and add 11,9 r meta is altiva, within 5 hours the precipitate is filtered. Then produce a concentrated, treated with water and extracted using ethyl acetate. The organic phase is washed with water, dried, filtered and concentrated. So get to 20.9 g of crude desired product, which was subjected to purification by salt formation using oxalic acid and allocation base with ammonia. The result is 15, 16 g of the desired product (tPL210 - 212oC).

Stage B: 2'-acetate 11-deoxy 10,11-didehydro 3-de (2,6 - dideoxy 3-C-methyl 3-O-methyl-L-abovecaptionskip) oxy) 6-O - methyl 3-oxo erythromycin.

When shaking injected compared to 8.26 g of the product obtained at Stage A, in 35 ml of acetone. After that, drop by drop add 2,19 ml of DBU. Stirring at room temperature continued for 20 hours Then the reaction mixture is treated with methylene chloride. The organic phase is washed with water, dried on sodium sulfate, filtered and concentrated. Thus obtain 10 g of the product, which is treated with ether. This is followed by centrifugation and washing with ethyl ether. The result 6,33 g of the desired product (tPL230 - 232oC).

Stage: 2'-acetate-deoxy] 1 the l 3-oxo erythromycin.

96 mg of a 50 percent solution of sodium hydride in oil is introduced into 15 ml of tetrahydrofuran. The resulting suspension is cooled to 0oC and one drop of injected solution 611 mg of the product obtained in the previous step, in 17 ml of tetrahydrofuran. Then at a temperature of 0oC enter a solution of 486 mg of carbonyldiimidazole in 15 ml of tetrahydrofuran. Stirring continued for 4 hours 30 minutes After the temperature of the reaction mixture is allowed to rise to the level of room and perform the filtering and concentrating. Then treated with ethyl acetate, washed with dihydrogenphosphate sodium, extracted using ethyl acetate, dried, filtered and concentrated. The result 852 mg of the desired product.

Step G: 2'-acetate 11,12-dideoxy 3-de ((2,6-dideoxy 3-C-methyl 3-O-methyl-L-abovecaptionskip) oxy) 6-O-methyl 3-oxo 12,11- (oxycarbonyl ((4-phenyl 3-butenyl) imino)) erythromycin;

Within 5 h 30 min at a temperature of +55oC shake the mixture consisting of 0.9 g of 2'-acetate 11-deoxy 10,11-didehydro 3-de ((2,6 - dideoxy 3-C-methyl 3-O-methyl-L-abovecaptionskip)oxy) 12-O-((1H-imidazol-1-yl)carbonyl) 6-O-methyl 3-oxo erythromycin, 3 ml of acetonitrile and 0.6 g of 4-phenyl 3-butenylamine. Then the reaction mixture was poured into an aqueous solution devout water, dried, filtered and concentrated. Thus obtain 0.9 g of a viscous liquid, which is subjected to chromatography on silica (eluant : ethyl acetate/triethylamine (96 : 4)). Homogeneous phase is collected in the CCM*and concentrate (CCM - thin layer chromatography). The result of 0.32 g of product, which is thickened with hexane, centrifuged and dried at a temperature of +70oC. Thus emit 0,215 r of the desired product (tPL201-203oC).

Stage D: 11,12-dideoxy 3-de((2,6-dideoxy 3-C-methyl 3-O-methyl-L-abovecaptionskip)oxy) 6-O-methyl 3-oxo 12, 11- (oxycarbonyl ((4 - phenyl 3-butenyl) imine)) erythromycin.

The solution, including 0,194 g of the product obtained at Stage A, and 6 mg of methanol, shake for 15 h at room temperature. Then the methanol is evaporated using the "Rotavapor". The resulting product is subjected to chromatography on silica (eluant : methylene chloride/methanol/ ammonia (95 : 5 : 0,2)). Homogeneous phase is collected, concentrated, dried, filtered and concentrated. So get 0,155 g of the product; which is centrifuged and dried at a temperature of +70oC. the result 0.124 g of the target product (tPL257-259oC).


Example 2. ((Z) 11,12-dideoxy 3-de ((2,6-dideoxy 3-C-methyl 3-O-methyl-L-abovecaptionskip)oxy) 6-0-methyl 3-oxo 12,11-(oxycarbonyl ((4-(4-forfinal 3-butenyl)imino)) - erythromycin

tPL222oC.

Example 3. (Z) 11,12-dideoxy 3-de ((2,6-dideoxy 3-C-methyl 3-O - methyl-L-abovecaptionskip)oxy) 6-O-methyl 3-oxo 12,11- (oxycarbonyl((4-trifluoromethyl 3-butenyl)imino)) - erythromycin

tPL230oC

Example 4. (CIS) 11,12-dideoxy 3-de ((2,6-dideoxy 3-C-methyl 3-O-methyl-L-abovecaptionskip)oxy) 6-O-methyl 3-oxo 12,11-(oxycarbonyl ((4 - phenyl 3-butenyl)imino)) - erythromycin

tPL220 - 225oC

[]D= + 10,5C (c = 0.9 % of CHCl3)

Example 5. (E) 11,12 - dideoxy 3-de ((2,6-dideoxy 3-C-methyl 3-O-methyl-L-abovecaptionskip) oxy) 6-O-methyl 3-oxo 12,11-(oxycarbonyl((4-phenyl 2-butenyl)imino)) - erythromycin

tPL78oC

Example 6. (Z) 11,12-dideoxy 3-de ((2,6-dideoxy 3-C-methyl 3-O-methyl-L-abovecaptioned)oxy) 6-O-methyl 3-oxo 12,11-(oxycarbonyl((4 - phenyl 3-butenyl)imino)) - erythromycin

tPL220oC

[]D= + 16C (c = 1 % CHCl3)

Example 7. 11,12-dideoxy 3-de ((2,6-dideoxy 3-C-methyl 3-O-methyl-L-abovecaptionskip)oxy) 6-O-methyl 3-oxo 12,11-(oxycarbonyl ((4-phenyl 3-butenyl)imino)) Abernathy)oxy) 6-O-methyl 3-oxo 12,11- (oxycarbonyl ((4-phenyl 2-butenyl)imino)) - erythromycin

tPL98oC

Example 9. (E) 11,12-dideoxy 3-de((2,6-dideoxy 3-C-methyl 3-O-methyl-L-abovecaptionskip) oxy) 6-O-methyl 3-oxo 12,11-(oxycarbonyl ((4-(1,2'-biphenyl-4-yl)3-butenyl)imino)) - erythromycin

tPL215 - 217oC

[]D= - 46,5C (c = 1% CHCl3)

Example 10. (Z) 11,12-dideoxy 3-de((2,6-dideoxy 3-C-methyl 3-O-methyl-L-abovecaptionskip)oxy) 6-O-methyl 3-oxo 12,11-(oxycarbonyl((4- (1,2'-iphenyl 4-yl)3-butenyl)imino)) - erythromycin

tPL133-137oC

[]D= - 2.5 toC (c = 1 % CHCl3)

Acting in the same way, there were obtained the following products that are listed in the table. 1.

Preparation 1: [4-forfinal-4-yl] 3-butenylamine.

Step A : N-[[4-forfinal-4-yl] 3-butenyl]phthalimide.

The suspension, containing 150 ml of tetrahydrofuran, 6 g of 4-forventelige and 25.6 g of bromide triphenylphosphine N-(3-bromopropyl)phthalimide, cooled to -40oC. Then injected 5,42 g of potassium tert-butylate. The temperature is allowed to rise to -15oC and incubated with shaking for 1 h

The mixture is then poured on ice, extracted using ethyl acetate, washed with water, dried the organic phase in Na2SO4filter and concentrate. So about mnia (eluant : ethyl acetate/hexane (1 : 9)). Then perform concentration under reduced pressure and release of 5.2 g of the desired product (tPL94oC).

The microanalysis.

Calculated, %: C 73,40; H of 4.77; N 4,74; F 4,43

Received, %: C 73,2; H 4,8; N 4,6; F 6,6

Step B: [4-forfinal-4-yl] 3-butenylamine.

For 16 hours at a temperature of 0oC shake the mixture comprising 200 ml of ethanol, 5.5 g of the product obtained at Stage A, and 1.5 ml of hydrazine hydrate is added. Then the temperature is allowed to rise to the level of room temperature, the solvent is evaporated, the residue taken in ether, acidified to pH 1 with 2 n hydrochloric acid, the solvent is removed, take in water, add a solution of sodium carbonate, extracted using ether and evaporated solvents. After chromatography of the precipitate on silica (eluant : methylene chloride/methanol/ammonia (9 : 1 : 0,5)) are obtained 2.2 g of the target product.

Preparation 2: [4-triptoreline-4-yl] 3-butenylamine.

Step A: N-[[4-trifluoromethyl-4-yl]3-butenyl]phthalimide.

The operations are carried out as in stage a of Preparation 1, using, at the initial stage, 6 g of 4-(trifluoromethyl) benzaldehyde. The result is 4 g of the desired product (tPL88oC).

This use at the initial stage of 2.13 g of the product obtained at Stage A, and 0.84 cm3hydrazine hydrate is added. The result 0,850 g of the target amine.

Preparation of 3: 4-[(1,1'-iphenyl)4-yl] 3-butenylamine.

Step A:N-[4[(1,1'-biphenyl)4-yl] 3-butenyl]phthalimide.

The suspension, containing 150 ml of tetrahydrofuran, 5,46 g of 4-phenylbenzene and 15.9 bromodiphenylmethane N-(3-bromopropyl) phthalimide, cooled to a temperature of -40oC. Then injected 3,37 g tetrabutyrate potassium, give the temperature allowed to rise to -15oC and incubated for 1 h with agitation at a temperature of -15oC.

The mixture is then poured on ice, extracted using ethyl acetate, washed with water, dried the organic phase in Na2SO4filter and concentrate. Thus obtain 19 g of the product, which is dissolved in methylene chloride and subjected to chromatography on silica (eluant : ethyl acetate/hexane (3 : 7)). Then carry out the concentration, the concentrated hexane, centrifuged and dried under reduced pressure and release 8.5 g of the desired product (tPL112114oC).

The microanalysis.

Calculated, %: C 81,56; H 5,42; N 3,96.

Received, %: C 81,4; H 5,3; N 3,8.

Stage B: 4-[(1,1-bite the hydrazine hydrate is added, bring to boiling point. The temperature is allowed to fall to the level of the room, the precipitate is filtered and washed with ethanol. After that make the concentration, poured into 2 n hydrochloric acid and extracted using ethyl acetate. Then the organic phase is washed with water, dried, filtered and concentrated under reduced pressure. The result 2,89 g of the target product (tPL188194oC).

An example of pharmaceutical compounds. There were prepared tablets that meet the following formula:

The product of example 1, 150 mg

The basis for the finished tablets - 1 g

Detailing the basics - starch, talc, magnesium stearate.

Pharmacological study of the products of the invention. Method of cultivation in liquid medium.

Prepare a series of tubes, which is allocated the same amount of sterile nutrient medium. Then in each tube pour in increasing the number of the investigated product, after which each tube is sown bacterial strain.

After incubation in an oven for 24 h at a temperature of +37oC growth inhibition is assessed by radiographic what Yes is SUP>.

For the product of Example 1 were obtained the following results (the reading of the results was performed after 24 h):

Pharmacological research. Method of breeding in the liquid phase.

Prepare a series of tubes, which distribute the same amount of sterile nutrient medium, and introduce a growing number of the investigated product in each tube. Then, each tube being sown by a bacterial strain and after incubation for 24 h in a drying Cabinet at a temperature of 37oC, inhibition of growth estimated by x-ray that allows you to determine the minimum inhibitory concentration (M. I. K.), expressed in micrograms per milliliter.

For the compounds of examples 5, 7 and 10 were the results (reading occurs after 24 h), below.

Application; the test results of the compounds of examples 5, 7 and 10, are given in table. 4 - 6. The chemical structure of the compounds according to the examples described in table. 4.

Derivatives of erythromycin a General formula I

< / BR>
where R is the radical

< / BR>
where m = 1 or 2;

n = 1 or 2;

Ar is phenyl, possibly substituted by one or more atoms, alkyl - or alkoxygroup, CF3

2. The compounds of formula I on p. 1, wherein Z is a hydrogen atom.

3. The compounds of formula I under item 1 or 2, characterized in that A and B are both hydrogen atoms.

4. The compounds of formula I under item 1 or 2, characterized in that A and B form a third bond between the carbon atoms to which they are linked.

5. The compounds of formula I on PP.1 to 4, wherein m = 1 or 2.

6. The compounds of formula I on PP.1 to 5, characterized in that n = 1.

7. The compounds of formula I on PP.1 - 6, wherein Ar is phenyl, substituted by the substituents listed in paragraph 1.

8. The compounds of formula I on p. 7, wherein Ar is phenyl, possibly substituted by a fluorine atom, a radical CF3, phenyl.

9. The compounds of formula I on p. 8, wherein Ar is phenyl.

10. The compounds of formula I on p. 1, representing 11,12-di-deoxy-3-de[(2,6-dideoxy-3-C-methyl-3-0-methyl--L-abovecaptionskip)oxy] 6-0-methyl-3-oxo-12,11-(oxycarbonyl[(4-phenyl-3-butenyl)imino)erythromycin or its salts with acids.

11. The compounds of formula I on PP.1 to 9, has antibiotic activity.

12. The compound of formula I on p. 10 with antibiotic active ingredient and pharmaceutically acceptable carriers, characterized in that the active substance contains a compound of formula I in an effective amount.

14. The method of obtaining erythromycin derivatives of General formula I on PP.1 - 12, characterized in that the compound of General formula IV

< / BR>
where Z' is the residue of carboxylic acids comprising up to 18 carbon atoms,

expose carbonyldiimidazole to obtain compounds of General formula VII

< / BR>
and then the effects of the compounds of formula VIII

RNH2,

where R is specified in paragraph 1 values

to obtain compounds of General formula VI

< / BR>
where Z' and R have the above values,

which spontaneously cyclized by heating or exposed ciclismo means for obtaining compounds of General formula IA

< / BR>
then, if necessary, release the hydroxy-group in position 2' or apply acid to obtain the salt.

 

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FIELD: medicine.

SUBSTANCE: method involves carrying out hernia removal in intralaminar way. Posterior longitudinal ligament defect is covered with Tacho-Comb plate after having done disk cavity curettage. Subcutaneous fat fragment on feeding pedicle is brought to dorsal surface of radix and dural sac.

EFFECT: enhanced effectiveness of treatment; reduced risk of traumatic complications.

1 dwg

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